Stress Facilitation of Fear Memory: Cellular Mechanisms

恐惧记忆的压力促进：细胞机制

• 批准号: 8888968
• 负责人: JEFFREY G TASKER
• 金额: $ 37.63万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8888968
• 关键词: Acute; Adrenal Cortex Hormones; Adrenal Glands; Amygdaloid structure; Anxiety; Anxiety Disorders; Arousal; Behavior; Behavioral; Blood; Brain; CNR1 gene; Cannabinoids; Chemosensitization; Clinical; Cognitive; Complex; Dependence; Depressed mood; Electric Stimulation; Elements; Emotional; Endocannabinoids; Equilibrium; Etiology; Exposure to; Extinction (Psychology); Frequencies; Fright; Future; Genetic; Glucocorticoid Receptor; Glucocorticoids; Hormones; Hypothalamic structure; In Vitro; Intervention; Knock-out; Knockout Mice; Knowledge; Lateral; Light; Long-Term Depression; Long-Term Potentiation; Mediating; Membrane; Memory; Mental Depression; Mental disorders; Molecular; Mus; Neurons; Neurosecretory Systems; Norepinephrine; Output; Pharmacologic Substance; Pituitary Gland; Play; Post-Traumatic Stress Disorders; Prevention; Regulation; Reporting; Role; Sensory; Signal Transduction; Site; Slice; Stress; Structure; Synapses; Synaptic plasticity; Testing; Therapeutic Intervention; Transgenic Mice; Trauma; acute stress; base; conditioned fear; desensitization; emotional behavior; experience; fear memory; gamma-Aminobutyric Acid; genetic approach; genetic manipulation; hypothalamic-pituitary-adrenal axis; in vivo; memory consolidation; memory retrieval; neural circuit; neurotransmission; noradrenergic; novel; patch clamp; public health relevance; receptor; research study; response; restraint stress; synaptic inhibition; therapeutic target; transmission process; traumatic event; treatment of anxiety disorders

 DESCRIPTION (provided by applicant): Stress plays a critical role in emotional memory formation. The emotional content of an experience often dictates which elements of the experience are remembered, and an important site in the brain for the formation of these emotional memories is the amygdala, particularly the basal lateral complex of the amygdala (BLA). The formation of emotional memories is caused by changes in the neural signaling in the BLA, and fear memory formation is characterized by the potentiation of excitatory synaptic circuits impacting the principal output neurons of the BLA. One means by which excitatory synaptic circuits in the BLA can be potentiated is by depressing inhibitory synaptic circuits, which leads to an increase in the excitability of the BLA neurons and a lower threshold for the long-term potentiation (LTP) of BLA excitatory circuits. Thus, the long-term depression of synaptic inhibition (LTDi) in the BLA promotes the LTP of excitatory circuits, which should increase anxiogenic output from the BLA to downstream target structures, including the hypothalamic-pituitary-adrenal neuroendocrine stress axis. Stress and the stress-induced increase in circulating glucocorticoids facilitate the anxiogenic output from the BLA, and this is mediated by intra-BLA endocannabinoid- and norepinephrine- dependent mechanisms. We have compelling preliminary evidence from patch-clamp recordings in brain slices for the induction by acute restraint stress of a form of LTDi that is mediated by rapid glucocorticoid-induced endocannabinoid depression of inhibitory transmission in the BLA. This represents, therefore, a form of stress and glucocorticoid-induced LTDi in the BLA. In this proposed project, we will distinguish the glucocorticoid and endocannabinoid mechanisms responsible for this stress-induced LTDi using pharmacological and genetic approaches, and we will determine whether stress-induced LTDi elicits anxiogenic behavior and facilitates fear memory formation by promoting LTP at excitatory synaptic circuits in the BLA. We will determine the noradrenergic mechanisms involved in the stress and glucocorticoid facilitation of anxiogenesis and fear memory formation. These studies will culminate in a fundamental understanding at the cellular level of how stress facilitates anxiogenesis and fear memory formation by inducing synaptic plasticity of inhibitory circuits in the BLA, and will provide possible cellular and molecular targts for future therapeutic intervention for the prevention and/or treatment of anxiety disorders. A potentially invaluable finding that may emerge from these studies is the identification of cannabinoid and/or noradrenergic pharmaceutical targets for the prevention of fear memory formation following exposure to trauma, when therapeutic intervention is feasible.

 描述（由申请人提供）：压力在情绪记忆的形成中起着至关重要的作用，体验的情绪内容通常决定了体验的哪些元素被记住，而大脑中形成这些情绪记忆的一个重要部位是杏仁核。尤其是杏仁核的基底外侧复合体（BLA）。情绪记忆的形成是由 BLA 中神经信号的变化引起的，而恐惧记忆的形成则以兴奋性突触回路的增强为特征。增强 BLA 中的兴奋性突触回路的一种方法是抑制抑制性突触回路，这会导致 BLA 神经元的兴奋性增加并降低长期阈值。 BLA 兴奋性回路的增强 (LTP) 因此，BLA 中突触抑制 (LTDi) 的长期抑制会促进兴奋性回路的 LTP，从而增加。从 BLA 到下游目标结构（包括下丘脑-垂体-肾上腺神经内分泌应激轴）的致焦虑输出促进了 BLA 的致焦虑输出，这是由 BLA 内的内源性大麻素和内源性大麻素介导的。我们从脑切片的膜片钳记录中获得了令人信服的初步证据，证明了一种LTDi的急性束缚应激的诱导作用。因此，这代表了 BLA 中的一种压力和糖皮质激素诱导的 LTDi，在这个拟议项目中，我们将区分导致这种压力的糖皮质激素和内源性大麻素机制。 -使用药理学和遗传学方法诱导LTDi，我们将确定应激诱导的LTDi是否会引发焦虑行为并通过促进兴奋性LTP来促进恐惧记忆形成我们将确定参与压力和糖皮质激素促进焦虑生成和恐惧记忆形成的去甲肾上腺素能机制，这些研究将最终在细胞水平上对压力如何通过诱导突触促进焦虑生成和恐惧记忆形成有一个基本的了解。 BLA 中抑制回路的可塑性，将为未来预防和/或治疗焦虑症的治疗干预提供可能的细胞和分子靶标。这些研究可能会产生大麻素和/或去甲肾上腺素能药物靶点的鉴定，以在治疗干预可行时预防创伤后恐惧记忆的形成。