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

• 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
• 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

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，尤其是那些以情绪失调和情绪控制为特征的疾病，如 抑郁症，双相情感障碍，创伤后应激障碍（PTSD）和精神分裂症，与 生理和认知特征的破坏昼夜节律功能。昼夜节律调节是必要的 适当的锚定的最佳性能几乎每一个细胞和系统的身体波动 日常需求。虽然下丘脑的视交叉上核（SCN）是身体的主人， 除了昼夜节律起搏器外，大脑其他区域和外周组织中的细胞也表达许多相同的 分子时钟元件（即时钟基因），如在SCN中发现的那些。最近的进展是 确定外周组织中细胞时钟的功能作用和调节。这些研究 证明内源性糖皮质激素（CORT）的重要昼夜节律影响 对外周组织细胞时钟功能的影响然而，人们对它的功能了解甚少， SCN外脑区细胞时钟的调节过程。前额叶皮层（PFC）是一个大脑区域， 它在组织和协调生理、行为和情绪反应中起着核心作用。 动物和人类研究表明，PFC中存在节律性时钟基因表达。 发现大鼠PFC中正常的时钟基因表达取决于CORT分泌的适当特征。 此外，CORT携带的PFC时钟基因表达的破坏导致受损的昼夜模式， 条件性恐惧消退记忆创伤后应激障碍与昼夜节律功能受损，PFC受损有关 CORT分泌的功能和失调。此外，患有PTSD的人患有持续的 条件性恐惧反应改善条件性恐惧消退学习是一个主要的治疗目标， 治疗创伤后应激障碍因此，本项目将使用大鼠动物模型，通过以下方式确定机制基础： PFC时钟基因表达与CORT相互依赖地调节条件性恐惧消退记忆。 该项目围绕3个具体目标组织：目标1]为了确定一天中的时间、昼夜CORT和CORT之间的关系， 腹内侧PFC（vmPFC）时钟基因表达调节神经元投射的活动， 在条件性恐惧消退训练和回忆过程中，VMPFC对基底内侧杏仁核（BMA）的影响。目标2] 确定一天中的时间、昼夜CORT和vmPFC时钟基因表达如何调节神经可塑性- 支持条件性恐惧消退回忆的VMPFC相关过程。目的3]测试必要性 以及vmPFC对BMA预测的充分性，用于介导一天中的时间、昼夜CORT和vmPFC时钟 条件性恐惧消退回忆的基因表达调控这些研究将提供新的 了解昼夜节律和CORT因子如何动态地相互作用以调节PFC功能。这些研究 也将导致更好地理解条件性恐惧消退记忆的潜在机制， 神经过程，具有重要的临床意义的昼夜节律和压力相关的疾病。