ORCID Profile
0000-0002-2478-8416
Current Organisation
UNSW Sydney
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Central Nervous System | Animal Physiology - Systems | Physiology | Sensory Systems
Respiratory System and Diseases (incl. Asthma) | Expanding Knowledge in the Biological Sciences |
Publisher: American Physiological Society
Date: 10-2014
Abstract: Glutamatergic synapses on pyramidal neurons are formed on dendritic spines where glutamate activates ionotropic receptors, and calcium influx via N-methyl-d-aspartate receptors leads to a localized rise in spine calcium that is critical for the induction of synaptic plasticity. In the basolateral amygdala, activation of metabotropic receptors is also required for synaptic plasticity and amygdala-dependent learning. Here, using acute brain slices from rats, we show that, in basolateral amygdala principal neurons, high-frequency synaptic stimulation activates metabotropic glutamate receptors and raises spine calcium by releasing calcium from inositol trisphosphate-sensitive calcium stores. This spine calcium release is unevenly distributed, being present in proximal spines, but largely absent in more distal spines. Activation of metabotropic receptors also generated calcium waves that differentially invaded spines as they propagated toward the soma. Dendritic wave invasion was dependent on diffusional coupling between the spine and parent dendrite which was determined by spine neck length, with waves preferentially invading spines with short necks. Spine calcium is a critical trigger for the induction of synaptic plasticity, and our findings suggest that calcium release from inositol trisphosphate-sensitive calcium stores may modulate homosynaptic plasticity through store-release in the spine head, and heterosynaptic plasticity of unstimulated inputs via dendritic calcium wave invasion of the spine head.
Publisher: Informa UK Limited
Date: 21-07-2020
Publisher: American Psychological Association (APA)
Date: 06-2021
DOI: 10.1037/BNE0000445
Publisher: Wiley
Date: 16-04-2007
Publisher: Society for Neuroscience
Date: 10-03-2022
DOI: 10.1523/JNEUROSCI.0088-22.2022
Abstract: Decisions to act while pursuing goals in the presence of danger must be made quickly but safely. Premature decisions risk injury or death, whereas postponing decisions risk goal loss. Here we show how mice resolve these competing demands. Using microstructural behavioral analyses, we identified the spatiotemporal dynamics of approach–avoidance decisions under motivational conflict in male mice. Then we used cognitive modeling to show that these dynamics reflect the speeded decision-making mechanisms used by humans and nonhuman primates, with mice trading off decision speed for safety of choice when danger loomed. Using calcium imaging in paraventricular thalamus and optogenetic inhibition of the prelimbic cortex to paraventricular thalamus pathway, we show that this speed-safety trade off occurs because increases in paraventricular thalamus activity increase decision caution, thereby increasing approach–avoid decision times in the presence of danger. Our findings demonstrate that a discrete brain circuit involving the paraventricular thalamus and its prefrontal input adjusts decision caution during motivational conflict, trading off decision speed for decision safety when danger is close. We identify the corticothalamic pathway as central to cognitive control during decision-making under conflict. SIGNIFICANCE STATEMENT Foraging animals balance the need to seek food and energy against the conflicting needs to avoid injury and predation. This competition is fundamental to survival but rarely has a stable, correct solution. Here we show that approach–avoid decisions under motivational conflict involve strategic adjustments in decision caution controlled via a top-down corticothalamic pathway from the prelimbic cortex to the paraventricular thalamus. We identify a novel corticothalamic mechanism for cognitive control that is applicable across a range of motivated behaviors and mark paraventricular thalamus and its prefrontal cortical input as targets to remediate the deficits in decision caution characteristic of unsafe and impulsive choices.
Publisher: Cold Spring Harbor Laboratory
Date: 26-11-2020
DOI: 10.1101/2020.11.25.399220
Abstract: It is well established that the activity of VTA dopamine neurons is sufficient to serve as a Pavlovian reinforcer but whether this activity can also serve as instrumental reinforcer is less well understood. Here we studied the effects of optogenetic inhibition of VTA dopamine neurons in instrumental conditioning preparations. We show that optogenetic inhibition of VTA dopamine neurons causes a response-specific, contingency-sensitive suppression of instrumental responding. This suppression was due to instrumental response, not Pavlovian stimulus, learning and could not be attributed to deepened instrumental extinction learning. These effects of optogenetic inhibition of VTA dopamine neurons on instrumental responding are formally similar to the effects of aversive events in instrumental preparations and show that optogenetic inhibition of VTA dopamine neurons is sufficient to serve as an instrumental punisher.
Publisher: Frontiers Media SA
Date: 17-05-2022
DOI: 10.3389/FNINS.2022.848821
Abstract: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a range of motor symptoms. Treatments are focused on dopamine replacement therapy or deep brain stimulation (DBS). The subthalamic nucleus (STN) is a common target for DBS treatment of PD. However, the function of the STN in normal conditions and pathology is poorly understood. Here, we show in rats that optogenetic modulation of STN neuronal activity exerts bidirectional control of motor function, where inhibition of the STN increases movement and STN activation decreases movement. We also examined the effect of bidirectional optogenetic manipulation STN neuronal activity under dopamine depleted condition using the bilateral rodent 6-hydroxydopamine (6-OHDA) model of Parkinson’s disease. Optogenetic inhibition of the STN in the absence of dopamine had no impact on motor control yet STN excitation led to pronounced abnormal involuntary movement. Administration of levodopa rescued the abnormal involuntary movements induced by STN excitation. Although dopamine and STN dysfunction are well established in PD pathology, here we demonstrate simultaneous STN over activity and loss of dopamine lead to motor deficits. Moreover, we show the dysfunction of the STN is dependent on dopamine. This study provides evidence that the loss of dopamine and the over activity of the STN are key features of PD motor deficits. These results provide insight into the STN pathology in PD and therapeutic mechanism of targeting the STN for the treatment for PD.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-01-2002
Abstract: Background — Atrial flutter (AFL) and atrial fibrillation (AF) frequently coexist, yet the specific relationship between these arrhythmias, and particularly whether sustained AFL leads to AF, is unknown. Methods and Results — We investigated the electrophysiological consequences of chronic AFL using an ovine anatomic right atrial Y-lesion model. AFL was induced in 7 animals, and 4 remained in sinus rhythm (controls). Sheep were monitored for spontaneous conversion of AFL to AF. Six of 7 sheep sustained AFL for 28 days. In 1 of 7 sheep, spontaneous conversion of AFL to AF occurred on day 5. AFL produced a highly significant fall in right and left atrial refractoriness (AERP, P .001), with 74±10% of the reduction occurring by day 3. Right atrial conduction velocity also fell significantly (baseline 89±9 cm/s versus day 28 64±14 cm/s, P .001) but over a slower time course. AERP and conduction velocity changes coincided with a characteristic biphasic decrease and increase in the AFL cycle length. The excitable gap (percent of AFL cycle length) increased from 13±3% at baseline to 46±8% by day 28 ( P .001). Sustained AF ( seconds) was not inducible at baseline but after 28 days of AFL could be induced in 6 of 6 sheep by critically timed single or multiple extrastimuli delivered either in sinus rhythm or AFL. There was no significant change in any parameter in control sheep. Conclusions — In this model, AFL produced electrical remodeling and the substrate for sustained AF. However, spontaneous conversion to AF was uncommon, and the development of AF was dependent on specific triggers.
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.BBI.2014.04.001
Abstract: Obesity is a growing problem worldwide and is associated with a range of comorbidities, including cognitive dysfunction. In this review we will address the evidence that obesity and high fat feeding can lead to cognitive dysfunction. We will also examine the idea that obesity-associated systemic inflammation leads to inflammation within the brain, particularly the hypothalamus, and that this is partially responsible for these negative cognitive outcomes. Thus, obesity, and high fat feeding, lead to systemic inflammation and excess circulating free fatty acids. Circulating cytokines, free fatty acids and immune cells reach the brain at the level of the hypothalamus and initiate local inflammation, including microglial proliferation. This local inflammation likely causes synaptic remodeling and neurodegeneration within the hypothalamus, altering internal hypothalamic circuitry and hypothalamic outputs to other brain regions. The result is disruption to cognitive function mediated by regions such as hippoc us, amygdala, and reward-processing centers. Central inflammation is also likely to affect these regions directly. Thus, central inflammation in obesity leads not just to disruption of hypothalamic satiety signals and perpetuation of overeating, but also to negative outcomes on cognition.
