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）：慢性压力与抑郁症，焦虑症和各种认知缺陷有关。基本机制知之甚少，但被认为涉及在边缘脑区域的树突状脊柱丧失，部分原因是长期暴露于糖皮质激素。这些激素是从肾上腺中释放出来的，响应压力，它们也与昼夜节律同步振荡。最近，我们已经表明，糖皮质激素对浅表皮质中的树突状脊柱重塑具有快速而有效的作用。尽管如此，对压力如何影响这种动态重塑的知识知之甚少 边缘区域的过程，或者昼夜节律糖皮质激素振荡是否在调节其调节中起任何特定的作用。应力诱导的刺发生可能与边缘电路中功能连通性的变化有关。该项目的中心假设是昼夜节律糖皮质激素振荡通过产生边缘电路中的突触重塑 并稳定新的刺，并通过破坏这些振荡而导致重塑和电路功能障碍的失调。在指导阶段进行的实验将集中于糖皮质激素活性水平的快速影响。 AIM 1将使用延时微观镜检查来评估对树突状脊柱形成和消除的影响，这是一种最近开发的用于体内成像深脑结构的工具。 AIM 2将使用光遗传学工具t刺激杏仁核的投影到插度皮层，同时使用Optrode记录和功能磁共振成像测量诱发的活性。在独立阶段的研究（AIM 3）将通过评估长期糖皮质激素暴露对脊柱重塑，功能连通性和焦虑的慢性作用来建立这些结果。 在此过程中，候选人将精通上述工具的使用，利用类似方法的先前经验。这将在导师和顾问团队的监督下（Deisseroth，Schatzberg。Raichle，de Lecea，Barretto），他们开创了这些方法，并具有丰富的经验培训其他人使用它们。他们在为初级调查人员做准备以使其过渡到独立性方面还具有非常成功的记录。我们预计该项目将产生有关 昼夜节律在糖皮质激素活性中的重要性，尤其是在稳定树突刺并保持边缘电路内的连通性的重要性。结果还将为未来研究健康受试者和临床人群中功能连通性的影响和糖皮质激素影响的未来努力。 公共卫生相关性：慢性压力可能会导致情绪，焦虑和认知的问题。由于长期暴露于糖皮质激素激素，因此认为这些症状是由于长期暴露而产生的。巧合的是，合成的糖皮质激素也是各种神经系统和自身免疫性疾病的治疗中的主要治疗方法，但是这些治疗方法与认知副作用和对情绪的影响有关，而对情绪的影响很差。该项目的主要目的是促进我们对糖皮质激素应力激素如何调节在多种神经精神疾病中起着核心作用的脑电路中的连通性和功能。长期目标是为旨在治疗和预防这些疾病的未来研究提供信息。