Jennifer Rodger

Transient up-regulation of the rostrocaudal gradient of ephrin A2 in the tectum coincides with reestablishment of orderly projections during optic nerve regeneration in goldfish

Publisher: Elsevier BV

Date: 11-2000

DOI: 10.1006/EXNR.2000.7486

Integrated analyses of zebrafish miRNA and mRNA expression profiles identify miR-29b and miR-223 as potential regulators of optic nerve regeneration

Publisher: Springer Science and Business Media LLC

Date: 12-08-2015

DOI: 10.1186/S12864-015-1772-1

Nutritional and environmental effects on reproduction in small ruminants

Publisher: CSIRO Publishing

Date: 2004

DOI: 10.1071/RD04035

Abstract: Animals live in environments that are both complex and continually changing, so they have to respond to short- and long-term variations in a wide range of factors, such as photoperiod, nutrition and sociosexual signals. Before they were domesticated, animals developed reproductive strategies that coped with these changes and often took advantage of them. The physiological processes that implement these strategies have been modified to some extent during several millennia of controlled breeding, but most persist. Thus, many genotypes still exhibit profound responses to external inputs, such as the induction of ovulation by sociosexual signals and the doubling of litter size by a change in nutrition. The complexity in these responses is now becoming clearer. For ex le, with sociosexual signals, we now need to consider the stimulatory effects of males on females, of females on males and of females on females. Similarly, the impact of nutrition has been extended beyond the control of puberty and the production of gametes to include phenomena such as ‘fetal programming’, with its potentially profound effects on the life-long performance of the animals. Fortunately, our capacity to research these phenomena has been greatly enhanced by technical improvements in hormone assays, molecular and cellular biology, and real-time ultrasound. This has brought us a better understanding of several of the environmental influences on reproduction, including: the cellular processes within ovarian follicles that mediate the effect of nutrition on ovulation rate the neuroendocrine pathways through which nutritional inputs affect the brain centres that control appetite and reproduction and the intracerebral pathways through which sociosexual signals (olfactory and non-olfactory) stimulate the reproductive axis. Importantly, we are now beginning to realise that, as well as considering interactions between environmental inputs and genotype, we need to take into account interactions between the environmental factors themselves, just as the animals do. We still have a long way to go for a complete understanding, but we are nevertheless in a position where we can begin to use this information to develop new management systems for our animals to improve their productivity.

Failure to restore vision after optic nerve regeneration in reptiles : interspecies variation in response to axotomy

Publisher: Wiley

Date: 14-09-2004

DOI: 10.1002/CNE.20299

Abstract: Optic nerve regeneration within the reptiles is variable. In a snake, Viper aspis, and the lizard Gallotia galloti, regeneration is slow, although some retinal ganglion cell (RGC) axons eventually reach the visual centers (Rio et al. [1989] Brain Res 479:151-156 Lang et al. [1998] Glia 23:61-74). By contrast, in a lizard, Ctenophorus ornatus, numerous RGC axons regenerate rapidly to the visual centers, but unless animals are stimulated visually, the regenerated projection lacks topography and animals remain blind via the experimental eye (Beazley et al. [2003] J. Neurotrauma 20:1263-1269). V. aspis, G. galloti, and C. ornatus belong respectively to the Serpentes, Lacertidae, and Agamidae within the Eureptilia, the major modern group of living reptiles comprising the Squamata (snakes, lizards, and geckos) and the Crocodyllia. Here we have extended the findings on Eureptilia to include two geckos (Gekkonidae), Cehyra variegata and Nephrurus stellatus. We also examined a turtle, Chelodina oblonga, the Testudines being the sole surviving representatives of the Parareptilia, the more ancient reptilian group. In all three species, visually elicited behavioral responses were absent throughout regeneration, a result supported electrophysiologically axonal tracing revealed that only a small proportion of RGC axons crossed the lesion and none entered the contralateral optic tract. RGC axons failed to reach the chiasm in C. oblonga, and in G. variegata, and N. stellatus RGC axons entered the opposite optic nerve a limited ipsilateral projection was seen in G. variegata. Our results support a heterogeneous response to axotomy within the reptiles, each of which is nevertheless dysfunctional.

Acoustic trauma evokes hyperactivity and changes in gene expression in guinea‐pig auditory brainstem

Publisher: Wiley

Date: 30-04-2010

DOI: 10.1111/J.1460-9568.2010.07183.X

Abstract: Hearing loss from acoustic trauma is a risk factor for tinnitus. Animal models using acoustic trauma have demonstrated hyperactivity in central auditory pathways, which has been suggested as a substrate for tinnitus. We used a guinea-pig model of unilateral acoustic trauma. Within the same animals, measurements of peripheral hearing loss, spontaneous activity of single neurons in the inferior colliculus and gene expression in cochlear nucleus and inferior colliculus were combined, acutely and after recovery from acoustic trauma. Genes investigated related to inhibitory (GABA-A receptor subunit alpha 1 glycine receptor subunit alpha 1) and excitatory neurotransmission (glutamate decarboxylase 1 glutamate receptor AMPA subunit alpha 2 glutamate receptor NMDA subunit 1), regulation of transmitter release (member of RAB family of small GTPase RAB3 GTPase activating protein subunit 1) and neuronal excitability (potassium channel subfamily K member 15). Acoustic trauma resulted in unilateral hearing loss and hyperactivity bilaterally in inferior colliculus. Changes in expression of different mRNAs were observed in ipsilateral cochlear nucleus and in ipsi- and contralateral inferior colliculus, immediately after acoustic trauma, and after 2 and 4 weeks' recovery. Gene expression was generally reduced immediately after trauma, followed by a return to near normal levels or over-expression as recovery time increased. Different mechanisms appear to underlie the spontaneous hyperactivity observed. There is evidence of down-regulation of genes associated with neuronal inhibition in the contralateral inferior colliculus, whereas in ipsilateral cochlear nucleus, competing actions of inhibitory and excitatory systems seem to play a major role in determining overall excitability.

The role of ephrin-A2 and ephrin-A5 in sensorimotor control and gating

Publisher: Elsevier BV

Date: 12-2014

DOI: 10.1016/J.BBR.2014.08.061

Abstract: Many factors influence neurodevelopment. However, their contribution to adult neural function is often unclear. This is often due to complex expression profiles, cell signalling, neuroanatomy, and a lack of effective tests to assess the function of neural circuits in vivo. Ephrin-A2 and ephrin-A5 are cell surface proteins implicated in multiple aspects of neurodevelopment. While the role of ephrin-As in visual, auditory and learning behaviours has been explored, little is known about their role in dopaminergic and neuromotor pathways, despite expression in associated brain regions. Here we probe the function of ephrin-A2 and ephrin-A5 in the development of the dopaminergic and neuromotor pathways using counts of tyrosine hydroxylase (TH) positive cells in the substantia nigra pars compacta (SNpc) and the ventral tegmental area (VTA), the acoustic startle reflex (ASR), and a measure of sensorimotor gating, prepulse inhibition (PPI). Analysis of the ASR and PPI in ephrin-A2 and/or ephrin-A5 knock-out mice revealed that both genes play distinct roles in mediating ASR circuits, but are unlikely to play a role in PPI. Knock-out of either gene resulted in robust changes in startle response magnitude and measures of startle onset and peak latencies. However, ephrin-A2 and ephrin-A5 regulate aspects of the ASR differently: ephrin-A2 KO mice have increased startle litude, increased sensitivity and reduced latency to startle, whilst ephrin-A5 KO mice show opposite effects. Neither of the gene knock outs affected PPI, despite ephrin-A5 KO mice showing changes in dopamine cell numbers in nuclei thought to regulate PPI. We propose that majority of the changes observed ephrin-A2 and ephrin-A5 KO mice appear to be mediated by the effects on motor neurons and their muscle targets, rather than changes in auditory sensitivity.

The role of Eph receptors and Ephrins in the skin

Publisher: Wiley

Date: 24-10-2016

DOI: 10.1111/IJD.12968

Abstract: Eph receptors and Ephrin ligands are widely expressed in the skin. Various studies have been carried out to identify the effects of these molecules on many aspects of skin development. Here we summarize the literature that has identified roles for Eph receptors and Ephrins in the skin, focusing mainly on the epidermis, hair follicles, and cutaneous innervation. This review may help direct and focus further investigations into the role of Eph receptors and Ephrins in the development, maintenance, and repair processes in cutaneous biology.

Regional and cellular distribution of ephrin-B1 in adult mouse brain

Publisher: Elsevier BV

Date: 2009

DOI: 10.1016/J.BRAINRES.2008.09.100

Abstract: The membrane-bound proteins ephrins and their receptors, Eph receptor tyrosine kinases, are known for their key role during development of the central nervous system (CNS). Ligand/receptor interactions as a result of cell-cell contacts activate intracellular signalling pathways which mediate specific cellular responses. Activation can occur bidirectionally in both the receptor and the ligand-bearing cells. Eph receptor and ephrin families have been implicated in synaptic plasticity in the mature brain: effects include long-term potentiation/depression of excitatory transmission (LTP/LTD) and an action on the structure and number of synaptic contacts. However, due to the redundancy of binding between receptors and ligands, the role of in idual proteins has not yet been completely elucidated. Ephrin-B1 has been suggested to play a role in synaptic plasticity in the hippoc us, but its expression and localization at pre- or post-synaptic sites has been poorly documented, most likely due to the apparent low activity of the corresponding gene in mature brain. Here we present immunohistochemical data demonstrating a broad but highly regulated cellular distribution of ephrin-B1 in the mature mouse brain. We show that ephrin-B1 is expressed post-synaptically on dendritic spines in the cortex, supporting a role in synaptic plasticity in this region. However, the prevalent extra-synaptic distribution in regions such as the hippoc us and cerebellum suggests an additional structural role, perhaps at the neuron/glia interface.

A method for introducing non-silencing siRNA into the guinea pig cochlea in vivo

Publisher: Elsevier BV

Date: 2008

DOI: 10.1016/J.JNEUMETH.2007.08.026

Abstract: The aim of this preliminary study was to establish the methodology by which siRNA can be introduced into the adult guinea pig cochlea in vivo whilst preserving auditory function with a view to using targeted siRNAs to knockdown genes essential for auditory transduction. Initially a fluorescently tagged non-silencing siRNA complexed with a lipid-based transfection reagent was introduced into the perilymphatic compartment of the cochlea. Although auditory function was fully preserved, siRNA uptake was only observed in cells lining the perilymphatic space that are not critically involved in auditory transduction and therefore of little interest. Another approach was therefore adopted, in which siRNA was introduced directly into the scala media (endolymphatic compartment) of the apical (fourth) cochlear turn by slow pressure injection. During endolymphatic perfusion, the endocochlear potential (EP) and compound action potential (CAP) thresholds for basal turn frequencies from 6 to 20 kHz could be preserved, while CAP thresholds for 1-4 kHz were often elevated by 10-20 dB. CAP thresholds and EP were preserved 24 and 48 h after perfusion in some animals but reduced in others. siRNA uptake was observed predominantly in marginal and intermediate cells of the stria vascularis in all cochlear turns but not in cells of the organ of Corti.

Significant changes in endogenous retinal gene expression assessed 1 year after a single intraocular injection of AAV-CNTF or AAV-BDNF

Publisher: Elsevier BV

Date: 2016

DOI: 10.1038/MTM.2016.78

ACNP 58th Annual Meeting: Poster Session I

Publisher: Springer Science and Business Media LLC

Date: 12-2019

DOI: 10.1038/S41386-019-0545-Y

Dissecting the functional contributions of different neuronal subtypes in the dorsal striatum to perseverative behaviour in ephrin-A2/A5^-/-mice

Publisher: Cold Spring Harbor Laboratory

Date: 28-10-2022

DOI: 10.1101/2022.10.28.514217

Abstract: Overreliance on habit is linked with disorders such as drug addiction and obsessive-compulsive disorder and there is increasing interest in the use of repetitive transcranial magnetic stimulation (rTMS) to alter neuronal activity in the relevant pathways and reduce relapse or accelerated shift towards habit formation. Here we studied the brains of ephrin-A2A5 -/- mice, which previously showed perseverative behaviour in progressive-ratio tasks, associated with low cellular activity in nucleus accumbens. We investigated if rTMS treatment had altered the hierarchical recruitment of brain regions from ventral to dorsal striatum associated with abnormal habit formation in these mice. Brain sections of mice that underwent progressive-ratio tasks with and without low intensity rTMS (LI-rTMS) were taken from a previous study. We take advantage of the previous characterisation of perseverative behaviour to investigate the contribution of different neuronal subtypes and striatal regions. Striatal regions were stained for neuronal activation with c-Fos and for medium spiny neurons with DARPP32. Qualitative analysis was carried out for other neuronal subtypes in the striatum - GABAergic, parvalbumin-expressing and cholinergic interneurons. Contrary to our hypothesis, we found neuronal activity in ephrin-A2A5 -/- mice still reflected goal-directed behaviour. However, we saw that the dorsolateral striatum contributed more to total striatal activity in untreated ephrin-A2/A5 -/- mice. This supported our hypothesis that ephrin-A2/A5 -/- mice have greater c-Fos activity in habit-associated striatal regions. LI-rTMS in ephrin-A2A5 -/- mice also appeared to delay the shift from goal-directed to habitual behaviour as suggested by increased activation in dorsomedial striatum and nucleus accumbens.

Low intensity repetitive transcranial magnetic stimulation modulates brain-wide functional connectivity to promote anti-correlated c-Fos expression

Publisher: Springer Science and Business Media LLC

Date: 29-11-2022

DOI: 10.1038/S41598-022-24934-8

Abstract: Repetitive transcranial magnetic stimulation (rTMS) induces action potentials to induce plastic changes in the brain with increasing evidence for the therapeutic importance of brain-wide functional network effects of rTMS however, the influence of sub-action potential threshold (low-intensity LI-) rTMS on neuronal activity is largely unknown. We investigated whether LI-rTMS modulates neuronal activity and functional connectivity and also specifically assessed modulation of parvalbumin interneuron activity. We conducted a brain-wide analysis of c-Fos, a marker for neuronal activity, in mice that received LI-rTMS to visual cortex. Mice received single or multiple sessions of excitatory 10 Hz LI-rTMS with custom rodent coils or were sham controls. We assessed changes to c-Fos positive cell densities and c-Fos arvalbumin co-expression. Peak c-Fos expression corresponded with activity during rTMS. We also assessed functional connectivity changes using brain-wide c-Fos-based network analysis. LI-rTMS modulated c-Fos expression in cortical and subcortical regions. c-Fos density changes were most prevalent with acute stimulation, however chronic stimulation decreased parvalbumin interneuron activity, most prominently in the amygdala and striatum. LI-rTMS also increased anti-correlated functional connectivity, with the most prominent effects also in the amygdala and striatum following chronic stimulation. LI-rTMS induces changes in c-Fos expression that suggest modulation of neuronal activity and functional connectivity throughout the brain. Our results suggest that LI-rTMS promotes anticorrelated functional connectivity, possibly due to decreased parvalbumin interneuron activation induced by chronic stimulation. These changes may underpin therapeutic rTMS effects, therefore modulation of subcortical activity supports rTMS for treatment of disorders involving subcortical dysregulation.

Resting-state fMRI study of brain activation using low-intensity repetitive transcranial magnetic stimulation in rats

Publisher: Springer Science and Business Media LLC

Date: 30-04-2018

DOI: 10.1038/S41598-018-24951-6

Abstract: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique used to treat many neuropsychiatric conditions. However, the mechanisms underlying its mode of action are still unclear. This is the first rodent study using resting-state functional MRI (rs-fMRI) to examine low-intensity (LI) rTMS effects, in an effort to provide a direct means of comparison between rodent and human studies. Using anaesthetised Sprague-Dawley rats, rs-fMRI data were acquired before and after control or LI-rTMS at 1 Hz, 10 Hz, continuous theta burst stimulation (cTBS) or biomimetic high-frequency stimulation (BHFS). Independent component analysis revealed LI-rTMS-induced changes in the resting-state networks (RSN): (i) in the somatosensory cortex, the synchrony of resting activity decreased ipsilaterally following 10 Hz and bilaterally following 1 Hz stimulation and BHFS, and increased ipsilaterally following cTBS (ii) the motor cortex showed bilateral changes following 1 Hz and 10 Hz stimulation, a contralateral decrease in synchrony following BHFS, and an ipsilateral increase following cTBS and (iii) hippoc al synchrony decreased ipsilaterally following 10 Hz, and bilaterally following 1 Hz stimulation and BHFS. The present findings demonstrate that LI-rTMS modulates functional links within the rat RSN with frequency-specific outcomes, and the observed changes are similar to those described in humans following rTMS.

The balance of NMDA- and AMPA/kainate receptor-mediated activity in normal adult goldfish and during optic nerve regeneration

Publisher: Elsevier BV

Date: 10-2005

DOI: 10.1016/J.EXPNEUROL.2005.05.015

Abstract: Retinotectal topography is established during development and relies on the sequential recruitment of glutamate receptors within postsynaptic tectal cells. NMDA receptors underpin plastic changes at early stages when retinal ganglion cell (RGC) terminal arbors are widespread and topography is coarse AMPA/kainate receptors mediate fast secure neurotransmission characteristic of mature circuits once topography is refined. Here, we have examined the relative contributions of these receptors to visually evoked activity in normal adult goldfish, in which retinotectal topography is constantly adjusted to compensate for the continual neurogenesis and the addition of new RGC arbors. Furthermore, we examined animals at two stages of optic nerve regeneration. In the first, RGC arbors are widespread and receptive fields large resulting in coarse topography in the second, RGC arbors are pruned to reduce receptive fields leading to refined topography. Antagonists were applied to the tectum during multiunit recording of postsynaptic responses. Normal goldfish have low levels of NMDA receptor-mediated activity and high levels of AMPA/kainate. When coarse topography has been restored, NMDA receptor-mediated activity is increased and that of AMPA/kainate decreased. Once topography has been refined, the balance of NMDA and AMPA/kainate receptor-mediated activity returns to normal. The data suggest that glutamatergic neurotransmission in normal adult goldfish is dual with NMDA receptors fine-tuning topography and AMPA receptors allowing stable synaptic function. Furthermore, the normal operation of both receptors allows a response to injury in which the balance can be transiently reversed to restore topography and vision.

Dexamphetamine widens temporal and spatial binding windows in healthy participants

Publisher: CMA Impact Inc.

Date: 14-03-2023

DOI: 10.1503/JPN.220149

Environmental enrichment intervention for Rett syndrome: An individually randomised stepped wedge trial

Publisher: Springer Science and Business Media LLC

Date: 10-01-0015

DOI: 10.1186/S13023-017-0752-8

Brain Structure and Task‐specific Increase in Expression of the Gene Encoding Syntaxin 1B During Learning in the Rat: A Potential Molecular Marker for Learning‐induced Synaptic Plasticity in Neural Ne

Publisher: Wiley

Date: 10-1996

DOI: 10.1111/J.1460-9568.1996.TB00727.X

Abstract: The mRNAs encoding the synaptic vesicle proteins syntaxin 1B and synapsin I were measured using in situ hybridization in several brain regions--the dentate gyrus, CA3 and CA1 of the hippoc us, the parietal, the motor and prefrontal cortices and the core and shell of the accumbens--of rats that were learning a spatial reference or working memory task on a radial arm maze. The mRNA encoding syntaxin 1B was significantly increased in all hippoc al regions in rats learning the working memory task, whereas it was increased in the prelimbic area of the prefrontal cortex and the shell of the accumbens in rats learning the spatial reference memory task. No change in mRNA encoding syntaxin 1B was observed in the motor and parietal and cortices or the core of the accumbens, and the mRNA encoding synapsin I was not significantly different from that of naive caged controls or rats running the maze for continuous reinforcement in any of the brain structures examined. These results demonstrate that the gene encoding a key member of synaptic vesicle function is up-regulated in a task- and brain-specific manner during learning. They are discussed in terms of the potential role this protein may play in trans-synaptic propagation of plasticity within specific neural networks as a function of the information required in the laying down of different types of memory.

Differential expression of TrkB isoforms switches climbing fiber‐Purkinje cell synaptogenesis to selective synapse elimination

Publisher: Wiley

Date: 12-10-2009

DOI: 10.1002/DNEU.20756

Physiological and anatomical investigation of the auditory brainstem in the Fat-tailed Dunnart (Sminthopsis crassicaudata)

Publisher: PeerJ

Date: 30-09-2019

DOI: 10.7717/PEERJ.7773

Abstract: The fat-tailed dunnart ( Sminthopsis crassicaudata ) is a small (10–20 g) native marsupial endemic to the south west of Western Australia. Currently little is known about the auditory capabilities of the dunnart, and of marsupials in general. Consequently, this study sought to investigate several electrophysiological and anatomical properties of the dunnart auditory system. Auditory brainstem responses (ABR) were recorded to brief (5 ms) tone pips at a range of frequencies (4–47.5 kHz) and intensities to determine auditory brainstem thresholds. The dunnart ABR displayed multiple distinct peaks at all test frequencies, similar to other mammalian species. ABR showed the dunnart is most sensitive to higher frequencies increasing up to 47.5 kHz. Morphological observations (Nissl stain) revealed that the auditory structures thought to contribute to the first peaks of the ABR were all distinguishable in the dunnart. Structures identified include the dorsal and ventral sub isions of the cochlear nucleus, including a cochlear nerve root nucleus as well as several distinct nuclei in the superior olivary complex, such as the medial nucleus of the trapezoid body, lateral superior olive and medial superior olive. This study is the first to show functional and anatomical aspects of the lower part of the auditory system in the Fat-tailed dunnart.