Publisher: Elsevier BV
Date: 03-1999
DOI: 10.1016/S0166-4328(98)00096-5
Abstract: The effect of hippoc al aspiration lesions on trace eyeblink conditioning was examined in young, freely-moving F1 hybrid rats (Fisher 344 x Brown Norway). Rats which received either bilateral neocortical or bilateral hippoc al aspiration lesions were compared with each other or with sham lesioned control rats. The rats were trained with a 250 ms tone conditioning stimulus (CS), a 250 ms stimulus free trace interval and a 100 ms corneal airpuff unconditioned stimulus (US). Rats with lesions of the hippoc us were significantly impaired relative to the neocortical and sham lesioned control rats. Analyses of different behavioral parameters (e.g. percent conditioned responses, litude, and area of response) indicated that all of the measures for the conditioned response were significantly impaired by the hippoc al lesion. The unconditioned response was not significantly affected by the lesion, and there was no significant difference among the groups after 2 days of subsequent conditioning with the delay paradigm (zero trace interval). We conclude that the hippoc us is required for rats to learn the association between a tone CS and an airpuff US when a 250 ms trace interval is interposed between the two stimuli.
Publisher: Proceedings of the National Academy of Sciences
Date: 03-02-2009
Abstract: Learning-related reductions of the postburst afterhyperpolarization (AHP) in hippoc al pyramidal neurons have been shown ex vivo, after trace eyeblink conditioning. The AHP is also reduced by many neuromodulators, such as norepinephrine, via activation of protein kinases. Trace eyeblink conditioning, like other hippoc us-dependent tasks, relies on protein synthesis for consolidating the learned memory. Protein kinase A (PKA) has been shown to be a key contributor for protein synthesis via the cAMP-response element-binding pathway. Here, we have explored a potential involvement of PKA and protein kinase C (PKC) in maintaining the learning-related postburst AHP reduction observed in CA1 pyramidal neurons. Bath application of isoproterenol (1 μM), a β-adrenergic agonist that activates PKA, significantly reduced the AHP in CA1 neurons from control animals, but not from rats that learned. This occlusion suggests that PKA activity is involved in maintaining the AHP reduction measured ex vivo after successful learning. In contrast, bath application of the PKC activator, (–) indolactam V (0.2 μM), significantly reduced the AHP in CA1 neurons from both control and trained rats, indicating that PKC activity is not involved in maintaining the AHP reduction at this point after learning.
Publisher: Cold Spring Harbor Laboratory
Date: 08-2021
DOI: 10.1101/2021.07.30.454487
Abstract: Neuroscience techniques, including in vivo recording, have allowed for a great expansion in knowledge however, this technology may also affect the very phenomena researchers set out to investigate. Including both female and male mice in our associative learning experiments shed light on sex differences on the impact of chronic implantation of tetrodes on learning. While previous research showed intact female mice acquired trace eyeblink conditioning faster than male and ovariectomized females, implantation of chronic microdrive arrays showed sexually dimorphic effects on learning. Microdrive implanted male mice acquired the associative learning paradigm faster than both intact and ovariectomized females. These effects were not due to the weight of the drive alone, as there were no significant sex-differences in learning of animals that received “dummy drive” implants without tetrodes lowered into the brain. Tandem mass tag mass spectrometry and western blot analysis suggest that significant alterations in the MAPK pathway, acute inflammation, and brain derived neurotrophic factor may underlie these observed sex- and surgery-dependent effects on learning.
Publisher: Society for Neuroscience
Date: 09-12-2020
DOI: 10.1523/JNEUROSCI.0262-19.2019
Abstract: The ventral pallidum (VP) is a key node in the neural circuits controlling relapse to drug seeking. How this role relates to different VP cell types and their projections is poorly understood. Using male rats, we show how different forms of relapse to alcohol-seeking are assembled from VP cell types and their projections to lateral hypothalamus (LH) and ventral tegmental area (VTA). Using RNAScope in situ hybridization to characterize activity of different VP cell types during relapse to alcohol-seeking provoked by renewal (context-induced reinstatement), we found that VP Gad1 and parvalbumin (PV), but not vGlut2, neurons show relapse-associated changes in c-Fos expression. Next, we used retrograde tracing, chemogenetic, and electrophysiological approaches to study the roles of VP Gad1 and VP PV neurons in relapse. We show that VP Gad1 neurons contribute to contextual control over relapse (renewal), but not to relapse during reacquisition, via projections to LH, where they converge with ventral striatal inputs onto LH Gad1 neurons. This convergence of striatopallidal inputs at the level of in idual LH Gad1 neurons may be critical to balancing propensity for relapse versus abstinence. In contrast, VP PV neurons contribute to relapse during both renewal and reacquisition via projections to VTA. These findings identify a double dissociation in the roles for different VP cell types and their projections in relapse. VP Gad1 neurons control relapse during renewal via projections to LH. VP PV neurons control relapse during both renewal and reacquisition via projections to VTA. Targeting these different pathways may provide tailored interventions for different forms of relapse. SIGNIFICANCE STATEMENT Relapse to drug or reward seeking after a period of extinction or abstinence remains a key impediment to successful treatment. The ventral pallidum, located in the ventral basal ganglia, has long been recognized as an obligatory node in a 'final common pathway' for relapse. Yet how this role relates to the considerable VP cellular and circuit heterogeneity is not well understood. We studied the cellular and circuit architecture for VP in relapse control. We show that different forms of relapse have complementary VP cellular and circuit architectures, raising the possibility that targeting these different neural architectures may provide tailored interventions for different forms of relapse.
Publisher: Society for Neuroscience
Date: 23-09-2015
DOI: 10.1523/JNEUROSCI.1262-15.2015
Abstract: The anterior cingulate cortex (ACC) and prefrontal cortex (PFC) are believed to coactivate during goal-directed behavior to identify, select, and monitor relevant sensory information. Here, we tested whether coactivation of neurons across macaque ACC and PFC would be evident at the level of pairwise neuronal correlations during stimulus selection in a spatial attention task. We found that firing correlations emerged shortly after an attention cue, were evident for 50–200 ms time windows, were strongest for neuron pairs in area 24 (ACC) and areas 8 and 9 (dorsal PFC), and were independent of overall firing rate modulations. For a subset of cell pairs from ACC and dorsal PFC, the observed functional spike-train connectivity carried information about the direction of the attention shift. Reliable firing correlations were evident across area boundaries for neurons with broad spike waveforms (putative excitatory neurons) as well as for pairs of putative excitatory neurons and neurons with narrow spike waveforms (putative interneurons). These findings reveal that stimulus selection is accompanied by slow time scale firing correlations across those ACC/PFC subfields implicated to control and monitor attention. This functional coupling was informative about which stimulus was selected and thus indexed possibly the exchange of task-relevant information. We speculate that interareal, transient firing correlations reflect the transient coordination of larger, reciprocally interacting brain networks at a characteristic 50–200 ms time scale. SIGNIFICANCE STATEMENT Our manuscript identifies interareal spike-train correlations between primate anterior cingulate and dorsal prefrontal cortex during a period where attentional stimulus selection is likely controlled by these very same circuits. Interareal correlations emerged during the covert attention shift to one of two peripheral stimuli, proceeded on a slow 50–200 ms time scale, and occurred between putative pyramidal and putative interneurons. Spike-train correlations emerged particularly for cell pairs tuned to similar contralateral target locations, thus indexing the interareal coordination of attention-relevant information. These findings characterize a possible way by which prefrontal and anterior cingulate cortex circuits implement their control functions through coordinated firing when macaque monkeys select and monitor relevant stimuli for goal-directed behaviors.
