Bio

Bio

My career in neuroscience spans 17 years of work in diverse areas of the mental health field. There is a clear trajectory of my commitment to investigating mental health disorders seen from the various positions have that led to my current stage. My training has endowed me with a strong skill set for interrogating neurobiological systems. In addition, conducting research in numerous distinct settings has left me with a well-developed scientific philosophy, and a nuanced understanding of different mental health disorders, ranging from Alzheimer?s disease, to Depression, to Autism Spectrum Disorder, all of which are complex brain disorders with severe public health implications.

Honors & Awards

  • Sammy Kuo Award in Neuroscience, Stanford University (2018)
  • Ruth L. Kirschstein National Research Service for Individual Postdoctoral Fellows, National Institute of Mental Health, Bethesda, Maryland (2014)

Contact

Publications

All Publications

  • Loss of the neural-specific BAF subunit ACTL6B relieves repression of early response genes and causes recessive autism. Proceedings of the National Academy of Sciences of the United States of America Wenderski, W., Wang, L., Krokhotin, A., Walsh, J. J., Li, H., Shoji, H., Ghosh, S., George, R. D., Miller, E. L., Elias, L., Gillespie, M. A., Son, E. Y., Staahl, B. T., Baek, S. T., Stanley, V., Moncada, C., Shipony, Z., Linker, S. B., Marchetto, M. C., Gage, F. H., Chen, D., Sultan, T., Zaki, M. S., Ranish, J. A., Miyakawa, T., Luo, L., Malenka, R. C., Crabtree, G. R., Gleeson, J. G. 2020

    Abstract

    Synaptic activity in neurons leads to the rapid activation of genes involved in mammalian behavior. ATP-dependent chromatin remodelers such as the BAF complex contribute to these responses and are generally thought to activate transcription. However, the mechanisms keeping such "early activation" genes silent have been a mystery. In the course of investigating Mendelian recessive autism, we identified six families with segregating loss-of-function mutations in the neuronal BAF (nBAF) subunit ACTL6B (originally named BAF53b). Accordingly, ACTL6B was the most significantly mutated gene in the Simons Recessive Autism Cohort. At least 14 subunits of the nBAF complex are mutated in autism, collectively making it a major contributor to autism spectrum disorder (ASD). Patient mutations destabilized ACTL6B protein in neurons and rerouted dendrites to the wrong glomerulus in the fly olfactory system. Humans and mice lacking ACTL6B showed corpus callosum hypoplasia, indicating a conserved role for ACTL6B in facilitating neural connectivity. Actl6b knockout mice on two genetic backgrounds exhibited ASD-related behaviors, including social and memory impairments, repetitive behaviors, and hyperactivity. Surprisingly, mutation of Actl6b relieved repression of early response genes including AP1 transcription factors (Fos, Fosl2, Fosb, and Junb), increased chromatin accessibility at AP1 binding sites, and transcriptional changes in late response genes associated with early response transcription factor activity. ACTL6B loss is thus an important cause of recessive ASD, with impaired neuron-specific chromatin repression indicated as a potential mechanism.

    View details for DOI 10.1073/pnas.1908238117

    View details for PubMedID 32312822

  • Distinct neural mechanisms for the prosocial and rewarding properties of MDMA. Science translational medicine Heifets, B. D., Salgado, J. S., Taylor, M. D., Hoerbelt, P. n., Cardozo Pinto, D. F., Steinberg, E. E., Walsh, J. J., Sze, J. Y., Malenka, R. C. 2019; 11 (522)

    Abstract

    The extensively abused recreational drug (±)3,4-methylenedioxymethamphetamine (MDMA) has shown promise as an adjunct to psychotherapy for treatment-resistant psychiatric disease. It is unknown, however, whether the mechanisms underlying its prosocial therapeutic effects and abuse potential are distinct. We modeled both the prosocial and nonsocial drug reward of MDMA in mice and investigated the mechanism of these processes using brain region-specific pharmacology, transgenic manipulations, electrophysiology, and in vivo calcium imaging. We demonstrate in mice that MDMA acting at the serotonin transporter within the nucleus accumbens is necessary and sufficient for MDMA's prosocial effect. MDMA's acute rewarding properties, in contrast, require dopaminergic signaling. MDMA's prosocial effect requires 5-HT1b receptor activation and is mimicked by d-fenfluramine, a selective serotonin-releasing compound. By dissociating the mechanisms of MDMA's prosocial effects from its addictive properties, we provide evidence for a conserved neuronal pathway, which can be leveraged to develop novel therapeutics with limited abuse liability.