Rapid Induction of Cell Proliferation in the Adult Female Ungulate Brain (Ovis aries) Associated with Activation of the Reproductive Axis by Exposure to Unfamiliar Males1

Publisher: Oxford University Press (OUP)

Date: 06-2009

DOI: 10.1095/BIOLREPROD.108.075341

Abstract: In many species, the reproductive centers of the brain are profoundly affected by sociosexual stimuli. This is particularly evident in female ungulates such as sheep, in which exposure to males switches them from reproductively quiescent to fertile. In two experiments with female sheep, we tested whether the brain centers that control gonadotropin-releasing hormone (GnRH) neuronal activity respond differentially to "novel" vs. familiar males and whether the neuroendocrine response is associated with increased cell proliferation in the hippoc us, a site associated with memory formation. In experiment 1, groups of 10 female sheep that had previously been habituated to males for 3 mo were re-exposed to familiar males or were exposed to novel males. Only the novel males increased luteinizing hormone (LH) pulse frequency, indicating stimulation of GnRH neuronal activity. In experiment 2, groups of six female sheep were injected with bromodeoxyuridine (BrdU) and then maintained in isolation from males or exposed to novel males. Two days later, the hippoc us and hypothalamus were removed and processed for fluorescence immunohistochemistry. Again, exposure to males increased LH pulse frequency. Most important, male exposure also doubled the number of BrdU-positive cells in the dentate gyrus of the hippoc us. No BrdU-positive cells were detected in the hypothalamus. We conclude that the stimulus from novel males switches on the reproductive centers of the brain of female sheep and rapidly doubles the rate of cell proliferation in the hippoc us. The rapidity of this response contrasts with rodents, in which several days of exposure to male pheromones seem necessary for an effect on neurogenesis.

Long term delivery of pulsed magnetic fields does not improve learning or alter dendritic spine density in the mouse hippocampus

Publisher: F1000 Research Ltd

Date: 09-09-2013

DOI: 10.12688/F1000RESEARCH.2-180.V1

Abstract: Repetitive transcranial magnetic stimulation (rTMS) is thought to facilitate brain plasticity. However, few studies address anatomical changes following rTMS in relation to behaviour. We delivered 5 weeks of daily pulsed rTMS stimulation to ephrin-A2 -/- and wildtype mice (n=10 per genotype) undergoing a visual learning task and analysed learning performance, as well as spine density, in the dentate gyrus molecular and CA1 pyramidal cell layers in Golgi-stained brain sections. We found that neither learning behaviour, nor hippoc al spine density was affected by long term rTMS. Our negative results highlight the lack of deleterious side effects in normal subjects and are consistent with previous studies suggesting that rTMS has a bigger effect on abnormal or injured brain substrates than on normal/control structures.

A Comparison of Corneal Cellular Responses After 213-nm Compared With 193-nm Laser Photorefractive Keratectomy in Rabbits

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 05-2009

DOI: 10.1097/ICO.0B013E31818C2C89

Repetitive Transcranial Magnetic Stimulation of the Brain

Publisher: SAGE Publications

Date: 09-07-2016

DOI: 10.1177/1073858415618897

Abstract: Since the development of transcranial magnetic stimulation (TMS) in the early 1980s, a range of repetitive TMS (rTMS) protocols are now available to modulate neuronal plasticity in clinical and non-clinical populations. However, despite the wide application of rTMS in humans, the mechanisms underlying rTMS-induced plasticity remain uncertain. Animal and in vitro models provide an adjunct method of investigating potential synaptic and non-synaptic mechanisms of rTMS-induced plasticity. This review summarizes in vitro experimental studies, in vivo studies with intact rodents, and preclinical models of selected neurological disorders—Parkinson’s disease, depression, and stroke. We suggest that these basic research findings can contribute to the understanding of how rTMS-induced plasticity can be modulated, including novel mechanisms such as neuroprotection and neurogenesis that have significant therapeutic potential.

Long term delivery of pulsed magnetic fields does not alter visual discrimination learning or dendritic spine density in the mouse CA1 pyramidal or dentate gyrus neurons

Publisher: F1000 Research Ltd

Date: 04-12-2013

DOI: 10.12688/F1000RESEARCH.2-180.V2

Abstract: Repetitive transcranial magnetic stimulation (rTMS) is thought to facilitate brain plasticity. However, few studies address anatomical changes following rTMS in relation to behaviour. We delivered 5 weeks of daily pulsed rTMS stimulation to adult ephrin-A2 -/- and wildtype (C57BI/6j) mice (n=10 per genotype) undergoing a visual learning task and analysed learning performance, as well as spine density, in the dentate gyrus molecular and CA1 pyramidal cell layers in Golgi-stained brain sections. We found that neither learning behaviour, nor hippoc al spine density was affected by long term rTMS. Our negative results highlight the lack of deleterious side effects in normal subjects and are consistent with previous studies suggesting that rTMS has a bigger effect on abnormal or injured brain substrates than on normal/control structures.

Ephrin-A2 regulates excitatory neuron differentiation and interneuron migration in the developing neocortex.

Publisher: Springer Science and Business Media LLC

Date: 18-09-2017

DOI: 10.1038/S41598-017-12185-X

Abstract: The development of the neocortex requires co-ordination between proliferation and differentiation, as well as the precise orchestration of neuronal migration. Eph/ephrin signaling is crucial in guiding neurons and their projections during embryonic development. In adult ephrin-A2 knockout mice we consistently observed focal patches of disorganized neocortical laminar architecture, ranging in severity from reduced neuronal density to a complete lack of neurons. Loss of ephrin-A2 in the pre-optic area of the diencephalon reduced the migration of neocortex-bound interneurons from this region. Furthermore, ephrin-A2 participates in the creation of excitatory neurons by inhibiting apical progenitor proliferation in the ventricular zone, with the disruption of ephrin-A2 signaling in these cells recapitulating the abnormal neocortex observed in the knockout. The disturbance to the architecture of the neocortex observed following deletion of ephrin-A2 signaling shares many similarities with defects found in the neocortex of children diagnosed with autism spectrum disorder.

Histological Changes and Unscheduled DNA Synthesis in the Rabbit Cornea Following 213-nm, 193-nm, and 266-nm Irradiation

Publisher: SLACK, Inc.

Date: 05-2007

DOI: 10.3928/1081-597X-20070501-10

Abstract: ABSTRACT PURPOSE: To examine the acute outcome of corneal irradiation in adult rabbits for 193-, 213-, and 266-nm laser wavelengths. METHODS: Animals were randomly allocated to one of three groups and were treated with 213-nm quintupled Nd:YAG laser, a 193-nm excimer laser, or a 266-nm quadrupled Nd:YAG laser (n=6 per group, two exposure durations). Thermal damage was assessed histologically and the extent of DNA damage estimated by measuring unscheduled DNA synthesis in corneal epithelial and stromal cells using p 3 H thymidine autoradiography. RESULTS: For the 193- and 213-nm groups, irradiation did not induce thermal damage. Moreover, cells displaying unscheduled DNA synthesis represented % of the total cell numbers with no difference between groups (P .05). By contrast, the 266-nm laser led to stromal melting and vacuolation unscheduled DNA synthesis levels were elevated over the other groups (P .05). CONCLUSIONS: Corneal laser ablation with the 213-nm Nd:YAG laser resulted in similarly low levels of thermal and DNA damage to those produced using the clinically accepted 193-nm excimer laser. [J Refract Surg. 2007 :477-481.]

Training on a visual task improves the outcome of optic nerve regeneration

Publisher: Mary Ann Liebert Inc

Date: 11-2003

DOI: 10.1089/089771503770802925

Abstract: Optic nerve regeneration in a lizard, Ctenophorus ornatus, is dysfunctional despite survival of most retinal ganglion cells and axon regeneration to the optic tectum. The regenerated retino-tectal projection at 6 months has crude topography but by 1 year is disordered visually-elicited behavior is absent via the experimental eye. Here, we assess the influence of training on the outcome of optic nerve regeneration. Lizards were trained to catch prey presented within the monocular field of either eye. One optic nerve was then severed and visual stimulation resumed throughout regeneration. In the trained group, presentation was restricted to the eye undergoing optic nerve regeneration for the untrained group, the unoperated eye was stimulated. Pupil responses returned in trained but not in untrained animals. At 1 year, trained animals oriented to and captured prey untrained animals demonstrated minimal orienting and failed to capture prey. Regenerated retino-tectal projections were topographic in the trained but not in the untrained group as assessed by in vitro electrophysiological recording and by carbocyanine dye tracing. In vitro electrophysiological recording during application of neurotransmitter antagonists to the tectum revealed that the level of GABAergic inhibition was modest in trained animals but elevated in the untrained group responses were mainly AMPA-mediated in both groups. We conclude that training improves the behavioral outcome of regeneration, presumably by stabilizing and refining the transient retino-tectal map and preventing a build-up of tectal inhibition. The results suggest that for successful central nerve regeneration to occur in mammals, it may be necessary to introduce training to complement procedures stimulating axon regeneration.

The development and mature organisation of the end-artery retinal vasculature in a marsupial, the dunnart Sminthopsis crassicaudata

Publisher: Elsevier BV

Date: 2001

DOI: 10.1016/S0042-6989(00)00246-7

Abstract: The end-artery retinal vasculature of a marsupial, the fat-tailed dunnart, was defined by India ink injection and studied in wholemounts. In the adult, the vitreal vasculature supplying the ganglion-cell layer has major paired-vessels in a horizontal H shape. These vessels skirt the area centralis and visual streak that are supplied by fine end-loops. A second vascular layer of uniformly distributed endloops arises from the superficial vessels and lies at the inner nuclear/outer plexiform border. During development, vessels enter the eye via the optic nerve head to form the upper vasculature, assuming an essentially mature arrangement prior to the formation of the area centralis and visual streak. Vessels then descend to form the lower bed. Unlike the cat, the dunnart has retinal vessels that are patent throughout development, their growth is interstitial and reductive remodelling is not seen. A retinal end-artery system may have evolved in marsupials because their precocity requires a vasculature that is functional from early stages of development.

Evidence that regenerating optic axons maintain long-term growth in the Lizard Ctenophorus ornatus: Growth-associated protein-43 and gefiltin expression

Publisher: Elsevier BV

Date: 02-2001

DOI: 10.1016/S0306-4522(00)00506-6

Abstract: In the lizard, Ctenophorus ornatus, the optic nerve regenerates but animals remain blind via the experimental eye, presumably as a result of axons failing to consolidate a retinotopic map in the optic tectum. Here we have examined immunohistochemically the expression of the growth-associated protein GAP-43 and the low-molecular-weight intermediate filament protein gefiltin, up to one year after optic nerve crush. Both proteins were found to be permanently up-regulated, suggesting that regenerating axons are held in a permanent state of re-growth. We speculate that, in the lizard, the continued expression of GAP-43 and the failure to switch from the expression of low- to high-molecular-weight intermediate filament proteins are associated with the inability to consolidate a retinotopic projection.

Synapsin I and syntaxin 1B: Key elements in the control of neurotransmitter release are regulated by neuronal activation and long-term potentiation in vivo

Publisher: Elsevier BV

Date: 05-1997

DOI: 10.1016/S0306-4522(96)00700-2

Abstract: The messenger RNAs encoding proteins of the exocytotic machinery were measured at different times following the induction of long-term potentiation or increasing neuronal activity in the dentate gyrus of the rat in vivo. In situ hybridization revealed that from the many messenger RNAs that encode proteins involved in regulated exocytosis, only those encoding synapsin I and syntaxin 1B were specifically increased. The levels of messenger RNA encoding both synapsin I and syntaxin 1B were increased on the ipsilateral side of the dorsal dentate gyrus 2 and 5 h following the induction of long-term potentiation. Syntaxin 1B was also increased in the ventral dentate gyrus at the same time-points. On the contralateral side of the dentate gyrus there was an increase in both synapsin I and syntaxin 1B at 5 h only. All of these long-term potentiation-induced changes were prevented when the tetanus was delivered in the presence of the N-methyl-D-aspartate receptor antagonist. (D(-)-2-amino-5-phosphonopentanoic acid. Immunocytochemical staining revealed that protein levels for both synapsin I and syntaxin 1B were elevated in the mossy fibre terminal zone of CA3 5 h after the induction of long-term potentiation. In addition to these plasticity-induced changes, a transient increase in the messenger RNA encoding syntaxin 1B was observed at 2 h in conditions of high intensity stimulation of the perforant path to increase the level of cellular activation, but this change was not maintained even when high intensity stimulation was sustained for 5 h. No changes in either of the messenger RNAs were observed under low frequency stimulation and pseudotetanus at either time-points. These results show that an overall increase in neuronal excitation within a neuronal network can be differentiated from a change in synaptic strength at a specific subset of the synapses, where only synaptic plasticity leads to long-term changes in the expression of selective members of the exocytotic machinery. Altered concentrations of key vesicle proteins may thus provide the means for modulation of neurotransmitter release over long time-periods. The persistent long-term potentiation-induced postsynaptic increase in messenger RNAs encoding these presynaptic proteins has important implications for the propagation of signals downstream from the site of long-term potentiation induction in hippoc al neural networks, and highlights a candidate molecular mechanism for mediating the propagation of synaptic plasticity in such networks.

Low-intensity repetitive transcranial magnetic stimulation requires concurrent visual system activity to modulate visual evoked potentials in adult mice

Publisher: Springer Science and Business Media LLC

Date: 11-04-2018

DOI: 10.1038/S41598-018-23979-Y

Abstract: Repetitive transcranial stimulation (rTMS) is an increasingly popular method to non-invasively modulate cortical excitability in research and clinical settings. During rTMS, low-intensity magnetic fields reach areas perifocal to the target brain region, however, effects of these low-intensity (LI-) fields and how they interact with ongoing neural activity remains poorly defined. We evaluated whether coordinated neural activity during electromagnetic stimulation alters LI-rTMS effects on cortical excitability by comparing visually evoked potentials (VEP) and densities of parvalbumin-expressing (PV+) GABAergic interneurons in adult mouse visual cortex after LI-rTMS under different conditions: LI-rTMS applied during visually evoked (strong, coordinated) activity or in darkness (weak, spontaneous activity).We also compared response to LI-rTMS in wildtype and ephrin-A2A5 −/− mice, which have visuotopic anomalies thought to disrupt coherence of visually-evoked cortical activity. Demonstrating that LI-rTMS effects in V1 require concurrent sensory-evoked activity, LI-rTMS delivered during visually-evoked activity increased PV+ immunoreactivity in both genotypes however, VEP peak litudes changed only in wildtypes, consistent with intracortical disinhibition. We show, for the first time, that neural activity and the degree of coordination in cortical population activity interact with LI-rTMS to alter excitability in a context-dependent manner.

The Acquisition of Target Dependence by Developing Rat Retinal Ganglion Cells(1,2,3).

Publisher: Society for Neuroscience

Date: 05-2015

DOI: 10.1523/ENEURO.0044-14.2015

Abstract: Similar to neurons in the peripheral nervous system, immature CNS-derived RGCs become dependent on target-derived neurotrophic support as their axons reach termination sites in the brain. To study the factors that influence this developmental transition we took advantage of the fact that rat RGCs are born, and target innervation occurs, over a protracted period of time. Early-born RGCs have axons in the SC by birth (P0), whereas axons from late-born RGCs do not innervate the SC until P4-P5. Birth dating RGCs using EdU allowed us to identify RGCs (1) with axons still growing toward targets, (2) transitioning to target dependence, and (3) entirely dependent on target-derived support. Using laser-capture microdissection we isolated ∼34,000 EdU + RGCs and analyzed transcript expression by custom qPCR array. Statistical analyses revealed a difference in gene expression profiles in actively growing RGCs compared with target-dependent RGCs, as well as in transitional versus target-dependent RGCs. Prior to innervation RGCs expressed high levels of BDNF and CNTFR α but lower levels of neurexin 1 mRNA. Analysis also revealed greater expression of transcripts for signaling molecules such as MAPK, Akt, CREB, and STAT. In a supporting in vitro study, purified birth-dated P1 RGCs were cultured for 24-48 h with or without BDNF lack of BDNF resulted in significant loss of early-born but not late-born RGCs. In summary, we identified several important changes in RGC signaling that may form the basis for the switch from target independence to dependence.

Should I Stay or Should I Go? Ephs and Ephrins in Neuronal Migration

Publisher: S. Karger AG

Date: 2012

DOI: 10.1159/000333784

Abstract: In neuroscience, Ephs and ephrins are perhaps best known for their role in axon guidance. It was first shown in the visual system that graded expression of these proteins is instrumental in providing molecular coordinates that define topographic maps, particularly in the visual system, but also in the auditory, vomeronasal and somatosensory systems as well as in the hippoc us, cerebellum and other structures. Perhaps unsurprisingly, the role of these proteins in regulating cell-cell interactions also has an impact on cell mobility, with evidence that Eph-ephrin interactions segregate cell populations based on contact-mediated attraction or repulsion. Consistent with these studies, evidence has accumulated that Ephs and ephrins play important roles in the migration of specific cell populations in the developing and adult brain. This review focusses on two ex les of neuronal migration that require Eph/ephrin signalling - radial and tangential migration of neurons in cortical development and the migration of newly generated neurons along the rostral migratory stream to the olfactory bulb in the adult brain. We discuss the challenge involved in understanding how cells determine whether they respond to signals by migration or axon guidance.

Mineralocorticoids Restore Quiescent Morphology and Reduce VEGF Receptor Expression in Inflamed Choroidal Endothelial Cells in vitro

Publisher: S. Karger AG

Date: 22-10-2009

DOI: 10.1159/000164799

Abstract: i Background/Aims: /i While the glucocorticoid triamcinolone acetonide (9α-fluoro-16α-hydroxyprednisolone, TA) has been widely administered as a treatment of ocular inflammation, mineralocorticoids have not been tested for their efficacy. i Methods: /i We assessed cellular morphology and actin distribution by immunomicroscopy and light microscopy, membrane permeability with transendothelial resistance and cell surface vascular endothelial growth factor receptor-1 (VEGF-R1) expression by flow cytometry. i Results: /i Fludrocortisone acetate was more effective than TA in restoring quiescent morphology and reducing membrane permeability in phorbol-12-myristate-acetate (PMA)-stimulated choroidal endothelial cells (CECs). Each of the corticosteroids inhibited VEGF-R1 cell surface expression in PMA-responsive CECs. i Conclusion: /i Mineralocorticoids may be of potential use in reducing vascular permeability in ocular disease.

Magnetic temporal interference for noninvasive and focal brain stimulation

Publisher: IOP Publishing

Date: 18-01-2023

DOI: 10.1088/1741-2552/ACB015

Abstract: Objective . Noninvasive focal stimulation of deep brain regions has been a major goal for neuroscience and neuromodulation in the past three decades. Transcranial magnetic stimulation (TMS), for instance, cannot target deep regions in the brain without activating the overlying tissues and has poor spatial resolution. In this manuscript, we propose a new concept that relies on the temporal interference (TI) of two high-frequency magnetic fields generated by two electromagnetic solenoids. Approach . To illustrate the concept, custom solenoids were fabricated and optimized to generate temporal interfering electric fields for rodent brain stimulation. C-Fos expression was used to track neuronal activation. Main result . C-Fos expression was not present in regions impacted by only one high-frequency magnetic field indicating ineffective recruitment of neural activity in non-target regions. In contrast, regions impacted by two fields that interfere to create a low-frequency envelope display a strong increase in c-Fos expression. Significance . Therefore, this magnetic temporal interference solenoid-based system provides a framework to perform further stimulation studies that would investigate the advantages it could bring over conventional TMS systems.

Safety of low-intensity repetitive transcranial magneTic brAin stimUlation foR people living with mUltiple Sclerosis (TAURUS): study protocol for a randomised controlled trial

Publisher: Springer Science and Business Media LLC

Date: 03-08-2022

DOI: 10.1186/S13063-022-06526-Z

Abstract: Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease, characterised by oligodendrocyte death and demyelination. Oligodendrocyte progenitor cells can differentiate into new replacement oligodendrocytes however, remyelination is insufficient to protect neurons from degeneration in people with MS. We previously reported that 4 weeks of daily low-intensity repetitive transcranial magnetic stimulation (rTMS) in an intermittent theta-burst stimulation (iTBS) pattern increased the number of new myelinating oligodendrocytes in healthy adult mice. This study translates this rTMS protocol and aims to determine its safety and tolerability for people living with MS. We will also perform magnetic resonance imaging (MRI) and symptom assessments as preliminary indicators of myelin addition following rTMS. Participants ( N = 30, aged 18–65 years) will have a diagnosis of relapsing-remitting or secondary progressive MS. ≤2 weeks before the intervention, eligible, consenting participants will complete a physical exam, baseline brain MRI scan and participant-reported MS symptom assessments [questionnaires: Fatigue Severity Scale, Quality of Life (AQoL-8D), Hospital Anxiety and Depression Scale and smartphone-based measures of cognition (electronic symbol digit modalities test), manual dexterity (pinching test, draw a shape test) and gait (U-Turn test)]. Participants will be pseudo-randomly allocated to rTMS ( n =20) or sham (placebo n =10), stratified by sex. rTMS or sham will be delivered 5 days per week for 4 consecutive weeks (20 sessions, 6 min per day). rTMS will be applied using a 90-mm circular coil at low-intensity (25% maximum stimulator output) in an iTBS pattern. For sham, the coil will be oriented 90° to the scalp, preventing the magnetic field from stimulating the brain. Adverse events will be recorded daily. We will evaluate participant blinding after the first, 10th and final session. After the final session, participants will repeat symptom assessments and brain MRI, for comparison with baseline. Participant-reported assessments will be repeated at 4-month post-allocation follow-up. This study will determine whether this rTMS protocol is safe and tolerable for people with MS. MRI and participant-reported symptom assessments will serve as preliminary indications of rTMS efficacy for myelin addition to inform further studies. Australian New Zealand Clinical Trials Registry ACTRN12619001196134 . Registered on 27 August 2019

Optimising repetitive transcranial magnetic stimulation for neural circuit repair following traumatic brain injury

Publisher: Medknow

Date: 2015

DOI: 10.4103/1673-5374.153676

Pre- and post-synaptic regulation of synapsin I and syntaxin 1B expression in neuronal networks: Differential effects of neuronal activity and long-term potentiation in vivo

Publisher: Elsevier BV

Date: 1996

DOI: 10.1016/S0928-4257(97)87940-5

An overview of nanomedicines for neuron targeting

Publisher: Future Medicine Ltd

Date: 07-2020

DOI: 10.2217/NNM-2020-0088

Abstract: Medical treatments of neuron-related disorders are limited due to the difficulty of targeting brain cells. Major drawbacks are the presence of the blood–brain barrier and the lack of specificity of the drugs for the diseased cells. Nanomedicine-based approaches provide promising opportunities for overcoming these limitations. Although many previous reviews are focused on brain targeting with nanomedicines in general, none of those are concerned explicitly on the neurons, while targeting neuronal cells in central nervous diseases is now one of the biggest challenges in nanomedicine and neuroscience. We review the most relevant advances in nanomedicine design and strategies for neuronal drug delivery that might successfully bridge the gap between laboratory and bedside treatment in neurology.

