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

项目总结/摘要 根据定义，抑郁症是一种基本的偶发性精神疾病， 期间，在明显的健康时期之间插入。神经生物学机制驱动 随着时间的推移，抑郁发作的诱导、缓解和复发还没有得到很好的理解，特别是在 在电路水平，但汇聚的证据表明，突触重塑在前额叶皮层（PFC）电路 扮演着重要的角色。尽管在这一领域进行了几十年的开创性工作， 突触后树突棘重塑如何导致PFC电路功能和抑郁症的变化- 随着时间的推移相关的行为仍然难以捉摸。迄今为止，大多数研究都依赖于横截面比较， 在单个时间点固定组织中的棘密度，模糊了对棘形成的动态影响， 稳定化和修剪-不同的过程，对确定新的治疗目标有不同的影响。 压力如何影响女性前额叶皮层的动态脊柱重塑过程也不清楚， 事实上，性是与压力有关的精神疾病的一个关键风险因素。也许最重要的是， 脊柱重塑是否引起或仅仅与特定的行为改变和功能改变相关， PFC电路未知。本研究将探讨压力诱导的前额叶皮层脊柱重塑 会导致快感缺失，这是抑郁症的核心特征。PFC电路通过以下方式支持奖励寻求行为： 调解行动估值计算，其中整合了有关预期行动规模的信息， 利用新开发的光遗传学和2 P成像技术， 可视化和操纵脊柱动力学和定义其对电路功能的影响的方法，我们将 研究拓扑学定义的投射神经元亚型中的脊柱重塑如何有助于 快感缺失行为状态的诱导、缓解和复发。我们将使用两次打击压力模型， 由此，早期生活应激（ELS）诱导对HPA轴的应激敏感性提高和性别特异性效应， 在成年期的反应，成像PFC投射神经元之前和之后的慢性应激和纵向 在恢复过程中。奖励寻求行为将在2 P成像兼容的动作评估任务中量化， 我们可以独立地操纵预期的奖励大小和预期的努力。我们将测试 假设压力通过选择性地消除树突棘和破坏行为评价， PFC投射中的多细胞系综活动在编码奖励预测线索中起着关键作用。 接下来，我们将测试药理学和基于电路的策略，以促进压力恢复和恢复。

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.