Examining the neuronal mechanisms underlying stress-accelerated habit

检查压力加速习惯背后的神经机制

• 批准号: 10463492
• 负责人: Jacqueline Giovanniello
• 金额: $ 4.9万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10463492
• 关键词: Acceleration; Amygdaloid structure; Animals; Aversive Stimulus; Basal Ganglia; Behavior; Behavior Control; Behavioral; Behavioral Paradigm; Biological; Brain; Calcium; Cell Nucleus; Chronic stress; Compulsive Behavior; Control Animal; Corpus striatum structure; Data; Data Analyses; Decision Making; Desire for food; Dorsal; Environment; Equilibrium; Evaluation; Fiber; Foundations; Future; Goals; Growth; Habits; Human; Image; Individual; Lead; Learning; Mental disorders; Mentors; Modernization; Molecular; Mus; Neurobiology; Neurodegenerative Disorders; Neurons; Neurosciences; Operant Conditioning; Outcome; Pathologic; Pathway interactions; Photometry; Physiological; Predisposing Factor; Process; Reflex action; Research; Resolution; Rewards; Role; Stress; Substance Use Disorder; System; Techniques; Testing; Training; Work; addiction; career; cell type; comorbidity; experience; habit learning; improved; in vivo; in vivo calcium imaging; insight; neuromechanism; novel; optogenetics; prevent; prospective; recruit; stress state; substance use treatment

The brain has two strategies for behavioral control. Goal-directed actions which rely on prospective consideration of potential outcomes and consequences, and habits, reflexive behaviors executed without forethought of their consequences. Overreliance on habit causes maladaptive compulsive behavior that characterizes substance use disorder and other psychiatric conditions. Stress is a major predisposing factor to substance use disorder and can also cause an overreliance on habit. However, our understanding of the brain mechanisms by which stress influences habits is lacking, limiting our understanding of how stress promotes maladaptive compulsive behavior in substance use disorder. Therefore, the broad goal of this project is to reveal the neuronal mechanisms by which stress promotes habit formation. Accumulating evidence suggests that the dorsomedial striatum, part of the basal ganglia, is responsible for controlling goal-directed actions. Inhibition of the dorsomedial striatum, particularly Drd1+ direct pathway neurons, disrupts goal-directed control, resulting in a bias toward habits. The central amygdala (CeA), a majority inhibitory nucleus, is known to be a hub for stress-responsivity in the brain. Until recently, it was thought that the CeA and dorsal striatum are not directly connected. However, modern tracing techniques have revealed direct projections between these two regions, which I have found are biased towards the dorsomedial striatum. Interestingly, in my graduate work I discovered that CeA projections to other parts of the basal ganglia convey information about aversive stimuli. This led me to the intriguing hypothesis that amygdala-striatal projections convey information about stress to block goal-directed actions, biasing behavior toward habits. Through the proposed research I will reveal the mechanistic role of central amygdala-striatal projections in the context of stress-potentiated habit formation. I will accomplish this using a multifaceted approach of cutting-edge neuroscience techniques in mice. In Aim 1, I will apply in vivo fiber photometry imaging and optogenetic manipulation during a sophisticated behavioral paradigm to determine the temporal dynamics and sufficiency of central amygdala-striatal projections in controlling habits after stress. In Aim 2, I will reveal the endogenous activity dynamics of dorsomedial Drd1+ striatal ensembles during habit formation and how this activity is altered by stress and differs in the absence of CeA input using chemogenetics. The resulting findings will provide a mechanistic understanding of habit formation in both the normal context and after stress exposure. This will facilitate future work into the molecular and cellular mechanisms of this phenomenon and serve my goal of improving treatment approaches for substance use disorder and other stress-related conditions. I will conduct this project in the Wassum Lab at UCLA, with the guidance of a remarkable mentoring team. This environment will provide me with exceptional intellectual and technical training in systems and behavioral neuroscience, fully preparing me for an independent research career studying the role of stress in addiction.

大脑有两种行为控制策略。依靠前瞻性的目标导向行动 考虑潜在的结果和后果，以及习惯，在没有执行的情况下执行的反射行为 预见到它们的后果。过度依赖习惯会导致适应不良的强迫行为 其特征是物质使用障碍和其他精神疾病。压力是主要诱发因素 物质使用障碍，也可能导致过度依赖习惯。然而，我们对大脑的了解 缺乏压力影响习惯的机制，限制了我们对压力如何促进习惯的理解 物质使用障碍中的适应不良强迫行为。因此，该项目的总体目标是揭示 压力促进习惯形成的神经机制。 越来越多的证据表明，背内侧纹状体（基底神经节的一部分）负责 控制目标导向的行动。抑制背内侧纹状体，特别是 Drd1+ 直接通路 神经元，破坏目标导向的控制，导致对习惯的偏见。中央杏仁核 (CeA) 众所周知，抑制核是大脑中压力反应的枢纽。直到最近，人们还认为 CeA 和背侧纹状体不直接相连。然而，现代追踪技术已经直接揭示了 我发现这两个区域之间的投影偏向背内侧纹状体。 有趣的是，在我的研究生工作中，我发现 CeA 投射到基底神经节的其他部分传达了 有关厌恶刺激的信息。这让我想到了一个有趣的假设：杏仁核纹状体投射 传达有关压力的信息，以阻止目标导向的行动，使行为偏向习惯。通过 拟议的研究我将揭示中央杏仁核纹状体投射的机制作用 压力增强的习惯形成。我将使用尖端的多方面方法来实现这一目标 小鼠神经科学技术。在目标1中，我将应用体内光纤光度成像和光遗传学 在复杂的行为范式中进行操纵，以确定时间动态和充分性 中央杏仁核纹状体投射在压力后控制习惯。在目标 2 中，我将揭示内生性 习惯形成过程中背内侧 Drd1+ 纹状体群的活动动态以及这种活动是如何改变的 受应激影响，并且在没有 CeA 输入的情况下使用化学遗传学有所不同。由此产生的结果将提供 对正常情况下和压力暴露后习惯形成的机械理解。这将 促进未来对这种现象的分子和细胞机制的研究，并服务于我的目标 改进药物滥用障碍和其他压力相关疾病的治疗方法。 我将在加州大学洛杉矶分校的 Wassum 实验室中，在出色的指导团队的指导下开展这个项目。 这种环境将为我提供系统和行为方面卓越的智力和技术培训 神经科学，为我从事研究压力在成瘾中的作用的独立研究生涯做好了充分的准备。