Regulation of prefrontal cortical circuit function and reward-seeking behavior by stress-induced dendritic spine remodeling

通过压力诱导的树突棘重塑调节前额皮质回路功能和寻求奖励行为

• 批准号: 10054105
• 负责人: Conor M Liston
• 金额: $ 58.51万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-20 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054105
• 关键词: Adult; Affect; Anhedonia; Antidepressive Agents; Area; Automobile Driving; Behavior; Behavioral; Brain; Calcium; Cells; Chronic stress; Cues; Dendritic Spines; Disease remission; Dose; Female; Genetic; Image; Intervention; Ketamine; Maintenance; Mediating; Mental Depression; Mental disorders; Modeling; Molecular Target; Moods; Neurons; Nucleus Accumbens; Optics; Pharmacology; Play; Process; Pyramidal Cells; Recovery; Recurrence; Regulation; Rewards; Risk Factors; Role; Shapes; Signal Pathway; Stress; Synapses; Testing; Thalamic structure; Theoretical model; Time; Tissues; Vertebral column; Work; base; density; depressive symptoms; early life stress; high reward; hypothalamic-pituitary-adrenal axis; imaging modality; neurobiological mechanism; optogenetics; postsynaptic; restoration; sex; stress resilience; synaptogenesis; tool

Project Summary / Abstract Depression is by definition a fundamentally episodic form of mental illness featuring discrete symptomatic periods, interposed between periods of apparent wellness. The neurobiological mechanisms driving the induction, remission, and recurrence of depressive episodes over time are not well understood, especially at the circuit level, but converging evidence indicates that synaptic remodeling in prefrontal cortical (PFC) circuits plays an important role. Still, despite decades of pioneering work in this area, a mechanistic understanding of how postsynaptic dendritic spine remodeling contributes to changes in PFC circuit function and depression- related behaviors over time remains elusive. To date, most studies have relied on cross-sectional comparisons of spine density in fixed tissue at a single time point, obscuring dynamic effects on spine formation, stabilization, and pruning—distinct processes with differing implications for identifying new treatment targets. How stress affects dynamic spine remodeling processes differently in the female PFC is also unclear, despite the fact that sex is a critical risk factor for stress-related psychiatric disorders. Perhaps most importantly, whether spine remodeling causes or merely correlates with behavioral changes and altered function in specific PFC circuits is unknown. This proposal will investigate how stress-induced spine remodeling in the PFC contributes to anhedonia, a core feature of depression. PFC circuits support reward-seeking behavior by mediating action valuation computations, which integrate information about the magnitude of an anticipated reward and the expected effort required to obtain it. Leveraging newly developed optogenetic and 2P imaging methods for visualizing and manipulating spine dynamics and defining their effects on circuit function, we will investigate how spine remodeling in topologically defined projection neuron subtypes contributes to the induction, remission, and recurrence of anhedonic behavioral states. We will use a two-hit stress model, whereby early life stress (ELS) induces heightened stress sensitivity and sex-specific effects on HPA axis reactivity in adulthood, imaging PFC projection neurons before and after chronic stress and longitudinally during recovery. Reward-seeking behavior will be quantified in a 2P imaging-compatible action valuation task, in which we can independently manipulate anticipated reward magnitude and expected effort. We will test the hypothesis that stress disrupts action valuation by selectively eliminating dendritic spines and disrupting multicellular ensemble activity in PFC projections that play a critical role in encoding reward predictive cues. Next, we will test pharmacological and circuit-based strategies for promoting stress resilience and recovery.

项目摘要 /摘要 深度默认是一种基本的情节形式的精神疾病，具有离散性的精神疾病 周期，在明显的健康期之间插入。 随着时间的推移，depisode发作的指示，缓解，缓解和复发尚不清楚，尤其是在 电路水平，但融合的证据表明，在额叶皮质（PFC）电路中进行突触重塑 尽管在这一领域进行了数十年的开创性工作，但仍发挥着重要的作用 突触后树突状脊柱重塑了PFC电路功能和深度变化的贡献 随着时间的流逝，相关行为仍然难以捉摸。 固定组织中脊柱密度在一个时间点上，掩盖了对脊柱形成的动态影响， 稳定和提出的 - 不同的过程，对识别新的治疗靶标有不同的影响。 在女性PFC中，压力如何影响动态脊柱重塑过程也不清楚，尽管 性行为是与压力有关的精神疾病的关键风险因素。 脊柱重塑是否导致或仅与行为变化和特定的功能变化相关 PFC电路尚不清楚。 由于深度而导致Anhedonia，这是DEP的核心特征。 中介行动估值计算，该计算整合了有关预期的大小的信息 奖励和获得新开发的光遗传学和2P成像所需的预期努力 可视化和操纵脊柱动力学并防御其对电路功能的影响的方法，我们将 研究拓扑定义的投影神经元亚型中的脊柱重塑如何有助于 表明Anhedonic行为状态的指示，缓解和复发。 生命早期应力（ELS）在HPA轴上诱导压力敏感性和斑点 成年后的反应性，在前和慢性应激和纵向应激之前成像PFC投影神经元 在恢复期间，奖励行为将在2p成像兼容的行动估值任务中进行量化 我们可以独立操纵预期的奖励幅度和预期的工作。 假设通过有选择地消除树突旋转并破坏压力纪律行动估值 PFC预测中的多细胞合奏活动在编码奖励预测提示中起着至关重要的作用。 接下来，我们将测试基于药理和电路的静脉曲张，以促进压力弹性和恢复。