ORCID Profile
0000-0001-9752-8175
Current Organisation
University of New South Wales
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Biological Psychology (Neuropsychology, Psychopharmacology, Physiological Psychology) | Psychology | Central Nervous System |
Mental Health | Expanding Knowledge in Psychology and Cognitive Sciences | Substance Abuse | Expanding Knowledge in the Biological Sciences
Publisher: Society for Neuroscience
Date: 24-11-2010
DOI: 10.1523/JNEUROSCI.4508-10.2010
Abstract: Monoaminergic neurons [serotonergic (5-HT) and dopaminergic (mdDA)] in the brainstem project axons along the anterior–posterior axis. Despite their important physiological functions and implication in disease, the molecular mechanisms that dictate the formation of these projections along the anterior–posterior axis remain unknown. Here we reveal a novel requirement for Wnt lanar cell polarity signaling in the anterior–posterior organization of the monoaminergic system. We find that 5-HT and mdDA axons express the core planar cell polarity components Frizzled3, Celsr3, and Vangl2. In addition, monoaminergic projections show anterior–posterior guidance defects in Frizzled3 , Celsr3 , and Vangl2 mutant mice. The only known ligands for planar cell polarity signaling are Wnt proteins. In culture, Wnt5a attracts 5-HT but repels mdDA axons, and Wnt7b attracts mdDA axons. However, mdDA axons from Frizzled3 mutant mice are unresponsive to Wnt5a and Wnt7b. Both Wnts are expressed in gradients along the anterior–posterior axis, consistent with their role as directional cues. Finally, Wnt5a mutants show transient anterior–posterior guidance defects in mdDA projections. Furthermore, we observe during development that the cell bodies of migrating descending 5-HT neurons eventually reorient along the direction of their axons. In Frizzled3 mutants, many 5-HT and mdDA neuron cell bodies are oriented abnormally along the direction of their aberrant axon projections. Overall, our data suggest that Wnt lanar cell polarity signaling may be a global anterior–posterior guidance mechanism that controls axonal and cellular organization beyond the spinal cord.
Publisher: Mary Ann Liebert Inc
Date: 08-2013
Abstract: Ryk is an atypical transmembrane receptor tyrosine kinase that has been shown to play multiple roles in development through the modulation of Wnt signaling. Within the developing ventral midbrain (VM), Wnts have been shown to contribute to the proliferation, differentiation, and connectivity of dopamine (DA) neurons however, the Wnt-related receptors regulating these events remain less well described. In light of the established roles of Wnt5a in dopaminergic development (regulating DA differentiation as well as axonal growth and repulsion), and its interaction with Ryk elsewhere within the central nervous system, we investigated the potential role of Ryk in VM development. Here we show temporal and spatial expression of Ryk within the VM, suggestive of a role in DA neurogenesis and axonal plasticity. In VM primary cultures, we show that the effects of Wnt5a on VM progenitor proliferation, DA differentiation, and DA axonal connectivity can be inhibited using an Ryk-blocking antibody. In support, Ryk knockout mice showed reduced VM progenitors and DA precursor populations, resulting in a significant decrease in DA cells. However, Ryk(-/-) mice displayed no defects in DA axonal growth, guidance, or fasciculation of the MFB, suggesting other receptors may be involved and/or compensate for the loss of this receptor. These findings identify for the first time Ryk as an important receptor for midbrain DA development.
Publisher: Frontiers Media SA
Date: 14-09-2022
DOI: 10.3389/FNINS.2022.948523
Abstract: Parkinson’s disease (PD) is a progressive neurodegenerative disorder, pathologically hallmarked by the loss of dopamine neurons in the substantia nigra (SN) and alpha-synuclein aggregation. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a common target to treat the motor symptoms in PD. However, we have less understanding of the cellular changes in the STN during PD, and the impact of DBS on the STN and SN is limited. We examined cellular changes in the SN and STN in PD patients with and without STN-DBS treatment. Post-mortem brain tissues from 6 PD non-STN-DBS patients, 5 PD STN-DBS patients, and 6 age-matched controls were stained with markers for neurodegeneration (tyrosine hydroxylase, alpha-synuclein, and neuronal loss) and astrogliosis (glial fibrillary acidic protein). Changes were assessed using quantitative and semi-quantitative microscopy techniques. As expected, significant neuronal cell loss, alpha-synuclein pathology, and variable astrogliosis were observed in the SN in PD. No neuronal cell loss or astrogliosis was observed in the STN, although alpha-synuclein deposition was present in the STN in all PD cases. DBS did not alter neuronal loss, astrogliosis, or alpha-synuclein pathology in either the SN or STN. This study reports selective pathology in the STN with deposits of alpha-synuclein in the absence of significant neuronal cell loss or inflammation in PD. Despite being effective for the treatment of PD, this small post-mortem study suggests that DBS of the STN does not appear to modulate histological changes in astrogliosis or neuronal survival, suggesting that the therapeutic effects of DBS mechanism may transiently affect STN neural activity.