    View details for DOI 10.1126/scitranslmed.aaw6435

    View details for PubMedID 31826983

  • 5-HT release in nucleus accumbens rescues social deficits in mouse autism model. Nature Walsh, J. J., Christoffel, D. J., Heifets, B. D., Ben-Dor, G. A., Selimbeyoglu, A., Hung, L. W., Deisseroth, K., Malenka, R. C. 2018

    Abstract

    Dysfunction in prosocial interactions is a core symptom of autism spectrum disorder. However, the neural mechanisms that underlie sociability are poorly understood, limiting the rational development of therapies to treat social deficits. Here we show in mice that bidirectional modulation of the release of serotonin (5-HT) from dorsal raphe neurons in the nucleus accumbens bidirectionally modifies sociability. In a mouse model of a common genetic cause of autism spectrum disorder-a copy number variation on chromosome 16p11.2-genetic deletion of the syntenic region from 5-HT neurons induces deficits in social behaviour and decreases dorsal raphe 5-HT neuronal activity. These sociability deficits can be rescued by optogenetic activation of dorsal raphe 5-HT neurons, an effect requiring and mimicked by activation of 5-HT1b receptors in the nucleus accumbens. These results demonstrate an unexpected role for 5-HT action in the nucleus accumbens in social behaviours, and suggest that targeting this mechanism may prove therapeutically beneficial.

    View details for PubMedID 30089910

  • Gating of social reward by oxytocin in the ventral tegmental area. Science (New York, N.Y.) Hung, L. W., Neuner, S. n., Polepalli, J. S., Beier, K. T., Wright, M. n., Walsh, J. J., Lewis, E. M., Luo, L. n., Deisseroth, K. n., Dölen, G. n., Malenka, R. C. 2017; 357 (6358): 1406?11

    Abstract

    The reward generated by social interactions is critical for promoting prosocial behaviors. Here we present evidence that oxytocin (OXT) release in the ventral tegmental area (VTA), a key node of the brain's reward circuitry, is necessary to elicit social reward. During social interactions, activity in paraventricular nucleus (PVN) OXT neurons increased. Direct activation of these neurons in the PVN or their terminals in the VTA enhanced prosocial behaviors. Conversely, inhibition of PVN OXT axon terminals in the VTA decreased social interactions. OXT increased excitatory drive onto reward-specific VTA dopamine (DA) neurons. These results demonstrate that OXT promotes prosocial behavior through direct effects on VTA DA neurons, thus providing mechanistic insight into how social interactions can generate rewarding experiences.

    View details for PubMedID 28963257

  • Excitatory transmission at thalamo-striatal synapses mediates susceptibility to social stress. Nature neuroscience Christoffel, D. J., Golden, S. A., Walsh, J. J., Guise, K. G., Heshmati, M., Friedman, A. K., Dey, A., Smith, M., Rebusi, N., Pfau, M., Ables, J. L., Aleyasin, H., Khibnik, L. A., Hodes, G. E., Ben-Dor, G. A., Deisseroth, K., Shapiro, M. L., Malenka, R. C., Ibanez-Tallon, I., Han, M., Russo, S. J. 2015; 18 (7): 962-964

    Abstract

    Postsynaptic remodeling of glutamatergic synapses on ventral striatum (vSTR) medium spiny neurons (MSNs) is critical for shaping stress responses. However, it is unclear which presynaptic inputs are involved. Susceptible mice exhibited increased synaptic strength at intralaminar thalamus (ILT), but not prefrontal cortex (PFC), inputs to vSTR MSNs following chronic social stress. Modulation of ILT-vSTR versus PFC-vSTR neuronal activity differentially regulated dendritic spine plasticity and social avoidance.

