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(由申请者提供)：压力在情绪记忆的形成中起着关键作用。体验的情绪内容往往决定了该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，特别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，而恐惧记忆的形成是通过影响BLA的主要输出神经元的兴奋性突触电路的增强来表征的。增强BLA兴奋性突触回路的一种方法是抑制抑制性突触回路，从而增加BLA神经元的兴奋性，降低BLA兴奋性回路的长时程增强(LTP)阈值。因此，BLA中突触抑制的长期抑制(LTDI)促进了兴奋回路的LTP，这将增加从BLA到下游靶结构的焦虑性输出，包括下丘脑-垂体-肾上腺神经内分泌轴。应激和应激诱导的循环糖皮质激素的增加促进了BLA产生焦虑的输出，这是通过BLA内的内源性大麻素和去甲肾上腺素依赖的机制来调节的。我们从脑片膜片钳记录中获得了令人信服的初步证据，证明急性束缚应激诱导了一种形式的LTDI，这种形式的LTDI是由糖皮质激素诱导的抑制血乳酸传递的内源性大麻素抑制所介导的。因此，这代表了一种应激和糖皮质激素诱导的BLA中LTDI的形式。在这个拟议的项目中，我们将用药理学和遗传学的方法区分导致应激诱导LTDI的糖皮质激素和内源性大麻激素机制，并将确定应激诱导的LTDI是否通过促进BLA中兴奋性突触回路的LTP而引起焦虑行为和促进恐惧记忆的形成。我们将确定去甲肾上腺素参与应激和糖皮质激素促进焦虑发生和恐惧记忆形成的机制。这些研究将在细胞水平上对应激如何通过诱导BLA中抑制回路的突触可塑性来促进焦虑产生和恐惧记忆的形成有一个基本的理解，并将为未来预防和/或治疗焦虑症的治疗干预提供可能的细胞和分子靶标。这些研究可能产生的一个潜在的宝贵发现是，在治疗干预可行的情况下，确定用于预防暴露于创伤后形成恐惧记忆的大麻素和/或去甲肾上腺素能药物靶标。