Investigating the impact of chronic stress on distinct axes of dopamine signaling

点击翻译按钮获取中文摘要

Project Summary Impairments in recognizing and pursuing potential rewards, and detecting and avoiding potential threats, are core elements of psychiatric disease and often both present in a single individual. However, the neurobiological mechanisms underlying these impairments, and whether the neurobiology involved in each domain is distinct or related, remains largely unknown. In rodents, chronic stress induces changes in reward and threat processing, but the neural bases of these changes, and how they interact with one another, are unresolved. Recently, our lab has developed two naturalistic “approach/avoidance” paradigms in which potential reward and potential threat are simultaneously presented, causing a conflict between motivation to approach reward and avoid threat. These paradigms are an ideal setting to test how chronic stress influences reward approach, threat avoidance, and the interaction between the two. We discovered that a distinct population of midbrain dopamine neurons which project to the tail of the striatum (TS) facilitate threat avoidance in these paradigms. In past work, we have extensively characterized that midbrain dopamine neurons which project to the ventral striatum (VS) underlie response to and conditioning for reward, and complementary work suggests this population facilitates reward approach. How these distinct dopaminergic populations are affected by chronic stress, and whether this accounts for stress-induced changes in reward approach and threat avoidance, is an open question. Interestingly, our preliminary data suggests that different chronic stressors shift reward approach/threat avoidance behavior in unique ways. I hypothesize that these changes in behavior are underpinned by changes in the balance of activity between VS-projecting and TS-projecting dopamine neurons. Aim 1 will characterize how varied chronic stressors impact approach/avoidance behavior, using machine learning approaches DeepLabCut and MoSeq to conduct this investigation in a fine-grained, data-driven manner. Aim 2a will explore the contributions of VS-projecting and TS-projecting dopamine neurons to approach/avoidance behavior, how these subsystems interact to produce a behavioral decision in healthy mice, and whether aberrations in one subsystem or another account for altered behavior in stressed mice. Aim 2b will test whether optogenetic manipulations of VS-projecting or TS-projecting dopamine neurons are sufficient to restore approach/avoidance behavior in stressed mice to the range seen in healthy controls. The translational implications of this work are significant. Should alterations in reward and threat processing following stress involve distinct dopaminergic subcircuits with opposing behavioral effects, treatments may be most effective when targeting the specific subcircuit underlying a particular behavioral presentation, rather than changing dopamine signaling universally.