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。目标导向的行动，依赖于预期的 考虑潜在的结果和后果，以及习惯，没有执行的反射行为 预见到了后果。过度依赖习惯会导致适应不良的强迫行为， 以物质使用障碍和其他精神疾病为特征。压力是一个主要的诱发因素 物质使用障碍，也可能导致过度依赖习惯。然而，我们对大脑的理解 缺乏压力影响习惯的机制，限制了我们对压力如何促进 物质使用障碍中的适应不良强迫行为因此，本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，是负责 控制目标导向的行动。抑制背内侧纹状体，特别是Drd 1+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），占大多数 抑制核，被认为是大脑中应激反应的枢纽。直到最近，人们还认为 CeA和背侧纹状体没有直接联系。然而，现代追踪技术已经揭示了 这两个区域之间的投射，我发现偏向背内侧纹状体。 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， 关于厌恶性刺激的信息。这让我产生了一个有趣的假设， 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的背景下， 压力增强的习惯形成。我将使用多方面的尖端方法来实现这一目标 神经科学技术在老鼠身上在目标1中，我将应用在体内纤维光度成像和光遗传学 在一个复杂的行为范式，以确定时间动态和充分的操纵 中央杏仁核-纹状体投射在应激后控制习惯中的作用在目标2中，我将揭示内源性 在习性形成过程中背内侧Drd 1+纹状体系综的活动动力学以及这种活动是如何改变的 的压力和不同的情况下，CeA输入使用化学遗传学。调查结果将提供一个 在正常情况下和压力暴露后对习惯形成的机械理解。这将 促进未来的工作到这种现象的分子和细胞机制，并服务于我的目标， 改进药物使用障碍和其他与压力有关的疾病的治疗方法。 我将在加州大学洛杉矶分校的Wassum实验室进行这个项目，在一个出色的指导团队的指导下。 这种环境将为我提供系统和行为方面的特殊智力和技术培训 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充分准备。