Publisher: Public Library of Science (PLoS)
Date: 17-10-2014
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: American Psychological Association (APA)
Date: 2015
DOI: 10.1037/BNE0000036
Abstract: The ventral pallidum (VP) is a key component of the neural circuitry mediating relapse to drug seeking, but the critical afferent pathways to VP recruited during relapse remain poorly understood. We studied the role of the nucleus accumbens core (AcbC) → VP pathway in ABA renewal and reacquisition of alcohol seeking. Rats received application of adenoviral vectors encoding eYFP, ChR2(H134R), or eNpHr3.0 to AcbC and implantation of fiber optic cannulas into VP to permit photostimulation of AcbC terminals there. Rats were then trained to self-administer alcoholic beer in 1 context (A), extinguished in a second context (B), tested in the extinction (ABB) and training (ABA) contexts, and were then tested for reacquisition of alcoholic beer seeking. There was ABA renewal of alcohol seeking, but neither optogenetic excitation nor inhibition of the AcbC → VP pathway affected this renewal. In contrast, optogenetic inhibition of the AcbC → VP striatopallidal pathway reduced reacquisition of alcohol seeking-measured either by the number of active nosepokes emitted or by the number of alcohol rewards earned and consumed. Moreover, optogenetic excitation of the AcbC → VP striatopallidal pathway increased magazine entries during reacquisition test. This finding shows the importance of the AcbC → VP pathway in controlling relapse when the drug reinforcer is present on test and is consistent with a role for the AcbC → VP pathway in regulating the hedonic or incentive motivational properties of drug reinforcers.
Publisher: Society for Neuroscience
Date: 07-10-2009
DOI: 10.1523/JNEUROSCI.2521-09.2009
Abstract: Dopaminergic neurons in the mesodiencephalon (mdDA neurons) make precise synaptic connections with targets in the forebrain via the mesostriatal, mesolimbic, and mesoprefrontal pathways. Because of the functional importance of these remarkably complex ascending axon pathways and their implication in human disease, the mechanisms underlying the development of these connections are of considerable interest. Despite extensive in vitro studies, the molecular determinants that ensure the perfect formation of these pathways in vivo remain mostly unknown. Here, we determine the embryonic origin and ontogeny of the mouse mesoprefrontal pathway and use these data to reveal an unexpected requirement for semaphorin 3F (Sema3F) and its receptor neuropilin-2 (Npn-2) during mdDA pathway development using tissue culture approaches and analysis of sema3F −/− , npn-2 −/− , and npn-2 −/− TH-Cre mice. We show that Sema3F is a bifunctional guidance cue for mdDA axons, some of which have the remarkable ability to regulate their responsiveness to Sema3F as they develop. During early developmental stages, Sema3F chemorepulsion controls previously uncharacterized aspects of mdDA pathway development through both Npn-2-dependent (axon fasciculation and channeling) and Npn-2-independent (rostral growth) mechanisms. Later on, chemoattraction mediated by Sema3F and Npn-2 is required to orient mdDA axon projections in the cortical plate of the medial prefrontal cortex. This latter finding demonstrates that regulation of axon orientation in the target field occurs by chemoattractive mechanisms, and this is likely to also apply to other neural systems. In all, this study provides a framework for additional dissection of the molecular basis of mdDA pathway development and disease.
