Chronic Stress Effects on Connectivity in a Limbic Circuit

项目摘要 慢性压力与抑郁症、焦虑症和各种认知缺陷有关。的 其潜在机制知之甚少，但被认为涉及边缘脑中树突棘的缺失 部分由长时间暴露于糖皮质激素介导的区域。这些激素是从 肾上腺对压力的反应，它们也与昼夜节律同步振荡。最近， 我们已经发现糖皮质激素对表皮细胞树突棘重塑有快速和有效的作用， 皮层尽管如此，人们对压力如何影响边缘系统区域的动态重塑过程知之甚少， 昼夜糖皮质激素振荡是否在调节它中发挥任何特定的作用。 棘的变化可能与边缘系统回路中功能连接的变化有关，这也是未知的。的 该项目的中心假设是昼夜糖皮质激素振荡调节突触重塑， 边缘回路通过产生和稳定新的棘，慢性压力导致失调， 重塑和电路功能障碍。试验期间进行的试验 指导阶段将侧重于糖皮质激素活性水平振荡的快速效应。目标1将评估 使用时间推移对边缘下皮层中树突棘形成和消除的快速影响 显微内窥镜是最近开发的用于脑深部结构体内成像的工具。目标2将测试 对应功能连接，使用光遗传学工具刺激杏仁核投射， 利用光电极记录和功能磁共振测量边缘下皮层诱发活动 显像在独立阶段（目标3）的研究将通过评估慢性 长期糖皮质激素暴露对脊柱重塑、功能连接和焦虑的影响。 在此过程中，候选人将熟练使用上述工具， 有类似方法的经验。这将在导师团队的监督下完成 和顾问（Deisseroth，Schatzberg. Raichle，de Lecea，Barretto）是这些方法的先驱， 有丰富的经验来训练他人使用它们。他们也有非常成功的记录，在准备 初级调查员向独立过渡。我们预计，该项目将产生新的见解 关于昼夜节律振荡在糖皮质激素活性中的重要性，特别是对于稳定树突状细胞， 保持边缘回路的连通性研究结果还将为未来的研究工作提供信息。 应激和糖皮质激素对健康受试者和临床人群功能连接的影响。

Project Summary Chronic stress has been implicated in depression, anxiety disorders, and various cognitive deficits. The underlying mechanisms are poorly understood but are thought to involve dendritic spine loss in limbic brain areas mediated in part by prolonged exposure to glucocorticoids. These hormones are released from the adrenal gland in response to stress, and they also oscillate in synchrony with the circadian rhythm. Recently, we have shown that glucocorticoids have rapid and potent effects on dendritic spine remodeling in superficial cortex. Still, very little is known about how stress affects this dynamic remodeling process in limbic areas or whether circadian glucocorticoid oscillations play any specific role in regulating it. How stress-induced changes in spines may relate to changes in functional connectivity in limbic circuitry is also unknown. The central hypothesis of this project is that circadian glucocorticoid oscillations regulate synaptic remodeling in limbic circuits by generating and stabilizing new spines, and that chronic stress leads to dysregulated remodeling and circuit dysfunction by disrupting these oscillations. Experiments to be conducted during the mentored phase will focus on the rapid effects of oscillating levels of glucocorticoid activity. Aim 1 will evaluate rapid effects on dendritic spine formation and elimination in infralimbic cortex using time-lapse microendoscopy, a recently developed tool for in vivo imaging of deep brain structures. Aim 2 will test for corresponding on functional connectivity, using optogenetic tools to stimulate amygdala projections to infralimbic cortex while measuring evoked activity using optrode recordings and functional magnetic resonance imaging. Research during the independent phase (Aim 3) will build on these results by evaluating the chronic effects of prolonged glucocorticoid exposure on spine remodeling, functional connectivity, and anxiety. In the process, the candidate will become proficient in the use of the tools described above, leveraging prior experience with similar methods. This will be accomplished under the supervision of a team of mentors and consultants (Deisseroth, Schatzberg. Raichle, de Lecea, Barretto) who pioneered these methods and have extensive experience training others to use them. They also have highly successful track records in preparing junior investigators for the transition to independence. We anticipate that this project will yield novel insights regarding the importance of circadian oscillations in glucocorticoid activity, particularly for stabilizing dendritic spines and preserving connectivity within limbic circuits. The results will also inform future efforts to study stress and glucocorticoid effects on functional connectivity in healthy human subjects and clinical populations.