Publisher: Elsevier BV
Date: 06-2007
DOI: 10.1016/J.EXPNEUROL.2007.02.006
Abstract: Zinc release is a primary mediator of neuronal death. Here we show that zinc-mediated death of neurons in vitro is dependent on nerve growth factor (NGF) stimulation and does not occur in response to exposure to leukemia inhibitory factor. NGF priming is regulated, not by the traditional neurotrophin death receptor, p75NTR, but by TrkA, in a protein- and mRNA synthesis-dependent manner. Furthermore, Trk signaling promotes raised free intracellular zinc, mediating neuronal death after extracellular application of zinc. Thus, regulators of Trk signaling provide attractive targets for future treatment of zinc-associated neurological diseases, including stroke, epilepsy and brain trauma.
Publisher: Springer Science and Business Media LLC
Date: 06-2005
DOI: 10.1007/S10741-005-4639-8
Abstract: To utilise an ovine model of tachycardia induced progressive dilated cardiomyopathy and heart failure to investigate the efficacy of passive ventricular constraint with the Acorn cardiac support device as a heart failure treatment. (a) Moderate heart failure was produced in 16 sheep by pacing for 3 weeks. Half were implanted and half sham implanted with the CSD. Pacing continued at a higher rate for an additional 3 weeks. Cardiac function was assessed by echocardiography and manometry. (b) Moderate heart failure was produced (as above) in 27 sheep, 9 were implanted with CSD, pacing was restarted for 4 weeks, the initial CSD implants were terminated and another 9 animals were CSD implanted (severe heart failure), pacing was restarted in the remaining 18 animals for an additional 4 weeks (total 12 weeks) and then all animals were terminated. Cardiac function was assessed using echocardiography and treadmill exercise testing. (a) After 6 weeks of rapid pacing CSD implant animals had significantly better cardiac function both when compared with pre implant values and with non-implanted animals at termination. (b) CSD implantation at both moderate and severe failure resulted in significant improvements in cardiac function both when compared with pre implant values and with non-implanted animals at termination. When compared to pre implant values the improvement was greatest in severe implant animals. In this ovine model of tachycardia induced progressive heart failure, CSD implantation in either moderate or severe heart failure resulted in improved cardiac function, reduced left ventricular volume and mitral regurgitation both when compared with function at time of implant and with non implanted control animals.
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.NLM.2022.107649
Abstract: Neuroscience techniques, including in vivo recording, have allowed for a great expansion in knowledge however, this technology may also affect the very phenomena researchers set out to investigate. Including both female and male mice in our associative learning experiments shed light on sex differences on the impact of chronic implantation of tetrodes on learning. While previous research showed intact female mice acquired trace eyeblink conditioning faster than male and ovariectomized females, implantation of chronic microdrive arrays showed sexually dimorphic effects on learning. Microdrive implanted male mice acquired the associative learning paradigm faster than both intact and ovariectomized females. These effects were not due to the weight of the drive alone, as there were no significant sex-differences in learning of animals that received "dummy drive" implants without tetrodes lowered into the brain. Tandem mass tag mass spectrometry and western blot analysis suggest that significant alterations in the MAPK pathway, acute inflammation, and brain derived neurotrophic factor may underlie these observed sex- and surgery-dependent effects on learning.
Publisher: American Physiological Society
Date: 15-03-2012
Abstract: Ifenprodil is a selective blocker of NMDA receptors that are heterodimers composed of GluN1/GluN2B subunits. This pharmacological profile has been extensively used to test the role of GluN2B-containing NMDA receptors in learning and memory formation. However, ifenprodil has also been reported to have actions at a number of other receptors, including high voltage-activated calcium channels. Here we show that, in the basolateral amygdala, ifenprodil dose dependently blocks excitatory transmission to principal neurons by a presynaptic mechanism. This action of ifenprodil has an IC 50 of ∼10 μM and is fully occluded by the P/Q type calcium channel blocker ω-agatoxin. We conclude that ifenprodil reduces synaptic transmission in the basolateral amygdala by partially blocking P-type voltage-dependent calcium channels.
Publisher: Proceedings of the National Academy of Sciences
Date: 10-06-2008
Abstract: Classical conditioning paradigms, such as trace conditioning, in which a silent period elapses between the offset of the conditioned stimulus (CS) and the delivery of the unconditioned stimulus (US), and delay conditioning, in which the CS and US coterminate, are widely used to study the neural substrates of associative learning. However, there are significant gaps in our knowledge of the neural systems underlying conditioning in humans. For ex le, evidence from animal and human patient research suggests that the hippoc us plays a critical role during trace eyeblink conditioning, but there is no evidence to date in humans that the hippoc us is active during trace eyeblink conditioning or is differentially responsive to delay and trace paradigms. The present work provides a direct comparison of the neural correlates of human delay and trace eyeblink conditioning by using functional MRI. Behavioral results showed that humans can learn both delay and trace conditioning in parallel. Comparable delay and trace activation was measured in the cerebellum, whereas greater hippoc al activity was detected during trace compared with delay conditioning. These findings further support the position that the cerebellum is involved in both delay and trace eyeblink conditioning whereas the hippoc us is critical for trace eyeblink conditioning. These results also suggest that the neural circuitry supporting delay and trace eyeblink classical conditioning in humans and laboratory animals may be functionally similar.
Publisher: Elsevier BV
Date: 12-2002
Abstract: We examined heterozygous transgenic (Tg) mice that overexpress V717F amyloid precursor protein (APP) for delay eyeblink conditioning (EBC) and hippoc al volume with magnetic resonance imaging (MRI). Platelet-derived APP mice were significantly impaired on EBC relative to wild type (WT) litter-mate controls. T2-weighted spin echo images (62.5 x 125 x 500 microm) of the same mice were acquired under anesthesia using a 9.4T magnet. Tg mice had hippoc al to brain volume ratios that were significantly smaller than WT controls (31% smaller in the rostral dorsal hippoc us, 13-22% smaller among equal dorsal-ventral thirds of a caudal section). These results indicate that overexpression of APP or beta amyloid profoundly affects learning and memory and hippoc al volume. The results also indicate that eyeblink conditioning and quantitative MRI in mice may be useful assays to follow the progression of disease-related changes, and to test the effectiveness of potential therapeutics against Alzheimer's disease.
Publisher: Society for Neuroscience
Date: 24-09-2021
DOI: 10.1523/JNEUROSCI.2461-20.2021
Abstract: The basolateral amygdala (BLA) is obligatory for fear learning. This learning is linked to BLA excitatory projection neurons whose activity is regulated by complex networks of inhibitory interneurons, dominated by parvalbumin (PV)-expressing GABAergic neurons. The roles of these GABAergic interneurons in learning to fear and learning not to fear, activity profiles of these interneurons across the course of fear learning, and whether or how these change across the course of learning all remain poorly understood. Here, we used PV cell-type-specific recording and manipulation approaches in male transgenic PV-Cre rats during pavlovian fear conditioning to address these issues. We show that activity of BLA PV neurons during the moments of aversive reinforcement controls fear learning about aversive events, but activity during moments of nonreinforcement does not control fear extinction learning. Furthermore, we show expectation-modulation of BLA PV neurons during fear learning, with greater activity to an unexpected than expected aversive unconditioned stimulus (US). This expectation-modulation was specifically because of BLA PV neuron sensitivity to aversive prediction error. Finally, we show that BLA PV neuron function in fear learning is conserved across these variations in prediction error. We suggest that aversive prediction-error modulation of PV neurons could enable BLA fear-learning circuits to retain selectivity for specific sensory features of aversive USs despite variations in the strength of US inputs, thereby permitting the rapid updating of fear associations when these sensory features change. SIGNIFICANCE STATEMENT The capacity to learn about sources of danger in the environment is essential for survival. This learning depends on complex microcircuitries of inhibitory interneurons in the basolateral amygdala. Here, we show that parvalbumin-positive GABAergic interneurons in the rat basolateral amygdala are important for fear learning during moments of danger, but not for extinction learning during moments of safety, and that the activity of these neurons is modulated by expectation of danger. This may enable fear-learning circuits to retain selectivity for specific aversive events across variations in expectation, permitting the rapid updating of learning when aversive events change.
