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)
Doctor of Philosophy, Ican School of Medicine at Mount Sinai (2013)
Bachelor of Arts, Columbia University (2008)
Current Research and Scholarly Interests
Background: Autism spectrum disorder (ASD) has prevalence rate of more than 1 in 59, with a strong male predominance. ASDs comprise a heterogenous group of disorders with many documented genetic abnormalities and comorbidities. Nonetheless, there are several core features to ASD, in particular deficits in social interaction, which was first characterized in 1943 by Kanner as “extreme autistic aloneness”. Despite the prevalence of social phenotypes in ASD, the cell types and neural circuit mechanisms that account for these social deficits are largely unknown. Therefore, it is imperative to increase our understanding of the neural circuit mechanisms and physiology underlying social deficits to provide insight into future treatment strategies.
My recent work shows that optogenetic activation of dorsal raphe (DR)-to-nucleus accumbens (NAc) serotonin (5-HT) neurons increases sociability as measured by several assays. Not only was selective activation of this neural circuit sufficient to enhance social behavior, but was also necessary, as inhibiting DR-to-NAc 5-HT neurons decreased sociability. Taken together, these data suggest a fundamental role for DR-to-NAc 5-HT neurons in normal social behavior, and raise the possibility that dysfunction of this pathway may underlie some social deficits observed in ASD. I examined the role of this pathway in sociability using a mouse model of a prevalent copy number variation (CNV) found in ASD, deletion of chromosomal segment 16p11.2. I selectively knocked out a homologous region in DR 5-HT neurons. The resulting decrease in sociability was rescued both through optogenetic release of 5-HT and direct infusion of a selective 5-HT receptor (5-HT1b) agonist into the NAc.
5-HT release in nucleus accumbens rescues social deficits in mouse autism model.
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 DOI 10.1038/s41586-018-0416-4
View details for PubMedID 30089910
Gating of social reward by oxytocin in the ventral tegmental area.
Science (New York, N.Y.)
2017; 357 (6358): 1406–11
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.
2015; 18 (7): 962-964
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
THE HETEROGENEITY OF VENTRAL TEGMENTAL AREA NEURONS: PROJECTION FUNCTIONS IN A MOOD-RELATED CONTEXT
2014; 282: 101–8
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
Enhancing Depression Mechanisms in Midbrain Dopamine Neurons Achieves Homeostatic Resilience
2014; 344 (6181): 313–19
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
2014; 17 (1): 27-29
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
2013; 493 (7433): 532-?
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
Midbrain circuit regulation of individual alcohol drinking behaviors in mice
2017; 8: 2220
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
2016; 80 (6): 469–78
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
2016; 534 (7609): 688-?
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
2016; 7: 11671
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
Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors
2014; 17 (12): 1720–27
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
2014; 14 (9): 1007-1017
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
Reinforcement-Related Regulation of AMPA Glutamate Receptor Subunits in the Ventral Tegmental Area Enhances Motivation for Cocaine
JOURNAL OF NEUROSCIENCE
2011; 31 (21): 7927-7937
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
2010; 30 (49): 16453–58
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 μg) or DK-AH 269 (0.6 μg) 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