Despite the increased prevalence of major depressive disorder (MDD) and the continued investment into identifying effective cures, most treatments merely alleviate symptoms rather than addressing causes. Long-term treatments are generally required for this disease and often include many side-effects. The onset of depression is often precipitated by stressful and/or aversive stimuli. Animals, too, are susceptible to the effects of stress. For example, repeated social defeat stress in rodents induces pervasive and long-lasting behavioral changes similar to the symptoms seen in patients with MDD including impaired social interaction, lack of motivation, helplessness and anhedonia. While the behavioral changes associated with depression have been well-studied, there is relatively little knowledge about the accompanying changes in the neural circuitry. Thus, we will anatomically and functionally dissect the distinct neural circuits mediating social stress-induced behaviors in mice to better understand the mechanistic changes in the brain accompanying MDD in human patients, which will help to devise revolutionary circuit-specific and stage-specific diagnosis and treatments. To accomplish this, we will examine the neural circuit mechanism of ventral pallidum (VP), one of the major components of reward circuitry, underlying depressive behaviors elicited by repeated social defeat stress in combination with a variety techniques to address circuit-level mechanisms, including optogenetics, viral mediated tracing, electrophysiology, and real time in vivo fiber photometry. Our preliminary findings showed that parvalbumin-positive (PV) neurons in VP project to different target structures which may be involved in different aspects of depressive behaviors. First, we will anatomically define the efferent connections of VP PV neurons. Second, we will define projection specific roles of VP PV neurons in depressive behaviors induced by repeated social defeat stress using optogenetics and viral tracing methods. Third, using ex vivo electrophysiology analysis we will examine the circuit-specific electrophysiological and synaptic changes induced by the stress. The accomplishment of the proposed works will be greatly beneficial to both the research and treatment of MDD, and will also provide a fundamental framework for studying mental disorders in circuit-specific manner.

Public Health Relevance

Nearly 5% of adults in the United States are affected by depressive disorder, a neuropsychiatric affliction that comprises a diverse set of symptoms such as the inability to feel pleasure, lack of motivation, changes in appetite and cognitive difficultis. The goal of this proposal is to take advantage of recent technological advances to dissect and identify specific neural circuitry and neural adaptions that underlie depression, with the ultimate goal of contributing to the treatment of this devastating disorder.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Simmons, Janine M
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University of California San Diego
Schools of Arts and Sciences
La Jolla
United States
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Knowland, Daniel; Lilascharoen, Varoth; Pacia, Christopher Pham et al. (2017) Distinct Ventral Pallidal Neural Populations Mediate Separate Symptoms of Depression. Cell 170:284-297.e18
Yoo, Ji Hoon; Zell, Vivien; Wu, Johnathan et al. (2017) Activation of Pedunculopontine Glutamate Neurons Is Reinforcing. J Neurosci 37:38-46