    View details for DOI 10.1038/nn.4034

    View details for PubMedID 26030846

    View details for PubMedCentralID PMC4482771

  • Enhancing Depression Mechanisms in Midbrain Dopamine Neurons Achieves Homeostatic Resilience SCIENCE Friedman, A. K., Walsh, J. J., Juarez, B., Ku, S. M., Chaudhury, D., Wang, J., Li, X., Dietz, D. M., Pan, N., Vialou, V. F., Neve, R. L., Yue, Z., Han, M. 2014; 344 (6181): 313?19

    Abstract

    Typical therapies try to reverse pathogenic mechanisms. Here, we describe treatment effects achieved by enhancing depression-causing mechanisms in ventral tegmental area (VTA) dopamine (DA) neurons. In a social defeat stress model of depression, depressed (susceptible) mice display hyperactivity of VTA DA neurons, caused by an up-regulated hyperpolarization-activated current (I(h)). Mice resilient to social defeat stress, however, exhibit stable normal firing of these neurons. Unexpectedly, resilient mice had an even larger I(h), which was observed in parallel with increased potassium (K(+)) channel currents. Experimentally further enhancing Ih or optogenetically increasing the hyperactivity of VTA DA neurons in susceptible mice completely reversed depression-related behaviors, an antidepressant effect achieved through resilience-like, projection-specific homeostatic plasticity. These results indicate a potential therapeutic path of promoting natural resilience for depression treatment.

    View details for DOI 10.1126/science.1249240

    View details for Web of Science ID 000334474500040

    View details for PubMedID 24744379

    View details for PubMedCentralID PMC4334447

  • Stress and CRF gate neural activation of BDNF in the mesolimbic reward pathway NATURE NEUROSCIENCE Walsh, J. J., Friedman, A. K., Sun, H., Heller, E. A., Ku, S. M., Juarez, B., Burnham, V. L., Mazei-Robison, M. S., Ferguson, D., Golden, S. A., Koo, J. W., Chaudhury, D., Christoffe, D. J., Pomeranz, L., Friedman, J. M., Russo, S. J., Nestler, E. J., Han, M. 2014; 17 (1): 27-29

    Abstract

    Mechanisms controlling release of brain-derived neurotrophic factor (BDNF) in the mesolimbic dopamine reward pathway remain unknown. We report that phasic optogenetic activation of this pathway increases BDNF amounts in the nucleus accumbens (NAc) of socially stressed mice but not of stress-naive mice. This stress gating of BDNF signaling is mediated by corticotrophin-releasing factor (CRF) acting in the NAc. These results unravel a stress context-detecting function of the brain's mesolimbic circuit.

    View details for DOI 10.1038/nn.3591

    View details for Web of Science ID 000329080000009

    View details for PubMedID 24270188

    View details for PubMedCentralID PMC3984932

  • Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons NATURE Chaudhury, D., Walsh, J. J., Friedman, A. K., Juarez, B., Ku, S. M., Koo, J. W., Ferguson, D., Tsai, H., Pomeranz, L., Christoffel, D. J., Nectow, A. R., Ekstrand, M., Domingos, A., Mazei-Robison, M. S., Mouzon, E., Lobo, M. K., Neve, R. L., Friedman, J. M., Russo, S. J., Deisseroth, K., Nestler, E. J., Han, M. 2013; 493 (7433): 532-?

    Abstract

    Ventral tegmental area (VTA) dopamine neurons in the brain's reward circuit have a crucial role in mediating stress responses, including determining susceptibility versus resilience to social-stress-induced behavioural abnormalities. VTA dopamine neurons show two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing. Phasic firing of the neurons, which is well known to encode reward signals, is upregulated by repeated social-defeat stress, a highly validated mouse model of depression. Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no apparent change in firing rate in resilient individuals. However, direct evidence--in real time--linking dopamine neuron phasic firing in promoting the susceptible (depression-like) phenotype is lacking. Here we took advantage of the temporal precision and cell-type and projection-pathway specificity of optogenetics to show that enhanced phasic firing of these neurons mediates susceptibility to social-defeat stress in freely behaving mice. We show that optogenetic induction of phasic, but not tonic, firing in VTA dopamine neurons of mice undergoing a subthreshold social-defeat paradigm rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference. Optogenetic phasic stimulation of these neurons also quickly induced a susceptible phenotype in previously resilient mice that had been subjected to repeated social-defeat stress. Furthermore, we show differences in projection-pathway specificity in promoting stress susceptibility: phasic activation of VTA neurons projecting to the nucleus accumbens (NAc), but not to the medial prefrontal cortex (mPFC), induced susceptibility to social-defeat stress. Conversely, optogenetic inhibition of the VTA-NAc projection induced resilience, whereas inhibition of the VTA-mPFC projection promoted susceptibility. Overall, these studies reveal novel firing-pattern- and neural-circuit-specific mechanisms of depression.

