Chronic Stress Effects on Connectivity in a Limbic Circuit

慢性压力对边缘回路连接的影响

• 批准号: 8353522
• 负责人: Conor M Liston
• 金额: $ 10.47万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8353522
• 关键词: Acute; Adrenal Glands; Adverse effects; Affect; Amygdaloid structure; Anxiety; Anxiety Disorders; Area; Atrophic; Autoimmune Diseases; Behavioral; Brain; Chronic; Chronic stress; Circadian Rhythms; Clinical; Cognition; Cognitive; Cognitive deficits; Dendritic Spines; Development; Disease; Exposure to; Feedback; Functional Magnetic Resonance Imaging; Functional disorder; Future; Glucocorticoids; Goals; Hormones; Hour; Image; Influentials; Lead; Link; Measures; Medial; Mediating; Memory; Mental Depression; Mentors; Methods; Modeling; Moods; Morphology; Phase; Plastics; Play; Population; Prefrontal Cortex; Process; Pyramidal Cells; Records; Research; Research Personnel; Rest; Role; Speed; Stress; Structure; Supervision; Symptoms; Synapses; Synaptic plasticity; Techniques; Testing; Time; Training; Vertebral column; experience; frontal lobe; functional disability; human subject; in vivo; insight; nervous system disorder; neuropsychiatry; novel; optogenetics; prevent; research study; response; stressor; time use; tissue fixing; tool

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.

描述（由申请人提供）：慢性压力与抑郁、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域的树突棘损失，部分是由长期暴露于糖皮质激素介导的。这些激素是肾上腺因压力而释放的，它们也与昼夜节律同步振荡。最近，我们发现糖皮质激素对浅表皮质的树突棘重塑具有快速而有效的作用。尽管如此，人们对压力如何影响这种动态重塑知之甚少 边缘区域的过程或昼夜节律糖皮质激素振荡是否在调节过程中发挥任何特定作用。压力引起的脊柱变化如何与边缘回路功能连接的变化相关尚不清楚。该项目的中心假设是昼夜节律糖皮质激素振荡通过产生 并稳定新的脊柱，而慢性压力会通过破坏这些振荡而导致重塑失调和回路功能障碍。在指导阶段进行的实验将集中于糖皮质激素活性水平振荡的快速影响。目标 1 将使用延时显微内窥镜评估对边缘下皮层树突棘形成和消除的快速影响，延时显微内窥镜是最近开发的用于深层大脑结构体内成像的工具。目标 2 将测试相应的功能连接，使用光遗传学工具刺激杏仁核投射到下边缘皮层，同时使用光极记录和功能磁共振成像测量诱发活动。独立阶段（目标 3）的研究将基于这些结果，评估长期糖皮质激素暴露对脊柱重塑、功能连接和焦虑的慢性影响。 在此过程中，候选人将利用类似方法的先前经验，熟练使用上述工具。这将在导师和顾问团队（Deisseroth、Schatzberg、Raichle、de Lecea、Barretto）的监督下完成，他们是这些方法的先驱，并且在培训他人使用这些方法方面拥有丰富的经验。他们在为初级调查员过渡到独立做好准备方面也拥有非常成功的记录。我们预计该项目将产生有关以下方面的新颖见解： 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棘和保持边缘回路内的连接性。研究结果还将为未来研究压力和糖皮质激素对健康人类受试者和临床人群功能连接的影响提供信息。 公共卫生相关性：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暴露于糖皮质激素应激激素的结果。巧合的是，合成糖皮质激素也是治疗多种神经系统和自身免疫性疾病的主要药物，但这些治疗方法与认知副作用和情绪影响有关，但人们对此知之甚少。该项目的主要目标是增进我们对糖皮质激素应激激素如何调节在多种神经精神疾病中发挥核心作用的脑回路连接和功能的理解。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。