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

项目摘要 识别和追求潜在回报以及检测和避免潜在威胁的障碍， 精神疾病的核心要素，往往同时存在于一个人身上。然而，神经生物学 这些损伤的潜在机制，以及每个领域中涉及的神经生物学是否不同， 与此相关的，在很大程度上仍然未知。在啮齿类动物中，慢性压力会引起奖励和威胁处理的变化， 但这些变化的神经基础，以及它们如何相互作用，还没有得到解决。最近我们 实验室发展了两种自然主义的“接近/回避”范式，其中潜在的奖励和潜在的 威胁同时呈现，导致接近奖励和回避动机之间的冲突 威胁这些范例是一个理想的设置，以测试慢性压力如何影响奖励的做法，威胁 避免，以及两者之间的互动。我们发现中脑多巴胺的一个独特群体 在这些范例中，投射到纹状体（TS）尾部的神经元促进威胁回避。在过去的工作中， 我们已经广泛地描述了投射到腹侧纹状体（VS）的中脑多巴胺神经元的特征， 对奖励的反应和条件反射的基础，补充工作表明，这一人群促进了 奖励方法。这些不同的多巴胺能群体如何受到慢性应激的影响，以及这是否 解释压力引起的奖励方式和威胁回避的变化，是一个悬而未决的问题。 有趣的是，我们的初步数据表明，不同的慢性压力源会改变奖励接近/威胁。 以独特的方式逃避行为。我假设这些行为上的改变是由 VS投射和TS投射多巴胺神经元之间的活动平衡。目标1将描述 不同的慢性压力源如何影响接近/回避行为，使用机器学习方法 DeepLabCut和MoSeq以细粒度，数据驱动的方式进行这项调查。Aim 2a将探索 VS投射和TS投射多巴胺神经元对接近/回避行为的贡献， 这些子系统相互作用，在健康小鼠中产生行为决定， 子系统或另一种解释应激小鼠行为改变的机制。Aim 2b将测试光遗传学是否 操纵VS投射或TS投射多巴胺神经元足以恢复接近/回避 行为在应激小鼠中的范围在健康对照中可见。这项工作的翻译含义是 显著应激后奖赏和威胁处理的改变是否涉及不同的多巴胺能神经元 子回路具有相反的行为效应，治疗可能是最有效的，当针对特定的 这是一个特定的行为表现下的子回路，而不是普遍改变多巴胺信号。

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.