Publisher: Society for Neuroscience
Date: 21-10-2015
DOI: 10.1523/JNEUROSCI.1840-15.2015
Abstract: The striatum is a large brain nucleus with an important role in the control of movement and emotions. Medium spiny neurons (MSNs) are striatal output neurons forming prominent descending axon tracts that target different brain nuclei. However, how MSN axon tracts in the forebrain develop remains poorly understood. Here, we implicate the Wnt binding receptor Frizzled3 in several uncharacterized aspects of MSN pathway formation [i.e., anterior–posterior guidance of MSN axons in the striatum and their subsequent growth into the globus pallidus (GP), an important (intermediate) target]. In Frizzled3 knock-out mice, MSN axons fail to extend along the anterior–posterior axis of the striatum, and many do not reach the GP. Wnt5a acts as an attractant for MSN axons in vitro , is expressed in a posterior high, anterior low gradient in the striatum, and Wnt5a knock-out mice phenocopy striatal anterior–posterior defects observed in Frizzled3 mutants. This suggests that Wnt5a controls anterior–posterior guidance of MSN axons through Frizzled3. Axons that reach the GP in Frizzled3 knock-out mice fail to enter this structure. Surprisingly, entry of MSN axons into the GP non–cell-autonomously requires Frizzled3, and our data suggest that GP entry may be contingent on the correct positioning of “corridor” guidepost cells for thalamocortical axons by Frizzled3. Together, these data dissect MSN pathway development and reveal (non)cell-autonomous roles for Frizzled3 in MSN axon guidance. Further, they are the first to identify a gene that provides anterior–posterior axon guidance in a large brain nucleus and link Frizzled3 to corridor cell development. SIGNIFICANCE STATEMENT Striatal axon pathways mediate complex physiological functions and are an important therapeutic target, underscoring the need to define how these connections are established. Remarkably, the molecular programs regulating striatal pathway development remain poorly characterized. Here, we determine the embryonic ontogeny of the two main striatal pathways (striatonigral and striatopallidal) and identify novel (non)cell-autonomous roles for the axon guidance receptor Frizzled3 in uncharacterized aspects of striatal pathway formation (i.e., anterior–posterior axon guidance in the striatum and axon entry into the globus pallidus). Further, our results link Frizzled3 to corridor guidepost cell development and suggest that an abnormal distribution of these cells has unexpected, widespread effects on the development of different axon tracts (i.e., striatal and thalamocortical axons).
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: 16-11-2016
DOI: 10.1523/JNEUROSCI.2580-16.2016
Abstract: Ventral pallidum (VP) is a well-established locus for the reinforcing effects of drugs of abuse and reinstatement of drug seeking. However, VP neurons are at the origin of multiple output pathways, with strong projections to ventral tegmental area (VTA), subthalamic nucleus (STN), lateral hypothalamus, among others, and the roles of these VP output pathways in reinstatement of drug seeking remain poorly understood. Here we addressed these issues using a combination of neuroanatomical tracing and chemogenetic approaches. First, using dual-retrograde tracing, we show that VP neurons projecting to either VTA or STN are recruited during context-induced reinstatement of extinguished alcohol seeking in rats. Then, using chemogenetics, we show modulation of context-induced reinstatement and reacquisition of alcohol seeking via designer receptors exclusively activated by designer drugs excitation or inhibition of the VP. To determine the causal roles of VP → VTA and VP → STN pathways in context-induced reinstatement and reacquisition we used a chemogenetic disconnection approach and show that silencing either the VP → VTA or VP → STN pathways is sufficient to reduce both reinstatement and reacquisition of alcohol seeking. Moreover, these disconnections also each reduced responding and motivation during a progressive ratio test but had no effect on locomotor activity. Together, these results show that multiple ventral pallidal output pathways contribute to relapse to alcohol seeking. SIGNIFICANCE STATEMENT Ventral pallidum (VP) serves important roles in reward and motivation and is a critical node in the neural circuitry for reinstatement of drug seeking. Despite being a common locus for different forms of reinstatement, fundamental aspects of neural circuitry for these VP contributions to reinstatement of drug seeking remain unknown. Here we used a combination of neuroanatomical tracing and chemogenetic approaches to map the VP output pathways for context-induced reinstatement and reacquisition of alcohol seeking. We show that VP output pathways to the subthalamic nucleus and also to the ventral tegmental area are necessary for these forms of reinstatement.
Publisher: Wiley
Date: 09-07-2020
DOI: 10.1111/BPH.15160
Publisher: Elsevier BV
Date: 07-2008
DOI: 10.1016/J.CUB.2008.06.070
Abstract: PolycombGroup (PcG) proteins are epigenetic silencers involved in maintaining cellular identity, and their deregulation can result in cancer [1]. Mice without the PcG gene Bmi1 are runted and suffer from progressive loss of hematopoietic and neural stem cells [2-4]. Here, we assess the effects of Bmi1 on stem cells and differentiation of an epithelial tissue in vivo. We chose the mammary gland because it allows limiting dilution transplantations [5, 6] and because Bmi1 is overexpressed in breast cancer [7, 8]. Our analyses show that Bmi1 is expressed in all cells of the mouse mammary gland and is especially high in luminal cells. Loss of Bmi1 results in a severe mammary-epithelium growth defect, which can be rescued by codeletion of the Ink4a/Arf locus or pregnancy. Even though mammary stem cells are present in the absence of Bmi1, their activity is reduced, and this is only partially due to Ink4a/Arf expression. Interestingly, loss of Bmi1 causes premature lobuloalveolar differentiation, whereas overexpression of Bmi1 inhibits lobuloalveolar differentiation induced by pregnancy hormones. Because Bmi1 affects not only mammary stem cells but also more committed cells, our data warrant a more detailed analysis of the different roles of Bmi1 in breast-cancer etiology.
