ORCID Profile
0000-0002-1723-4597
Current Organisation
University of Tasmania School of Medicine
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Neurosciences not elsewhere classified | Medical Molecular Engineering of Nucleic Acids and Proteins | Nanobiotechnology | Neurosciences
Expanding Knowledge in the Biological Sciences | Expanding Knowledge in Psychology and Cognitive Sciences | Expanding Knowledge in Technology |
Publisher: Elsevier BV
Date: 02-2017
Publisher: The Optical Society
Date: 19-05-2015
DOI: 10.1364/OL.40.002465
Publisher: Springer Science and Business Media LLC
Date: 22-12-2013
DOI: 10.1038/NMETH.2765
Publisher: Elsevier
Date: 2012
Publisher: Springer Science and Business Media LLC
Date: 08-2016
DOI: 10.1038/NMETH.3935
Publisher: Public Library of Science (PLoS)
Date: 09-05-2014
Publisher: Elsevier BV
Date: 03-2009
Publisher: EMBO
Date: 27-09-2016
Publisher: Society for Neuroscience
Date: 25-04-2019
Publisher: American Physiological Society
Date: 10-2003
Abstract: We examined the rostro-caudal dendritic spread of striatally projecting dopaminergic neurons of the Substantia Nigra pars compacta (SNc) and investigated the presence of dye-coupling after labeling these cells with a mixture of lucifer yellow (LY) and neurobiotin (NB) or with LY alone. Whole cell recordings were made from horizontal brain slices (400 μm) obtained from P5-P20 rats. SNc neurons retrogradely labeled with Fluoro-Gold and located in the region containing tyrosine hydroxylase-immunoreactive cells displayed I h current and other properties characteristic of SNc neurons. To prevent extracellular leakage, dyes were introduced into patch pipettes after the establishment of whole cell configuration, and cells were filled under visual control. In contrast to previous studies conducted in coronal sections that identified dendritic projections of SNc neurons mainly in the medio-lateral and ventral directions, almost all neurons labeled in our study (53/54) additionally displayed a large rostro-caudal dendritic span (649 ± 219 μm). Dye-coupling between SNc neurons was not observed under basal conditions, in the presence of gap junction “openers” (forskolin, trimethylamine), or after neurons were filled with LY using sharp intracellular microelectrodes. As a “positive control,” dye-coupling was demonstrated in four hippoc al dentate gyrus neurons that were filled using the same patch pipette technique. In addition, none of the tested SNc cells ( n = 12) showed expression of connexin 36 (the “neuronal” connexin) when tested with single-cell RT-PCR. In conclusion, this study revealed extensive rostro-caudal dendritic projections of SNc neurons. Under our in vitro conditions, no evidence was found for dye-coupling among these neurons.
Publisher: Elsevier BV
Date: 2003
DOI: 10.1016/S0006-8993(02)03757-5
Abstract: The output of GABAergic medium-sized spiny neurons in the dorsal striatum is controlled in part by glutamatergic input from the neocortex and the thalamus, and dopaminergic input from ventral midbrain. We acutely isolated these neurons from juvenile (P14-24) rats to study the consequences of the interaction between glutamate and dopamine for neuronal excitability. Single-cell RT-PCR analysis was used to identify the expression patterns of dopamine receptors. D1 and D2 dopamine receptor mRNA was detected in 11/22 and 3/22 of isolated neurons, respectively. Receptor mRNA co-expression was detected in 1/22 cells tested. Whole-cell voltage cl recording (V(h)=-70 mV) was combined with local or bath application of dopaminergic and glutamatergic agonists to explore dopamine receptor modulation of glutamatergic excitation. Glutamate-evoked inward currents (5 microM, Mg(2+)-free, 1 microM glycine) were attenuated by dopamine (5 microM) to 83.2+/-3.6% (n=31). NMDA-evoked (20 microM), APV-sensitive currents were attenuated by dopamine to 80.9+/-4.5% (n=24). NMDA-induced responses were also attenuated by the D1 receptor agonist SKF 38393 (1 microM n=28), while the D2/3 receptor agonist quinpirole (10 microM) had no effect. The currents evoked by application of AMPA (5 microM) displayed a steady rundown. Application of dopamine abolished or significantly reduced the rundown in the cells tested (n=17). A similar effect was observed after the application of SKF 38393 (1 microM), while quinpirole (10 microM) had no significant effect. Our results provide direct evidence for modulation by dopamine of glutamatergic responses of striatal medium spiny neurons, and demonstrate that the effects of this neuromodulator are receptor subtype specific. Disruption of this modulatory effect is likely to contribute to movement disorders associated with Parkinson's disease.
