Anxiety disorders are the most common psychiatric illness afflicting 273 million people worldwide. The symptoms of anxiety disorders are highly complex and the causes are poorly understood. Additionally, a substantial number of patients suffering from anxiety disorders also present with depressive-like symptoms, which make the diagnosis and treatment even more complicated. In this project, we propose to utilize the repeated social defeat stress (RSDS) model that induces anxiety or mixed anxiety/depression phenotypes in separate subgroups of mice to investigate neural mechanisms regulating these behaviors. Following RSDS, mice are separated into two subgroups based on their social interaction test behavior: profound avoidance-displaying mice (susceptible) and non-avoidance-displaying mice (resilient). While susceptible mice display several depression-related behaviors, including social avoidance, anhedonia and despair, these depressive abnormalities are absent in resilient mice. However, RSDS induces severe anxiety behaviors in both susceptible and resilient mice. Thus, in this project, we label them as anxiety/depression (A/D) and anxiety (A) subgroups. An increasing number of studies have implicated the role of mesocorticolimbic ventral tegmental area (VTA) dopamine (DA) reward circuitry in anxiety and depression. Utilizing neural circuit-probing techniques, we previously observed that maladaptive firing activity occurred in the VTA DA neurons projecting to the medial prefront cortex (VTA-mPFC) and VTA DA neurons projecting to the nucleus accumbens (VTA-NAc) selectively in A/D mice (depression-susceptible mice), but not in the A-mice (the depression-resilient group). Our optogenetic studies further demonstrated the causal link between the firing maladaptations in these circuits and depression-related behaviors. However, we strikingly found that the firing activity of VTA neurons projecting to the amygdala (VTA-Amg) was dramatically decreased in both A/D- and A-mice. Based on these unexpected preliminary findings, our central hypothesis is that the VTA-Amg circuit may play a crucial role in mediating the anxiety-like behaviors observed in both A/D- and A-mice following RSDS. To test this, we propose two Specific Aims: (a) to investigate the pathological alterations of VTA-Amg DA circuit neurons in A/D- and A-male and female mice by use of ex vivo brain slice preparation and in vivo optrode recordings from intact animals; and (b) to determine the functional role of VTA-Amg DA neurons in mediating RSDS-induced anxiety behaviors by optogenetically manipulating these circuits in male and female mice. By utilizing these cell type- and circuit-specific electrophysiological and optogenetic techniques, we will determine if a causal relationship exists between the neuronal activity of VTA-Amg DA circuit and anxiety-related behaviors.

Public Health Relevance

Anxiety disorders and major depressive disorder arise from different causes with individual behaviors and symptoms, but substantial patients with anxiety disorders often experience symptoms similar to those in depression. It is known that the rodent model repeated social defeat stress induces anxious-depressed and anxious-only subpopulations, which provides the unique opportunity to explore the neural mechanisms underlying the anxiety behavioral symptoms, and to investigate potential drug targets for these conditions.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MDCN-P (57)R)
Program Officer
Simmons, Janine M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
Zip Code
Ribeiro, Efrain A; Salery, Marine; Scarpa, Joseph R et al. (2018) Transcriptional and physiological adaptations in nucleus accumbens somatostatin interneurons that regulate behavioral responses to cocaine. Nat Commun 9:3149
Zhang, Song; Zhang, Hongxing; Ku, Stacy M et al. (2018) Sex Differences in the Neuroadaptations of Reward-related Circuits in Response to Subchronic Variable Stress. Neuroscience 376:108-116
Tan, Aaron; Costi, Sara; Morris, Laurel S et al. (2018) Effects of the KCNQ channel opener ezogabine on functional connectivity of the ventral striatum and clinical symptoms in patients with major depressive disorder. Mol Psychiatry :
Zhang, Hongxing; Chaudhury, Dipesh; Nectow, Alexander R et al. (2018) ?1- and ?3-Adrenergic Receptor-Mediated Mesolimbic Homeostatic Plasticity Confers Resilience to Social Stress in Susceptible Mice. Biol Psychiatry :
Guzman, Daniel; Carreira, Maria B; Friedman, Allyson K et al. (2018) Inactivation of NMDA Receptors in the Ventral Tegmental Area during Cocaine Self-Administration Prevents GluA1 Upregulation but with Paradoxical Increases in Cocaine-Seeking Behavior. J Neurosci 38:575-585
Morel, Carole; Montgomery, Sarah; Han, Ming-Hu (2018) Nicotine and alcohol: the role of midbrain dopaminergic neurons in drug reinforcement. Eur J Neurosci :
Wang, Jun; Hodes, Georgia E; Zhang, Hongxing et al. (2018) Epigenetic modulation of inflammation and synaptic plasticity promotes resilience against stress in mice. Nat Commun 9:477
Juarez, Barbara; Morel, Carole; Ku, Stacy M et al. (2017) Midbrain circuit regulation of individual alcohol drinking behaviors in mice. Nat Commun 8:2220
Ku, Stacy M; Han, Ming-Hu (2017) HCN Channel Targets for Novel Antidepressant Treatment. Neurotherapeutics 14:698-715
Calipari, Erin S; Juarez, Barbara; Morel, Carole et al. (2017) Dopaminergic dynamics underlying sex-specific cocaine reward. Nat Commun 8:13877

Showing the most recent 10 out of 19 publications