Publisher: MDPI AG
Date: 27-10-2020
DOI: 10.3390/MICROORGANISMS8111661
Abstract: Parkinson’s disease (PD) is a neurological disorder with motor dysfunction and a number of psychiatric symptoms. Symptoms such as anxiety and cognitive deficits emerge prior to motor symptoms and persist over time. There are limited treatments targeting PD psychiatric symptoms. Emerging studies reveal that the gut microbe is altered in PD patients. Here we assessed the effect of a probiotic treatment in a rat model of PD. We used the neurotoxin (6-hydroxydopamine, 6-OHDA) in a preclinical PD model to examine the impact of a probiotic treatment (Lacticaseibacillus rhamnosus HA-114) on anxiety and memory. Rats underwent either sham surgery or received 6-OHDA bilaterally into the striatum. Three weeks post-surgery, rats were ided into three experimental groups: a sham group that received probiotics, a 6-OHDA group that received probiotics, and the third group of 6-OHDA received the placebo formula. All rats had access to either placebo or probiotics formula for 6 weeks. All groups were assessed for anxiety-like behaviour using the elevated plus maze. Cognition was assessed for both non-hippoc al and hippoc al dependent tasks using the novel object recognition and novel place recognition. We report that the 6-OHDA lesion induced anxiety-like behaviour and deficits in hippoc al dependent cognition. Interestingly, the probiotics treatment had no impact on anxiety-like behaviour but selectively improved hippoc al dependent cognition deficits. Together, the results presented here highlight the utility of animal models in examining the neuropsychiatric symptoms of PD and the potential of probiotics as adjunctive treatment for non-motor symptoms of PD.
Publisher: Society for Neuroscience
Date: 15-07-2020
Publisher: Elsevier BV
Date: 12-2021
Publisher: Springer New York
Date: 2009
DOI: 10.1007/978-1-4419-0322-8_9
Abstract: Meso-diencephalic dopamine neurons (mdDA) neurons are located in the retrorubral field (RRF), substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) and give rise to prominent ascending axon projections. These so-called mesotelencephalic projections are organized into three main pathways: the mesostriatal, mesocortical and mesolimbic pathways. Mesotelencephalic pathways in the adult nervous system have been studied in much detail as a result of their important physiological functions and their implication in psychiatric, neurological and neurodegenerative disease. In comparison, relatively little is known about the formation of these projection systems during embryonic and postnatal development. However, understanding the formation of mdDA neurons and their projections is essential for the design of effective therapies for mdDA neuron-associated neurological and neurodegenerative disorders. Here we summarize our current knowledge of the ontogeny of mdDA axon projections in subsystems of the developing rodent central nervous system (CNS) and discuss the cellular and molecular mechanisms that mediate mdDA axon guidance in these CNS regions.
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: Frontiers Media SA
Date: 08-12-2021
Abstract: Clinical studies provide fundamental knowledge of substance use behaviors (substance of abuse, patterns of use, relapse rates). The combination of neuroimaging approaches reveal correlation between substance use disorder (SUD) and changes in neural structure, function, and neurotransmission. Here, we review these advances, placing special emphasis on sex specific findings from structural neuroimaging studies of those dependent on alcohol, nicotine, cannabis, psychostimulants, or opioids. Recent clinical studies in SUD analyzing sex differences reveal neurobiological changes that are differentially impacted in common reward processing regions such as the striatum, hippoc us, amygdala, insula, and corpus collosum. We reflect on the contribution of sex hormones, period of drug use and abstinence, and the potential impact of these factors on the interpretation of the reported findings. With the overall recognition that SUD impacts the brains of females and males differentially, it is of fundamental importance that future research is designed with sex as a variable of study in this field. Improved understanding of neurobiological changes in males and females in SUD will advance knowledge underlying sex-specific susceptibility and the neurobiological impact in these disorders. Together these findings will inform future treatments that are tailor designed for improved efficacy in females and males with SUD.
Start Date: 2017
End Date: 12-2021
Amount: $388,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2019
End Date: 2021
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 10-2022
End Date: 09-2025
Amount: $434,301.00
Funder: Australian Research Council
View Funded Activity