Publisher: Society for Neuroscience
Date: 11-03-2015
DOI: 10.1523/JNEUROSCI.3741-14.2015
Abstract: Cortical cells integrate synaptic input from multiple sources, but how these different inputs are distributed across in idual neurons is largely unknown. Differences in input might account for erse responses in neighboring neurons during behavior. We present a strategy for comparing the strengths of multiple types of input onto the same neuron. We developed methods for independent dual-channel photostimulation of synaptic inputs using ChR2 together with ReaChR, a red-shifted channelrhodopsin. We used dual-channel photostimulation to probe convergence of sensory information in the mouse primary motor cortex. Input from somatosensory cortex and thalamus converges in in idual neurons. Similarly, inputs from distinct somatotopic regions of the somatosensory cortex are integrated at the level of single motor cortex neurons. We next developed a ReaChR transgenic mouse under the control of both Flp- and Cre-recombinases that is an effective tool for circuit mapping. Our approach to dual-channel photostimulation enables quantitative comparison of the strengths of multiple pathways across all length scales of the brain.
Publisher: Springer Science and Business Media LLC
Date: 06-2014
DOI: 10.1038/NATURE13294
Publisher: Wiley
Date: 24-08-2010
Publisher: Springer Science and Business Media LLC
Date: 09-04-2006
DOI: 10.1038/NM1382
Abstract: The hypothalamus responds to circulating leptin and insulin in the control of food intake and body weight. A number of neurotransmitters in the hypothalamus, including gamma-aminobutyric acid (GABA), also have key roles in feeding. Huntingtin-associated protein 1 (Hap1) is expressed more abundantly in the hypothalamus than in other brain regions, and lack of Hap1 in mice leads to early postnatal death. Hap1 is also involved in intracellular trafficking of the GABA(A) receptor. Here, we report that fasting upregulates the expression of Hap1 in the rodent hypothalamus, whereas intracerebroventricular administration of insulin downregulates Hap1 by increasing its degradation through ubiquitination. Decreasing the expression of mouse hypothalamic Hap1 by siRNA reduces the level and activity of hypothalamic GABA(A) receptors and causes a decrease in food intake and body weight. These findings provide evidence linking hypothalamic Hap1 to GABA in the stimulation of feeding and suggest that this mechanism is involved in the feeding-inhibitory actions of insulin in the brain.
Publisher: Springer Science and Business Media LLC
Date: 09-2013
DOI: 10.1038/NN.3502
Publisher: Elsevier BV
Date: 06-2002
DOI: 10.1016/S1566-0702(02)00038-3
Abstract: Intracellular studies previously conducted in our laboratory on adult rats indicate that the activity of spinally projecting RVL neurons (neurons located in the Rostral Ventrolateral Medulla) results from synaptic inputs. The data obtained by others in medullary slices suggest that the firing of these neurons (RVL C1 and/or non-C1 type, depending on experimental conditions) is mainly determined by their 'beating' pacemaker properties. Interestingly, there is an analogy between the contrasting views on the role of the network vs. pacemakers in the generation of sympathetic tone, and a debate regarding the relative role of such mechanisms in other types of 'spontaneously' active neurons, including dopaminergic neurons of the Substantia Nigra/Ventral Tegmental Area (in ventral mesencephalon). This short review discusses our previous in vivo studies and more recent data obtained in vitro after acute cell isolation, showing that under both experimental conditions, the RVL neurons display no clear pacemaker-like properties. Interestingly, pacemaker activity of dopaminergic mesencephalic neurons can be easily demonstrated in brain slices and after acute isolation, but not in vivo. These findings strongly suggest that under normal in vivo conditions, in idual neurons belonging to these two neural systems function as elements of networks.
Publisher: American Physiological Society
Date: 03-2001
DOI: 10.1152/JN.2001.85.3.1336
Abstract: Activation of N-methyl-d-aspartate (NMDA) receptors in the Substantia Nigra zona compacta (SNc) may determine the degree of physiological apoptosis during the early postnatal period. However, the expression of these receptors during this stage of development is uncertain, as a recent study failed to detect responses to NMDA in unidentified SNc neurons isolated from 2-wk-old rats. Using conventional or perforated-patch whole cell recordings, we examined the presence of NMDA-evoked responses in SNc neurons acutely dissociated from P4 to P16 rats, applying strict criteria for identification of these neurons as nigrostriatal and dopaminergic. The SNc neurons were identified by retrograde labeling after striatal injection of Fluoro-Gold the presence of I h current and the inhibition of firing by dopamine (50 μM). NMDA (100 μM, V hold = −60 mV) evoked inward, APV-sensitive currents (56.4 ± 8.6 pA) in all tested neurons ( n = 29). Strong depolarizing responses were observed under current-cl . These results indicate that NMDA receptors play a functional role in SNc neurons during the first two postnatal weeks.
