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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要识别和追求潜在回报以及检测和避免潜在威胁方面的障碍然而，精神疾病的核心要素通常同时存在于单个个体中。这些损伤背后的机制，以及每个领域涉及的神经生物学是否不同或相关的，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，最近我们还没有解决。实验室开发了两种自然主义的“接近/回避”范式，其中潜在奖励和潜在威胁同时出现，导致奖励动机与回避动机之间的冲突这些范式是测试长期压力如何影响奖励方法、威胁的理想环境。我们发现中脑多巴胺的独特群体。在过去的工作中，投射到纹状体（TS）尾部的神经元有助于避免威胁。我们主要表征了投射到腹侧纹状体（VS）的中脑多巴胺神经元是对奖励的反应和调节的基础，补充工作表明这个群体促进这些不同的多巴胺能人群如何受到慢性压力的影响，以及这是否会影响奖励方法。解释压力引起的奖励方法和威胁避免的变化是一个悬而未决的问题。暗示，我们的初步数据表明不同的慢性压力源会改变奖励方法/威胁我努力以独特的方式回避行为，因为这些行为的变化是由变化支撑的。 VS 投射和 TS 投射多巴胺神经元之间的活动平衡是目标 1 的特征。使用机器学习方法了解各种慢性压力源如何影响接近/回避行为 DeepLabCut 和 MoSeq 将以细粒度、数据驱动的方式进行这项调查，Aim 2a 将进行探索。 VS 投射和 TS 投射多巴胺神经元对接近/回避行为的贡献，如何这些子系统相互作用，在健康小鼠中产生行为决策，以及其中一个子系统是否出现异常。子系统或其他解释应激小鼠行为改变的方法，Aim 2b 将测试光遗传学是否有效。 VS 投射或 TS 投射多巴胺神经元的操作足以恢复接近/回避应激小鼠的行为与健康对照组的范围一致。这项工作的转化意义是压力后奖励和威胁处理的变化是否涉及明显的多巴胺能。由于子电路具有相反的行为效应，因此针对特定的治疗可能是最有效的子电路是特定行为表现的基础，而不是普遍改变多巴胺信号传导。