Major depressive disorder (MDD) is a chronic and life-threatening illness, afflicting over 10% of the adult population in the United States. However nearly 40% of MDD patients are treatment resistant. The lack of universally effective antidepressant treatments may be due to our incomplete understanding of the brain regions responsible for mediating depression. Studies with preclinical animal models of depression and brain imaging of human patients have implicated the mesocorticolimbic ventral tegmental area (VTA) reward circuitry, which has been understudied in depression. Recent studies have implicated VTA hyperactivity in mediating susceptibility to depression-related behaviors in chronic social defeat stress, a well-established animal model of depression. Further research is required to fully characterize the mechanisms by which stress induces pathological alterations in the VTA at the level of neural circuitry. Our preliminary studies focusing on the lateral hypothalamus (LH) input to the VTA (LH-VTA) indicate that LH-VTA hyperactivity mediates susceptibility. Mimicking the increase in firing activity of LH-VTA neurons by the use of photostimulation with optogenetics, an approach that can increase neuronal activity through light-sensitive channels in behaving animals, induces depression-like behaviors. In addition, our preliminary work indicates that LH-released hypocretin (orexin), a neuropeptide known to regulate reward, arousal and wakefulness, may mediate the VTA neuron responses to social defeat stress. In this proposal, I will use in vivo and in vitro electrophysiology and optogenetic approaches to investigate whether there are pathophysiological alterations in VTA neuron subpopulations induced by LH-VTA photostimulation, as well as how hypocretin regulates VTA neuron subpopulations in social defeat stress. These studies will provide insight into the role of LH-VTA neural circuitry in depression and reveal novel targets for antidepressant development.

Public Health Relevance

Depression is one of the most common and costly brain diseases that is characterized by insufficient therapeutic strategies and an incomplete understanding of the brain regions responsible for depression pathology. This proposal will explore the role of the two brain regions, the lateral hypothalamus and ventral tegmental area, in regulating social avoidance and depression-like behaviors in a rodent chronic stress model. The proposed studies will provide insight into the role of neural circuits in depression and inform more effective therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31MH108326-02
Application #
9233753
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Driscoll, Jamie
Project Start
2016-02-22
Project End
2018-02-21
Budget Start
2017-02-22
Budget End
2018-02-21
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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
Ku, Stacy M; Han, Ming-Hu (2017) HCN Channel Targets for Novel Antidepressant Treatment. Neurotherapeutics 14:698-715
Juarez, Barbara; Morel, Carole; Ku, Stacy M et al. (2017) Midbrain circuit regulation of individual alcohol drinking behaviors in mice. Nat Commun 8:2220
von Schimmelmann, Melanie; Feinberg, Philip A; Sullivan, Josefa M et al. (2016) Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration. Nat Neurosci 19:1321-30
Friedman, Allyson K; Juarez, Barbara; Ku, Stacy M et al. (2016) KCNQ channel openers reverse depressive symptoms via an active resilience mechanism. Nat Commun 7:11671
Vialou, Vincent; Bagot, Rosemary C; Cahill, Michael E et al. (2014) Prefrontal cortical circuit for depression- and anxiety-related behaviors mediated by cholecystokinin: role of ?FosB. J Neurosci 34:3878-87
Walsh, Jessica J; Friedman, Allyson K; Sun, Haosheng et al. (2014) Stress and CRF gate neural activation of BDNF in the mesolimbic reward pathway. Nat Neurosci 17:27-9
Friedman, Allyson K; Walsh, Jessica J; Juarez, Barbara et al. (2014) Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience. Science 344:313-9
Chaudhury, Dipesh; Walsh, Jessica J; Friedman, Allyson K et al. (2013) Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 493:532-6
Vialou, Vincent; Feng, Jian; Robison, Alfred J et al. (2012) Serum response factor and cAMP response element binding protein are both required for cocaine induction of ?FosB. J Neurosci 32:7577-84