Development of visual projections follows an avian/mammalian-like sequence in the lizard Ctenophorus ornatus

Publisher: Wiley

Date: 30-09-2002

DOI: 10.1002/CNE.10394

Abstract: Development of primary visual projections was examined in a lizard Ctenophorus ornatus by anterograde and retrograde tracing with DiI and by GAP-43 immunohistochemistry. Visual pathway development was essentially similar to that in birds and mammals and thus differed from patterns in fish or hibians. A number of features characterised the development as mammalian-like. Three phases occurred in rapid succession after laying: outgrowth (2-3 weeks, early), exuberance (4-5 weeks, intermediate), and retraction to the adult pattern (6-8 weeks, late) at about the time of hatching and eye opening. Furthermore, ipsilateral projections developed with only a slight lag relative to the contralateral ones. The dorsally located fovea could be identified from early stages. Optic axons formed transient exuberant projections to the ipsilateral optic tectum, to the opposite optic nerve, and to nonvisual regions. The pattern resembled that formed in the long term by regenerating optic axons in C. ornatus (Dunlop et al. [2000b] J. Comp. Neurol. 416:188-200), suggesting that axons recognise molecular signals associated with the initial exuberant innervation but not those associated with subsequent refinement.

Secondary degeneration of the optic nerve following partial transection : the benefits of lomerizine

Publisher: Elsevier BV

Date: 03-2009

DOI: 10.1016/J.EXPNEUROL.2008.11.026

Abstract: Secondary degeneration is a form of 'bystander' damage that can affect neural tissue both nearby and remote from an initial injury. Partial optic nerve transection is an excellent model in which to unequivocally differentiate events occurring during secondary degeneration from those resulting from primary CNS injury. We analysed the primary injury site within the optic nerve (ON) and intact areas vulnerable to secondary degeneration. Areas affected by the primary injury showed morphological disruption, loss of beta-III tubulin axonal staining, reduced myelinated axon density, greater proteoglycan expression (phosphacan), increased microglia and macrophage numbers and increased oxidative stress. Similar, but less extreme, changes were seen in areas of the optic nerve undergoing secondary degeneration. The CNS-specific L- and T-type calcium channel blocker lomerizine alleviated some of the changes in areas vulnerable to secondary degeneration. Lomerizine reduced morphological disruption, oxidative stress and phosphacan expression, and limited early increases in macrophage numbers. However, lomerizine failed to prevent progressive de-myelination of ON axons. Within the retina, secondary retinal ganglion cell (RGC) death was significant in areas vulnerable to secondary degeneration. Lomerizine protected RGCs from secondary death at 4 weeks but did not fully restore behavioural function (optokinetic nystagmus). We conclude that blockade of calcium channels is neuroprotective and limits secondary degenerative changes following CNS injury. However such an approach may need to be combined with other treatments to ensure long-term maintenance of full visual function.

Large-scale reconstitution of a retina-to-brain pathway in adult rats using gene therapy and bridging grafts: An anatomical and behavioral analysis.

Publisher: Elsevier BV

Date: 05-2016

DOI: 10.1016/J.EXPNEUROL.2016.03.006

Abstract: Peripheral nerve (PN) grafts can be used to bridge tissue defects in the CNS. Using a PN-to-optic nerve (ON) graft model, we combined gene therapy with pharmacotherapy to promote the long-distance regeneration of injured adult retinal ganglion cells (RGCs). Autologous sciatic nerve was sutured onto the transected ON and the distal end immediately inserted into contralateral superior colliculus (SC). Control rats received intraocular injections of saline or adeno-associated virus (AAV) encoding GFP. In experimental groups, three bi-cistronic AAV vectors encoding ciliary neurotrophic factor (CNTF) were injected into different regions of the grafted eye. Each vector encoded a different fluorescent reporter to assess retinotopic order in the regenerate projection. To encourage sprouting/synaptogenesis, after 6 weeks some AAV-CNTF injected rats received an intravitreal injection of recombinant brain-derived neurotrophic factor (rBDNF) or AAV-BDNF. Four months after surgery, cholera toxin B was used to visualize regenerate RGC axons. RGC viability and axonal regrowth into SC were significantly greater in AAV-CNTF groups. In some cases, near the insertion site, regenerate axonal density resembled retinal terminal densities seen in normal SC. Complex arbors were seen in superficial but not deep SC layers and many terminals were immunopositive for presynaptic proteins vGlut2 and SV2. There was improvement in visual function via the grafted eye with significantly greater pupillary constriction in both AAV-CNTF+BDNF groups. In both control and AAV-CNTF+rBDNF groups the extent of light avoidance correlated with the maximal distance of axonal penetration into superficial SC. Despite the robust regrowth of RGC axons back into the SC, axons originating from different parts of the retina were intermixed at the PN graft/host SC interface, indicating that there remained a lack of order in this extensive regenerate projection.

rTMS-Induced Changes in Glutamatergic and Dopaminergic Systems: Relevance to Cocaine and Methamphetamine Use Disorders

Publisher: Frontiers Media SA

Date: 06-03-2020

DOI: 10.3389/FNINS.2020.00137

Expression of ephrin‐A2 in the superior colliculus and EphA5 in the retina following optic nerve section in adult rat

Publisher: Wiley

Date: 12-2001

DOI: 10.1046/J.0953-816X.2001.01822.X

Abstract: The vertebrate retina projects topographically to visual brain centres. In the developing visual system, gradients of ephrins and Eph receptors play a role in defining topography. At maturity, ephrins but not Ephs are downregulated. Here we show that optic nerve section in adult rat differentially regulates the expression of ephrin-A2 in the superior colliculus (SC) and of EphA5 in the retina. Expression was quantified immunohistochemically ephrin-A2 levels were also estimated by semiquantitative reverse transcriptase polymerase chain reaction. In the normal SC, ephrin-A2 was expressed at low levels. At 1 month, levels of protein and of mRNA were upregulated across the contralateral SC giving rise to an increasing rostro-caudal gradient. At 6 months, levels had fallen but a gradient remained. In the retina of normal animals, EphA5 was expressed as an increasing naso-temporal gradient. By 1 month, expression was decreased in far temporal retina, resulting in a uniform expression across the naso-temporal axis. We suggest that denervation-induced plastic changes within the SC modify expression of these molecules.

Topographies of retinal cone photoreceptors in two Australian marsupials

Publisher: Cambridge University Press (CUP)

Date: 05-2003

DOI: 10.1017/S0952523803203096

Abstract: Microspectrophotometry indicates the presence of at least three cone visual pigments in two Australian marsupials, the fat-tailed dunnart ( Sminthopsis crassicaudata ) and honey possum ( Tarsipes rostratus ). Here we have examined the distribution of cone types using antisera, JH455 and JH492, that recognize short-wavelength-sensitive (SWS) and medium-to-long-wavelength-sensitive (M/LWS) cone opsins, respectively. SWS cones were concentrated in dorso-temporal retina in the dunnart with a shallow decreasing gradient extending to the periphery (2300–1500/mm 2 ). In the honey possum, SWS cones showed a uniform distribution (2700/mm 2 ), except for a slight increase in a narrow peripheral band (3100/mm 2 ). In both species, M/LWS cones dominated and their distributions were similar to those of retinal ganglion cells: a horizontal streak in the dunnart (31,000–21,000/mm 2 ) and a shallow mid-ventral to peripheral gradient in the honey possum (37,000–26,000/mm 2 ). A low number of cones remained unlabeled when the antisera were combined revealing further minority cone population(s). We discuss cone distributions in relation to visual capabilities and requirements of the species.

Age Related Response of Neonatal Rat Retinal Ganglion Cells to Reduced TrkB Signaling in vitro and in vivo

Publisher: Frontiers Media SA

Date: 04-06-2021

DOI: 10.3389/FCELL.2021.671087

Abstract: During development of retinofugal pathways there is naturally occurring cell death of at least 50% of retinal ganglion cells (RGCs). In rats, RGC death occurs over a protracted pre- and early postnatal period, the timing linked to the onset of axonal ingrowth into central visual targets. Gene expression studies suggest that developing RGCs switch from local to target-derived neurotrophic support during this innervation phase. Here we investigated, in vitro and in vivo , how RGC birthdate affects the timing of the transition from intra-retinal to target-derived neurotrophin dependence. RGCs were pre-labeled with 5-Bromo-2′-Deoxyuridine (BrdU) at embryonic (E) day 15 or 18. For in vitro studies, RGCs were purified from postnatal day 1 (P1) rat pups and cultured with or without: (i) brain derived neurotrophic factor (BDNF), (ii) blocking antibodies to BDNF and neurotrophin 4/5 (NT-4/5), or (iii) a tropomyosin receptor kinase B fusion protein (TrkB-Fc). RGC viability was quantified 24 and 48 h after plating. By 48 h, the survival of purified βIII-tubulin immunopositive E15 but not E18 RGCs was dependent on addition of BDNF to the culture medium. For E18 RGCs, in the absence of exogenous BDNF, addition of blocking antibodies or TrkB-Fc reduced RGC viability at both 24 and 48 h by 25–40%. While this decrease was not significant due to high variance, importantly, each blocking method also consistently reduced complex process expression in surviving RGCs. In vivo , survival of BrdU and Brn3a co-labeled E15 or E18 RGCs was quantified in rats 24 h after P1 or P5 injection into the eye or contralateral superior colliculus (SC) of BDNF and NT-4/5 antibodies, or serum vehicle. The density of E15 RGCs 24 h after P1 or P5 injection of blocking antibodies was reduced after SC but not intraretinal injection. Antibody injections into either site had little obvious impact on viability of the substantially smaller population of E18 RGCs. In summary, most early postnatal RGC death in the rat involves the elimination of early-born RGCs with their survival primarily dependent upon the availability of target derived BDNF during this time. In contrast, late-born RGC survival may be influenced by additional factors, suggesting an association between RGC birthdate and developmental death mechanisms.

Nabilone Impairs Spatial and Verbal Working Memory in Healthy Volunteers

Publisher: Mary Ann Liebert Inc

Date: 05-10-2022

DOI: 10.1089/CAN.2022.0099

Discrete ephrin-B1 expression by specific layers of the primate retinogeniculostriate system continues throughout postnatal and adult life

Publisher: Wiley

Date: 07-07-2012

DOI: 10.1002/CNE.23077

Abstract: The molecular guidance cue ephrin-B1 has traditionally been associated with the early development of the visual system, encompassing retinocollicular mapping as well as development and maturation of synapses. Although little is known about its role in the visual system during the postnatal period and in adulthood, recent studies have demonstrated the expression of ephrin-B1 in the adult mouse brain, indicating a sustained role beyond early development. Therefore, we explored the spatiotemporal expression of ephrin-B1 in the postnatal and adult nonhuman primate visual system and demonstrated that a modulated expression continued following birth into adulthood in the lateral geniculate nucleus (LGN) and primary visual cortex (V1, striate cortex). This occurred in the layers involved in bidirectional geniculostriate communication: layers 3Bβ, 4, and 6 of V1 and the parvocellular (P) and magnocellular (M) layers of the LGN. Furthermore, discrete gradients between the ipsi- and contralateral inputs of the P and M layers of the LGN evolved between 1 month following birth and the start of the critical period (3 months), and continued into adulthood. We also detected the postsynaptic expression of ephrin-B1 by excitatory cells in adult LGN and V1 and a subset of interneurons in adult V1, suggestive of a more global rather than subtype-specific role. Together these results suggest a possible role for ephrin-B1 in the maturation of the primate retinogeniculostriate pathway throughout postnatal life, extending into adulthood.

Transcranial Magnetic Stimulation

Publisher: Wiley

Date: 17-04-2019

DOI: 10.1002/9780470015902.A0028620

Low-Intensity Repetitive Transcranial Magnetic Stimulation Improves Abnormal Visual Cortical Circuit Topography and Upregulates BDNF in Mice

Publisher: Society for Neuroscience

Date: 06-08-2014

DOI: 10.1523/JNEUROSCI.0723-14.2014

Association between temperament related traits and single nucleotide polymorphisms in the serotonin and oxytocin systems in Merino sheep

Publisher: Wiley

Date: 18-11-2021

DOI: 10.1111/GBB.12714

Abstract: Animal temperament is defined as the consistent behavioral and physiological differences that are seen between in iduals in response to the same stressor. Neurotransmitter systems, like serotonin and oxytocin in the central nervous system, underlie variation in behavioral traits in humans and other animals. Variations like single nucleotide polymorphisms (SNPs) in the genes for tryptophan 5-hydroxylase (TPH2), the serotonin transporter (SLC6A4), the serotonin receptor (HTR2A), and the oxytocin receptor (OXTR) are associated with behavioral phenotype in humans. Thus, the objective of this study was to identify SNPs in those genes and to test if those variations are associated with the temperament in Merino sheep. Using ewes from the University of Western Australia temperament flock, which has been selected on emotional reactivity for more than 20 generations, eight SNPs (rs107856757, rs107856818, rs107856856 and rs107857156 in TPH2, rs20917091 in SLC6A4, rs17196799 and rs17193181 in HTR2A, and rs17664565 in OXTR) were found to be distributed differently between calm and nervous sheep. These eight SNPs were then genotyped in 260 sheep from a flock that has never been selected on emotional reactivity, followed by the estimation of the behavioral traits of those 260 sheep using an arena test and an isolation box test. We found that several SNPs in TPH2 (rs107856757, rs107856818, rs107856856 and rs107857156) were in strong linkage disequilibrium, and all were associated with behavioral phenotype in the nonselected sheep. Similarly, rs17196799 in HTR2A was also associated with the behavioral phenotype.

Ephrin-A2 affects wound healing and scarring in a murine model of excisional injury

Publisher: Elsevier BV

Date: 05-2019

DOI: 10.1016/J.BURNS.2018.10.002

Abstract: Ephrin ligand/Eph receptor signaling is important in both tissue development and homeostasis. There is increasing evidence that Ephrin/Eph signaling is important in the skin, involved in hair follicle cycling, epidermal differentiation, cutaneous innervation and skin cancer. However, there is currently limited information on the role of Ephrin/Eph signaling in cutaneous wound healing. Here we report the effects of the Ephrin-A2 and A5 ligands on wound healing. Using Ephrin-A2

What Does Low-Intensity rTMS Do to the Cerebellum?

Publisher: Springer Science and Business Media LLC

Date: 28-10-2014

DOI: 10.1007/S12311-014-0617-9

Abstract: Non-invasive stimulation of the human cerebellum, such as by transcranial magnetic stimulation (TMS), is increasingly used to investigate cerebellar function and identify potential treatment for cerebellar dysfunction. However, the effects of TMS on cerebellar neurons remain poorly defined. We applied low-intensity repetitive TMS (LI-rTMS) to the mouse cerebellum in vivo and in vitro and examined the cellular and molecular sequelae. In normal C57/Bl6 mice, 4 weeks of LI-rTMS using a complex biomimetic high-frequency stimulation (BHFS) alters Purkinje cell (PC) dendritic and spine morphology the effects persist 4 weeks after the end of stimulation. We then evaluated whether LI-rTMS could induce climbing fibre (CF) reinnervation to denervated PCs. After unilateral pedunculotomy in adult mice and 2 weeks sham or BHFS stimulation, VGLUT2 immunohistochemistry was used to quantify CF reinnervation. In contrast to sham, LI-rTMS induced CF reinnervation to the denervated hemicerebellum. To examine potential mechanisms underlying the LI-rTMS effect, we verified that BHFS could induce CF reinnervation using our in vitro olivocerebellar explants in which denervated cerebellar tissue is co-cultured adjacent to intact cerebella and treated with brain-derived neurotrophic factor (BDNF) (as a positive control), sham or LI-rTMS for 2 weeks. Compared with sham, BDNF and BHFS LI-rTMS significantly increased CF reinnervation, without additive effect. To identify potential underlying mechanisms, we examined intracellular calcium flux during the 10-min stimulation. Complex high-frequency stimulation increased intracellular calcium by release from intracellular stores. Thus, even at low intensity, rTMS modifies PC structure and induces CF reinnervation.

Neurotrophic Factors and the Regeneration of Adult Retinal Ganglion Cell Axons

Publisher: Elsevier

Date: 2012

DOI: 10.1016/B978-0-12-407178-0.00002-8

Simultaneous quantification of dopamine, serotonin, their metabolites and amino acids by LC-MS/MS in mouse brain following repetitive transcranial magnetic stimulation

Publisher: Elsevier BV

Date: 12-2019

DOI: 10.1016/J.NEUINT.2019.104546

Abstract: Repetitive Transcranial Magnetic Stimulation (rTMS) is a form of non-invasive brain stimulation that has shown therapeutic potential for various nervous system disorders. In addition to its modulatory effects on neuronal excitability, rTMS is capable of altering neurotransmitter (e.g., glutamate, GABA, dopamine and serotonin) concentrations in cortical and subcortical brain regions. Here we used a modified liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) to quantify changes in 27 free amino acids and the monoamines: dopamine (DA), serotonin (5HT) and their metabolites (DOPAC, HVA 5HIAA) in the mouse brain. Awake C57BL/6 J mice (either sex, 8-12 weeks old) received 10 Hz rTMS using two devices that can deliver low (LI- 12 mT custom built) or high (Fo8- 1.2 T MagVenture) intensity rTMS. Sham (unstimulated) mice were used as controls. S les were collected immediately following a single session of rTMS or sham and processed for LC-MS/MS. The modified LC-MS/MS method used to detect DA, 5-HT and their metabolites showed good accuracy and precision with regression coefficients greater than 0.999, and an intra- and inter-day reproducibility with values < 13%. Fo8-rTMS induced a significant reduction in cortical 5-HT turnover rates, hippoc al DOPAC and an increase in striatal DOPAC concentrations. Fo8-rTMS also reduced concentrations of hippoc al α-aminoadipic acid, and striatal serine, threonine, sarcosine, aspartate and glutamate. There were no changes in the level of any compounds following LI-rTMS as compared to sham. The rapid change in monoamine turnover and amino acid concentrations following Fo8-rTMS but not LI-rTMS suggests that different stimulation parameters recruit different cellular mechanisms related to rTMS-induced plasticity. The described method can be used for the characterisation of trace levels of neurotransmitters and amino acids in brain tissue homogenates, providing a useful and precise tool to investigate localised neurotransmitter changes in animal models of health and disease.

Validation of Chronic Restraint Stress Model in Young Adult Rats for the Study of Depression Using Longitudinal Multimodal MR Imaging

Publisher: Society for Neuroscience

Date: 07-2020

DOI: 10.1523/ENEURO.0113-20.2020

Abstract: Prior research suggests that the neurobiological underpinnings of depression include aberrant brain functional connectivity, neurometabolite levels, and hippoc al volume. Chronic restraint stress (CRS) depression model in rats has been shown to elicit behavioral, gene expression, protein, functional connectivity, and hippoc al volume changes similar to those in human depression. However, no study to date has examined the association between behavioral changes and brain changes within the same animals. This study specifically addressed the correlation between the outcomes of behavioral tests and multiple 9.4 T magnetic resonance imaging (MRI) modalities in the CRS model using data collected longitudinally in the same animals. CRS involved placing young adult male Sprague Dawley rats in in idual transparent tubes for 2.5 h daily over 13 d. Elevated plus maze (EPM) and forced swim tests (FSTs) confirmed the presence of anxiety-like and depression-like behaviors, respectively, postrestraint. Resting-state functional MRI (rs-fMRI) data revealed hypoconnectivity within the salience and interoceptive networks and hyperconnectivity of several brain regions to the cingulate cortex. Proton magnetic resonance spectroscopy revealed decreased sensorimotor cortical glutamate (Glu), glutamine (Gln), and combined Glu-Gln (Glx) levels. Volumetric analysis of T2-weighted images revealed decreased hippoc al volume. Importantly, these changes parallel those found in human depression, suggesting that the CRS rodent model has utility for translational studies and novel intervention development for depression.