Publisher: Wiley
Date: 09-2004
Publisher: Society for Neuroscience
Date: 10-11-2010
DOI: 10.1523/JNEUROSCI.4190-10.2010
Abstract: This mini-symposium aims to provide an integrated perspective on recent developments in optogenetics. Research in this emerging field combines optical methods with targeted expression of genetically encoded, protein-based probes to achieve experimental manipulation and measurement of neural systems with superior temporal and spatial resolution. The essential components of the optogenetic toolbox consist of two kinds of molecular devices: actuators and reporters, which respectively enable light-mediated control or monitoring of molecular processes. The first generation of genetically encoded calcium reporters, fluorescent proteins, and neural activators has already had a great impact on neuroscience. Now, a second generation of voltage reporters, neural silencers, and functionally extended fluorescent proteins hold great promise for continuing this revolution. In this review, we will evaluate and highlight the limitations of presently available optogenic tools and discuss where these technologies and their applications are headed in the future.
Publisher: Cold Spring Harbor Laboratory
Date: 08-05-2023
DOI: 10.1101/2023.05.06.539674
Abstract: Optogenetic techniques provide genetically targeted, spatially and temporally precise approaches to correlate cellular activities and physiological outcomes. In the nervous system, G-protein-coupled receptors (GPCRs) have essential neuromodulatory functions through binding extracellular ligands to induce intracellular signaling cascades. In this work, we develop and validate a new optogenetic tool that disrupt Gα q signaling through membrane recruitment of a minimal Regulator of G-protein signaling (RGS) domain. This approach, P hoto- i nduced M odulation of G α protein – I nhibition of Gα q (PiGM-Iq), exhibited potent and selective inhibition of Gα q signaling. We alter the behavior of C. elegans and Drosophila with outcomes consistent with GPCR-Gα q disruption. PiGM-Iq also changes axon guidance in culture dorsal root ganglia neurons in response to serotonin. PiGM-Iq activation leads to developmental deficits in zebrafish embryos and larvae resulting in altered neuronal wiring and behavior. By altering the choice of minimal RGS domain, we also show that this approach is amenable to Gα i signaling.
Publisher: Elsevier BV
Date: 07-2013
Publisher: Proceedings of the National Academy of Sciences
Date: 24-01-2012
Abstract: Fluorescence imaging is an attractive method for monitoring neuronal activity. A key challenge for optically monitoring voltage is development of sensors that can give large and fast responses to changes in transmembrane potential. We now present fluorescent sensors that detect voltage changes in neurons by modulation of photo-induced electron transfer (PeT) from an electron donor through a synthetic molecular wire to a fluorophore. These dyes give bigger responses to voltage than electrochromic dyes, yet have much faster kinetics and much less added capacitance than existing sensors based on hydrophobic anions or voltage-sensitive ion channels. These features enable single-trial detection of synaptic and action potentials in cultured hippoc al neurons and intact leech ganglia. Voltage-dependent PeT should be amenable to much further optimization, but the existing probes are already valuable indicators of neuronal activity.
Publisher: Springer Science and Business Media LLC
Date: 11-10-2019
DOI: 10.1038/S41467-019-12236-Z
Abstract: Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for human applications as well. The prototypical DREADD agonist clozapine N- oxide (CNO) lacks brain entry and converts to clozapine, making it difficult to apply in basic and translational applications. Here we report the development of two novel DREADD agonists, JHU37152 and JHU37160, and the first dedicated 18 F positron emission tomography (PET) DREADD radiotracer, [ 18 F]JHU37107. We show that JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [ 18 F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons, and at their long-range projections, enabling noninvasive and longitudinal neuronal projection mapping.
