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

研究慢性压力对多巴胺信号传导不同轴的影响

• 批准号: 10825107
• 负责人: Isobel Wouk Green
• 金额: $ 3.7万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2026-09-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10825107
• 关键词: Affect; Anhedonia; Animals; Anxiety Disorders; Automobile Driving; Behavior; Behavioral; Chronic; Chronic stress; Conflict (Psychology); Corpus striatum structure; Data; Detection; Distress; Dopamine; Elements; Equilibrium; Food; Goals; Grain; Human; Impairment; Individual; Investigation; Laboratories; Learning; Life; Literature; Machine Learning; Maps; Mediating; Mental disorders; Midbrain structure; Monsters; Mood Disorders; Motivation; Mus; Natural Disasters; Neurobiology; Play; Population; Post-Traumatic Stress Disorders; Process; Psychotic Disorders; Resolution; Rewards; Rodent; Role; Shelter facility; Signal Transduction; Social Interaction; Stress; Sucrose; Symptoms; Tail; Techniques; Testing; Theft; Variant; Ventral Striatum; Work; approach behavior; avoidance behavior; base; behavioral response; biological adaptation to stress; brain circuitry; cohort; conditioning; dopaminergic neuron; neural; neurobehavioral; neurobiological mechanism; novel; optogenetics; preference; response; stressor; tool

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.

项目摘要 承认和追求潜在奖励以及发现和避免潜在威胁的障碍是 精神病的核心元素，通常都存在于一个人中。但是，神经生物学 这些障碍的基础机制以及每个领域涉及的神经生物学是不同的还是 相关，仍然是未知的。在啮齿动物中，慢性压力会导致奖励和威胁处理的变化， 但是，这些变化的神经底座以及它们之间的相互作用方式尚未解决。最近，我们的 实验室已经开发了两个自然主义的“方法/避免”范式，其中潜在的奖励和潜在 简单地提出威胁，导致动机接近奖励与避免 威胁。这些范式是测试慢性压力如何影响奖励方法，威胁的理想场所 回避和两者之间的相互作用。我们发现中脑多巴胺的独特人群 投射到纹状体（TS）尾部的神经元有助于在这些范式中避免威胁。在过去的工作中 我们已经广泛地表征了将腹侧纹状体投射的中脑多巴胺神经元（VS） 对奖励的回应和条件的基础，补充工作表明这一人口有助于 奖励方法。这些独特的多巴胺能种群如何受到慢性压力的影响，以及这是否是否 一个悬而未决的问题是压力引起的奖励方法变化和避免威胁的变化。 有趣的是，我们的初步数据表明，不同的慢性压力源转移奖励方法/威胁 以独特的方式回避行为。我假设行为上的这些变化是由变化的基础 在VS项目和TS射击多巴胺神经元之间的活性平衡中。 AIM 1将表征 使用机器学习方法，多样化的慢性压力源如何影响方法/回避行为 DeepLabcut和Moseq以细粒度，数据驱动的方式进行这项投资。 AIM 2A将探索 VS项目和TS-Projecting多巴胺神经元对接近/回避行为的贡献，如何 这些子系统相互作用以在健康小鼠中产生行为决策，以及是否存在 子系统或另一个解释了压力小鼠行为的改变。 AIM 2B将测试是否光遗传学 对vs项目的操纵或TS射击多巴胺神经元足以恢复方法/避免 压力小鼠在健康对照中看到的范围。这项工作的翻译含义是 重要的。压力下的奖励和威胁处理的改变应涉及不同的多巴胺能 具有相反行为影响的亚电路，靶向特定的治疗可能最有效 在特定行为呈现的基础上的子电路，而不是普遍改变多巴胺信号。