Combined rTMS/fMRI Studies: An Overlooked Resource in Animal Models

Publisher: Frontiers Media SA

Date: 23-03-2018

DOI: 10.3389/FNINS.2018.00180

Seeing with Two Eyes: Integration of Binocular Retinal Projections in the Brain

Publisher: InTech

Date: 19-06-2013

DOI: 10.5772/56491

Inter- and intra-individual variability following intermittent theta burst stimulation: implications for rehabilitation and recovery

Publisher: Elsevier BV

Date: 05-2014

DOI: 10.1016/J.BRS.2014.01.004

Abstract: The continued refinement of non-invasive brain stimulation (NBS) techniques is indicative of promising clinical and rehabilitative interventions that are able to modulate cortical excitability. Intermittent theta burst stimulation (iTBS) is one such technique that can increase cortical excitability, purportedly via LTP-like mechanisms. While iTBS may have the capacity to promote recovery after neurological injury, and to combat cognitive and motor decline, recent reports observed highly variable effects across in iduals, questioning the efficacy of iTBS as a clinical tool. The aim of this study was to examine intra-in idual reliability and inter-in idual variability in responses to iTBS. Thirty healthy participants completed two experimental sessions of the iTBS protocol 1-3 weeks apart. Motor evoked potentials in response to single pulse TMS were used to assess corticospinal excitability prior to, and up to 36 min following, iTBS. At the group level, iTBS evoked statistically significant increases in motor cortical excitability across both sessions (P < 0.001), with 22 out of 30 participants exhibiting increases in excitability in both sessions. A strong intraclass correlation demonstrated that both the direction, and magnitude of the plastic changes were reliable at the in idual level. Overall, our results suggest that iTBS is capable of inducing relatively robust and consistent effects within and between young in iduals. As such, the capacity for iTBS to be exploited in clinical and rehabilitative interventions should continue to be explored.

cAMP regulates axon outgrowth and guidance during optic nerve regeneration in goldfish

Publisher: Elsevier BV

Date: 11-2005

DOI: 10.1016/J.MCN.2005.08.009

Abstract: Increased cAMP improves neuronal survival and axon regeneration in mammals. Here, we assess cAMP levels and identify activated pathways in a spontaneously regenerating central nervous system. Following optic nerve crush in goldfish, almost all retinal ganglion cells (RGC) survive and regenerate retinotectal topography. Goldfish received injections of a cAMP analogue (CPT-cAMP), a protein kinase A (PKA) inhibitor (KT5720), both compounds combined, or PBS (control). RGC survival in experimental groups was unaffected at any stage. The rate of axon regeneration was accelerated by the activator and decelerated both by the inhibitor and by combined injections, suggesting a PKA-dependent pathway. In addition, errors in regenerate retinotectal topography were observed when agents were applied in vivo and RGC response to the guidance cue ephrin-A5 in vitro was altered by the inhibitor. Our results highlight that therapeutic manipulation of cAMP levels to enhance axonal regeneration in mammals must ensure that topography, and consequently function, is not disrupted.

Medium- and high-intensity rTMS reduces psychomotor agitation with distinct neurobiologic mechanisms

Publisher: Springer Science and Business Media LLC

Date: 05-07-2018

DOI: 10.1038/S41398-018-0129-3

Abstract: Definitive data are lacking on the mechanism of action and biomarkers of repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression. Low-intensity rTMS (LI-rTMS) has demonstrated utility in preclinical models of rTMS treatments but the effects of LI-rTMS in murine models of depression are unknown. We examined the behavioral and neurobiologic changes in olfactory bulbectomy (OB) mice with medium-intensity rTMS (MI-rTMS) treatment and fluoxetine hydrochloride. We then compared 10-Hz rTMS sessions for 3 min at intensities (measured at the cortical surface) of 4 mT (LI-rTMS), 50 mT (medium-intensity rTMS [MI-rTMS]), or 1 T (high-intensity rTMS [HI-rTMS]) 5 days per week over 4 weeks in an OB model of agitated depression. Behavioral effects were assessed with forced swim test neurobiologic effects were assessed with brain levels of 5-hydroxytryptamine, brain-derived neurotrophic factor (BDNF), and neurogenesis. Peripheral metabolomic changes induced by OB and rTMS were monitored through enzyme-linked immunosorbent assay and ultrapressure liquid chromatography-driven targeted metabolomics evaluated with ingenuity pathway analysis (IPA). MI-rTMS and HI-rTMS attenuated psychomotor agitation but only MI-rTMS increased BDNF and neurogenesis levels. HI-rTMS normalized the plasma concentration of α-amino- n -butyric acid and 3-methylhistidine. IPA revealed significant changes in glutamine processing and glutamate signaling in the OB model and following MI-rTMS and HI-rTMS treatment. The present findings suggest that MI-rTMS and HI-rTMS induce differential neurobiologic changes in a mouse model of agitated depression. Further, α-amino- n -butyric acid and 3-methylhistidine may have utility as biomarkers to objectively monitor the response to rTMS treatment of depression.

Changing Pax6 expression correlates with axon outgrowth and restoration of topography during optic nerve regeneration

Publisher: Elsevier BV

Date: 2021

DOI: 10.1016/J.NEUROSCIENCE.2006.07.057

Abstract: Pax6, a member of the highly conserved developmental Pax gene family, plays a crucial role in early eye development and continues to be expressed in adult retinal ganglion cells (RGCs). Here we have used Western blots and immunohistochemistry to investigate the expression of Pax6 in the formation and refinement of topographic projections during optic nerve regeneration in zebrafish and lizard. In zebrafish with natural (12-h light/dark cycle) illumination, Pax6 expression in RGCs was decreased during axon outgrowth and increased during the restoration of the retinotectal map. Rearing fish in stroboscopic illumination to prevent retinotopic refinement resulted in a prolonged decrease in Pax6 levels return to natural light conditions resulted in map refinement and restoration of normal Pax6 levels. In lizard, RGC axons spontaneously regenerate but remain in a persistent state of regrowth and do not restore topography visual training during regeneration, however, allows a stabilization of connections and return of topography. Pax6 was persistently decreased in untrained animals but remained increased in trained ones. In both species, changes in expression were not due to cell ision or cell death. The results suggest that decreased Pax6 expression is permissive for axon regeneration and extensive searching, while higher levels of Pax6 are associated with restoration of topography.

Moving back in the brain to drive the field forward: Targeting neurostimulation to different brain regions in animal models of depression and neurodegeneration

Publisher: Elsevier BV

Date: 08-2021

DOI: 10.1016/J.JNEUMETH.2021.109261

Patterns of preoptic–hypothalamic neuronal activation and LH secretion in female sheep following the introduction and withdrawal of novel males

Publisher: CSIRO Publishing

Date: 2019

DOI: 10.1071/RD19079

Abstract: The neuroendocrine response of female sheep to a novel male involves neural activation in the hypothalamus. However, if males are removed, the gonadotrophic signal declines, so the neural activity is likely to change. We examined Fos-immunoreactive (IR) cells in hypothalamic tissues from seasonally anovulatory female sheep exposed to males for 2 or 6h, or for 2h followed by 4h isolation from males. Control females were killed in the absence of male exposure. Male introduction increased LH secretion in all females male removal was associated with a reduction only in mean and basal LH concentrations. Females exposed to males for 2h had more Fos-IR cells in the arcuate nucleus (ARC), ventromedial nucleus of the hypothalamus (VMH) and organum vasculosum of the lamina terminalis (OVLT) than control females. Fos-IR cells in the preoptic area (POA) were only greater than in control females after 6h exposure to a male. Removal of males decreased the number of Fos-IR cells in the ARC, VMH and OVLT, but not in the POA. Thus, hypothalamic neural activation and LH secretion in female sheep are stimulated by males and decline after male removal. However, activation in the POA persists after removal and may explain the incomplete decline in the LH response.

Developmental retinal ganglion cell death and retinotopicity of the murine retinocollicular projection

Publisher: Wiley

Date: 19-11-2017

DOI: 10.1002/DNEU.22559

Abstract: During mammalian visual system development, retinal ganglion cells (RGCs) undergo extensive apoptotic death. In mouse retina, approximately 50% of RGCs present at birth (postnatal day 0 P0) die by P5, at a time when axons innervate central targets such as the superior colliculus (SC). We examined whether RGCs that make short-range axonal targeting errors within the contralateral SC are more likely to be eliminated during the peak period of RGC death (P1-P5), compared with RGCs initially making more accurate retinotopic connections. A small volume (2.3 nL) of the retrograde nucleophilic dye Hoechst 33342 was injected into the superficial left SC of anesthetized neonatal C57Bl/6J mice at P1 (n = 5) or P4 (n = 8), and the contralateral retina wholemounted 12 hr later. Retrogradely labelled healthy and dying (pyknotic) RGCs were identified by morphological criteria and counted. The percentage of pyknotic RGCs was analyzed in relation to distance from the area of highest density RGC labelling, presumed to represent the most topographically accurate population. As expected, pyknotic RGC density at P1 was significantly greater than P4 (p < 0.05). At P4, the density of healthy RGCs 500-750 µm away from the central region was significantly less, although this was not reflected in altered pyknotic rates. However, at P1 there was a trend (p = 0.08) for an increased proportion of pyknotic RGCs, specifically in temporal parts of the retina outside the densely labelled center. Overall, the lack of consistent association between short-range targeting errors and cell death suggests that most postnatal RGC loss is not directly related to topographic accuracy. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 51-60, 2018.

Gene therapy and transplantation in the retinofugal pathway

Publisher: Elsevier

Date: 2009

DOI: 10.1016/S0079-6123(09)17510-6

Low intensity repetitive magnetic stimulation reduces expression of genes related to inflammation and calcium signalling in cultured mouse cortical astrocytes

Publisher: Elsevier BV

Date: 2021

DOI: 10.1016/J.BRS.2020.12.007

Transient up-regulation of retinal EphA3 and EphA5, but not ephrin-A2, coincides with re-establishment of a topographic map during optic nerve regeneration in goldfish

Publisher: Elsevier BV

Date: 10-2003

DOI: 10.1016/S0014-4886(03)00211-5

Abstract: Eph tyrosine kinase receptors and their ligands, the ephrins, play a key role in the establishment of retinotectal topography during development. Tectal up-regulation of ephrin-A2 in goldfish, coincident with the reestablishment of a retinotectal map, suggests a similar role during optic nerve regeneration. Here we report a complementary study of EphA3, EphA5 and ephrin-A2 expression in the retina. EphA3 and EphA5 are transiently up-regulated as ascending naso-temporal gradients, whereas ephrin-A2 remains uniform. The expression profiles differ from those in developing chick and mouse, suggesting that different combinations of retinal Eph receptors and ligands can generate topographic guidance information.

Expression of BDNF and NT‐3 during the ontogeny and regeneration of the lacertidian (Gallotia galloti) visual system

Publisher: Wiley

Date: 12-09-2011

DOI: 10.1002/DNEU.20939

Abstract: Retinal ganglion cell (RGC) axons regrow spontaneously after optic nerve (ON) transection in G. galloti. Because brain-derived neurotrophic factor (BDNF) is considered the major neurotrophin participating in vertebrate visual system development and promotes RGC survival, we investigated its distribution using dual-labeling immunohistochemistry for neuronal and glial markers. We examined the developing and regenerating lizard visual system at 1, 3, 6, 9, and 12 months postlesion to comparatively evaluate BDNF expression patterns. BDNF was detected from midembryonic stages (E35) in both retinal plexiform layers, and in radial glial processes in the tectum. Moreover, RGC axon staining was detected at late prenatal stages (E39), showing a transient punctate staining which progressed in a temporo-spatial pattern that was similar to myelination. Strong expression in RGC axons was maintained in adults. However, transient downregulation of BDNF staining occurred on the experimental side one month after ON transection followed by a gradual recovery with extensive punctate/swelling distribution and persistent upregulation at 12 months. Conversely, quantitative PCR analysis for 1 and 12 months regenerate lizards showed downregulation of the ratio of BDNF mRNA expression at 12 months and nonsignificant changes of NT-3 transcripts. In summary, we demonstrate that BDNF and NT-3 are abundantly expressed during lizard visual system ontogeny and regeneration suggesting their participation in the development, maintenance and plasticity of the system.

Induction of Long‐Term Potentiation In Vivo Regulates Alternate Splicing to Alter Syntaxin 3 Isoform Expression in Rat Dentate Gyrus

Publisher: Wiley

Date: 08-1998

DOI: 10.1046/J.1471-4159.1998.71020666.X

Abstract: The regulation and specificity of the interactions between the proteins involved in neurotransmitter release are obvious targets for the cellular control of synaptic plasticity. Previous research has identified one of these proteins, syntaxin 1B, as a potential target for mediating the propagation of synaptic plasticity through neural networks. The expression of syntaxin 1B is modified in the hippoc us after the induction of long-term potentiation (LTP) and during learning. Here, we describe the identification of two other members of the syntaxin family from rat brain, syntaxins 3A and 3B, and show that they are generated from the same gene by alternate splicing. In situ hybridization and immunohistochemical staining confirm the expression of syntaxins 3A and 3B in the adult rat brain. The transcripts and proteins show a lower abundance but a similar pattern of expression as syntaxins 1A and 1 B. By using quantitative competitive PCR, we show that the mRNAs that encode syntaxins 1B and 3A are increased in dentate granule cells 6 h after the induction of LTP in vivo, whereas syntaxin 3B mRNA is decreased as rapidly as 30 min, and lasts for at least 6 h, after the induction of LTP. These findings identify coordinated changes in the expression of several syntaxin isoforms with different substrate specificities and suggest that regulation of the splicing machinery by LTP induction is one of the erse strategies used during the long-term modification of the synapse in the vertebrate nervous system.

Comparison of ion channel inhibitor combinations for limiting secondary degeneration following partial optic nerve transection

Publisher: Springer Science and Business Media LLC

Date: 26-10-2019

DOI: 10.1007/S00221-018-5414-0

Abstract: Following neurotrauma, secondary degeneration of neurons and glia adjacent to the injury leads to further functional loss. A combination of ion channel inhibitors (lomerizine + oxATP + YM872) has been shown to be effective at limiting structural and functional loss due to secondary degeneration. Here we assess efficacy of the combination where oxATP is replaced with Brilliant Blue G (BBG), a more clinically applicable P2X

Effects of Neonatal Dexamethasone Exposure on Adult Neuropsychiatric Traits in Rats

Publisher: Public Library of Science (PLoS)

Date: 09-12-2016

DOI: 10.1371/JOURNAL.PONE.0167220

Untangling the structure and function of complex neuronal networks

Publisher: Elsevier BV

Date: 09-2023

DOI: 10.1016/J.PLREV.2023.07.004

In vitro Magnetic Stimulation: A Simple Stimulation Device to Deliver Defined Low Intensity Electromagnetic Fields

Publisher: Frontiers Media SA

Date: 03-11-2016

DOI: 10.3389/FNCIR.2016.00085

Validation of chronic restraint stress model in rats for the study of depression using longitudinal multimodal MR imaging

Publisher: Cold Spring Harbor Laboratory

Date: 23-03-2020

DOI: 10.1101/2020.03.20.998195

Abstract: Prior research suggests that the neurobiological underpinnings of depression include disruptions in functional connectivity, neurometabolite levels, and hippoc al volume. This study examined the validity of a chronic restraint stress (CRS) paradigm in male Sprague Dawley rats for the study of depression using longitudinal behavioural tests and multiple 9.4 T MRI modalities (resting-state functional MRI, proton magnetic resonance spectroscopy, and volumetric studies). In the CRS protocol, rats were placed in in idual transparent tubes for 2.5 h daily over 13 days. Elevated plus-maze test (EPM) and forced swim test (FST) confirmed the presence of anxiety-like and depression-like behaviours respectively post-restraint. Brain changes were also detected by MR. The rs-fMRI data revealed hypoconnectivity within the salience and interoceptive networks and hyperconnectivity of several brain regions to the cingulate cortex. The 1 H-MRS data revealed decreased sensorimotor cortical glutamate, glutamine and combined glutamate-glutamine levels. Volumetric analysis of T2-weighted images revealed decreased hippoc al volume, which was also correlated with salience network connectivity. Depression-like behaviours were correlated with salience and interoceptive network connectivity, glutamate and combined glutamate-glutamine levels and hippoc al volume. Anxiety-like behaviours were correlated with both hippoc us connectivity and interoceptive network connectivity. The present findings identify significant changes in brain connectivity, neurometabolites and structure that are correlated with abnormal behaviour in CRS rats. Importantly, these changes parallel those found in human depression, suggesting that the CRS rodent model has utility for translational studies and novel intervention development for depression.

Antenatal Corticosteroid Exposure Disrupts Myelination in the Auditory Nerve of Preterm Sheep

Publisher: S. Karger AG

Date: 2018

DOI: 10.1159/000487914

Abstract: b i Background: /i /b Antenatal corticosteroids (ACS) improve preterm neonatal outcomes. However, uncertainty remains regarding the safety of ACS exposure for the developing fetus, particularly its neurosensory development. b i Objectives: /i /b We investigated the effect of single and multiple ACS exposures on auditory nerve development in an ovine model of pregnancy. b i Methods: /i /b Ewes with a single fetus (gestational age [GA] 100 days) received an intramuscular injection of 150 mg medroxyprogesterone-acetate, followed by intramuscular (i) betamethasone (0.5 mg/kg) on days 104, 111, and 118 GA (ii) betamethasone on day 104 and saline on days 111 and 118 GA or (iii) saline on days 104, 111, and 118 GA, with delivery on day 125 GA. Transmission electron microscope images of lamb auditory nerve preparations were digitally analyzed to determine auditory nerve morphology and myelination. b i Results: /i /b Relative to the control, mean auditory nerve myelin area was significantly increased in the multiple-treatment group ( i & #x3c /i 0.001), but not in the single-treatment group. Increased myelin thickness was significantly changed only in a subgroup analysis for those axons with myelin thickness greater than the median value ( i & #x3c /i 0.001). Morphological assessments showed that the increased myelin area was due to an increased likelihood of decompacted areas ( i /i = 0.005 OR = 2.14, 95% CI 1.26–3.63 31.6 vs. 18.2% in controls) and irregular myelin deposition ( i /i = 0.001 OR = 5.91, 95% CI 2.16–16.19 49.0 vs. 16.8% in controls) in the myelin sheath. b i Conclusions: /i /b In preterm sheep, ACS exposure increased auditory nerve myelin area, potentially due to disruption of normal myelin deposition.

Online LI-rTMS during a Visual Learning Task: Differential Impacts on Visual Circuit and Behavioral Plasticity in Adult Ephrin-A2A5^–/–Mice

Publisher: Society for Neuroscience

Date: 2018

DOI: 10.1523/ENEURO.0163-17.2018

Abstract: Repetitive transcranial magnetic stimulation (rTMS) induces plasticity in normal and abnormal neural circuitries, an effect that may be influenced by intrinsic brain activity during treatment. Here, we study potential synergistic effects between low-intensity rTMS (LI-rTMS) and concurrent neural activity in promoting circuit reorganization and enhancing visual behavior. We used ephrin-A2A5 –/– mice, which are known to possess visuotopic mapping errors that are ameliorated by LI-rTMS, and assessed the impact of stimulation when mice were engaged in a visual learning task. A detachable coil was affixed to each mouse, and animals underwent 2 wk of 10-min daily training in a two-choice visual discrimination task with concurrent LI-rTMS or sham stimulation. No-task controls (+LI-rTMS/sham) were placed in the task arena without visual task training. At the end of the experiment, visuomotor tracking behavior was assessed, and corticotectal and geniculocortical pathway organization was mapped by injections of fluorescent tracers into the primary visual cortex. Consistent with previous results, LI-rTMS alone improved geniculocortical and corticotectal topography, but combining LI-rTMS with the visual learning task prevented beneficial corticotectal reorganization and had no additional effect on geniculocortical topography or visuomotor tracking performance. Unexpectedly, there was a significant increase in the total number of trials completed by task + LI-rTMS mice in the visual learning task. Comparison with wild-type mice revealed that ephrin-A2A5 –/– mice had reduced accuracy and response rates, suggesting a goal-directed behavioral deficit, which was improved by LI-rTMS. Our results suggest that concurrent brain activity during behavior interacts with LI-rTMS, altering behavior and different visual circuits in an abnormal system.

Differences in Motor Evoked Potentials Induced in Rats by Transcranial Magnetic Stimulation under Two Separate Anesthetics: Implications for Plasticity Studies

Publisher: Frontiers Media SA

Date: 06-10-2016

DOI: 10.3389/FNCIR.2016.00080

Ephrin-B2 immunoreactivity distribution in adult mouse brain

Publisher: Elsevier BV

Date: 11-2007

DOI: 10.1016/J.BRAINRES.2007.08.065

Abstract: Ephrin ligands and their receptors Eph receptor tyrosine-kinases have received extensive attention for their multiple key roles during development, particularly in the central nervous system (CNS). For ex le, at early stages of brain and spinal cord development, membrane-bound ephrins provide signals that direct migrating cells and axons. However, much less is known about the role of ephrins and Eph receptors in the adult CNS. Here, we investigated the distribution of ephrin-B2 protein expression in the adult mouse brain to gain insight into its possible function(s). We show that ephrin-B2 is expressed in areas with high levels of synaptic plasticity, such as the cerebral cortex, hippoc us and cerebellum. However, at the cellular level, ephrin-B2 was localized to neuronal cell bodies rather than to the dendritic synaptic sites where mechanisms of long-term modifications of excitatory transmission are located. Our results suggest a role for ephrin-B2 in the membrane at the cell body, possibly in relation to axonal-somatic inhibitory synapses.