    View details for DOI 10.1038/nature11713

    View details for Web of Science ID 000313871400038

    View details for PubMedID 23235832

    View details for PubMedCentralID PMC3554860

  • Role of vascular risk factors and vascular dysfunction in Alzheimer's disease. The Mount Sinai journal of medicine, New York Dickstein, D. L., Walsh, J. n., Brautigam, H. n., Stockton, S. D., Gandy, S. n., Hof, P. R. ; 77 (1): 82?102

    Abstract

    Recent findings indicate that vascular risk factors and neurovascular dysfunction play integral roles in the pathogenesis of Alzheimer's disease. In addition to aging, the most common risk factors for Alzheimer's disease are apolipoprotein e4 allele, hypertension, hypotension, diabetes, and hypercholesterolemia. All of these can be characterized by vascular pathology attributed to conditions such as cerebral amyloid angiopathy and subsequent blood-brain barrier dysfunction. Many epidemiological, clinical, and pharmacotherapeutic studies have assessed the associations between such risk factors and Alzheimer's disease and have found positive associations between hypertension, hypotension, and diabetes mellitus. However, there are still many conflicting results from these population-based studies, and they should be interpreted carefully. Recognition of these factors and the mechanisms by which they contribute to Alzheimer's disease will be beneficial in the current treatment regimens for Alzheimer's disease and in the development of future therapies. Here we discuss vascular factors with respect to Alzheimer's disease and dementia and review the factors that give rise to vascular dysfunction and contribute to Alzheimer's disease.

    View details for PubMedID 20101718

    View details for PubMedCentralID PMC2918901

  • Midbrain circuit regulation of individual alcohol drinking behaviors in mice NATURE COMMUNICATIONS Juarez, B., Morel, C., Ku, S. M., Liu, Y., Zhang, H., Montgomery, S., Gregoire, H., Ribeiro, E., Crumiller, M., Roman-Ortiz, C., Walsh, J. J., Jackson, K., Croote, D. E., Zhu, Y., Zhang, S., Vendruscolo, L. F., Edward, S., Roberts, A., Hodes, G. E., Lu, Y., Calipari, E. S., Chaudhury, D., Friedman, A. K., Han, M. 2017; 8: 2220

    Abstract

    Alcohol-use disorder (AUD) is the most prevalent substance-use disorder worldwide. There is substantial individual variability in alcohol drinking behaviors in the population, the neural circuit mechanisms of which remain elusive. Utilizing in vivo electrophysiological techniques, we find that low alcohol drinking (LAD) mice have dramatically higher ventral tegmental area (VTA) dopamine neuron firing and burst activity. Unexpectedly, VTA dopamine neuron activity in high alcohol drinking (HAD) mice does not differ from alcohol naive mice. Optogenetically enhancing VTA dopamine neuron burst activity in HAD mice decreases alcohol drinking behaviors. Circuit-specific recordings reveal that spontaneous activity of nucleus accumbens-projecting VTA (VTA-NAc) neurons is selectively higher in LAD mice. Specifically activating this projection is sufficient to reduce alcohol consumption in HAD mice. Furthermore, we uncover ionic and cellular mechanisms that suggest unique neuroadaptations between the alcohol drinking groups. Together, these data identify a neural circuit responsible for individual alcohol drinking behaviors.