Publisher: Wiley
Date: 2004
DOI: 10.1002/NRC.20027
Publisher: Wiley
Date: 2000
DOI: 10.1002/1520-6769(200009/10)27:2<117::AID-NRC5>3.0.CO;2-Z
Publisher: Elsevier BV
Date: 1999
DOI: 10.1016/S0024-3205(98)00599-2
Abstract: The hippoc us is importantly involved in learning and memory, and is severely impacted by aging. In in vitro hippoc al slices, both the post-burst afterhyperpolarization (AHP) and spike-frequency accommodation are reduced in hippoc al pyramidal neurons after hippoc ally-dependent trace eyeblink conditioning, indications of increased cellular excitability. The AHP results from the activation of outward potassium currents, including sI(AHP) and muscarine-sensitive I(M). The AHP is significantly increased in aging hippoc al neurons, potentially contributing to age-associated learning deficits. Compounds which reduce the AHP and spike-frequency accommodation could facilitate learning in normal aging or in age-associated dementias such as Alzheimer's disease. The cholinesterase inhibitor metrifonate enhances trace eyeblink conditioning by aging rabbits and reduces the AHP and accommodation in hippoc al CA1 neurons in a dose-dependent manner. These reductions are mediated by muscarinic cholinergic transmission as they are blocked by atropine. Hippoc al neurons from metrifonate treated but behaviorally naive rabbits were more excitable and not desensitized to the effects of metrifonate since the AHP and accommodation were further reduced when metrifonate was bath applied to the neurons. These observations suggest that the facilitating effect of chronic metrifonate on acquisition of hippoc ally dependent tasks is mediated at least partially by increasing the baseline excitability of CA1 pyramidal neurons. The issue of whether learning can be facilitated with muscarinic cholinergic agonists, in addition to cholinesterase inhibitors, was addressed by training aging rabbits during intravenous treatment with the M1 agonist CI1017. A dose-dependent enhancement of acquisition was observed, with rabbits receiving 1.0 or 5.0 mg/ml CI1017 showing comparably improved learning rates as those receiving 0.5 mg/ml or vehicle. Sympathetic side effects, mainly excess salivation, were seen with the 5.0 mg/ml dose. Post-training evaluations suggested that the effective doses of CI1017 were enhancing responsivity to the tone conditioned stimulus. These studies suggest that muscarinic cholinergic neurotransmission is importantly involved in associative learning that learning in aging animals may be facilitated by enhancing cholinergic transmission and that the facilitation may be mediated through actions on hippoc al neurons.
Publisher: Springer Science and Business Media LLC
Date: 23-08-2019
Publisher: Springer Science and Business Media LLC
Date: 29-04-2019
Publisher: Wiley
Date: 07-01-2005
Publisher: Informa UK Limited
Date: 1995
DOI: 10.3109/01677069509083461
Abstract: The mutation no action potential (nap) induces arrhythmia in the heartbeat of Drosophila melanogaster larvae at temperatures above 20 degrees C heartbeat becomes normally rhythmic again after a shift back to 20 degrees C. For this phenotype, napa is almost completely recessive to the wild type, napa also reduces the temperature-sensitivity of heart rate over a wide range of temperature, for this phenotype, napa is dominant over the wild type, napa causes reversible paralysis in adults by epistatic effects on the expression of paralyrica, a gene encoding a voltage-dependent sodium channel. However, the paramutation, which induces paralysis in adults at 29 degrees C, has no effect on larval heartbeat at temperatures between 20 degrees and 37.5 degrees C. The period gene, contra earlier reports, has no effect on heartbeat.
Publisher: Cold Spring Harbor Laboratory
Date: 28-02-0004
DOI: 10.1101/2021.04.11.435530
Abstract: Foraging, pursuit, and predation rapidly transition into behavioral quiescence during reward capture and consumption. While appetitive-consummatory dissociations are embedded at both psychological and neural levels, the mechanisms controlling switches or transitions between appetitive seeking and consummatory behaviors remain poorly understood. Here we identify the BLA→AcbSh pathway as critical to these transitions by showing that this pathway inhibits the appetitive seeking response in the presence of consummatory demands. Using an appetitive cue-discrimination task in male rats, we show that reward delivery is a significant driver of seeking inhibition and that a BLA→AcbSh pathway mediates this inhibition. This role in suppressing seeking responses during periods of consumption was not due to a general suppression of behavior because responding to other cues during the same test was unaffected. Moreover, it was specific to the BLA→AcbSh pathway, because the contribution of the BLA→AcbC pathway to appetitive switching was distinct and modest. State-dependent silencing of BLA→AcbSh revealed that the modulation of seeking before and after reward delivery are co-dependent. Finally, we found that BLA terminals in AcbSh have functional connectivity to LH-projecting AcbSh neurons, thereby identifying a BLA→AcbSh→LH pathway as a putative route for the rapid regulation of appetitive behaviors. Taken together, these findings suggest that the BLA→AcbSh pathway is a core component of an appetitive switching system, recruited under conditions requiring rapid or dynamic shifts in appetitive behavior, and that this pathway enables these shifts by actively inhibiting seeking. Foraging, pursuit, and predation quickly transition into behavioral quiescence during reward capture and consumption. These transitions are critical for flexible and responsive sequences of behavior. Here we show that behavioral transitions are actively controlled at the limbic-striatal interface. We identify reward receipt as a proximal trigger for transition between reward seeking and taking, we identify active inhibition as the functional operation of this transition, and we identify the basolateral amygdala→accumbens shell pathway as critical to this functional operation.
Publisher: Springer Science and Business Media LLC
Date: 18-07-2023
DOI: 10.1007/S12975-023-01173-1
Abstract: Canonical transient receptor potential (TRPC) non-selective cation channels, particularly those assembled with TRPC3, TRPC6, and TRPC7 subunits, are coupled to G αq -type G protein-coupled receptors for the major classes of excitatory neurotransmitters. Sustained activation of this TRPC channel-based pathophysiological signaling hub in neurons and glia likely contributes to prodigious excitotoxicity-driven secondary brain injury expansion. This was investigated in mouse models with selective Trpc gene knockout (KO). In adult cerebellar brain slices, application of glutamate and the class I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine to Purkinje neurons expressing the GCaMP5g Ca 2+ reporter demonstrated that the majority of the Ca 2+ loading in the molecular layer dendritic arbors was attributable to the TRPC3 effector channels ( Trpc3 KO compared with wildtype (WT)). This Ca 2+ dysregulation was associated with glutamate excitotoxicity causing progressive disruption of the Purkinje cell dendrites (significantly abated in a GAD67-GFP - Trpc3 KO reporter brain slice model). Contribution of the G αq -coupled TRPC channels to secondary brain injury was evaluated in a dual photothrombotic focal ischemic injury model targeting cerebellar and cerebral cortex regions, comparing day 4 post-injury in WT mice, Trpc3 KO , and Trpc1/3/6/7 quadruple knockout ( Trpc QKO ), with immediate 2-h (primary) brain injury. Neuroprotection to secondary brain injury was afforded in both brain regions by Trpc3 KO and Trpc QKO models, with the Trpc QKO showing greatest neuroprotection. These findings demonstrate the contribution of the G αq -coupled TRPC effector mechanism to excitotoxicity-based secondary brain injury expansion, which is a primary driver for mortality and morbidity in stroke, traumatic brain injury, and epilepsy.
