Lateral habenula circuit in reward/conflict mediation

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Project Summary Reward is often present in risky environments, requiring individuals to weigh the benefits of rewards against the associated risks. There are several psychiatric disorders in which patients are unable to choose an appropriate response during risky reward opportunities. Some patients with addiction disorders are driven to seek reward at the expense of high costs and quality of life detriment, whereas some patients with major depression disorder are often too sensitive to punishment and miss out on reward opportunities. Recent research has shown that the lateral habenula (LHb), the ventral pallidum (VP), and the nucleus accumbens (NAc) are key structures that mediate positive and negative motivation, and a circuit involving these structures may govern conflict behavior. In this proposal, we will investigate the role of cell-type specific NAc-VP-LHb circuits in conflict behavior in mice. We will employ a novel conflict task in which thirsty, freely-behaving mice actively choose between seeking water reward or avoiding punishment from a signaled foot-shock by moving to a safety platform. Because the water port and the safety platform are far apart, mice are posed with a conflict of whether to go for reward or to avoid punishment. We will use optogenetic, chemogenetic and photometry imaging approaches to characterize how cell-type specific projections in an NAc-VP-LHb circuit mediate conflict behavior. Aim 1 (K99), we will characterize the role of LHb in conflict behavior. In Aim 2 (K99), we will characterize the role of VP-LHb circuits in conflict behavior. In Aim 3 (R00), we will characterize the role of Drd1 and Drd2-containing NAc-VP projections in conflict. In the independent phase, we will also characterize the role of NAc afferents, such as the medial prefrontal cortex, the amygdala and the paraventricular thalamus, in the control of conflict behavior. Characterizing circuits controlling conflict behavior will help guide treatment for several psychiatric disorders. Additional to the research program, this proposal includes a training plan to foster development of expertise in 1) cutting-edge genetic tools, such as chemogenetics and fiber photometry; 2) programming languages for data analyses and for running experiments; 3) scientific communication for writing for grants, manuscripts and communicating with non- scientists; 4) responsible conduct of research in the stimulating environment of Cold Spring Harbor Laboratory. Moreover, the Applicant will receive training from his co-mentor in behavioral depression models such as chronic social defeat stress and learned helplessness, will have access to the necessary transgenic mouse lines, and will be exposed to the latest molecular techniques on viral manipulations and transcriptomic analyses in a cell/circuit type specific manner at the co-mentor's laboratory. The training plan is tailored to pave a path for research independence and bolster the scientific capabilities of a highly motivated Applicant.