Circadian regulation of prefrontal cortex dependent emotional memories

前额叶皮层依赖性情绪记忆的昼夜节律调节

基本信息

批准号：
10320389
负责人：
ROBERT L SPENCER
金额：
$ 39.82万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320389
关键词：
Acute Amygdaloid structure Animal Model Animals Anxiety Disorders Auditory Behavior Control Behavioral Bipolar Disorder Brain region Cell physiology Cells Circadian Dysregulation Circadian Rhythms Clinical Cognitive Corticosterone Development Disease Effectiveness Electrophysiology (science)Elements Emotional Ensure Extinction (Psychology)FRAP1 gene Female Functional disorder Gene Expression Gene Expression Regulation Genes Glucocorticoids Hormone secretion Hormones Human Hypothalamic structure Impairment Individual Lead Learning Major Depressive Disorder Manic Measures Medial Mediating Memory Mental Depression Mental disorders Moods Morphology Neural Pathways Neuroanatomy Neuronal Plasticity Neurons Neuropsychology Pattern Performance Periodicity Peripheral Phase Physiologic pulse Physiological Physiological Processes Play Post-Traumatic Stress Disorders Prefrontal Cortex Process Prosencephalon Rattus Research Resolution Role Schizophrenia Signal Pathway Signal Transduction System Testing Therapeutic Time Tissues Training Translating Vertebral column Viral Work body system cell growth regulation circadian circadian pacemaker circadian regulation clinically relevant conditioned fear effective therapy experimental study improved in vivo innovation insight knock-down learning extinction male molecular clock neural circuit neurobiological mechanism neuromechanism nodal myocyte novel therapeutic intervention optogenetics pre-clinical relating to nervous system response stress related disorder suprachiasmatic nucleus treatment of anxiety disorders virtual

项目摘要

Psychiatric disorders, especially those marked by dysregulated mood and emotional control, such as depression, bipolar disorder, post traumatic stress disorder (PTSD) and schizophrenia, are associated with physiological and cognitive features of disrupted circadian function. Circadian regulation is necessary for appropriate anchoring of the optimal performance of virtually every cell and system of the body to fluctuating daily demands. Although the suprachiasmatic nucleus (SCN) of the hypothalamus serves as the body’s master circadian pacemaker, cells in other brain regions and in peripheral tissues express many of the same molecular clock elements (i.e. clock genes) as those found in the SCN. Recent advances have been made in determining the functional role and regulation of cellular clocks in peripheral tissues. Those studies demonstrate an important circadian entraining influence of the endogenous glucocorticoid hormones (CORT) on peripheral tissue cellular clock function. However, there is very little understanding of the function and regulatory processes of cellular clocks in extra-SCN brain regions. The prefrontal cortex (PFC) is a brain region that plays a central role in organizing and coordinating physiological, behavioral and emotional responses. Animal and human studies show that there is rhythmic clock gene expression in the PFC. Recent studies have found that normal clock gene expression in the PFC of rats depends on appropriate profiles of CORT secretion. Moreover, disruption of CORT-entrained PFC clock gene expression results in impaired diurnal patterns of conditioned fear extinction memory. PTSD is associated with impaired circadian function, compromised PFC function and dysregulation of CORT secretion. In addition, individuals with PTSD suffer from persistent conditioned fear responses. Improving conditioned fear extinction learning is a primary therapeutic objective for treating PTSD. Consequently, this project will use a rat animal model to determine the mechanistic basis by which PFC clock gene expression and CORT interdependently regulate conditioned fear extinction memory. The project is organized around 3 specific aims: Aim 1] To determine how time of day, circadian CORT and ventral medial PFC (vmPFC) clock gene expression modulate the activity of neuronal projections from the vmPFC to the basal medial amygdala (BMA) during conditioned fear extinction training and recall. Aim 2] To determine how time of day, circadian CORT and vmPFC clock gene expression modulate neuroplasticity- related processes in the vmPFC that support conditioned fear extinction recall. Aim 3] To test the necessity and sufficiency of vmPFC to BMA projections for mediating time of day, circadian CORT and vmPFC clock gene expression regulation of conditioned fear extinction recall. The proposed studies will provide new understanding of how circadian and CORT factors dynamically interact to regulate PFC function. These studies will also lead to better understanding of the underlying mechanisms of conditioned fear extinction memory, a neuroprocess that has important clinical relevance for circadian and stress-related disorders.

精神疾病，尤其是那些心情失调和情感控制的那些疾病，例如抑郁症，躁郁症，创伤后应激障碍（PTSD）和精神分裂症与昼夜节律功能中断的生理和认知特征。昼夜节律是必要的适当地锚定身体的最佳性能，以使身体的每个细胞和系统波动每日需求。尽管下丘脑的上核（SCN）是人体的主人昼夜节奏起搏器，其他大脑区域和周围组织中的细胞表达许多相同的细胞分子时钟元素（即时钟基因）如SCN中发现的。最近的进步已经取得确定外周组织中细胞钟的功能作用和调节。这些研究展示了内源性糖皮质激素（Cort）的重要昼夜节律启蒙影响在周围组织细胞时钟功能上。但是，对功能的了解很少超级SCN脑区域中细胞钟的调节过程。前额叶皮层（PFC）是大脑区域这在组织和协调生理，行为和情感反应中起着核心作用。动物和人类研究表明，PFC中有节奏的时钟基因表达。最近的研究发现大鼠PFC中的正常时钟基因表达取决于皮质分泌的适当特征。此外，侵入式PFC时钟基因表达的破坏会导致昼夜模式受损有条件的恐惧扩展记忆。 PTSD与昼夜节律受损，PFC受损有关 Cort分泌的功能和失调。此外，患有PTSD的人持续存在有条件的恐惧反应。改善条件的恐惧扩展学习是主要的治疗目标治疗PTSD。因此，该项目将使用大鼠动物模型来确定机械基础 PFC时钟基因表达和Cort相互依存的调节恐惧扩展记忆。该项目围绕3个特定目的组织：目标1]确定一天中的时间，昼夜节律和腹介质PFC（VMPFC）时钟基因表达调节神经元投影的活性在有条件的恐惧扩展训练和召回期间，VMPFC到基本的内侧杏仁核（BMA）。目标2] 确定一天中的时间，昼夜节律和VMPFC时钟基因表达调节神经可塑性 - VMPFC中的相关过程支持有条件的恐惧扩展召回。目标3]测试必要的 VMPFC对BMA项目的充分性，用于调解一天中的时间，昼夜节律和VMPFC时钟条件恐惧扩展回忆的基因表达调节。拟议的研究将提供新的了解昼夜节律因素如何动态相互作用以调节PFC功能。这些研究还将更好地理解条件恐惧扩展记忆的潜在机制，一个具有重要的临床相关性的神经素化学对昼夜节律和与压力有关的疾病具有重要的临床相关性。