Publisher: Wiley
Date: 04-1998
DOI: 10.1111/J.1540-8167.1998.TB00930.X
Abstract: The development of susceptibility to atrial fibrillation (AF) is a common consequence of many forms of cardiovascular disease, especially heart failure. In this study we used a sheep model of pacing-induced stable early heart failure to describe, quantify, and relate the level of susceptibility to AF to changes in structural and electrophysiologic parameters. Epicardial electrodes were implanted on the atria and right ventricles of nine sheep. The AF threshold, atrial vulnerability period, atrial effective refractory period (ERP), and interatrial conduction time were examined during control and over a 6-week period of ventricular pacing at 190 beats/min. Left atrial (LA) area and left ventricular (LV) fractional shortening were monitored using echocardiography. There were significant increases in LA susceptibility to AF (P < 0.0003), LA area (P < 0.0002), and LA ERP400 (P < 0.0002). Rate of increase in LA area was related positively to AF susceptibility (P = 0.02) and inversely to LA ERP400 (P = 0.002). LV fractional shortening decreased to approximately 50% of control value (P < 0.00001). No changes were observed in right atrial electrophysiology. In this study, susceptibility (the ability of an extrastimulus to induce AF) was rigorously measured within a predetermined format. Significant relationships were found to exist between susceptibility, certain of the observed changes in atrial electrophysiology and structure.
Publisher: Cold Spring Harbor Laboratory
Date: 29-01-2019
DOI: 10.1101/533554
Abstract: Ventral pallidum (VP) is a key node in the neural circuits controlling relapse to drug seeking but how this role relates to different VP cell types and their projections is poorly understood. Using male rats, we show how different forms of relapse to alcohol-seeking are assembled from VP cell types and their projections to lateral hypothalamus (LH) and ventral tegmental area (VTA). First, we used RNAScope in situ hybridization to characterize activity of different VP cell types during relapse to alcohol-seeking provoked by renewal (context-induced reinstatement). We found that VP Gad1 and parvalbumin (PV), but not vGlut2, neurons show relapse-associated changes in c-Fos expression. Next, we used retrograde tracing, chemogenetic, optogenetic, and electrophysiological approaches to study the roles of VP Gad1 and VP PV neurons in relapse. We show that VPGad1 neurons contribute to contextual control over relapse (renewal), but not to relapse during reacquisition, via projections to LH where they converge with ventral striatal inputs onto LH Gad1 neurons. This convergence of striatopallidal inputs at the level of in idual LH Gad1 neurons may be critical to balancing propensity for relapse versus abstinence. In contrast, VP PV neurons contribute to relapse during both renewal and reacquisition via projections to VTA but not LH. These findings show complementary roles for different VP cell types and their projections in relapse. VP Gad1 neurons control relapse during renewal via projections to LH whereas VP PV neurons control relapse during both renewal and reacquisition via projections to VTA. Targeting these different pathways may provide tailored interventions for different forms of relapse.
Publisher: Society for Neuroscience
Date: 19-03-2008
DOI: 10.1523/JNEUROSCI.4310-07.2008
Abstract: Acetylcholine (ACh) is an important modulator of learning, memory, and synaptic plasticity in the basolateral amygdala (BLA) and other brain regions. Activation of muscarinic acetylcholine receptors (mAChRs) suppresses a variety of potassium currents, including s I AHP , the calcium-activated potassium conductance primarily responsible for the slow afterhyperpolarization (AHP) that follows a train of action potentials. Muscarinic stimulation also produces inositol 1,4,5-trisphosphate (IP 3 ), releasing calcium from intracellular stores. Here, we show using whole-cell patch-cl recordings and high-speed fluorescence imaging that focal application of mAChR agonists evokes large rises in cytosolic calcium in the soma and proximal dendrites in rat BLA projection neurons that are often associated with activation of an outward current that hyperpolarizes the cell. This hyperpolarization results from activation of small conductance calcium-activated potassium (SK) channels, secondary to the release of calcium from intracellular stores. Unlike bath application of cholinergic agonists, which always suppressed the AHP, focal application of ACh often evoked a paradoxical enhancement of the AHP and spike-frequency adaptation. This enhancement was correlated with lification of the action potential-evoked calcium response and resulted from the activation of SK channels. When SK channels were blocked, cholinergic stimulation always reduced the AHP and spike-frequency adaptation. Conversely, suppression of the s I AHP by the β-adrenoreceptor agonist, isoprenaline, potentiated the cholinergic enhancement of the AHP. These results suggest that competition between cholinergic suppression of the s I AHP and cholinergic activation of the SK channels shapes the AHP and spike-frequency adaptation.
Publisher: Springer Science and Business Media LLC
Date: 29-11-2018
Publisher: American Psychological Association (APA)
Date: 2001
Publisher: Society for Neuroscience
Date: 12-01-2011
DOI: 10.1523/JNEUROSCI.1045-10.2011
Abstract: The basolateral amygdala (BLA) assigns emotional significance to sensory stimuli. This association results in a change in the output (action potentials) of BLA projection neurons in response to the stimulus. Neuronal output is controlled by the intrinsic excitability of the neuron. A major determinant of intrinsic excitability in these neurons is the slow afterhyperpolarization (sAHP) that follows action potential (AP) trains and produces spike-frequency adaptation. The sAHP is mediated by a slow calcium-activated potassium current (s I AHP ), but little is known about the channels that underlie this current. Here, using whole-cell patch-cl recordings and high-speed calcium imaging from rat BLA projection neurons, we examined the location and function of these channels. We determined the location of the s I AHP by applying a hyperpolarizing voltage step during the s I AHP and measuring the time needed for the current to adapt to the new command potential, a function of its electrotonic distance from the somatic recording electrode. Channel location was also probed by focally uncaging calcium using a UV laser. Both methodologies indicated that, in BLA neurons, the s I AHP is primarily located in the dendritic tree. EPSPs recorded at the soma were smaller, decayed faster, and showed less summation during the sAHP. Adrenergic stimulation and buffering calcium reduced the sAHP and the attenuation of the EPSP during the sAHP. The sAHP also modulated the AP in the dendrite, reducing the calcium response evoked by a single AP. Thus, in addition to mediating spike-frequency adaptation, the s I AHP modulates communication between the soma and the dendrite.
Publisher: Elsevier BV
Date: 2006
Publisher: Hindawi Limited
Date: 2016
DOI: 10.1155/2016/2371970
Abstract: Disruption of synaptic function at excitatory synapses is one of the earliest pathological changes seen in wide range of neurological diseases. The proper control of the segregation of neurotransmitter receptors at these synapses is directly correlated with the intact regulation of the postsynaptic cytoskeleton. In this review, we are discussing key factors that regulate the structure and dynamics of the actin cytoskeleton, the major cytoskeletal building block that supports the postsynaptic compartment. Special attention is given to the complex interplay of actin-associated proteins that are found in the synaptic specialization. We then discuss our current understanding of how disruption of these cytoskeletal elements may contribute to the pathological events observed in the nervous system under disease conditions with a particular focus on Alzheimer’s disease pathology.
Publisher: Society for Neuroscience
Date: 15-08-2012
DOI: 10.1523/JNEUROSCI.6446-11.2012
Abstract: Canonical transient receptor potential (TRPC3) nonselective cation channels are effectors of G-protein-coupled receptors (GPCRs), activated via phospholipase C–diacylglycerol signaling. In cerebellar Purkinje cells, TRPC3 channels cause the metabotropic glutamate receptor (mGluR)-mediated slow EPSC (sEPSC). TRPC3 channels also provide negative feedback regulation of cytosolic Ca 2+ , mediated by a C terminus “calmodulin and inositol trisphosphate receptor binding” (CIRB) domain. Here we report the alternative splicing of the TRPC3 mRNA transcript (designated TRPC3c), resulting in omission of exon 9 (approximately half of the CIRB domain) in mice, rats, and guinea pigs. TRPC3c expression is brain region specific, with prevalence in the cerebellum and brainstem. The TRPC3c channels expressed in HEK293 cells exhibit increased basal and GPCR-activated channel currents, and increased Ca 2+ fluorescence responses, compared with the previously characterized (TRPC3b) isoform when activated via either the endogenous M3 muscarinic acetylcholine receptor, or via coexpressed mGluR1. GPCR-induced TRPC3c channel opening rate (cell-attached patch) matched the maximum activation achieved with inside-out patches with zero cytosolic Ca 2+ , whereas the GPCR-induced TRPC3b activation frequency was significantly less. Both TRPC3 channel isoforms were blocked with 2 m m Ca 2+ , attributable to CIRB domain regulation. In addition, genistein blocked Purkinje cell ( S )-2-amino-2-(3,5-dihydroxyphenyl) acetic acid (mGluR1)-activated TPRC3 current as for recombinant TRPC3c current. This novel TRPC3c ion channel therefore has enhanced efficacy as a neuronal GPCR-Ca 2+ signaling effector, and is associated with sensorimotor coordination, neuronal development, and brain injury.