Changes in the rodent gut microbiome following chronic restraint stress and low-intensity rTMS

Publisher: Elsevier BV

Date: 03-2022

DOI: 10.1016/J.YNSTR.2022.100430

Pax7 is expressed in the capsules surrounding adult mouse neuromuscular spindles

Publisher: Canadian Science Publishing

Date: 1999

DOI: 10.1139/BCB-77-2-153

Low intensity repetitive transcranial magnetic stimulation modulates brain-wide functional connectivity to promote anti-correlated activity

Publisher: Cold Spring Harbor Laboratory

Date: 13-08-2022

DOI: 10.1101/2022.08.13.503840

Abstract: Repetitive transcranial magnetic stimulation (rTMS) induces action potentials to induce plastic changes in the brain with increasing evidence for the therapeutic importance of brain-wide functional network effects of rTMS however, the influence of sub-action potential threshold (low-intensity LI-) rTMS on neuronal activity is largely unknown. We investigated whether LI-rTMS modulates neuronal activity and functional connectivity. We also specifically assessed modulation of parvalbumin interneuron activity. We conducted a brain-wide analysis of c-Fos, a marker for neuronal activity, in mice that received LI-rTMS to visual cortex. Mice received single or multiple sessions of excitatory 10Hz LI-rTMS with custom rodent coils or were sham controls. We assessed changes to c-Fos positive cell densities and c-Fos arvalbumin co-expression. Peak c-Fos expression corresponded with activity during rTMS. We also assessed functional connectivity changes using brain-wide c-Fos-based network analysis. LI-rTMS modulated c-Fos expression in cortical and subcortical regions. c-Fos density changes were most prevalent with acute stimulation, however chronic stimulation decreased parvalbumin interneuron activity, most prominently in the amygdala and striatum. LI-rTMS also increased anti-correlated functional connectivity, with the most prominent effects also in the amygdala and striatum following chronic stimulation. LI-rTMS induces changes in c-Fos expression that suggest modulation of neuronal activity and functional connectivity throughout the brain. Our results suggest that LI-rTMS promotes anticorrelated functional connectivity, possibly due to decreased parvalbumin interneuron activation induced by chronic stimulation. These changes may underpin therapeutic rTMS effects, therefore modulation of subcortical activity supports rTMS for treatment of disorders involving subcortical dysregulation. - Low-intensity rTMS increases brain-wide anti-correlated functional connectivity - Acute excitatory LI-rTMS modulates cortical and subcortical neuronal activity - Decreased parvalbumin interneuron activity may promote anti-correlated activity - Striatum and amygdala show prominent modulation with LI-rTMS

PSA-NCAM is up-regulated during optic nerve regeneration in lizard but not in goldfish

Publisher: Elsevier BV

Date: 07-2003

DOI: 10.1016/S0014-4886(03)00081-5

Abstract: The addition of polysialic acid (PSA) to neural cell adhesion molecule (NCAM) facilitates axon growth. Here we use Western blots and immunohistochemistry to examine expression of PSA-NCAM during optic nerve regeneration. In lizard, retinal ganglion cell axons become transiently PSA-NCAM positive. By contrast, goldfish RGC axons are PSA-NCAM negative both in normal animals and throughout regeneration with the exception of a PSA-NCAM-positive fascicle arising from newly generated RGCs. Transient sialylation of NCAM in lizard may assist regeneration in the nonpermissive reptilian visual pathway and facilitate the reestablishment of a crude topographic map down-regulation in the long term may contribute to the breakdown in topography. The lack of sialylation in goldfish presumably reflects the permissive nature of the substrate allowing axon regeneration and the successful reestablishment of a topographic map.

Reinnervation of the Superior Colliculus Delays Down-regulation of Ephrin A2 in Neonatal Rat

Publisher: Elsevier BV

Date: 08-2001

DOI: 10.1006/EXNR.2001.7722

Dorsal striatum c-Fos activity in perseverative ephrin-A2A5−/− mice and the cellular effect of low-intensity rTMS

Publisher: Frontiers Media SA

Date: 15-06-2023

DOI: 10.3389/FNCIR.2023.1179096

Abstract: Overreliance on habit is linked with disorders, such as drug addiction and obsessive-compulsive disorder, and there is increasing interest in the use of repetitive transcranial magnetic stimulation (rTMS) to alter neuronal activity in the relevant pathways and for therapeutic outcomes. In this study, we researched the brains of ephrin-A2A5 −/− mice, which previously showed perseverative behavior in progressive-ratio tasks, associated with low cellular activity in the nucleus accumbens. We investigated whether rTMS treatment had altered the activity of the dorsal striatum in a way that suggested altered hierarchical recruitment of brain regions from the ventral striatum to the dorsal striatum, which is linked to abnormal habit formation. Brain sections from a limited number of mice that underwent training and performance on a progressive ratio task with and without low-intensity rTMS (LI-rTMS) were taken from a previous study. We took advantage of the previous characterization of perseverative behavior to investigate the contribution of different neuronal subtypes and striatal regions within this limited s le. Striatal regions were stained for c-Fos as a correlate of neuronal activation for DARPP32 to identify medium spiny neurons (MSNs) and for GAD67 to identify GABA-ergic interneurons. Contrary to our hypothesis, we found that neuronal activity in ephrin-A2A5 −/− mice still reflected the typical organization of goal-directed behavior. There was a significant difference in the proportion of neuronal activity across the striatum between experimental groups and control but no significant effects identifying a specific regional change. However, there was a significant group by treatment interaction which suggests that MSN activity is altered in the dorsomedial striatum and a trend suggesting that rTMS increases ephrin-A2A5 −/− MSN activity in the DMS. Although preliminary and inconclusive, the analysis of this archival data suggests that investigating circuit-based changes in striatal regions may provide insight into chronic rTMS mechanisms that could be relevant to treating disorders associated with perseverative behavior.

Graded ephrin-A2 expression in the developing hamster superior colliculus

Publisher: Springer Science and Business Media LLC

Date: 19-07-2006

DOI: 10.1007/S00221-006-0615-3

Abstract: During development, ephrin gradients guide retinal ganglion cell axons to their appropriate topographic locations in the superior colliculus (SC). Expression of ephrin-A2, assessed immunohistochemically in the developing hamster SC, revealed a rostral(low) to caudal (high) gradient that is most prominent at postnatal days P4 and P7 when topography is established. Double-labelling immunohistochemistry for ephrin-A2 and cell specific markers revealed that ephrin-A2 is expressed exclusively by a subset of neurons. The expression pattern has implications for mechanisms underlying establishment of topography during development and following injury.

Eph/ephrin expression in the adult rat visual system following localized retinal lesions: localized and transneuronal up‐regulation in the retina and superior colliculus

Publisher: Wiley

Date: 10-2005

DOI: 10.1111/J.1460-9568.2005.04381.X

Abstract: Following unilateral optic nerve section in adult PVG hooded rat, the axon guidance cue ephrin-A2 is up-regulated in caudal but not rostral superior colliculus (SC) and the EphA5 receptor is down-regulated in axotomised retinal ganglion cells (RGCs). Changes occur bilaterally despite the retino-collicular projection being mostly crossed. Here we investigate the dynamics of Eph/ephrin expression using in situ hybridization and semi-quantitative immunohistochemistry after localized retinal lesions. Unilateral krypton laser lesions to dorso-nasal retina ablated contralaterally projecting RGCs (DN group) ventro-temporal lesions ablated contralaterally and ipsilaterally projecting RGCs (VT group). Lesions of the entire retina served as controls (Total group). Results are compared to normal animals in which tectal ephrin-A2 and retinal EphA5 are expressed, respectively, as shallow ascending rostro-caudal and naso-temporal gradients. In both SCs of DN and Total groups, tectal ephrin-A2 was up-regulated caudally in the VT group, expression remained normal bilaterally. Unilateral collicular ablation indicated that bilateral changes in ephrin-A2 expression are mediated via intercollicular pathways. EphA5 expression in the VT group was elevated in the intact nasal region of experimental retinae. For each experimental group, EphA5 expression was also elevated in nasal retina of the opposite eye, resulting in uniform expression across the naso-temporal axis. Up-regulation of ephrin-A2 in caudal, but not rostral, SC suggests the enhancement of developmental positional information as a result of injury. Bilateral increases in retinal EphA5 expression demonstrate that signals for up-regulation operate interocularly. The study demonstrates that signals regulating guidance cue expression are both localized and relayed transneuronally.

Comparing modes of delivery of a combination of ion channel inhibitors for limiting secondary degeneration following partial optic nerve transection

Publisher: Springer Science and Business Media LLC

Date: 25-10-2019

DOI: 10.1038/S41598-019-51886-3

Abstract: Injury to the central nervous system is exacerbated by secondary degeneration. Previous research has shown that a combination of orally and locally administered ion channel inhibitors following partial optic nerve injury protects the myelin sheath and preserves function in the ventral optic nerve, vulnerable to secondary degeneration. However, local administration is often not clinically appropriate. This study aimed to compare the efficacy of systemic and local delivery of the ion channel inhibitor combination of lomerizine, brilliant blue G (BBG) and YM872, which inhibits voltage-gated calcium channels, P2X 7 receptors and Ca 2+ permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors respectively. Following a partial optic nerve transection, adult female PVG rats were treated with BBG and YM872 delivered via osmotic mini pump directly to the injury site, or via intraperitoneal injection, both alongside oral administration of lomerizine. Myelin structure was preserved with both delivery modes of the ion channel inhibitor combination. However, there was no effect of treatment on inflammation, either peripherally or at the injury site, or on the density of oligodendroglial cells. Taken together, the data indicate that even at lower concentrations, the combinatorial treatment may be preserving myelin structure, and that systemic and local delivery are comparable at improving outcomes following neurotrauma.

Pax7is expressed in the capsules surrounding adult mouse neuromuscular spindles

Publisher: Canadian Science Publishing

Date: 20-06-1999

DOI: 10.1139/O99-020

Abstract: The multigene Pax family of transcription factors plays an important role in the development of the central nervous system as well as in organ morphogenesis. Expression of one of the members of the family, Pax7, has been described in embryonic muscle and in both embryonic and adult brain. We recently detected Pax7 transcripts in RNA isolated from adult mouse skeletal muscle and brain and here use in situ hybridisation to localise the expression within these tissues. Pax7 expression was observed in neural cells of the brain and in cells of neural crest origin in the inner and outer capsules of neuromuscular spindles. The results suggest that Pax7 may be implicated in the formation and maintenance of neuromuscular contacts within the muscle spindle throughout life.Key words: Pax7 expression, skeletal muscle, neuromuscular spindle, basal lamina, Schwann cells.

Low Intensity Repetitive Transcranial Magnetic Stimulation Does Not Induce Cell Survival or Regeneration in a Mouse Optic Nerve Crush Model

Publisher: Public Library of Science (PLoS)

Date: 20-05-2015

DOI: 10.1371/JOURNAL.PONE.0126949

Subthreshold repetitive transcranial magnetic stimulation drives structural synaptic plasticity in the young and aged motor cortex

Publisher: Elsevier BV

Date: 11-2021

DOI: 10.1016/J.BRS.2021.10.001

Abstract: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive tool commonly used to drive neural plasticity in the young adult and aged brain. Recent data from mouse models have shown that even at subthreshold intensities (0.12 T), rTMS can drive neuronal and glial plasticity in the motor cortex. However, the physiological mechanisms underlying subthreshold rTMS induced plasticity and whether these are altered with normal ageing are unclear. To assess the effect of subthreshold rTMS, using the intermittent theta burst stimulation (iTBS) protocol on structural synaptic plasticity in the mouse motor cortex of young and aged mice. Longitudinal in vivo 2-photon microscopy was used to measure changes to the structural plasticity of pyramidal neuron dendritic spines in the motor cortex following a single train of subthreshold rTMS (in young adult and aged animals) or the same rTMS train administered on 4 consecutive days (in young adult animals only). Data were analysed with Bayesian hierarchical generalized linear regression models and interpreted with the aid of Bayes Factors (BF). We found strong evidence (BF > 10) that subthreshold rTMS altered the rate of dendritic spine losses and gains, dependent on the number of stimulation sessions and that a single session of subthreshold rTMS was effective in driving structural synaptic plasticity in both young adult and aged mice. These findings provide further evidence that rTMS drives synaptic plasticity in the brain and uncovers structural synaptic plasticity as a key mechanism of subthreshold rTMS induced plasticity.

Differential expression of the NMDA NR2B receptor subunit in motoneuron populations susceptible and resistant to amyotrophic lateral sclerosis

Publisher: Elsevier BV

Date: 05-2006

DOI: 10.1016/J.NEULET.2006.01.051

Abstract: We have compared the expression pattern of NMDA receptor subunits (NR1 and NR2A-D) and NR1 splice variants (NR1-1a/1b,-2a/2b,-3a/3b,-4a/4b) in motor neuron populations from adult Wistar rats that are vulnerable (hypoglossal, XII) or resistant (oculomotor, III) to death in amyotrophic lateral sclerosis (ALS). The major finding was higher levels of expression of the NR2B subunit in the hypoglossal nucleus. Quantitative real-time PCR showed that NR1 was expressed at a greater level than any of the NR2 subunits (>15 fold greater, P<or=0.05, n = 11 animals), while conventional RT-PCR showed no difference in NR1 splice variant expression (with all variants except NR1-3 detected in both nuclei n = 6 animals). Within III, the NR2B subunit was expressed 1.7 to 2.6-fold lower than the other NR2 subunits (P<or=0.05), while in XII all NR2 subunits were expressed at equal levels. When comparing levels between the 2 nuclei, mRNA for the NR2B subunit was expressed 2.1-fold higher in XII compared to III (P<or=0.05), while their was no difference in mRNA expression for the other subunits. Immunohistochemical analysis confirmed greater NR2B protein levels within in idual hypoglossal neurons compared to oculomotor neurons (1.8-fold greater, P<or=0.05, n = 5 animals). Lower expression of the NMDA NR2B subunit may constitute one factor conferring protection to oculomotor neurons in ALS.

Repetitive low intensity magnetic field stimulation in a neuronal cell line: a metabolomics study

Publisher: PeerJ

Date: 12-03-2018

DOI: 10.7717/PEERJ.4501

Abstract: Low intensity repetitive magnetic stimulation of neural tissue modulates neuronal excitability and has promising therapeutic potential in the treatment of neurological disorders. However, the underpinning cellular and biochemical mechanisms remain poorly understood. This study investigates the behavioural effects of low intensity repetitive magnetic stimulation (LI-rMS) at a cellular and biochemical level. We delivered LI-rMS (10 mT) at 1 Hz and 10 Hz to B50 rat neuroblastoma cells in vitro for 10 minutes and measured levels of selected metabolites immediately after stimulation. LI-rMS at both frequencies depleted selected tricarboxylic acid (TCA) cycle metabolites without affecting the main energy supplies. Furthermore, LI-rMS effects were frequency-specific with 1 Hz stimulation having stronger effects than 10 Hz. The observed depletion of metabolites suggested that higher spontaneous activity may have led to an increase in GABA release. Although the absence of organised neural circuits and other cellular contributors (e.g., excitatory neurons and glia) in the B50 cell line limits the degree to which our results can be extrapolated to the human brain, the changes we describe provide novel insights into how LI-rMS modulates neural tissue.

A dorso-ventral gradient of Pax6 in the developing retina suggests a role in topographic map formation

Publisher: Elsevier BV

Date: 02-2003

DOI: 10.1016/S0165-3806(02)00605-3

Abstract: Expression of the transcription factor Pax6 was assessed immunohistochemically in embryonic chick retina during retino-tectal map formation. A low dorsal to high ventral gradient was found that correlated with expression of the axonal guidance cue EphB2. Furthermore, transfection of Pax6 into undifferentiated P19 cells up-regulated EphB2. The results raise the possibility that Pax6 is upstream of EphB2 and that its graded expression defines the dorso-ventral axis of the retino-tectal projection.

Changes in neuronal activity and gene expression in guinea-pig auditory brainstem after unilateral partial hearing loss

Publisher: Elsevier BV

Date: 03-2009

DOI: 10.1016/J.NEUROSCIENCE.2009.01.043

Abstract: Spontaneous neural hyperactivity in the central auditory pathway is often associated with deafness, the most common form of which is partial hearing loss. We quantified both peripheral hearing loss and spontaneous activity in single neurons of the contralateral inferior colliculus in a guinea-pig model 1 week after a unilateral partial deafness induced by cochlear mechanical lesion. We also measured mRNA levels of candidate genes in the same animals using quantitative real-time PCR. Spontaneous hyperactivity was most marked in the frequency region of the peripheral hearing loss. Expression of glutamate decarboxylase 1 (GAD1), GABA-A receptor subunit alpha-1 (GABRA1), and potassium channel subfamily K member 15 (KCNK15) was decreased ipsilaterally in the cochlear nucleus and bilaterally in the inferior colliculus. A member of RAB family of small GTPase (RAB3A) was decreased in both ipsilateral cochlear nucleus and contralateral inferior colliculus. RAB3 GTPase activating protein subunit 1 (RAB3GAP1) and glycine receptor subunit alpha-1 (GLRA1) were reduced ipsilaterally in the cochlear nucleus only. These results suggest that a decrease in inhibitory neurotransmission and an increase in membrane excitability may contribute to elevated neuronal spontaneous activity in the auditory brainstem following unilateral partial hearing loss.

Offline Parietal Intermittent Theta Burst Stimulation or Alpha Frequency Transcranial Alternating Current Stimulation Has No Effect on Visuospatial or Temporal Attention

Publisher: Frontiers Media SA

Date: 14-06-2022

DOI: 10.3389/FNINS.2022.903977

Abstract: Non-invasive brain stimulation is a growing field with potentially wide-ranging clinical and basic science applications due to its ability to transiently and safely change brain excitability. In this study we include two types of stimulation: repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS). Single session stimulations with either technique have previously been reported to induce changes in attention. To better understand and compare the effectiveness of each technique and the basis of their effects on cognition we assessed changes to both temporal and visuospatial attention using an attentional blink task and a line bisection task following offline stimulation with an intermittent theta burst (iTBS) rTMS protocol or 10 Hz tACS. Additionally, we included a novel rTMS stimulation technique, low-intensity (LI-)rTMS, also using an iTBS protocol, which uses stimulation intensities an order of magnitude below conventional rTMS. Animal models show that low-intensity rTMS modulates cortical excitability despite sub-action potential threshold stimulation. Stimulation was delivered in healthy participants over the right posterior parietal cortex (rPPC) using a within-subjects design ( n = 24). Analyses showed no evidence for an effect of any stimulation technique on spatial biases in the line bisection task or on magnitude of the attentional blink. Our results suggests that rTMS and LI-rTMS using iTBS protocol and 10 Hz tACS over rPPC do not modulate performance in tasks assessing visuospatial or temporal attention.

Tonotopic changes in GABA receptor expression in guinea pig inferior colliculus after partial unilateral hearing loss

Publisher: Elsevier BV

Date: 06-2010

DOI: 10.1016/J.BRAINRES.2010.04.067

Abstract: Immunohistochemistry was used to investigate the topographic distribution of the alpha1 subunit of the GABA receptor (GABRA1) in guinea pig inferior colliculus after treatments that caused a unilateral loss of peripheral neural sensitivity in the high-frequency regions of the cochlea. Both forms of treatment (direct mechanical lesion of the cochlea and acoustic overstimulation) resulted in a significant decrease in GABRA1 labeling in regions of the contralateral inferior colliculus in which high-frequency sound stimuli are represented. This localized region of reduced inhibitory receptor expression corresponds to the region in which hyperactivity of inferior colliculus neurons has been shown to develop after such treatments. The results strengthen the notion of a causal link between reduced GABRA1 expression and neural hyperactivity in central auditory nuclei and provide a possible mechanism for the development of phantom auditory sensations, or tinnitus.

The gut-brain axis and gut inflammation in Parkinson’s disease

Publisher: Informa UK Limited

Date: 05-05-2020

DOI: 10.1080/14728222.2020.1763956

Copy number variation in tRNA isodecoder genes impairs mammalian development and balanced translation

Publisher: Springer Science and Business Media LLC

Date: 18-04-2023

DOI: 10.1038/S41467-023-37843-9

Abstract: The number of tRNA isodecoders has increased dramatically in mammals, but the specific molecular and physiological reasons for this expansion remain elusive. To address this fundamental question we used CRISPR editing to knockout the seven-membered phenylalanine tRNA gene family in mice, both in idually and combinatorially. Using ATAC-Seq, RNA-seq, ribo-profiling and proteomics we observed distinct molecular consequences of single tRNA deletions. We show that tRNA-Phe-1-1 is required for neuronal function and its loss is partially compensated by increased expression of other tRNAs but results in mistranslation. In contrast, the other tRNA-Phe isodecoder genes buffer the loss of each of the remaining six tRNA-Phe genes. In the tRNA-Phe gene family, the expression of at least six tRNA-Phe alleles is required for embryonic viability and tRNA-Phe-1-1 is most important for development and survival. Our results reveal that the multi-copy configuration of tRNA genes is required to buffer translation and viability in mammals.

Erratum

Publisher: S. Karger AG

Date: 21-12-2018

DOI: 10.1159/000495278

EphA5 and ephrin‐A2 expression during optic nerve regeneration: a ‘two‐edged sword’

Publisher: Wiley

Date: 02-2007

DOI: 10.1111/J.1460-9568.2007.05321.X

Abstract: During development, gradients of EphA receptors (nasal(low)-temporal(high)) and their ligands ephrin-As (rostral(low)-caudal(high)) are involved in establishing topography between retinal ganglion cells (RGCs) and the superior colliculus (SC). EphA5-expressing RGC axons are repulsed by ephrin-A2-expressing SC neurones. In adult rats RGCs maintain graded EphA5 expression but ephrin-A2 expression is down-regulated in the SC to a weak gradient. At 1 month after optic nerve transection, EphA5 expression is reduced in the few remaining RGCs and is no longer graded by contrast, SC ephrin-A2 is up-regulated to a rostral(low)-caudal(high) gradient. Here we examined expression in adult rat 1 month after bridging the retina and SC with a peripheral nerve graft, a procedure that enhances RGC survival and permits RGC axon regeneration. Double labelling with cell markers revealed preservation of a nasal(low)-temporal(high) EphA5 gradient in RGCs and establishment of a rostral(low)-caudal(high) ephrin-A2 gradient within neurones of the SC. The results suggest a potential for guidance cues to restore the topography of RGC axons in the SC. However, high ephrin-A2 levels were also found in astrocytes surrounding the peripheral nerve graft insertion site. The repulsive ephrin-A2 environment offers at least a partial explanation for the observation that only a limited number of RGC axons can exit the graft to enter target central nervous system tissue.