    View details for DOI 10.1038/s41467-017-02365-8

    View details for Web of Science ID 000418566800016

    View details for PubMedID 29263389

    View details for PubMedCentralID PMC5738419

  • Essential Role of Mesolimbic Brain-Derived Neurotrophic Factor in Chronic Social Stress-Induced Depressive Behaviors BIOLOGICAL PSYCHIATRY Koo, J., Labonte, B., Engmann, O., Calipari, E. S., Juarez, B., Lorsch, Z., Walsh, J. J., Friedman, A. K., Yorgason, J. T., Han, M., Nestler, E. J. 2016; 80 (6): 469?78

    Abstract

    Previous work has shown that chronic social defeat stress (CSDS) induces increased phasic firing of ventral tegmental area (VTA) dopamine (DA) neurons that project to the nucleus accumbens (NAc) selectively in mice that are susceptible to the deleterious effects of the stress. In addition, acute optogenetic phasic stimulation of these neurons promotes susceptibility in animals exposed to acute defeat stress. These findings are paradoxical, as increased DA signaling in NAc normally promotes motivation and reward, and the influence of chronic phasic VTA firing in the face of chronic stress is unknown.We used CSDS with repeated optogenetic activation and pharmacologic manipulations of the mesolimbic VTA-NAc pathway to examine the role of brain-derived neurotrophic factor (BDNF) and DA signaling in depressive-like behaviors. We measured BDNF protein expression and DA release in this model.Pharmacologic blockade of BDNF-tyrosine receptor kinase B (TrkB) signaling, but not DA signaling, in NAc prevented CSDS-induced behavioral abnormalities. Chronic optogenetic phasic stimulation of the VTA-NAc circuit during CSDS exacerbated the defeat-induced behavioral symptoms, and these aggravated symptoms were also normalized by BDNF-TrkB blockade in NAc. The aggravated behavioral deficits induced by phasic stimulation of the VTA-NAc pathway were blocked as well by local knockdown of BDNF in VTA.These findings show that BDNF-TrkB signaling, rather than DA signaling, in the VTA-NAc circuit is crucial for facilitating depressive-like outcomes after CSDS and they establish BDNF-TrkB signaling as a pathologic mechanism during periods of chronic stress.

    View details for DOI 10.1016/j.biopsych.2015.12.009

    View details for Web of Science ID 000382260500013

    View details for PubMedID 26858215

    View details for PubMedCentralID PMC4909591

  • Basal forebrain projections to the lateral habenula modulate aggression reward NATURE Golden, S. A., Heshmati, M., Flanigan, M., Christoffel, D. J., Guise, K., Pfau, M. L., Aleyasin, H., Menard, C., Zhang, H., Hodes, G. E., Bregman, D., Khibnik, L., Tai, J., Rebusi, N., Krawitz, B., Chaudhury, D., Walsh, J. J., Han, M., Shapiro, M. L., Russo, S. J. 2016; 534 (7609): 688-?

    Abstract

    Maladaptive aggressive behaviour is associated with a number of neuropsychiatric disorders and is thought to result partly from the inappropriate activation of brain reward systems in response to aggressive or violent social stimuli. Nuclei within the ventromedial hypothalamus, extended amygdala and limbic circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behaviour. Here we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors develop a CPP, whereas non-aggressors develop a conditioned place aversion to the intruder-paired context. Furthermore, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF-lHb terminals of aggressors with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF-lHb terminals of non-aggressors with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Finally, we show that altering inhibitory transmission at BF-lHb terminals does not control the initiation of aggressive behaviour. These results demonstrate that the BF-lHb circuit has a critical role in regulating the valence of inter-male aggressive behaviour and provide novel mechanistic insight into the neural circuits modulating aggression reward processing.

    View details for DOI 10.1038/nature18601

    View details for Web of Science ID 000378676000037

    View details for PubMedID 27357796

    View details for PubMedCentralID PMC4930107

  • KCNQ channel openers reverse depressive symptoms via an active resilience mechanism NATURE COMMUNICATIONS Friedman, A. K., Juarez, B., Ku, S. M., Zhang, H., Calizo, R. C., Walsh, J. J., Chaudhury, D., Zhang, S., Hawkins, A., Dietz, D. M., Murrough, J. W., Ribadeneira, M., Wong, E. H., Neve, R. L., Han, M. 2016; 7: 11671

    Abstract

    Less than half of patients suffering from major depressive disorder, a leading cause of disability worldwide, achieve remission with current antidepressants, making it imperative to develop more effective treatment. A new therapeutic direction is emerging from the increased understanding of natural resilience as an active stress-coping process. It is known that potassium (K(+)) channels in the ventral tegmental area (VTA) are an active mediator of resilience. However, no druggable targets have been identified to potentiate active resilience mechanisms. In the chronic social defeat stress model of depression, we report that KCNQ-type K(+) channel openers, including FDA-approved drug retigabine (ezogabine), show antidepressant efficacy. We demonstrate that overexpression of KCNQ channels in the VTA dopaminergic neurons and either local infusion or systemic administration of retigabine normalized neuronal hyperactivity and depressive behaviours. These findings identify KCNQ as a target for conceptually novel antidepressants that function through the potentiation of active resilience mechanisms.