Publisher: No publisher found
Date: 2001
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NPP.2015.47
Publisher: Wiley
Date: 14-05-2013
DOI: 10.1002/HBM.22261
Publisher: Informa UK Limited
Date: 1995
DOI: 10.3109/01677069509084159
Abstract: Rearing Drosophila melanogaster in constant darkness (DD) for multiple generations disrupts the circadian activity rhythm of adults. In order to determine under what conditions normal rhythms can be initiated, DD-reared Drosophila (either the wild type or the periodshort [pers] mutant) were exposed to light either as embryos, third-instar larvae, or adults. Exposing DD-reared flies to light as embryos or larvae had no effect, while exposing them as adults fully restored normal rhythms in pers and partially restored normal rhythms in the wild type. The percentage of adults with normal rhythms was not significantly different between animals given a 1-h pulse of light as adults and animals given two LD cycles as adults. LD-reared and DD-reared animals given 2 LD cycles were synchronous. In the latter, offset of activity followed the LD transition (CT 12) by 2-6 subjective hours in pers and 2-3 subjective hours in per+. Circadian rhythms did not exhibit phase coherence in the other treatments.
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.NEURON.2018.03.033
Abstract: Contexts exert bi-directional control over relapse to drug seeking. Contexts associated with drug self-administration promote relapse, whereas contexts associated with the absence of self-administration protect against relapse. The nucleus accumbens shell (AcbSh) is a key brain region determining these roles of context. However, the specific cell types, and projections, by which AcbSh serves these dual roles are unknown. Here, we show that contextual control over relapse and abstinence is embedded within distinct output circuits of dopamine 1 receptor (Drd1) expressing AcbSh neurons. We report anatomical and functional segregation of Drd1 AcbSh output pathways during context-induced reinstatement and extinction of alcohol seeking. The AcbSh→ventral tegmental area (VTA) pathway promotes relapse via projections to VTA Gad1 neurons. The AcbSh→lateral hypothalamus (LH) pathway promotes extinction via projections to LH Gad1 neurons. Targeting these opposing AcbSh circuit contributions may reduce propensity to relapse to, and promote abstinence from, drug use.
Publisher: No publisher found
Date: 1999
Publisher: American Psychological Association (APA)
Date: 1999
Publisher: American Physiological Society
Date: 07-2003
DOI: 10.1152/PHYSREV.00002.2003
Abstract: Sah, P., E. S. L. Faber, M. Lopez de Armentia, and J. Power. The Amygdaloid Complex: Anatomy and Physiology. Physiol Rev 83: 803–834, 2003 10.1152 hysrev.00002.2003.—A converging body of literature over the last 50 years has implicated the amygdala in assigning emotional significance or value to sensory information. In particular, the amygdala has been shown to be an essential component of the circuitry underlying fear-related responses. Disorders in the processing of fear-related information are likely to be the underlying cause of some anxiety disorders in humans such as posttraumatic stress. The amygdaloid complex is a group of more than 10 nuclei that are located in the midtemporal lobe. These nuclei can be distinguished both on cytoarchitectonic and connectional grounds. Anatomical tract tracing studies have shown that these nuclei have extensive intranuclear and internuclear connections. The afferent and efferent connections of the amygdala have also been mapped in detail, showing that the amygdaloid complex has extensive connections with cortical and subcortical regions. Analysis of fear conditioning in rats has suggested that long-term synaptic plasticity of inputs to the amygdala underlies the acquisition and perhaps storage of the fear memory. In agreement with this proposal, synaptic plasticity has been demonstrated at synapses in the amygdala in both in vitro and in vivo studies. In this review, we examine the anatomical and physiological substrates proposed to underlie amygdala function.
Publisher: Elsevier BV
Date: 07-2020
Publisher: American Physiological Society
Date: 05-2021
Abstract: The lateral septum (LS) integrates information from hippoc us and other regions to provide context-dependent (top down or higher order) regulation of mood and motivated behavior. Learning and drugs of abuse induce long-term changes in the strength of glutamatergic projections to the LS however, the cellular mechanisms underlying such changes are poorly understood. Here, we demonstrate there are no apparent sex differences in fast excitatory transmission and that long-term synaptic depression in the LS is NMDA-R dependent.
Publisher: Cold Spring Harbor Laboratory
Date: 22-09-2020
DOI: 10.1101/2020.09.22.307561
Abstract: Animals, including humans, use prediction error to guide learning about danger in the environment. The basolateral amygdala (BLA) is obligatory for this learning and BLA excitatory projection neurons are instructed by aversive prediction error to form fear associations. Complex networks of inhibitory interneurons, dominated by parvalbumin (PV) expressing GABAergic neurons, form the intrinsic microcircuitry of the BLA to control projection neuron activity. Whether BLA PV interneurons are also sensitive to prediction error and how they use this error to control fear learning remains unknown. We used PV cell-type specific recording and manipulation approaches in male transgenic PV-Cre rats to address these issues. We show that BLA PV neurons control fear learning about aversive events but not learning about their omission. Furthermore, during fear learning BLA PV neurons express the activity signatures of aversive prediction error: greater activity to unexpected than expected aversive events and greater activity to better rather than poorer predictors of these events. Crucially, we show that BLA PV neurons act to limit fear learning across these variations in prediction error. Together, this demonstrates that prediction error instructs and regulates BLA fear association formation in a cell-type specific manner. Whereas BLA projection neurons use prediction error signals to form and store fear associations, BLA PV interneurons use prediction error signals to constrain fear association formation. The capacity to predict sources of danger in the environment is essential for survival. This capacity is supported by associative learning mechanisms that are triggered when the danger experienced is greater than the danger expected. Here we show that the activity of parvalbumin positive GABAergic interneurons in the rat basolateral amygdala neurons report this difference between the danger expected and the danger experienced and that they use this difference to limit the amount of fear which is learned.
Publisher: Society for Neuroscience
Date: 27-10-2018
DOI: 10.1523/JNEUROSCI.2460-17.2017
Abstract: BLA neurons serve a well-accepted role in fear conditioning and fear extinction. However, the specific learning processes related to their activity at different times during learning remain poorly understood. We addressed this using behavioral tasks isolating distinct aspects of fear learning in male rats. We show that brief optogenetic inhibition of BLA neurons around moments of aversive reinforcement or nonreinforcement causes reductions in the salience of conditioned stimuli, rendering these stimuli less able to be learned about and less able to control fear or safety behaviors. This salience reduction was stimulus-specific, long-lasting, and specific to learning about, or responding to, the same aversive outcome, precisely the goals of therapeutic interventions in human anxiety disorders. Our findings identify a core learning process disrupted by brief BLA optogenetic inhibition. They show that a primary function of the unconditioned stimulus-evoked activity of BLA neurons is to maintain the salience of conditioned stimuli that precede it. This maintenance of salience is a necessary precursor for these stimuli to gain and maintain control over fear and safety behavior. SIGNIFICANCE STATEMENT The amygdala is essential for learning to fear and learning to reduce fear. However, the specific roles served by activity of different amygdala neurons at different times during learning is poorly understood. We used behavioral tasks isolating distinct aspects of learning in rats to show that brief optogenetic inhibition of BLA neurons around moments of reinforcement or nonreinforcement disrupts maintenance of conditioned stimulus salience. This causes a stimulus-specific and long-lasting deficit in the ability of the conditioned stimulus to be learned about or control fear responses. These consequences are the precisely goals of therapeutic interventions in human anxiety disorders. Our findings identify a core learning process disrupted by brief BLA optogenetic inhibition.