The effects of repetitive transcranial magnetic stimulation in an animal model of tinnitus

Publisher: Springer Science and Business Media LLC

Date: 12-2016

DOI: 10.1038/SREP38234

Abstract: Tinnitus (phantom auditory perception associated with hearing loss) can seriously affect wellbeing. Its neural substrate is unknown however it has been linked with abnormal activity in auditory pathways. Though no cure currently exists, repetitive transcranial magnetic stimulation (rTMS) has been shown to reduce tinnitus in some patients, possibly via induction of cortical plasticity involving brain derived neurotrophic factor (BDNF). We examined whether low intensity rTMS (LI-rTMS) alleviates signs of tinnitus in a guinea pig model and whether this involves changes in BDNF expression and hyperactivity in inferior colliculus. Acoustic trauma was used to evoke hearing loss, central hyperactivity and tinnitus. When animals developed tinnitus, treatment commenced (10 sessions of 10 minutes 1 Hz LI-rTMS or sham over auditory cortex over 14 days). After treatment ceased animals were tested for tinnitus, underwent single-neuron recordings in inferior colliculus to assess hyperactivity and s les from cortex and inferior colliculus were taken for BDNF ELISA. Analysis revealed a significant reduction of tinnitus after LI-rTMS compared to sham, without a statistical significant effect on BDNF levels or hyperactivity. This suggests that LI-rTMS alleviates behavioural signs of tinnitus by a mechanism independent of inferior colliculus hyperactivity and BDNF levels and opens novel therapeutic avenues for tinnitus treatment.

Characterisation of tectal ephrin-A2 expression during optic nerve regeneration in goldfish: implications for restoration of topography

Publisher: Elsevier BV

Date: 06-2004

DOI: 10.1016/J.EXPNEUROL.2004.02.006

Neurite resposes to ephrin-A5 modulated by BDNF: Evidence for TrkB-EphA interactions

Publisher: Elsevier BV

Date: 10-2008

DOI: 10.1016/J.BBRC.2008.07.110

Abstract: In the developing visual system, growing retinal ganglion cell (RGC) axons are exposed to multiple guidance and growth factors. Furthermore, the relative levels of these factors are differentially regulated as topography is roughly established and then refined. We have shown that during the establishment of rough topography (P3), growth cones of pure and explanted RGCs treated with combinations of BDNF and ephrin-A5-Fc responded differently than RGCs treated with BDNF or ephrin-A5-Fc alone (p=0.0083). The response to the combined treatment mimicked that of RGCs cultured with ephrin-A5-Fc alone once topography refines. The guidance cue receptors EphA and TrkB were shown to co-localise in RGCs in vitro. Furthermore, EphA and TrkB receptors interacted directly in in vitro binding assays. Our results suggest that the conversion of growth cone responses from collapse to stabilisation as topography refines, occurs as a result of interactions between EphA and TrkB receptors.

Frequency-specific effects of low-intensity rTMS can persist for up to 2 weeks post-stimulation: A longitudinal rs-fMRI/MRS study in rats

Publisher: Elsevier BV

Date: 11-2019

DOI: 10.1016/J.BRS.2019.06.028

Abstract: Evidence suggests that repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique, alters resting brain activity. Despite anecdotal evidence that rTMS effects wear off, there are no reports of longitudinal studies, even in humans, mapping the therapeutic duration of rTMS effects. Here, we investigated the longitudinal effects of repeated low-intensity rTMS (LI-rTMS) on healthy rodent resting-state networks (RSNs) using resting-state functional MRI (rs-fMRI) and on sensorimotor cortical neurometabolite levels using proton magnetic resonance spectroscopy (MRS). Sprague-Dawley rats received 10 min LI-rTMS daily for 15 days (10 Hz or 1 Hz stimulation, n = 9 per group). MRI data were acquired at baseline, after seven days and after 14 days of daily stimulation and at two more timepoints up to three weeks post-cessation of daily stimulation. 10 Hz stimulation increased RSN connectivity and GABA, glutamine, and glutamate levels. 1 Hz stimulation had opposite but subtler effects, resulting in decreased RSN connectivity and glutamine levels. The induced changes decreased to baseline levels within seven days following stimulation cessation in the 10 Hz group but were sustained for at least 14 days in the 1 Hz group. Overall, our study provides evidence of long-term frequency-specific effects of LI-rTMS. Additionally, the transient connectivity changes following 10 Hz stimulation suggest that current treatment protocols involving this frequency may require ongoing "top-up" stimulation sessions to maintain therapeutic effects.

Manipulating the Level of Sensorimotor Stimulation during LI-rTMS Can Improve Visual Circuit Reorganisation in Adult Ephrin-A2A5-/- Mice

Publisher: MDPI AG

Date: 22-02-2022

DOI: 10.3390/IJMS23052418

Abstract: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that has the potential to treat a variety of neurologic and psychiatric disorders. The extent of rTMS-induced neuroplasticity may be dependent on a subject’s brain state at the time of stimulation. Chronic low intensity rTMS (LI-rTMS) has previously been shown to induce beneficial structural and functional reorganisation within the abnormal visual circuits of ephrin-A2A5-/- mice in ambient lighting. Here, we administered chronic LI-rTMS in adult ephrin-A2A5-/- mice either in a dark environment or concurrently with voluntary locomotion. One day after the last stimulation session, optokinetic responses were assessed and fluorescent tracers were injected to map corticotectal and geniculocortical projections. We found that LI-rTMS in either treatment condition refined the geniculocortical map. Corticotectal projections were improved in locomotion+LI-rTMS subjects, but not in dark + LI-rTMS and sham groups. Visuomotor behaviour was not improved in any condition. Our results suggest that the beneficial reorganisation of abnormal visual circuits by rTMS can be significantly influenced by simultaneous, ambient visual input and is enhanced by concomitant physical exercise. Furthermore, the observed pathway-specific effects suggest that regional molecular changes and/or the relative proximity of terminals to the induced electric fields influence the outcomes of LI-rTMS on abnormal circuitry.

The ipsilateral retinal projection in the fat-tailed dunnart, Sminthopsis crassicaudata

Publisher: Cambridge University Press (CUP)

Date: 04-1998

DOI: 10.1017/S095252389815407X

Abstract: The population of retinal ganglion cells which project ipsilaterally in the brain was examined in the fat-tailed dunnart, Sminthopsis crassicaudata , following injection of horseradish peroxidase into one optic tract. Retinae were examined as wholemounts and optic nerves as serial sections. In addition, visual fields were measured ophthalmoscopically. Ipsilaterally projecting ganglion cells were located temporal to a line which ran vertically through the middle of the area centralis and extended medially to define a ventrolateral crescent. Temporal to the naso-temporal ision, a mean of 77% of ganglion cells projected ipsilaterally these cells represented 20% of the total ganglion cell population. The magnitude and retinal location of the ipsilateral projection correlated with the extensive binocular field which measured 180 deg in the vertical (from 20 deg below the horizontal axis to 70 deg beyond the zenith) and 140 deg in horizontal meridian. Ipsilaterally projecting axons were restricted to the lateral third of the optic nerve along its length, sharing territory with contralaterally projecting axons.

The effects of caffeine and d-amphetamine on spatial span task in healthy participants

Publisher: Public Library of Science (PLoS)

Date: 13-07-2023

DOI: 10.1371/JOURNAL.PONE.0287538

Abstract: Studies that examined the effect of hetamine or caffeine on spatial working memory (SWM) and verbal working memory (VWM) have used various tasks. However, there are no studies that have used spatial span tasks (SSTs) to assess the SWM effect of hetamine and caffeine, although some studies have used digit span tasks (DST) to assess VWM. Previous reports also showed that increasing dopamine increases psychosis-like experiences (PLE, or schizotypy) scores which are in turn negatively associated with WM performance in people with high schizotypy and people with schizophrenia. Therefore, the present study aimed to examine the influence of d- hetamine (0.45 mg/kg, PO), a dopamine releasing stimulant, on SST, DST, and on PLE in healthy volunteers. In a separate study, we examined the effect of caffeine, a nonspecific adenosine receptor antagonist with stimulant properties, on similar tasks. Methods: Healthy participants (N = 40) took part in two randomized, double-blind, counter-balanced placebo-controlled cross-over pilot studies: The first group (N = 20) with d- hetamine (0.45 mg/kg, PO) and the second group (N = 20) with caffeine (200 mg, PO). Spatial span and digit span were examined under four delay conditions (0, 2, 4, 8 s). PLE were assessed using several scales measuring various aspects of psychosis and schizotypy. Results: We failed to find an effect of d- hetamine or caffeine on SWM or VWM, relative to placebo. However, d- hetamine increased a composite score of psychosis-like experiences (p = 0.0005), specifically: Scores on Brief Psychiatric Rating Scale, Perceptual Aberrations Scale, and Magical Ideation Scale were increased following d- hetamine. The degree of change in PLE following d- hetamine negatively and significantly correlated with changes in SWM, mainly at the longest delay condition of 8 s (r = -0.58, p = 0.006). Conclusion: The present results showed that moderate-high dose of d- hetamine and moderate dose of caffeine do not directly affect performances on DST or SST. However, the results indicate that d- hetamine indirectly influences SWM, through its effect on psychosis-like experiences. Trial registration. Clinical Trial Registration Number: CT-2018-CTN-02561 (Therapeutic Goods Administration Clinical Trial Registry) and ACTRN12618001292268 (The Australian New Zealand Clinical Trials Registry) for caffeine study, and ACTRN12608000610336 for d- hetamine study.

Ephrin-A2 and Ephrin-A5 are important for the functional development of cutaneous innervation in a mouse model

Publisher: Elsevier BV

Date: 02-2015

DOI: 10.1038/JID.2014.407

Intermittent Theta Burst Stimulation Improves Motor and Behavioral Dysfunction through Modulation of NMDA Receptor Subunit Composition in Experimental Model of Parkinson’s Disease

Publisher: MDPI AG

Date: 06-2023

DOI: 10.3390/CELLS12111525

Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by the progressive degeneration of the dopaminergic system, leading to a variety of motor and nonmotor symptoms. The currently available symptomatic therapy loses efficacy over time, indicating the need for new therapeutic approaches. Repetitive transcranial magnetic stimulation (rTMS) has emerged as one of the potential candidates for PD therapy. Intermittent theta burst stimulation (iTBS), an excitatory protocol of rTMS, has been shown to be beneficial in several animal models of neurodegeneration, including PD. The aim of this study was to investigate the effects of prolonged iTBS on motor performance and behavior and the possible association with changes in the NMDAR subunit composition in the 6-hydroxydopamine (6-OHDA)-induced experimental model of PD. Two-month-old male Wistar rats were ided into four groups: controls, 6-OHDA rats, 6-OHDA + iTBS protocol (two times/day/three weeks) and the sham group. The therapeutic effect of iTBS was evaluated by examining motor coordination, balance, spontaneous forelimb use, exploratory behavior, anxiety-like, depressive/anhedonic-like behavior and short-term memory, histopathological changes and changes at the molecular level. We demonstrated the positive effects of iTBS at both motor and behavioral levels. In addition, the beneficial effects were reflected in reduced degeneration of dopaminergic neurons and a subsequent increase in the level of DA in the caudoputamen. Finally, iTBS altered protein expression and NMDAR subunit composition, suggesting a sustained effect. Applied early in the disease course, the iTBS protocol may be a promising candidate for early-stage PD therapy, affecting motor and nonmotor deficits.

Compensatory and transneuronal plasticity after early collicular lesions

Publisher: Wiley

Date: 20-12-2007

DOI: 10.1002/CNE.21221

Abstract: Plasticity within the visual system was assessed in the quokka wallaby following unilateral superior collicular (SC) ablation at postnatal days (P) 8-10, prior to the arrival of retinal ganglion cell (RGC) axons. At maturity (P100), projections were traced from the eye opposite the ablation, and total RGC numbers were estimated for both eyes. Ablations were partial (28-89% of SC remaining) or complete (0-5% of SC remaining). Projections to the visual centers showed significant bilateral (P 0.05). Compared with normal, total RGC numbers were significantly (P < 0.05) reduced in the eye opposite the ablation but increased (P 0.05). As in rodents, the visual system in quokka compensates following injury by maintaining a set volume of arborization but does so by forming only minor anomalous projections. Furthermore, increased RGC numbers in the eye ipsilateral to the lesion indicate that compensation occurs transneuronally, thus maintaining total numbers of projecting neurons. The implication is that the visual system acts in concert following unilateral injury to maintain set values for RGC terminal arbors as well as their cell bodies.

A repeated measures cognitive affective bias test in rats: comparison with forced swim test

Publisher: Springer Science and Business Media LLC

Date: 12-2022

DOI: 10.1007/S00213-022-06281-8

Abstract: There is an urgent need to identify behaviours in animals that can provide insight into the aetiology and potential treatment of depression in humans. This study aimed to validate a repeated measures cognitive affective bias (CAB) test in a rat model of chronic stress and compare CAB with forced swim test (FST) measures. Male and female Sprague Dawley rats were trained to associate large and small rewards with scent, spatial, and tactile cues, and their response to an ambiguous tactile stimulus tested. Rats underwent weekly CAB testing for 4 weeks with no intervention, or for 2 weeks of chronic restraint stress (CRS), followed by 2 weeks of fluoxetine, vehicle, or no treatment. CRS rats also underwent the FST at selected timepoints. In control rats, CAB was positive and remained stable over the 4-week period. In CRS-fluoxetine and CRS-vehicle groups, CAB was initially positive, became negative during chronic restraint stress, and returned to positive by 2 weeks after treatment. However, in the CRS-no treatment group, CAB was variable at the outset and unstable over time. Behaviour in the FST was not affected by treatment, and there was no correlation between CAB and FST outcomes. Instability in the CRS-no treatment group precluded interpretation of the impact of fluoxetine on CAB post-CRS. Our results suggest that behaviour in the FST does not reflect or alter affective state and support the use of CAB tests as part of the behavioural testing repertoire for preclinical animal models of affective disorders.

A Tailored Music-Motor Therapy and Real-Time Biofeedback Mobile Phone App (‘GotRhythm’) to Promote Rehabilitation Following Stroke: A Pilot Study

Publisher: SAGE Publications

Date: 2022

DOI: 10.1177/26331055221100587

Abstract: Stroke persists as an important cause of long-term disability world-wide with the need for rehabilitation strategies to facilitate plasticity and improve motor function in stroke survivors. Rhythm-based interventions can improve motor function in clinical populations. This study tested a novel music-motor software application ‘GotRhythm’ on motor function after stroke. Participants were 22 stroke survivors undergoing inpatient rehabilitation in a subacute stroke ward. Participants were randomised to the GotRhythm intervention (combining in idualised music and augmented auditory feedback along with wearable sensors to deliver a personalised rhythmic auditory stimulation training protocol) or usual care. Intervention group participants were offered 6-weeks of the GotRhythm intervention, consisting of a supervised 20-minute music-motor therapy session using GotRhythm conducted 3 times a week for 6 weeks. The primary feasibility outcomes were adherence to the intervention and physical function (change in the Fugl-Meyer Assessment of Motor Recovery score) measured at baseline, after 3-weeks and at end of the intervention period (6-weeks). Three of 10 participants randomised to the intervention did not receive any of the GotRhythym music-motor therapy. Of the remaining 7 intervention group participants, only 5 completed the 3-week mid-intervention assessment and only 2 completed the 6-week post-intervention assessment. Participants who used the intervention completed 5 (IQR 4,7) sessions with total ‘dose’ of the intervention of 70 (40, 201) minutes. Overall, adherence to the intervention was poor, highlighting that application of technology assisted music-based interventions for stroke survivors in clinical environments is challenging along with usual care, recovery, and the additional clinical load.

A consensus protocol for functional connectivity analysis in the rat brain

Publisher: Springer Science and Business Media LLC

Date: 27-03-2023

DOI: 10.1038/S41593-023-01286-8

Accelerated low-intensity rTMS does not rescue anxiety behaviour or abnormal connectivity in young adult rats following chronic restraint stress

Publisher: Elsevier BV

Date: 09-2022

DOI: 10.1016/J.YNIRP.2022.100104

Utility of pharmacogenetic testing to optimise antidepressant pharmacotherapy in youth: a narrative literature review

Publisher: Frontiers Media SA

Date: 19-09-2023

DOI: 10.3389/FPHAR.2023.1267294

Maternal Intravenous Administration of Azithromycin Results in Significant Fetal Uptake in a Sheep Model of Second Trimester Pregnancy

Publisher: American Society for Microbiology

Date: 11-2014

DOI: 10.1128/AAC.03721-14

Abstract: Treatment of intrauterine infection is likely key to preventing a significant proportion of preterm deliveries before 32 weeks of gestation. Azithromycin (AZ) may be an effective antimicrobial in pregnancy however, few gestation age-approriate data are available to inform the design of AZ-based treatment regimens in early pregnancy. We aimed to determine whether a single intra-amniotic AZ dose or repeated maternal intravenous (i.v.) AZ doses would safely yield therapeutic levels of AZ in an 80-day-gestation (term is 150 days) ovine fetus. Fifty sheep carrying single pregnancies at 80 days gestation were randomized to receive either: (i) a single intra-amniotic AZ administration or (ii) maternal intravenous AZ administration every 12 h. Amniotic fluid, maternal plasma, and fetal AZ concentrations were determined over a 5-day treatment regimen. Markers of liver injury and amniotic fluid inflammation were measured to assess fetal injury in response to drug exposure. A single intra-amniotic administration yielded significant AZ accumulation in the amniotic fluid and fetal lung. In contrast, repeated maternal intravenous administrations achieved high levels of AZ accumulation in the fetal lung and liver and a statistically significant increase in the fetal plasma drug concentration at 120 h. There was no evidence of fetal injury in response to drug exposure. These data suggest that (i) repeated maternal i.v. AZ dosing yields substantial fetal tissue uptake, although fetal plasma drug levels remain low (ii) transfer of AZ from the amniotic fluid is less than transplacental transfer and (iii) exposure to high concentrations of AZ did not elicit overt changes in fetal white blood cell counts, amniotic fluid monocyte chemoattractant protein 1 concentrations, or hepatotoxicity, all consistent with an absence of fetal injury.

White Matter Changes Following Chronic Restraint Stress and Neuromodulation: A Diffusion Magnetic Resonance Imaging Study in Young Male Rats

Publisher: Elsevier BV

Date: 04-2022

DOI: 10.1016/J.BPSGOS.2021.08.006

Low intensity repetitive transcranial magnetic stimulation modulates skilled motor learning in adult mice

Publisher: Springer Science and Business Media LLC

Date: 05-03-2018

DOI: 10.1038/S41598-018-22385-8

Abstract: Repetitive transcranial magnetic stimulation (rTMS) is commonly used to modulate cortical plasticity in clinical and non-clinical populations. Clinically, rTMS is delivered to targeted regions of the cortex at high intensities ( T). We have previously shown that even at low intensities, rTMS induces structural and molecular plasticity in the rodent cortex. To determine whether low intensity rTMS (LI-rTMS) alters behavioural performance, daily intermittent theta burst LI-rTMS (120 mT) or sham was delivered as a priming or consolidating stimulus to mice completing 10 consecutive days of skilled reaching training. Relative to sham, priming LI-rTMS (before each training session), increased skill accuracy (~9%) but did not alter the rate of learning over time. In contrast, consolidating LI-rTMS (after each training session), resulted in a small increase in the rate of learning (an additional ~1.6% each day) but did not alter the daily skill accuracy. Changes in behaviour with LI-rTMS were not accompanied with long lasting changes in brain-derived neurotrophic factor (BDNF) expression or in the expression of plasticity markers at excitatory and inhibitory synapses for either priming or consolidation groups. These results suggest that LI-rTMS can alter specific aspects of skilled motor learning in a manner dependent on the timing of intervention.

Neurostructural Differences in Adolescents With Treatment-Resistant Depression and Treatment Effects of Transcranial Magnetic Stimulation

Publisher: Oxford University Press (OUP)

Date: 28-01-2022

DOI: 10.1093/IJNP/PYAC007

Abstract: Despite its morbidity and mortality, the neurobiology of treatment-resistant depression (TRD) in adolescents and the impact of treatment on this neurobiology is poorly understood. Using automatic segmentation in FreeSurfer, we examined brain magnetic resonance imaging baseline volumetric differences among healthy adolescents (n = 30), adolescents with major depressive disorder (MDD) (n = 19), and adolescents with TRD (n = 34) based on objective antidepressant treatment rating criteria. A pooled subs le of adolescents with TRD were treated with 6 weeks of active (n = 18) or sham (n = 7) 10-Hz transcranial magnetic stimulation (TMS) applied to the left dorsolateral prefrontal cortex. Ten of the adolescents treated with active TMS were part of an open-label trial. The other adolescents treated with active (n = 8) or sham (n = 7) were participants from a randomized controlled trial. Adolescents with TRD and adolescents with MDD had decreased total amygdala (TRD and MDD: −5%, P = .032) and caudal anterior cingulate cortex volumes (TRD: −3%, P = .030 MDD: −.03%, P = .041) compared with healthy adolescents. Six weeks of active TMS increased total amygdala volumes (+4%, P & .001) and the volume of the stimulated left dorsolateral prefrontal cortex (+.4%, P = .026) in adolescents with TRD. Amygdala volumes were reduced in this s le of adolescents with MDD and TRD. TMS may normalize this volumetric finding, raising the possibility that TMS has neurostructural frontolimbic effects in adolescents with TRD. TMS also appears to have positive effects proximal to the site of stimulation.

