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

项目摘要/摘要 根据定义，抑郁症是一种以离散症状为特征的精神疾病的基本形式 明显的健康时期之间的间歇期。神经生物学机制推动了 随着时间的推移，抑郁发作的诱导、缓解和复发还不是很清楚，特别是在 在电路水平，但聚合证据表明，前额叶皮质(PFC)电路中的突触重构 扮演着重要的角色。尽管如此，尽管在这一领域进行了数十年的开创性工作，但对 突触后树突棘重塑如何导致PFC回路功能改变和抑郁- 随着时间的推移，相关行为仍然难以捉摸。到目前为止，大多数研究都依赖于横断面比较 在单个时间点固定组织中的脊柱密度，掩盖了对脊柱形成的动态影响， 稳定和修剪-不同的过程，对确定新的治疗目标有不同的影响。 压力如何影响女性PFC的动态脊柱重塑过程也不清楚，尽管 性行为是压力相关精神障碍的关键风险因素。也许最重要的是， 脊柱重塑是否导致或仅仅与特定的行为改变和功能改变相关 PFC电路未知。这项建议将调查应激诱导的前额叶脊椎重塑 导致快感缺失，这是抑郁症的一个核心特征。PFC电路通过以下方式支持奖励行为 调解行动估值计算，其中整合了有关预期的 奖励和获得它所需的预期努力。利用新开发的光遗传和2P成像 可视化和操纵脊柱动力学并定义其对电路功能的影响的方法，我们将 研究在拓扑学上定义的投射神经元亚型中的脊柱重塑如何在 无快感行为状态的诱导、缓解和复发。我们将使用两次击打的压力模型， 早期生活应激(ELS)导致HPA轴的应激敏感性和性别特异性影响 慢性应激前后PFC投射神经元的成年期反应性及纵向成像 在康复期间。寻求奖励的行为将在2P成像兼容的动作评估任务中被量化， 我们可以独立地操纵预期奖励的大小和预期的努力。我们将测试 应激通过选择性地消除树突棘和破坏 PFC投射中的多细胞集合活动在编码奖赏预测线索方面起着关键作用。 下一步，我们将测试促进压力恢复和恢复的药理学和环路策略。

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.