Publisher: Elsevier BV
Date: 03-2019
Publisher: Society for Neuroscience
Date: 23-09-2015
DOI: 10.1523/JNEUROSCI.0627-15.2015
Abstract: The medial amygdala (MeA) is a central hub in the olfactory neural network. It receives vomeronasal information directly from the accessory olfactory bulb (AOB) and main olfactory information largely via odor-processing regions such as the olfactory cortical amygdala (CoA). How these inputs are processed by MeA neurons is poorly understood. Using the GAD67-GFP mouse, we show that MeA principal neurons receive convergent AOB and CoA inputs. Somatically recorded AOB synaptic inputs had slower kinetics than CoA inputs, suggesting that they are electrotonically more distant. Field potential recording, pharmacological manipulation, and Ca 2+ imaging revealed that AOB synapses are confined to distal dendrites and segregated from the proximally located CoA synapses. Moreover, unsynchronized AOB inputs had significantly broader temporal summation that was dependent on the activation of NMDA receptors. These findings show that MeA principal neurons process main and accessory olfactory inputs differentially in distinct dendritic compartments. SIGNIFICANCE STATEMENT In most vertebrates, olfactory cues are processed by two largely segregated neural pathways, the main and accessory olfactory systems, which are specialized to detect odors and nonvolatile chemosignals, respectively. Information from these two pathways ultimately converges at higher brain regions, one of the major hubs being the medial amygdala. Little is known about how olfactory inputs are processed by medial amygdala neurons. This study shows that in idual principal neurons in this region receive input from both pathways and that these synapses are spatially segregated on their dendritic tree. We provide evidence suggesting that this dendritic segregation leads to distinct input integration and impact on neuronal output hence, dendritic mechanisms control olfactory processing in the amygdala.
Publisher: Springer Science and Business Media LLC
Date: 17-02-2018
DOI: 10.1007/S12975-018-0615-1
Abstract: It is generally accepted that the cerebellum is particularly vulnerable to ischaemic injury, and this may contribute to the high mortality arising from posterior circulation strokes. However, this has not been systematically examined in an animal model. This study compared the development and resolution of matched photothrombotic microvascular infarcts in the cerebellar and cerebral cortices in adult 129/SvEv mice of both sexes. The photothrombotic lesions were made using tail vein injection of Rose Bengal with a 532 nm laser projected onto a 2 mm diameter aperture over the target region of the brain (with skull thinning). Infarct size was then imaged histologically following 2 h to 30-day survival using serial reconstruction of haematoxylin and eosin stained cryosections. This was complemented with immunohistochemistry for neuron and glial markers. At 2 h post-injury, the cerebellar infarct volume averaged ~ 2.7 times that of the cerebral cortex infarcts. Infarct volume reached maximum in the cerebellum in a quarter of the time (24 h) taken in the cerebral cortex (4 days). Remodelling resolved the infarcts within a month, leaving significantly larger residual injury volume in the cerebellum. The death of neurons in the core lesion at 2 h was confirmed by NeuN and Calbindin immunofluorescence, alongside activation of astrocytes and microglia. The latter persisted in the region within and surrounding the residual infarct at 30 days. This comparison of acute focal ischaemic injuries in cerebellar and cerebral cortices provides direct confirmation of exacerbation of neuropathology and faster kinetics in the cerebellum.
Publisher: MDPI AG
Date: 27-08-2021
DOI: 10.3390/IJMS22179303
Abstract: Tropomyosin (Tpm) has been regarded as the master regulator of actin dynamics. Tpms regulate the binding of the various proteins involved in restructuring actin. The actin cytoskeleton is the predominant cytoskeletal structure in dendritic spines. Its regulation is critical for spine formation and long-term activity-dependent changes in synaptic strength. The Tpm isoform Tpm3.1 is enriched in dendritic spines, but its role in regulating the synapse structure and function is not known. To determine the role of Tpm3.1, we studied the synapse structure and function of cultured hippoc al neurons from transgenic mice overexpressing Tpm3.1. We recorded hippoc al field excitatory postsynaptic potentials (fEPSPs) from brain slices to examine if Tpm3.1 overexpression alters long-term synaptic plasticity. Tpm3.1-overexpressing cultured neurons did not show a significantly altered dendritic spine morphology or synaptic activity. Similarly, we did not observe altered synaptic transmission or plasticity in brain slices. Furthermore, expression of Tpm3.1 at the postsynaptic compartment does not increase the local F-actin levels. The results suggest that although Tpm3.1 localises to dendritic spines in cultured hippoc al neurons, it does not have any apparent impact on dendritic spine morphology or function. This is contrary to the functional role of Tpm3.1 previously observed at the tip of growing neurites, where it increases the F-actin levels and impacts growth cone dynamics.
Publisher: Society for Neuroscience
Date: 15-07-2020
Publisher: Elsevier BV
Date: 10-2002
Publisher: Cold Spring Harbor Laboratory
Date: 07-09-2017
DOI: 10.1101/186072
Abstract: Basolateral amygdala (BLA) glutamatergic neurons serve a well-accepted role in fear conditioning and fear extinction. However, the specific learning processes related to their activity at different times during learning remain poorly understood. We addressed this using behavioral tasks isolating distinct aspects of fear learning in rats. We show that brief optogenetic inhibition of BLA glutamatergic neurons around moments of aversive reinforcement or non-reinforcement causes reductions in the salience of conditioned stimuli, rendering these stimuli less able to be learned about and less able to control fear or safety behaviours. This salience reduction was stimulus-specific, long-lasting, and specific to aversive emotional states - precisely the goals of therapeutic interventions in human anxiety disorders. Our findings identify a core learning process disrupted by brief BLA optogenetic inhibition. They show that a primary function of BLA glutamatergic neurons is to maintain the salience of conditioned stimuli. This is a necessary precursor for these stimuli to gain and maintain control over fear and safety behavior. The amygdala is essential for learning to fear and learning to reduce fear. However, the specific roles served by activity of different amygdala neurons at different times during learning is poorly understood. We used behavioral tasks isolating distinct aspects of learning in rats to show that brief optogenetic inhibition of BLA glutamatergic neurons around moments of reinforcement or non-reinforcement disrupts maintenance of conditioned stimulus (CS) salience. This causes a stimulus-specific, long-lasting, and aversive emotion specific deficit in the ability of the CS to be learned about or control fear responses. These consequences are the precisely goals of therapeutic interventions in human anxiety disorders. Our findings identify a core learning process disrupted by brief BLA optogenetic inhibition.
Publisher: Wiley
Date: 2000
DOI: 10.1002/1520-6769(200009/10)27:2<135::AID-NRC7>3.0.CO;2-X
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-11-1997
DOI: 10.1161/01.CIR.96.10.3710
Abstract: Background Recently, we developed a goat model of chronic atrial fibrillation (AF). Due to AF, the atrial effective refractory period (AERP) shortened and its physiological rate adaptation inversed, whereas the rate and stability of AF increased. The goal of the present study was to evaluate the role of (1) the autonomic nervous system, (2) ischemia, (3) stretch, (4) atrial natriuretic factor (ANF), and (5) rapid atrial pacing in this process of electrical remodeling. Methods and Results Twenty-five goats were chronically instrumented with multiple epicardial atrial electrodes. Infusion of atropine (1.0 mg/kg n=6) or propranolol (0.6 mg/kg n=6) did not abolish the AF-induced shortening of AERP or interval (AFI). Blockade of K + ATP channels by glibenclamide (10 μmol/kg n=6) slightly increased the AFI from 95±4 to 101±5 ms, but AFI remained considerably shorter than during acute AF (145 ms). Glibenclamide had no significant effect on AERP after electrical cardioversion of AF (69±14 versus 75±15 ms). Volume loading by 0.5 to 1.0 L of Hemaccel (n=12) did not shorten AERP. The median plasma level of ANF increased from 42 to 99 pg/mL after 1 to 4 weeks of AF (n=6), but ANF infusion (0.1 to 3.1 μg/min, n=4) did not shorten AERP. Rapid atrial pacing (24 to 48 hours n=10) progressively shortened AERP from 134±10 to 105±6 ms and inversed its physiological rate adaptation. Conclusions Electrical remodeling by AF is not mediated by changes in autonomic tone, ischemia, stretch, or ANF. The high rate of electrical activation itself provides the stimulus for the AF-induced changes in AERP.