Effects of trkB knockout on topography and ocular segregation of uncrossed retinal projections

Publisher: Springer Science and Business Media LLC

Date: 13-03-2009

DOI: 10.1007/S00221-009-1746-0

A Preclinical Study of Standard Versus Accelerated Transcranial Magnetic Stimulation for Depression in Adolescents

Publisher: Mary Ann Liebert Inc

Date: 04-2022

DOI: 10.1089/CAP.2021.0100

EphA/ephrin-A interactions during optic nerve regeneration: restoration of topography and regulation of ephrin-A2 expression

Publisher: Elsevier BV

Date: 2004

DOI: 10.1016/J.MCN.2003.09.010

Low‐intensity transcranial magnetic stimulation promotes the survival and maturation of newborn oligodendrocytes in the adult mouse brain

Publisher: Wiley

Date: 16-04-2019

DOI: 10.1002/GLIA.23620

Transcranial pulsed magnetic field stimulation facilitates reorganization of abnormal neural circuits and corrects behavioral deficits without disrupting normal connectivity

Publisher: Wiley

Date: 05-01-2012

DOI: 10.1096/FJ.11-194878

Abstract: Although the organization of neuronal circuitry is shaped by activity patterns, the capacity to modify and/or optimize the structure and function of whole projection pathways using external stimuli is poorly defined. We investigate whether neuronal activity induced by pulsed magnetic fields (PMFs) alters brain structure and function. We delivered low-intensity PMFs to the posterior cranium of awake, unrestrained mice (wild-type and ephrin-A2A5(-/-)) that have disorganized retinocollicular circuitry and associated visuomotor deficits. Control groups of each genotype received sham stimulation. Following daily stimulation for 14 d, we measured biochemical, structural (anterograde tracing), and functional (electrophysiology and behavior) changes in the retinocollicular projection. PMFs induced BDNF, GABA, and nNOS expression in the superior colliculus and retina of wild-type and ephrin-A2A5(-/-) mice. Furthermore, in ephrin-A2A5(-/-) mice, PMFs corrected abnormal neuronal responses and selectively removed inaccurate ectopic axon terminals to improve structural and functional organization of their retinocollicular projection and restore normal visual tracking behavior. In contrast, PMFs did not alter the structure or function of the normal projection in wild-type mice. Sham PMF stimulation had no effect on any mice. Thus, PMF-induced biochemical changes are congruent with its capacity to facilitate beneficial reorganization of abnormal neural circuits without disrupting normal connectivity and function.

Low intensity rTMS has sex-dependent effects on the local response of glia following a penetrating cortical stab injury

Publisher: Elsevier BV

Date: 09-2017

DOI: 10.1016/J.EXPNEUROL.2017.06.019

Abstract: Repetitive transcranial magnetic stimulation (rTMS), a non-invasive form of brain stimulation, has shown experimental and clinical efficacy in a range of neuromodulatory models, even when delivered at low intensity (i.e. subthreshold for action potential generation). After central nervous system (CNS) injury, studies suggest that reactive astrocytes and microglia can have detrimental but also beneficial effects thus modulating glial activity, for ex le through application of rTMS, could potentially be a useful therapeutic tool following neurotrauma. Immunohistochemistry was used to measure the effect of low intensity rTMS (LI-rTMS) on GFAP (astrocyte), IBA1 (microglial), and CS56 (proteoglycan) expression in a unilateral penetrating cortical stab injury model of glial scarring in young adult and aged male and female C57BL6/J mice. Mice received contralateral low frequency, ipsilateral low frequency, ipsilateral high frequency or sham LI-rTMS (4-5mT intensity), for two weeks following injury. There was no significant difference in the overall volume of tissue containing GFAP positive (

Erythropoietin is both neuroprotective and neuroregenerative following optic nerve transection

Publisher: Elsevier BV

Date: 05-2007

DOI: 10.1016/J.EXPNEUROL.2007.01.017

Abstract: The cytokine hormone erythropoietin (EPO) is neuroprotective in models of brain injury and disease, and protects retinal ganglion cells (RGC) from cell death after axotomy. Here, we assessed EPO's neuroprotective properties in vivo by examining RGC survival and axon regeneration at 4 weeks following intraorbital optic nerve transection in adult rat. EPO was administered as a single intravitreal injection at the time of transection (5, 10, 25, 50 units, PBS control). Intravitreal EPO (5, 10 units) significantly increased RGC somata and axon survival between the eye and transection site. Twenty five units did not improve survival of RGC somata but did increase axon survival between the eye and transection site. In addition, a small proportion of axons penetrated the transection site and regenerated up to 1 mm into the distal nerve. In a second series, intravitreal EPO (25 units) doubled the number of RGC axons regenerating along a length of peripheral nerve grafted onto the retrobulbar optic nerve. Our in vivo evidence of both neuroregeneration and neuroprotection, taken together with the natural occurrence of EPO within the body and its ability to cross the blood-brain barrier, suggests that it offers promise as a therapeutic agent for central nerve repair.

Physiological and anatomical investigation of the auditory brainstem in the Fat-tailed Dunnart (Sminthopsis crassicaudata)

Publisher: PeerJ

Date: 05-06-2019

DOI: 10.7287/PEERJ.PREPRINTS.27783V1

Abstract: The fat-tailed Dunnart ( Sminthopsis crassicaudata ) is a small (10-20g) native marsupial endemic to the south west of Western Australia. Currently little is known about the auditory capabilities of the dunnart, and of marsupials in general. Consequently, this study sought to investigate several electrophysiological and anatomical properties of the dunnart auditory system. Auditory brainstem responses (ABR) were recorded to brief (5ms) tone pips at a range of frequencies (4-47.5 kHz) and intensities to determine auditory brainstem thresholds. The dunnart ABR displayed multiple distinct peaks at all test frequencies, similar to other mammalian species. ABR showed the dunnart is most sensitive to higher frequencies increasing up to 47.5 kHz. Morphological observations (Nissl stain) revealed that the auditory structures thought to contribute to the first peaks of the ABR were all distinguishable in the dunnart. Structures identified include the dorsal and ventral sub isions of the cochlear nucleus, including a cochlear nerve root nucleus as well as several distinct nuclei in the superior olivary complex, such as the medial nucleus of the trapezoid body, lateral superior olive and medial superior olive. This study is the first to show functional and anatomical aspects of the lower part of the auditory system in the Fat-tailed Dunnart.

Analysis of Activity Dependent Development of Topographic Maps in Neural Field Theory with Short Time Scale Dependent Plasticity

Publisher: Centre pour la Communication Scientifique Directe (CCSD)

Date: 11-03-2022

DOI: 10.46298/MNA.8390

Abstract: Topographic maps are a brain structure connecting pre-synpatic and post-synaptic brain regions. Topographic development is dependent on Hebbian-based plasticity mechanisms working in conjunction with spontaneous patterns of neural activity generated in the pre-synaptic regions. Studies performed in mouse have shown that these spontaneous patterns can exhibit complex spatial-temporal structures which existing models cannot incorporate. Neural field theories are appropriate modelling paradigms for topographic systems due to the dense nature of the connections between regions and can be augmented with a plasticity rule general enough to capture complex time-varying structures. We propose a theoretical framework for studying the development of topography in the context of complex spatial-temporal activity fed-forward from the pre-synaptic to post-synaptic regions. Analysis of the model leads to an analytic solution corroborating the conclusion that activity can drive the refinement of topographic projections. The analysis also suggests that biological noise is used in the development of topography to stabilise the dynamics. MCMC simulations are used to analyse and understand the differences in topographic refinement between wild-type and the $\\beta2$ knock-out mutant in mice. The time scale of the synaptic plasticity window is estimated as $0.56$ seconds in this context with a model fit of $R^2 = 0.81$.

The rod opsin pigments from two marsupial species, the South American bare-tailed woolly opossum and the Australian fat-tailed dunnart

Publisher: Elsevier BV

Date: 12-2003

DOI: 10.1016/J.GENE.2003.09.016

Abstract: Rod visual pigment genes have been studied in a wide range of vertebrates including a number of mammalian species. However, no marsupials have yet been examined. To correct this omission, we have studied the rod pigments in two marsupial species, the nocturnal and frugivorous bare-tailed woolly opossum, Caluromys philander, from Central and South America, and the arhythmic and insectivorous fat-tailed dunnart, Sminthopsis crassicaudata, from Australia. Phylogenetic analysis establishes that the cloned opsin sequences are orthologues of rod opsin genes from other vertebrate species. The deduced amino acid sequences show that both possess glutamate at residue 122, a feature of rod opsins, and the corresponding gene follows the typical vertebrate rod opsin pattern of five exons separated by four introns. Compared to other vertebrates, a stretch of five residues near the C-terminus is deleted in the rod opsin of both marsupials and all eutherian mammals. From microspectrophotometric measurements, the pigments in the two species show an 8 nm difference in peak absorbance the molecular basis for this spectral shift is discussed and two candidate substitutions are identified.

Different Levels of Food Restriction Reveal Genotype-Specific Differences in Learning a Visual Discrimination Task

Publisher: Public Library of Science (PLoS)

Date: 07-11-2012

DOI: 10.1371/JOURNAL.PONE.0048703

Translation of preclinical findings: The effect of low intensity repetitive Transcranial Magnetic Stimulation (rTMS) on depression score and biomarkers in patients with major depression

Publisher: Research Square Platform LLC

Date: 07-09-2022

DOI: 10.21203/RS.3.RS-1675887/V1

Abstract: Background: Major depressive disorder is one of the most prevalent and costly medical conditions, with approximately 280 million people affected worldwide. It is estimated that 30-60% of in iduals suffering from this disorder are treatment-resistant, not responding to psychotherapy or antidepressants. Non-invasive brain stimulation in the form of repetitive transcranial magnetic stimulation (rTMS) is often considered an alternative treatment with response rates of up to 60% in this population. However, outcomes are variable suggesting that treatment protocols remain suboptimal. Current clinical guidelines are poorly defined due to a lack of systematic evaluation when techniques were first developed. Our lab has compared a range of brain stimulation protocols in a preclinical model of treatment-resistant depression and has shown that rTMS delivered at a low intensity matches the behavioural effects obtained from the much higher intensities that are currently approved for the treatment of depression in the clinic. Structural brain changes were also observed at the lower intensity, which may lead to longer lasting beneficial effects as in seen in previous animal studies. It is hypothesised that the same outcomes will translate to patients in a clinical setting. Methods: Participants will be recruited from patients diagnosed with Major Depressive Disorder. The study will consist of 4 to 6 weeks of treatment comprising 20-30 sessions (weekdays-only) of rTMS to the left dorsolateral prefrontal cortex. A “head-to-head trial” has been established due to ethical considerations and the need to retain the current clinical protocol. Patients will be randomly assigned to the FDA-approved standard protocol or standard protocol plus an additional low intensity stimulation group. In addition, patients will undergo psychological testing and a blood test at baseline, post-treatment and again at a 6-month follow up appointment Discussion: This study will prospectively evaluate the antidepressant efficacy of a new rTMS parameter. Specifically, we will translate a novel low intensity rTMS protocol and compare its long-term effects to the current FDA-accredited standard protocol. We will also test the validity of blood biomarkers, including those identified in our previous animal studies, to objectively monitor in idual’s response to rTMS treatment. Trial registration: Registered with Australian New Zealand Clinical Trials Registry, prospectively registered 20/11/2018, Registration ACTRN12618001889246.

Central Nerve Regeneration in Reptiles

Publisher: Elsevier

Date: 2015

DOI: 10.1016/B978-0-12-801732-6.00003-3

Long-term gene therapy causes transgene-specific changes in the morphology of regenerating retinal ganglion cells

Publisher: Public Library of Science (PLoS)

Date: 08-02-2012

DOI: 10.1371/JOURNAL.PONE.0031061

Auditory brainstem responses of ephrin-A2, Ephrin-A5^-/- and Ephrin-A2A5^-/- Mice

Publisher: S. Karger AG

Date: 2014

DOI: 10.1159/000357029

Abstract: Eph receptors and ephrin ligands are large families of cell surface proteins which have established roles in axonal growth and guidance. These are well characterized in the visual and somatosensory systems but are less well documented in the auditory pathway. We examined the possible functional role of two ephrin genes (ephrin-A2 and ephrin-A5) in the auditory system by measuring auditory brainstem responses (ABR) to tone bursts from 6 to 30 kHz in ephrin-A2 sup -/- /sup , ephrin-A5 sup -/- /sup and ephrin-A2A5 sup -/- /sup (knockout) mice. At high frequencies, the ephrin-A2A5 sup -/- /sup mice exhibited thresholds that were significantly lower than in wild-type mice by approximately 20 dB, suggesting ephrin-A2 and ephrin-A5 may have frequency-specific effects on the auditory system. There were also alterations in ABR wave peak litudes that were specific to each mouse strain which suggested both peripheral and central involvement of EphA-ephrin-A signalling in auditory function.

Low-intensity repetitive magnetic stimulation lowers action potential threshold and increases spike firing in layer 5 pyramidal neurons in vitro

Publisher: Elsevier BV

Date: 10-2016

DOI: 10.1016/J.NEUROSCIENCE.2016.08.030

Abstract: Repetitive transcranial magnetic stimulation (rTMS) has become a popular method of modulating neural plasticity in humans. Clinically, rTMS is delivered at high intensities to modulate neuronal excitability. While the high-intensity magnetic field can be targeted to stimulate specific cortical regions, areas adjacent to the targeted area receive stimulation at a lower intensity and may contribute to the overall plasticity induced by rTMS. We have previously shown that low-intensity rTMS induces molecular and structural plasticity in vivo, but the effects on membrane properties and neural excitability have not been investigated. Here we investigated the acute effect of low-intensity repetitive magnetic stimulation (LI-rMS) on neuronal excitability and potential changes on the passive and active electrophysiological properties of layer 5 pyramidal neurons in vitro. Whole-cell current cl recordings were made at baseline prior to subthreshold LI-rMS (600 pulses of iTBS, n=9 cells from 7 animals) or sham (n=10 cells from 9 animals), immediately after stimulation, as well as 10 and 20min post-stimulation. Our results show that LI-rMS does not alter passive membrane properties (resting membrane potential and input resistance) but hyperpolarises action potential threshold and increases evoked spike-firing frequency. Increases in spike firing frequency were present throughout the 20min post-stimulation whereas action potential (AP) threshold hyperpolarization was present immediately after stimulation and at 20min post-stimulation. These results provide evidence that LI-rMS alters neuronal excitability of excitatory neurons. We suggest that regions outside the targeted region of high-intensity rTMS are susceptible to neuromodulation and may contribute to rTMS-induced plasticity.

Functional Topography and Integration of the Contralateral and Ipsilateral Retinocollicular Projections ofEphrin-A^−/−Mice

Publisher: Society for Neuroscience

Date: 16-07-2008

DOI: 10.1523/JNEUROSCI.1135-08.2008

Abstract: Topographically ordered projections are established by molecular guidance cues and refined by neuronal activity. Retinal input to a primary visual center, the superior colliculus (SC), is bilateral with a dense contralateral projection and a sparse ipsilateral one. Both projections are topographically organized, but in opposing anterior–posterior orientations. This arrangement provides functionally coherent input to each colliculus from the binocular visual field, supporting visual function. When guidance cues involved in contralateral topography (ephrin-As) are absent, crossed retinal ganglion cell (RGC) axons form inappropriate terminations within the SC. However, the organization of the ipsilateral projection relative to the abnormal contralateral input remains unknown, as does the functional capacity of both projections. We show here that in ephrin-A −/− mice, the SC contains an expanded, diffuse ipsilateral projection. Electrophysiological recording demonstrated that topography of visually evoked responses recorded from the contralateral superior colliculus of ephrin-A −/− mice displayed similar functional disorder in all genotypes, contrasting with their different degrees of anatomical disorder. In contrast, ipsilateral responses were retinotopic in ephrin-A2 −/− but disorganized in ephrin-A2/A5 −/− mice. The lack of integration of binocular input resulted in specific visual deficits, which could be reversed by occlusion of one eye. The discrepancy between anatomical and functional topography in both the ipsilateral and contralateral projections implies suppression of inappropriately located terminals. Moreover, the misalignment of ipsilateral and contralateral visual information in ephrin-A2/A5 −/− mice suggests a role for ephrin-As in integrating convergent visual inputs.

The challenges of producing effective small coils for transcranial magnetic stimulation of mice

Publisher: IOP Publishing

Date: 10-04-2018

DOI: 10.1088/2057-1976/AAB525

Low-intensity repetitive transcranial magnetic stimulation over prefrontal cortex in an animal model alters activity in the auditory thalamus but does not affect behavioural measures of tinnitus

Publisher: Springer Science and Business Media LLC

Date: 16-01-2019

DOI: 10.1007/S00221-018-05468-W

Abstract: Tinnitus, a phantom auditory percept, is strongly associated with cochlear trauma. The latter leads to central changes in auditory pathways such as increased spontaneous activity and this may be involved in tinnitus generation. As not all people with cochlear trauma develop tinnitus, recent studies argue that non-auditory structures, such as prefrontal cortex (PFC), play an important role in tinnitus development. As part of sensory gating circuitry, PFC may modify activity in auditory thalamus and consequently in auditory cortex. Human studies suggest that repetitive transcranial magnetic stimulation (rTMS), a non-invasive tool for neurostimulation, can alter tinnitus perception. This study used a guinea pig model of hearing loss and tinnitus to investigate effects of low-intensity rTMS (LI-rTMS) over PFC on tinnitus and spontaneous activity in auditory thalamus. In addition, immunohistochemistry for calbindin and parvalbumin in PFC was used to investigate the possible mechanism of action of LI-rTMS. Three treatment groups were compared: sham treatment, LI, low frequency (1 Hz) or LI, high frequency (10 Hz) rTMS (10 min/day, 2 weeks, weekdays only). None of the treatments affected the behavioural measures of tinnitus but spontaneous activity was significantly increased in auditory thalamus after 1 Hz and 10 Hz treatment. Immunostaining showed significant effects of rTMS on the density of calcium-binding protein expressing neurons in the dorsal regions of the PFC suggesting that rTMS treatment evoked plasticity in cortex. In addition, calbindin-positive neuron density in the superficial region of PFC was negatively correlated with spontaneous activity in auditory thalamus suggesting a possible mechanism for change in activity observed.

Long-Term Effects of Repetitive Transcranial Magnetic Stimulation on Tinnitus in a Guinea Pig Model

Publisher: MDPI AG

Date: 18-08-2022

DOI: 10.3390/BRAINSCI12081096

Abstract: The auditory phantom sensation of tinnitus is associated with neural hyperactivity. Modulating this hyperactivity using repetitive transcranial magnetic stimulation (rTMS) has shown beneficial effects in human studies. Previously, we investigated rTMS in a tinnitus animal model and showed that rTMS over prefrontal cortex (PFC) attenuated tinnitus soon after treatment, likely via indirect effects on auditory pathways. Here, we explored the duration of these beneficial effects. Acoustic trauma was used to induce hearing loss and tinnitus in guinea pigs. Once tinnitus developed, high-frequency (20 Hz), high-intensity rTMS was applied over PFC for two weeks (weekdays only 10 min/day). Behavioral signs of tinnitus were monitored for 6 weeks after treatment ended. Tinnitus developed in 77% of animals between 13 and 60 days post-trauma. rTMS treatment significantly reduced the signs of tinnitus at 1 week on a group level, but in idual responses varied greatly at week 2 until week 6. Three (33%) of the animals showed the attenuation of tinnitus for the full 6 weeks, 45% for 1–4 weeks and 22% were non-responders. This study provides further support for the efficacy of high-frequency repetitive stimulation over the PFC as a therapeutic tool for tinnitus, but also highlights in idual variation observed in human studies.

Acoustic trauma increases inhibitory effects of amygdala electrical stimulation on thalamic neurons in a rat model

Publisher: Elsevier BV

Date: 11-2023

DOI: 10.1016/J.HEARES.2023.108891

The long-chain sphingoid base of sphingolipids is acylated at the cytosolic surface of the endoplasmic reticulum in rat liver

Publisher: Portland Press Ltd.

Date: 15-03-1993

DOI: 10.1042/BJ2900751

Abstract: Ceramide, a key intermediate in sphingolipid metabolism, is synthesized by acylation of sphinganine followed by dehydrogenation of dihydroceramide to ceramide. Using radioactive sphinganine, we have examined the site and topology of dihydroceramide synthesis in well-characterized subcellular fractions from rat liver. [4,5-3H]Sphinganine was introduced as a complex with BSA and was metabolized to [4,5-3H]dihydroceramide upon incubation of rat liver homogenates or microsomes with fatty acyl CoA. Conditions were established in a detergent-free system in which dihydroceramide synthesis was not limited by either substrate availability or by amounts of microsomal protein or reaction time. The distribution of dihydroceramide synthesis was found to exactly parallel that of an endoplasmic reticulum (ER) marker upon subfractionation of microsomes, and no endogenous activity was detected in either purified Golgi apparatus or plasma membrane fractions. Limited protease digestion demonstrated that sphinganine N-acyltransferase is localized at the cytosolic surface of intact ER-derived vesicles. These results are discussed with regard to the subsequent transport of (dihydro)-ceramide from the ER to sites of further metabolism in a pre-Golgi apparatus compartment and in the cis and medial cisternae of the Golgi apparatus.

Periaxonal and nodal plasticities modulate action potential conduction in the adult mouse brain

Publisher: Elsevier BV

Date: 2021

DOI: 10.1016/J.CELREP.2020.108641

Abstract: Central nervous system myelination increases action potential conduction velocity. However, it is unclear how myelination is coordinated to ensure the temporally precise arrival of action potentials and facilitate information processing within cortical and associative circuits. Here, we show that myelin sheaths, supported by mature oligodendrocytes, remain plastic in the adult mouse brain and undergo subtle structural modifications to influence action potential conduction velocity. Repetitive transcranial magnetic stimulation and spatial learning, two stimuli that modify neuronal activity, alter the length of the nodes of Ranvier and the size of the periaxonal space within active brain regions. This change in the axon-glial configuration is independent of oligodendrogenesis and robustly alters action potential conduction velocity. Because aptitude in the spatial learning task was found to correlate with action potential conduction velocity in the fimbria-fornix pathway, modifying the axon-glial configuration may be a mechanism that facilitates learning in the adult mouse brain.