    View details for DOI 10.1038/ncomms11671

    View details for Web of Science ID 000376616700001

    View details for PubMedID 27216573

    View details for PubMedCentralID PMC4890180

  • THE HETEROGENEITY OF VENTRAL TEGMENTAL AREA NEURONS: PROJECTION FUNCTIONS IN A MOOD-RELATED CONTEXT NEUROSCIENCE Walsh, J. J., Han, M. H. 2014; 282: 101?8

    Abstract

    The ventral tegmental area (VTA) in the brain's reward circuitry is composed of a heterogeneous population of dopamine, GABA, and glutamate neurons that play important roles in mediating mood-related functions including depression. These neurons project to different brain regions, including the nucleus accumbens (NAc), the medial prefrontal cortex (mPFC), and the amygdala. The functional understanding of these projection pathways has been improved since the extensive use of advanced techniques such as viral-mediated gene transfer, cell-type-specific neurophysiology and circuit-probing optogenetics. In this article, we will discuss the recent progress in understanding these VTA projection-specific functions, focusing on mood-related disorders.

    View details for DOI 10.1016/j.neuroscience.2014.06.006

    View details for Web of Science ID 000345512600008

    View details for PubMedID 24931766

    View details for PubMedCentralID PMC4339667

  • Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors NATURE NEUROSCIENCE Heller, E. A., Cates, H. M., Pena, C. J., Sun, H., Shao, N., Feng, J., Golden, S. A., Herman, J. P., Walsh, J. J., Mazei-Robison, M., Ferguson, D., Knight, S., Gerber, M. A., Nievera, C., Han, M., Russo, S. J., Tamminga, C. S., Neve, R. L., Shen, L., Zhang, H., Zhang, F., Nestler, E. J. 2014; 17 (12): 1720?27

    Abstract

    Chronic exposure to drugs of abuse or stress regulates transcription factors, chromatin-modifying enzymes and histone post-translational modifications in discrete brain regions. Given the promiscuity of the enzymes involved, it has not yet been possible to obtain direct causal evidence to implicate the regulation of transcription and consequent behavioral plasticity by chromatin remodeling that occurs at a single gene. We investigated the mechanism linking chromatin dynamics to neurobiological phenomena by applying engineered transcription factors to selectively modify chromatin at a specific mouse gene in vivo. We found that histone methylation or acetylation at the Fosb locus in nucleus accumbens, a brain reward region, was sufficient to control drug- and stress-evoked transcriptional and behavioral responses via interactions with the endogenous transcriptional machinery. This approach allowed us to relate the epigenetic landscape at a given gene directly to regulation of its expression and to its subsequent effects on reward behavior.

    View details for DOI 10.1038/nn.3871

    View details for Web of Science ID 000345484000019

    View details for PubMedID 25347353

    View details for PubMedCentralID PMC4241193

  • Light and chemical control of neuronal circuits: possible applications in neurotherapy. Expert review of neurotherapeutics Whittle, A. J., Walsh, J., de Lecea, L. 2014; 14 (9): 1007-1017

    Abstract

    Millions of people worldwide suffer from diseases that result from a failure of central pathways to regulate behavioral and physiological processes. Advances in genetics and pharmacology have already allowed us to appreciate that rather than this dysregulation being systemic throughout the brain, it is usually rooted in specific subsets of dysfunctional cells within discrete neurological circuits. This article discusses the advent of opto- and chemogenetic tools and how they are providing the means to dissect these circuits with a degree of temporal and spatial sensitivity not previously possible. We also highlight the potential applications for treating disease and the key developments likely to have the greatest impact over the next 5 years.