Publisher: Society for Neuroscience
Date: 22-10-2008
DOI: 10.1523/JNEUROSCI.1796-08.2008
Abstract: Emotionally arousing events are particularly well remembered. This effect is known to result from the release of stress hormones and activation of β adrenoceptors in the amygdala. However, the underlying cellular mechanisms are not understood. Small conductance calcium-activated potassium (SK) channels are present at glutamatergic synapses where they limit synaptic transmission and plasticity. Here, we show that β adrenoceptor activation regulates synaptic SK channels in lateral amygdala pyramidal neurons, through activation of protein kinase A. We show that SK channels are constitutively recycled from the postsynaptic membrane and that activation of β adrenoceptors removes SK channels from excitatory synapses. This results in enhanced synaptic transmission and plasticity. Our findings demonstrate a novel mechanism by which β adrenoceptors control synaptic transmission and plasticity, through regulation of SK channel trafficking, and suggest that modulation of synaptic SK channels may contribute to β adrenoceptor-mediated potentiation of emotional memories.
Publisher: SAGE Publications
Date: 09-1995
DOI: 10.1177/074873049501000309
Abstract: Strains of Drosophila melanogaster homozygous for alleles of the period gene ( per 0 , per L , per S , and per + ) were reared for multiple generations either in light:dark cycles (LD), continuous illumination (LL), or chronic darkness (DD). The locomotor activity of adult flies from these cultures was monitored in either LL or DD. Flies that were reared and tested in DD had a lower proportion of in iduals with normal circadian rhythms than flies reared in LD or LL and tested in DD. The activity rhythms of DD-reared DD-tested animals, when present, showed phase coherence within two out of seven populations, while 8 out of 10 LL-reared DD-tested showed phase coherence. Flies tested in LL were largely devoid of circadian rhythms regardless of their rearing environment. Ultradian rhythms were more evident under conditions disruptive to circadian rhythmicity, but were observed in the presence and absence of circadian rhythms. The periods of the ultradian rhythms of LL-reared DD-tested and LD-reared DD-tested flies varied significantly among genotypes, while in other rearing and testing regimes, no relationship was found.
Publisher: Elsevier BV
Date: 2001
DOI: 10.1016/S0197-4580(00)00194-9
Abstract: Young, middle-aged, old, and senescent Fischer 344 x Brown Norway F1 hybrid rats were trained in either the trace or delay eyeblink conditioning task in order to investigate how aging affects associative learning and memory over the life span. Senescent rats at 34-35 months showed severe impairments in acquisition of the trace task with a 250 msec trace interval, which is hippoc ally-dependent, and were mildly impaired in the simple delay eyeblink conditioning task. Middle aged animals, varying in age from 18-24 months, acquired the trace and delay eyeblink paradigms as well as young rats (6 months). However, at 28-29 months, approximately 50% of the old animals showed impairments in the trace 250 msec eyeblink task. Our results show that trace eyeblink conditioning is an age-sensitive task useful for studying the neural substrates underlying associative learning and memory in rats, as has been previously shown in humans and rabbits.
Publisher: Cold Spring Harbor Laboratory
Date: 16-01-2020
Abstract: The role of awareness in differential delay eyeblink conditioning (EBC) has been a topic of much debate. We tested the idea that awareness is required for differential delay EBC when two cues are perceptually similar. The present study manipulated frequencies of auditory conditioned stimuli (CS) to vary CS similarity in three groups of participants. Our findings indicate that awareness was not necessary for differential delay EBC when two tones are easily discriminable, awareness was also not needed for relatively similar tones but may facilitate earlier conditioning, and awareness alone was not sufficient for differential delay EBC.
Publisher: Oxford University Press (OUP)
Date: 06-05-2020
Abstract: Hyperphosphorylation and deposition of tau in the brain characterizes frontotemporal dementia and Alzheimer’s disease. Disease-associated mutations in the tau-encoding MAPT gene have enabled the generation of transgenic mouse models that recapitulate aspects of human neurodegenerative diseases, including tau hyperphosphorylation and neurofibrillary tangle formation. Here, we characterized the effects of transgenic P301S mutant human tau expression on neuronal network function in the murine hippoc us. Onset of progressive spatial learning deficits in P301S tau transgenic TAU58/2 mice were paralleled by long-term potentiation deficits and neuronal network aberrations during electrophysiological and EEG recordings. Gene-expression profiling just prior to onset of apparent deficits in TAU58/2 mice revealed a signature of immediate early genes that is consistent with neuronal network hypersynchronicity. We found that the increased immediate early gene activity was confined to neurons harbouring tau pathology, providing a cellular link between aberrant tau and network dysfunction. Taken together, our data suggest that tau pathology drives neuronal network dysfunction through hyperexcitation of in idual, pathology-harbouring neurons, thereby contributing to memory deficits.
Publisher: Frontiers Media SA
Date: 22-12-2017
Publisher: Elsevier BV
Date: 04-2018
Publisher: Cold Spring Harbor Laboratory
Date: 08-03-2020
DOI: 10.1101/2020.03.06.981605
Abstract: The mesolimbic dopamine system comprises distinct compartments supporting different functions in learning and motivation. Less well understood is how complex addiction-related behaviors emerge from activity patterns across these compartments. Here we show how different forms of relapse to alcohol-seeking are assembled from activity across the ventral tegmental area and the nucleus accumbens. Using gCaMP and dLight fibre photometry, we show that self-administration and two forms of relapse (renewal/context-induced reinstatement and reacquisition) are associated with recruitment across the mesolimbic dopamine system. Using a variety of interventions, we show that this activity is causal to both forms of relapse. Finally, we use dissimilarity matrices to identify mesolimbic dopamine signatures of self-administration, extinction, and relapse. We show that signatures of relapse can be identified from heterogeneous activity profiles across the mesolimbic dopamine system and that these signatures differ for different forms of relapse.
Publisher: American Physiological Society
Date: 03-2013
Abstract: N-methyl-d-aspartate (NMDA) receptors are heteromultimeric ion channels that contain an essential GluN1 subunit and two or more GluN2 (GluN2A–GluN2D) subunits. The biophysical properties and physiological roles of synaptic NMDA receptors are dependent on their subunit composition. In the basolateral amygdala (BLA), it has been suggested that the plasticity that underlies fear learning requires activation of heterodimeric receptors composed of GluN1/GluN2B subunits. In this study, we investigated the subunit composition of NMDA receptors present at synapses on principal neurons in the BLA. Purification of the synaptic fraction showed that both GluN2A and GluN2B subunits are present at synapses, and co-immunoprecipitation revealed the presence of receptors containing both GluN2A and GluN2B subunits. The kinetics of NMDA receptor-mediated synaptic currents and pharmacological blockade indicate that heterodimeric GluN1/GluN2B receptors are unlikely to be present at glutamatergic synapses on BLA principal neurons. Selective RNA interference-mediated knockdown of GluN2A subunits converted synaptic receptors to a GluN1/GluN2B phenotype, whereas knockdown of GluN2B subunits had no effect on the kinetics of the synaptically evoked NMDA current. Blockade of GluN1/GluN2B heterodimers with ifenprodil had no effect, but knockdown of GluN2B disrupted the induction of CaMKII-dependent long-term potentiation at these synapses. These results suggest that, on BLA principal neurons, GluN2B subunits are only present as GluN1/GluN2A/GluN2B heterotrimeric NMDA receptors. The GluN2B subunit has little impact on the kinetics of the receptor, but is essential for the recruitment of signaling molecules essential for synaptic plasticity.
Location: Australia
Start Date: 06-2018
End Date: 12-2023
Amount: $399,083.00
Funder: Australian Research Council
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