Chronic Stress Effects on Connectivity in a Limbic Circuit

描述(申请人提供)：慢性压力与抑郁症、焦虑症和各种认知缺陷有关。其潜在机制尚不清楚，但被认为涉及边缘脑区树突棘的丧失，部分原因是长期接触糖皮质激素。这些荷尔蒙从肾上腺释放出来，以应对压力，它们也与昼夜节律同步振荡。最近，我们发现糖皮质激素对皮质浅层树突棘重塑有快速而有效的影响。然而，关于应力如何影响这种动态重建，我们知之甚少。 无论是边缘区域的糖皮质激素波动，还是昼夜节律的糖皮质激素波动对其起到了特定的调节作用。应激引起的脊椎变化与边缘回路功能连接性的变化之间的关系也是未知的。该项目的中心假设是，昼夜节律性糖皮质激素振荡通过产生 并稳定新的脊椎，而慢性应激通过破坏这些振荡导致失调的重塑和电路功能障碍。在指导阶段将进行的实验将集中在糖皮质激素活动水平波动的快速影响上。目的1使用延时显微内窥镜，一种新近开发的脑深部结构活体成像工具，评估对下缘皮质树突棘形成和消除的快速影响。Aim 2将测试相应的功能连接，使用光遗传学工具刺激杏仁核向边缘下皮质的投射，同时使用光学电极记录和功能磁共振成像测量诱发活动。独立阶段的研究(目标3)将以这些结果为基础，通过评估长期接触糖皮质激素对脊柱重塑、功能连通性和焦虑的慢性影响。在此过程中，应聘者将精通上述工具的使用，并利用以前使用类似方法的经验。这将在导师和顾问团队(Deisseroth，Schatzberg)的监督下完成。Raichle，De Lecea，Barretto)，他们是这些方法的先驱，并拥有丰富的培训他人使用这些方法的经验。他们在为过渡到独立做好初级调查人员准备方面也有非常成功的记录。我们预计这个项目将产生关于 昼夜节律振荡在糖皮质激素活动中的重要性，特别是对于稳定树突棘和维持边缘回路内的连通性。这一结果也将为未来研究压力和糖皮质激素对健康受试者和临床人群功能连接的影响提供信息。 与公共健康相关：慢性压力可能会引发情绪、焦虑和认知问题。这些症状被认为是长期接触糖皮质激素应激激素的结果。巧合的是，合成的糖皮质激素也是各种神经和自身免疫性疾病的主要治疗方法，但这些治疗方法与认知副作用和对情绪的影响有关，但人们对这些副作用知之甚少。这个项目的主要目的是促进我们对糖皮质激素应激激素如何调节大脑回路中的连接和功能的理解，这些回路在多种神经精神疾病中发挥着核心作用。长期目标是为未来旨在治疗和预防这些疾病的研究提供信息。

DESCRIPTION (provided by applicant): 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 t 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 dendrtic 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. PUBLIC HEALTH RELEVANCE: Chronic stress may precipitate problems with mood, anxiety, and cognition. These symptoms are thought to arise as a consequence of prolonged exposure to glucocorticoid stress hormones. Coincidentally, synthetic glucocorticoids are also mainstays of treatment for a variety of neurological and autoimmune diseases, but these treatments have been linked to cognitive side effects and effects on mood that are poorly understood. The main objective of this project is to advance our understanding of how glucocorticoid stress hormones regulate connectivity and function in brain circuits that play a central role in multiple neuropsychiatric diseases. The long-term goal is to inform future studies aimed at treating and prevent these disorders.