    View details for DOI 10.1586/14737175.2014.948850

    View details for PubMedID 25115180

  • Amyloid precursor protein (APP) regulates synaptic structure and function MOLECULAR AND CELLULAR NEUROSCIENCE Tyan, S., Shih, A., Walsh, J. J., Maruyama, H., Sarsoza, F., Ku, L., Eggert, S., Hof, P. R., Koo, E. H., Dickstein, D. L. 2012; 51 (1-2): 43?52

    Abstract

    The amyloid precursor protein (APP) plays a critical role in Alzheimer's disease (AD) pathogenesis. APP is proteolytically cleaved by ?- and ?-secretases to generate the amyloid ?-protein (A?), the core protein component of senile plaques in AD. It is also cleaved by ?-secretase to release the large soluble APP (sAPP) luminal domain that has been shown to exhibit trophic properties. Increasing evidence points to the development of synaptic deficits and dendritic spine loss prior to deposition of amyloid in transgenic mouse models that overexpress APP and A? peptides. The consequence of loss of APP, however, is unsettled. In this study, we investigated whether APP itself plays a role in regulating synaptic structure and function using an APP knock-out (APP-/-) mouse model. We examined dendritic spines in primary cultures of hippocampal neurons and CA1 neurons of hippocampus from APP-/- mice. In the cultured neurons, there was a significant decrease (~35%) in spine density in neurons derived from APP-/- mice compared to littermate control neurons that were partially restored with sAPP?-conditioned medium. In APP-/- mice in vivo, spine numbers were also significantly reduced but by a smaller magnitude (~15%). Furthermore, apical dendritic length and dendritic arborization were markedly diminished in hippocampal neurons. These abnormalities in neuronal morphology were accompanied by reduction in long-term potentiation. Strikingly, all these changes in vivo were only seen in mice that were 12-15 months in age but not in younger animals. We propose that APP, specifically sAPP, is necessary for the maintenance of dendritic integrity in the hippocampus in an age-associated manner. Finally, these age-related changes may contribute to AD pathology independent of A?-mediated synaptic toxicity.

    View details for DOI 10.1016/j.mcn.2012.07.009

    View details for Web of Science ID 000309374100005

    View details for PubMedID 22884903

    View details for PubMedCentralID PMC3538857

  • Deletion of the amyloid precursor-like protein 2 (APLP2) does not affect hippocampal neuron morphology or function MOLECULAR AND CELLULAR NEUROSCIENCE Midthune, B., Tyan, S., Walsh, J. J., Sarsoza, F., Eggert, S., Hof, P. R., Dickstein, D. L., Koo, E. H. 2012; 49 (4): 448?55

    Abstract

    Amyloid precursor protein (APP), the parent molecule to amyloid ? peptide, is part of a larger gene family with two mammalian homologues, amyloid precursor-like protein 1 (APLP1) and amyloid precursor-like protein 2 (APLP2). Initial knock-out studies demonstrated that while single APP family gene deletions produced relatively mild phenotypes, deficiency of APLP2 and one other member of the gene family resulted in perinatal lethality, suggesting vital roles masked by functional redundancy of the other homologues. Because of the importance of APP in Alzheimer's disease, the vast majority of studies to date have concentrated on the neuronal functions of APP, leaving limited data on its homologues. APLP2 is of particular interest as it contains high sequence homology with APP, is processed similarly, is expressed in overlapping spatial and temporal patterns, and is obligatory for lethality when combined with deficiency of either APLP1 or APP but does not contain the toxic amyloid ? sequence. Here we sought to test the role of APLP2 on neuronal structure and function using a combined approach involving in vitro and in vivo techniques in young and aged animals. Surprisingly, we found that unlike APP, APLP2 appears not to be essential for maintenance of dendritic structure, spine density, or synaptic function. Thus, there is clear divergence in the functional redundancy between APP and APLP2.