Concurrent LI-rTMS induces changes in c-Fos expression but not behavior during a progressive ratio task with adult ephrin-A2A5-/- mice

Publisher: Elsevier BV

Date: 02-2021

DOI: 10.1016/J.BBR.2020.113011

Differential expression of TrkB isoforms switches climbing fiber-Purkinje cell synaptogenesis to selective synapse elimination

Publisher: Wiley

Date: 09-2009

DOI: 10.1002/DNEU.20730

Abstract: Correct neural function depends on precisely organized connectivity, which is refined from broader projections through synaptic/collateral elimination. In the rat, olivocerebellar topography is refined by regression of multiple climbing fiber (CF) innervation of Purkinje cells (PC) during the first two postnatal weeks. The molecules that initiate this regression are not fully understood. We assessed the role of cerebellar neurotrophins by examining tropomycin receptor kinase (Trk) receptor expression in the inferior olive and cerebellum between postnatal days (P)3-7, when CF-PC innervation changes from synapse formation to selective synapse elimination, and in a denervation-reinnervation model when synaptogenesis is delayed. Trks A, B, and C are expressed in olivary neurons although TrkA was not transported to the cerebellum and TrkC was unchanged during innervation and reinnervation, suggesting that neither receptor is involved in CF-PC synaptogenesis. In contrast, both total and truncated TrkB (TrkB.T) increased in the olive and cerebellum from P4, whereas full-length and activated phosphorylated TrkB (phospho-TrkB) decreased from P4-5. This reveals less TrkB signaling at the onset of CF regression. This expression pattern was reproduced during CF-PC reinnervation: in the denervated hemicerebellum phospho-TrkB decreased as CF terminals degenerated, then increased in parallel with the delayed neosynaptogenesis as new CFs reinnervated the denervated hemicerebellum. In the absence of this signaling, CF reinnervation did not develop. Our data reveal that olivocerebellar TrkB activity parallels CF-PC synaptic formation and stabilization and is required for neosynaptogenesis. Furthermore, TrkB.T expression rises to reduce TrkB signaling and permit synapse elimination.

Failure to form a stable topographic map during optic nerve regeneration: abnormal activity-dependent mechanisms

Publisher: Elsevier BV

Date: 12-2003

DOI: 10.1016/J.EXPNEUROL.2003.08.013

Cellular and molecular changes to cortical neurons following low intensity repetitive magnetic stimulation at different frequencies

Publisher: Elsevier BV

Date: 2015

DOI: 10.1016/J.BRS.2014.09.012

Abstract: Repetitive transcranial magnetic stimulation is increasingly used as a treatment for neurological dysfunction. Therapeutic effects have been reported for low intensity rTMS (LI-rTMS) although these remain poorly understood. Our study describes for the first time a systematic comparison of the cellular and molecular changes in neurons in vitro induced by low intensity magnetic stimulation at different frequencies. We applied 5 different low intensity repetitive magnetic stimulation (LI-rMS) protocols to neuron-enriched primary cortical cultures for 4 days and assessed survival, and morphological and biochemical change. We show pattern-specific effects of LI-rMS: simple frequency pulse trains (10 Hz and 100 Hz) impaired cell survival, while more complex stimulation patterns (theta-burst and a biomimetic frequency) did not. Moreover, only 1 Hz stimulation modified neuronal morphology, inhibiting neurite outgrowth. To understand mechanisms underlying these differential effects, we measured intracellular calcium concentration during LI-rMS and subsequent changes in gene expression. All LI-rMS frequencies increased intracellular calcium, but rather than influx from the extracellular milieu typical of depolarization, all frequencies induced calcium release from neuronal intracellular stores. Furthermore, we observed pattern-specific changes in expression of genes related to apoptosis and neurite outgrowth, consistent with our morphological data on cell survival and neurite branching. Thus, in addition to the known effects on cortical excitability and synaptic plasticity, our data demonstrate that LI-rMS can change the survival and structural complexity of neurons. These findings provide a cellular and molecular framework for understanding what low intensity magnetic stimulation may contribute to human rTMS outcomes.

A little goes a long way: Neurobiological effects of low intensity rTMS and implications for mechanisms of rTMS

Publisher: Elsevier BV

Date: 2022

DOI: 10.1016/J.CRNEUR.2022.100033

Effects of Cochlear Trauma on BDNF Expression in Guinea Pig Cochlear Nucleus and Inferior Colliculus

Publisher: OMICS Publishing Group

Date: 2013

DOI: 10.4172/2161-119X.S3-006

A role for ephrin‐As in maintaining topographic organization in register across interconnected central visual pathways

Publisher: Wiley

Date: 02-2010

DOI: 10.1111/J.1460-9568.2010.07111.X

Abstract: The retina sends spatially ordered visual information to the superior colliculus (SC) directly and indirectly via the thalamus and primary visual cortex (V1). Gradients of Ephs and ephrins are present in all of these regions, and have been shown to be involved in establishing topography of at least some of these interconnected visual pathways. Studies in ephrin-A knockout mice show that abnormal retinotectal termination zones (TZs) are present in a majority of mice lacking (-/-) ephrin-A2 (57%), and ephrin-A2 and -A5 (89%). A similar but seemingly less disordered pattern is detected in the retina-to-dorsal lateral geniculate nucleus (dLGN) and dLGN-to-V1 projections. Here we analyse the dLGN-to-V1 and V1-to-SC projections in ephrin-A(-/-) mice to determine the extent to which topographic errors are transmitted across synaptic relays. Fluorescent tracers were injected into V1 of wild-type (WT), ephrin-A2(-/-) or ephrin-A2A5(-/-) mice. We examined the number, location and size of anterograde TZs in SC, and mapped the distribution of retrogradely labelled neurons in dLGN. Compared with WT and ephrin-A2(-/-) mice, the volume of in idual TZs in the SC was smaller in ephrin-A2A5(-/-) mice (P = 0.002). Single V1 injections labelled two foci of dLGN neurons in 70%, and two SC TZs in 80% of ephrin-A2A5(-/-) mice. Abnormalities in one or other of the projections were detected in 10% of ephrin-A2(-/-) mice. Importantly, there was no consistent correspondence between the organization of geniculocortical and corticotectal projections in either genotype, suggesting a role for ephrin-As in maintaining topographic organization in register across multiple interconnected central visual pathways.

Construction and Evaluation of Rodent-Specific rTMS Coils

Publisher: Frontiers Media SA

Date: 30-06-2016

DOI: 10.3389/FNCIR.2016.00047

Short-term low intensity PMF does not improve functional or histological outcomes in a rat model of transient focal cerebral ischemia

Publisher: Elsevier BV

Date: 06-2012

DOI: 10.1016/J.BRAINRES.2012.04.006

Abstract: Stimulation with pulsed magnetic fields (PMF) is a non-invasive technique that can modulate neural activity and has the potential to facilitate functional recovery and tissue preservation/repair following brain injury. The effect of low intensity (8 mT) PMF on functional recovery and infarct tissue volume was assessed in a middle cerebral artery occlusion model of transient focal ischemia in Spontaneously Hypertensive rats. Rats received a combination of PMF protocols, including high and low frequencies and recovery was monitored over eight days. PMF treatment had no effect on functional recovery or infarct volume. Infarcted tissue accounted for ≈8% of total brain volume, encompassing both cortical and subcortical structures. The microglial and astrocytic response to PMF treatment was monitored and there was no change in glial scarring, however there was increased macrophage infiltration in animals that received chronic high (6-9 Hz) and low (1 Hz) stimulation. There was no effect of PMF on the degree of cell death observed within the ischemic core, with no TUNEL positive cells observed in the non-infarcted tissue. No detrimental side-effects of PMF were observed, indicating that low-intensity PMF may have limited safety concerns for future human and animal studies.

Identifying reproducible resting state networks and functional connectivity alterations following chronic restraint stress in anaesthetized rats

Publisher: Frontiers Media SA

Date: 22-05-2023

DOI: 10.3389/FNINS.2023.1151525

Abstract: Resting-state functional MRI (rs-fMRI) in rodent models have the potential to bridge invasive experiments and observational human studies, increasing our understanding of functional alterations in the brains of patients with depression. A major limitation in current rodent rs-fMRI studies is that there has been no consensus on healthy baseline resting-state networks (RSNs) that are reproducible in rodents. Therefore, the present study aimed to construct reproducible RSNs in a large dataset of healthy rats and then evaluate functional connectivity changes within and between these RSNs following a chronic restraint stress (CRS) model within the same animals. A combined MRI dataset of 109 Sprague Dawley rats at baseline and after two weeks of CRS, collected during four separate experiments conducted by our lab in 2019 and 2020, was re-analysed. The mICA and gRAICAR toolbox were first applied to detect optimal and reproducible ICA components and then a hierarchical clustering algorithm (FSLNets) was applied to construct reproducible RSNs. Ridge-regularized partial correlation (FSLNets) was used to evaluate the changes in the direct connection between and within identified networks in the same animals following CRS. Four large-scale networks in anesthetised rats were identified: the DMN-like, spatial attention-limbic, corpus striatum, and autonomic network, which are homologous across species. CRS decreased the anticorrelation between DMN-like and autonomic network. CRS decreased the correlation between amygdala and a functional complex (nucleus accumbens and ventral pallidum) in the right hemisphere within the corpus striatum network. However, a high in idual variability in the functional connectivity before and after CRS within RSNs was observed. The functional connectivity changes detected in rodents following CRS differ from reported functional connectivity alterations in patients with depression. A simple interpretation of this difference is that the rodent response to CRS does not reflect the complexity of depression as it is experienced by humans. Nonetheless, the high inter-subject variability of functional connectivity within networks suggests that rats demonstrate different neural phenotypes, like humans. Therefore, future efforts in classifying neural phenotypes in rodents might improve the sensitivity and translational impact of models used to address aetiology and treatment of psychiatric conditions including depression.

Renal corpuscle and tubule morphology in ephrin-A2-/-, ephrin-A5-/- and ephrin-A2A5-/- mice

Publisher: F1000 Research Ltd

Date: 11-10-2013

DOI: 10.12688/F1000RESEARCH.2-212.V1

Abstract: The B family of Eph receptor tyrosine kinases and their ephrin ligands, best known for their role in the development of the nervous and vascular systems, have recently been implicated in mammalian kidney development and maintenance. However, the renal expression and function of the EphA and ephrin-A families have not been investigated. We performed immunohistochemistry for ephrin-A2 and ephrin-A5 in kidneys of normal adult wildtype (WT) mice and carried out quantitative morphological analysis of renal corpuscles and tubules in haematoxylin- and eosin-stained sections of WT, ephrin-A2 -/- , ephrin-A5 -/- and ephrin-A2A5 -/- (knockout) mice. Ephrin-A2 and ephrin-A5 were strongly expressed in the tubules and glomeruli of the adult mouse kidney. Despite the significant overlap in expression between the two proteins, only the lack of ephrin-A5 had an effect on kidney morphology with glomerular size being mildly reduced in mice lacking the gene for ephrin-A5. However, the magnitude of this change was very small and could only be detected when animals were pooled across genotypes lacking ephrin-A5. The subtle phenotype, together with the relatively infrequent incidence of kidney failure in our breeding colony, suggest that ephrin-A2 and ephrin-A5 play only minor roles in kidney development and function. It is likely that other members of the ephrin-A family are expressed in the mouse kidney and redundancy within this large family of “promiscuous” signalling molecules may compensate for the loss of in idual proteins in knockout mice.

Regenerating optic axons restore topography after incomplete optic nerve injury

Publisher: Wiley

Date: 29-08-2007

DOI: 10.1002/CNE.21477

Abstract: Following complete optic nerve injury in a lizard, Ctenophorus ornatus, retinal ganglion cell (RGC) axons regenerate but fail to restore retinotectal topography unless animals are trained on a visual task (Beazley et al. [ 1997] J Comp Neurol 370:105-120, [2003] J Neurotrauma 20:1263-1270). Here we show that incomplete injury, which leaves some RGC axons intact, restores normal topography. Strict RGC axon topography allowed us to preserve RGC axons on one side of the nerve (projecting to medial tectum) while lesioning those on the other side (projecting to lateral tectum). Topography and response properties for both RGC axon populations were assessed electrophysiologically. The majority of intact RGC axons retained appropriate topography in medial tectum and had normal, consistently brisk, reliable responses. Regenerate RGC axons fell into two classes: those that projected topographically to lateral tectum with responses that tended to habituate and those that lacked topography, responded weakly, and habituated rapidly. Axon tracing by localized retinal application of carbocyanine dyes supported the electrophysiological data. RGC soma counts were normal in both intact and axotomized RGC populations, contrasting with the 30% RGC loss after complete injury. Unlike incomplete optic nerve injury in mammals, where RGC axon regeneration fails and secondary cell death removes many intact RGC somata, lizards experience a "win-win" situation: intact RGC axons favorably influence the functional outcome for regenerating ones and RGCs do not succumb to either primary or secondary cell death.

Reliability of VEP recordings using chronically implanted screw electrodes in mice

Publisher: Association for Research in Vision and Ophthalmology (ARVO)

Date: 28-04-2015

DOI: 10.1167/TVST.4.2.15

Loss of the RNA-binding protein TACO1 causes late-onset mitochondrial dysfunction in mice

Publisher: Springer Science and Business Media LLC

Date: 20-06-2016

DOI: 10.1038/NCOMMS11884

Abstract: The recognition and translation of mammalian mitochondrial mRNAs are poorly understood. To gain further insights into these processes in vivo, we characterized mice with a missense mutation that causes loss of the translational activator of cytochrome oxidase subunit I (TACO1). We report that TACO1 is not required for embryonic survival, although the mutant mice have substantially reduced COXI protein, causing an isolated complex IV deficiency. We show that TACO1 specifically binds the mt-Co1 mRNA and is required for translation of COXI through its association with the mitochondrial ribosome. We determined the atomic structure of TACO1, revealing three domains in the shape of a hook with a tunnel between domains 1 and 3. Mutations in the positively charged domain 1 reduce RNA binding by TACO1. The Taco1 mutant mice develop a late-onset visual impairment, motor dysfunction and cardiac hypertrophy and thus provide a useful model for future treatment trials for mitochondrial disease.

Excitatory Repetitive Transcranial Magnetic Stimulation Over Prefrontal Cortex in a Guinea Pig Model Ameliorates Tinnitus

Publisher: Frontiers Media SA

Date: 22-07-2021

DOI: 10.3389/FNINS.2021.693935

Abstract: Tinnitus, a phantom auditory perception that can seriously affect quality of life, is generally triggered by cochlear trauma and associated with aberrant activity throughout the auditory pathways, often referred to as hyperactivity. Studies suggest that non-auditory structures, such as prefrontal cortex (PFC), may be involved in tinnitus generation, by affecting sensory gating in auditory thalamus, allowing hyperactivity to reach the cortex and lead to perception. Indeed, human studies have shown that repetitive transcranial magnetic stimulation (rTMS) of PFC can alleviate tinnitus. The current study investigated whether this therapeutic effect is achieved through inhibition of thalamic hyperactivity, comparing effects of two common clinical rTMS protocols with sham treatment, in a guinea pig tinnitus model. Animals underwent acoustic trauma and once tinnitus developed were treated with either intermittent theta burst stimulation (iTBS), 20 Hz rTMS, or sham rTMS (10 days, 10 min/day weekdays only). Tinnitus was reassessed and extracellular recordings of spontaneous tonic and burst firing rates in auditory thalamus made. To verify effects in PFC, densities of neurons positive for calcium-binding proteins, calbindin and parvalbumin, were investigated using immunohistochemistry. Both rTMS protocols significantly reduced tinnitus compared to sham. However, spontaneous tonic firing decreased following 20 Hz stimulation and increased following iTBS in auditory thalamus. Burst rate was significantly different between 20 Hz and iTBS stimulation, and burst duration was increased only after 20 Hz treatment. Density of calbindin, but not parvalbumin positive neurons, was significantly increased in the most dorsal region of PFC indicating that rTMS directly affected PFC. Our results support the involvement of PFC in tinnitus modulation, and the therapeutic benefit of rTMS on PFC in treating tinnitus, but indicate this is not achieved solely by suppression of thalamic hyperactivity.

Near infrared light reduces oxidative stress and preserves function in CNS tissue vulnerable to secondary degeneration following partial transection of the optic nerve

Publisher: Mary Ann Liebert Inc

Date: 11-2010

DOI: 10.1089/NEU.2010.1426

Abstract: Traumatic injury to the central nervous system (CNS) is accompanied by the spreading damage of secondary degeneration, resulting in further loss of neurons and function. Partial transection of the optic nerve (ON) has been used as a model of secondary degeneration, in which axons of retinal ganglion cells in the ventral ON are spared from initial dorsal injury, but are vulnerable to secondary degeneration. We have recently demonstrated that early after partial ON injury, oxidative stress spreads through the ventral ON vulnerable to secondary degeneration via astrocytes, and persists in the nerve in aggregates of cellular debris. In this study, we show that diffuse transcranial irradiation of the injury site with far red to near infrared (NIR) light (WARP 10 LED array, center wavelength 670 nm, irradiance 252 W/m(-2), 30 min exposure), as opposed to perception of light at this wavelength, reduced oxidative stress in areas of the ON vulnerable to secondary degeneration following partial injury. The WARP 10 NIR light treatment also prevented increases in NG-2-immunopositive oligodendrocyte precursor cells (OPCs) that occurred in ventral ON as a result of partial ON transection. Importantly, normal visual function was restored by NIR light treatment with the WARP 10 LED array, as assessed using optokinetic nystagmus and the Y-maze pattern discrimination task. To our knowledge, this is the first demonstration that 670-nm NIR light can reduce oxidative stress and improve function in the CNS following traumatic injury in vivo.

Interactions between Guidance Cues and Neuronal Activity: Therapeutic Insights from Mouse Models

Publisher: MDPI AG

Date: 09-04-2023

DOI: 10.3390/IJMS24086966

Abstract: Topographic mapping of neural circuits is fundamental in shaping the structural and functional organization of brain regions. This developmentally important process is crucial not only for the representation of different sensory inputs but also for their integration. Disruption of topographic organization has been associated with several neurodevelopmental disorders. The aim of this review is to highlight the mechanisms involved in creating and refining such well-defined maps in the brain with a focus on the Eph and ephrin families of axon guidance cues. We first describe the transgenic models where ephrin-A expression has been manipulated to understand the role of these guidance cues in defining topography in various sensory systems. We further describe the behavioral consequences of lacking ephrin-A guidance cues in these animal models. These studies have given us unexpected insight into how neuronal activity is equally important in refining neural circuits in different brain regions. We conclude the review by discussing studies that have used treatments such as repetitive transcranial magnetic stimulation (rTMS) to manipulate activity in the brain to compensate for the lack of guidance cues in ephrin-knockout animal models. We describe how rTMS could have therapeutic relevance in neurodevelopmental disorders with disrupted brain organization.

Learning spatial working and reference memory tasks induces region-specific increases in the expression of the gene encoding syntaxin 1B

Publisher: Elsevier BV

Date: 1996

DOI: 10.1016/S0928-4257(97)87934-X

The Pharmacokinetics of Medetomidine Administered Subcutaneously during Isoflurane Anaesthesia in Sprague-Dawley Rats

Publisher: MDPI AG

Date: 18-06-2020

DOI: 10.3390/ANI10061050

Abstract: Anaesthetic protocols involving the combined use of a sedative agent, medetomidine, and an anaesthetic agent, isoflurane, are increasingly being used in functional magnetic resonance imaging (fMRI) studies of the rodent brain. Despite the popularity of this combination, a standardised protocol for the combined use of medetomidine and isoflurane has not been established, resulting in inconsistencies in the reported use of these drugs. This study investigated the pharmacokinetic detail required to standardise the use of medetomidine and isoflurane in rat brain fMRI studies. Using mass spectrometry, serum concentrations of medetomidine were determined in Sprague-Dawley rats during medetomidine and isoflurane anaesthesia. The serum concentration of medetomidine for administration with 0.5% (vapouriser setting) isoflurane was found to be 14.4 ng/mL (±3.0 ng/mL). The data suggests that a steady state serum concentration of medetomidine when administered with 0.5% (vapouriser setting) isoflurane can be achieved with an initial subcutaneous (SC) dose of 0.12 mg/kg of medetomidine followed by a 0.08 mg/kg/h SC infusion of medetomidine. Consideration of these results for future studies will facilitate standardisation of medetomidine and isoflurane anaesthetic protocols during fMRI data acquisition.

University Of Western Australia

Location: Australia

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Perron Institute For Neurological And Translational Science

Location: Australia

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University Of Barcelona

Location: Spain

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University Of Bath

Location: United Kingdom of Great Britain and Northern Ireland

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Université Pierre Et Marie Curie

Location: France

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Use It Or Lose It: Training To Restore Vision After Optic Nerve Damage

Start Date: 2004

End Date: 2006

Funder: National Health and Medical Research Council

Harnessing Plasticity In The Brain To Improve Function And Repair

Start Date: 2010

End Date: 2012

Funder: National Health and Medical Research Council

Linkage Projects - Grant ID: LP0455580

Start Date: 12-2004

End Date: 10-2008

Amount: $324,618.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP110100201

Start Date: 10-2011

End Date: 12-2014

Amount: $260,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP180101494

Start Date: 07-2018

End Date: 12-2021

Amount: $487,460.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0989788

Start Date: 01-2009

End Date: 01-2010

Amount: $108,481.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE180100056

Start Date: 2018

End Date: 03-2019

Amount: $621,198.00

Funder: Australian Research Council

Industrial Transformation Training Centres - Grant ID: IC170100016

Start Date: 05-2018

End Date: 12-2024

Amount: $3,123,492.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE200100122

Start Date: 08-2020

End Date: 08-2021

Amount: $620,000.00

Funder: Australian Research Council