Publisher: Humana Press
Date: 2013
DOI: 10.1007/978-1-62703-351-0_31
Abstract: Recent discovery of the light-activated ion channel, channelrhodopsin (ChR), has provided researchers a powerful and convenient tool to manipulate the membrane potential of specific cells with light. With genetic targeting of these channels and illumination of light to a specific location, the experimenter can selectively activate the voltage-gated ion channels (VGICs) of ChR-expressing cells, initiating electrical signaling in temporally and spatially precise manners. In neuroscience research, this can be used to study electrical signal processing within one neuron at the cellular level, or the synaptic connectivity between neurons at the circuitry level. To conduct experiments with ChRs, these exogenous channels need to be introduced into the cells of interest, commonly through a viral approach. This chapter provides an overview of the design, production, and validation of recombinant adeno-associated virus (rAAV) for ChR expression that can be used in vitro or in vivo to infect neurons. The virus produced can be used to conduct "optogenetic" experiments in behaving animals, in vitro preparations and cultured cells, and can be used to study signal transduction and processing at a cellular or circuitry level.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 25-02-2000
DOI: 10.1126/SCIENCE.287.5457.1453
Abstract: The brain is generally considered immunoprivileged, although increasing ex les of immunological responses to brain antigens, neuronal expression of major histocompatibility class I genes, and neurological autoimmunity have been recognized. An adeno-associated virus (AAV) vaccine generated autoantibodies that targeted a specific brain protein, the NR1 subunit of the N -methyl- d -aspartate (NMDA) receptor. After peroral administration of the AAV vaccine, transgene expression persisted for at least 5 months and was associated with a robust humoral response in the absence of a significant cell-mediated response. This single-dose vaccine was associated with strong anti-epileptic and neuroprotective activity in rats for both a kainate-induced seizure model and also a middle cerebral artery occlusion stroke model at 1 to 5 months following vaccination. Thus, a vaccination strategy targeting brain proteins is feasible and may have therapeutic potential for neurological disorders.
Publisher: Springer Science and Business Media LLC
Date: 12-07-2023
DOI: 10.1038/S41467-023-39776-9
Abstract: The small Ultra-Red Fluorescent Protein (smURFP) represents a new class of fluorescent protein with exceptional photostability and brightness derived from allophycocyanin in a previous directed evolution. Here, we report the smURFP crystal structure to better understand properties and enable further engineering of improved variants. We compare this structure to the structures of allophycocyanin and smURFP mutants to identify the structural origins of the molecular brightness. We then use a structure-guided approach to develop monomeric smURFP variants that fluoresce with phycocyanobilin but not biliverdin. Furthermore, we measure smURFP photophysical properties necessary for advanced imaging modalities, such as those relevant for two-photon, fluorescence lifetime, and single-molecule imaging. We observe that smURFP has the largest two-photon cross-section measured for a fluorescent protein, and that it produces more photons than organic dyes. Altogether, this study expands our understanding of the smURFP, which will inform future engineering toward optimal FPs compatible with whole organism studies.
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.EXER.2018.09.003
Abstract: Inherited retinal disease (IRD) affects about 1 in 3000 to 1 in 5000 in iduals and is now believed to be the most common cause of blindness registration in developed countries. Until recently, the management of such conditions had been exclusively supportive. However, advances in molecular biology and medical engineering have now seen the rise of a variety of approaches to restore vision in patients with IRDs. Optogenetic approaches are primarily aimed at rendering secondary and tertiary neurons of the retina light-sensitive in order to replace degenerate or dysfunctional photoreceptors. Such approaches are attractive because they provide a "causative gene-independent" strategy, which may prove suitable for a variety of patients with IRD. We discuss theoretical and practical considerations in the selection of optogenetic molecules, vectors, surgical approaches and review previous trials of optogenetics for vision restoration. Optogenetic approaches to vision restoration have yielded promising results in pre-clinical trials and a phase I/II clinical trial is currently underway (ClinicalTrials.gov NCT02556736). Despite the significant inroads made in recent years, the ideal optogenetic molecule, vector and surgical approach have yet to be established.
Publisher: Springer International Publishing
Date: 2015
Location: United States of America
Start Date: 2016
End Date: 2018
Funder: National Eye Institute
View Funded ActivityStart Date: 2016
End Date: 2019
Funder: Australian Research Council
View Funded ActivityStart Date: 2014
End Date: 2018
Funder: National Institute of Neurological Disorders and Stroke
View Funded ActivityStart Date: 2018
End Date: 2020
Funder: National Eye Institute
View Funded ActivityStart Date: 2016
End Date: 2018
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2016
End Date: 2018
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2017
End Date: 12-2022
Amount: $680,540.00
Funder: Australian Research Council
View Funded Activity