    View details for DOI 10.1016/j.mcn.2012.02.001

    View details for Web of Science ID 000304492800007

    View details for PubMedID 22353605

    View details for PubMedCentralID PMC3348437

  • Reinforcement-Related Regulation of AMPA Glutamate Receptor Subunits in the Ventral Tegmental Area Enhances Motivation for Cocaine JOURNAL OF NEUROSCIENCE Choi, K. H., Edwards, S., Graham, D. L., Larson, E. B., Whisler, K. N., Simmons, D., Friedman, A. K., Walsh, J. J., Rahman, Z., Monteggia, L. M., Eisch, A. J., Neve, R. L., Nestler, E. J., Han, M., Self, D. W. 2011; 31 (21): 7927-7937

    Abstract

    Chronic cocaine use produces numerous biological changes in brain, but relatively few are functionally associated with cocaine reinforcement. Here we show that daily intravenous cocaine self-administration, but not passive cocaine administration, induces dynamic upregulation of the AMPA glutamate receptor subunits GluR1 and GluR2 in the ventral tegmental area (VTA) of rats. Increases in GluR1 protein and GluR1(S845) phosphorylation are associated with increased GluR1 mRNA in self-administering animals, whereas increased GluR2 protein levels occurred despite substantial decreases in GluR2 mRNA. We investigated the functional significance of GluR1 upregulation in the VTA on cocaine self-administration using localized viral-mediated gene transfer. Overexpression of GluR1(WT) in rat VTA primarily infected dopamine neurons (75%) and increased AMPA receptor-mediated membrane rectification in these neurons with AMPA application. Similar GluR1(WT) overexpression potentiated locomotor responses to intra-VTA AMPA, but not NMDA, infusions. In cocaine self-administering animals, overexpression of GluR1(WT) in the VTA markedly increased the motivation for cocaine injections on a progressive ratio schedule of cocaine reinforcement. In contrast, overexpression of protein kinase A-resistant GluR1(S845A) in the VTA reduced peak rates of cocaine self-administration on a fixed ratio reinforcement schedule. Neither viral vector altered sucrose self-administration, and overexpression of GluR1(WT) or GluR1(S845A) in the adjacent substantia nigra had no effect on cocaine self-administration. Together, these results suggest that dynamic regulation of AMPA receptors in the VTA during cocaine self-administration contributes to cocaine addiction by acting to facilitate subsequent cocaine use.

    View details for DOI 10.1523/JNEUROSCI.6014-10.2011

    View details for Web of Science ID 000290956400036

    View details for PubMedID 21613507

    View details for PubMedCentralID PMC3103081

  • Mesolimbic Dopamine Neurons in the Brain Reward Circuit Mediate Susceptibility to Social Defeat and Antidepressant Action JOURNAL OF NEUROSCIENCE Cao, J., Covington, H. E., Friedman, A. K., Wilkinson, M. B., Walsh, J. J., Cooper, D. C., Nestler, E. J., Han, M. 2010; 30 (49): 16453?58

    Abstract

    We previously reported that the activity of mesolimbic dopamine neurons of the ventral tegmental area (VTA) is a key determinant of behavioral susceptibility vs resilience to chronic social defeat stress. However, this was based solely on ex vivo measurements, and the in vivo firing properties of VTA dopamine neurons in susceptible and resilient mice, as well as the effects of antidepressant treatments, remain completely unknown. Here, we show that chronic (10 d) social defeat stress significantly increased the in vivo spontaneous firing rates and bursting events in susceptible mice but not in the resilient subgroup. Both the firing rates and bursting events were significantly negatively correlated with social avoidance behavior, a key behavioral abnormality induced by chronic social defeat stress. Moreover, the increased firing rates, bursting events, and avoidance behavior in susceptible mice were completely reversed by chronic (2 week), but not acute (single dose), treatments with the antidepressant medication fluoxetine (20 mg/kg). Chronic social defeat stress increased hyperpolarization-activated cation current (I(h)) in VTA dopamine neurons, an effect that was also normalized by chronic treatment with fluoxetine. As well, local infusion of I(h) inhibitors ZD7288 (0.1 ?g) or DK-AH 269 (0.6 ?g) into the VTA exerted antidepressant-like behavioral effects. Together, these data suggest that the firing patterns of mesolimbic dopamine neurons in vivo mediate an individual's responses to chronic stress and antidepressant action.

    View details for DOI 10.1523/JNEUROSCI.3177-10.2010

    View details for Web of Science ID 000285089100006

    View details for PubMedID 21147984

    View details for PubMedCentralID PMC3061337

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