Stress Facilitation of Fear Memory: Cellular Mechanisms

 描述（由申请人提供）：压力在情绪记忆形成中起着关键作用。一段经历的情感内容通常决定了哪些内容会被记住，而大脑中形成这些情感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中的神经信号的变化引起的，而恐惧记忆的形成的特征在于影响BLA的主要输出神经元的兴奋性突触回路的增强。可以增强BLA中的兴奋性突触回路的一种方法是通过抑制抑制性突触回路，这导致BLA神经元的兴奋性增加和BLA兴奋性回路的长时程增强（LTP）的阈值降低。因此，BLA中突触抑制的长期抑制（LTDi）促进兴奋性回路的LTP，这应该增加从BLA到下游靶结构（包括下丘脑-垂体-肾上腺神经内分泌应激轴）的焦虑输出。应激和应激诱导的循环糖皮质激素增加促进BLA的焦虑输出，这是由BLA内内源性大麻素和去甲肾上腺素依赖性机制介导的。我们有令人信服的初步证据，从膜片钳记录在脑切片的诱导急性束缚应激的一种形式的LTDi，是介导的快速糖皮质激素诱导的内源性大麻素抑郁症的抑制性传输中的BLA。因此，这代表了BLA中应激和糖皮质激素诱导的LTDi的一种形式。在这个拟议的项目中，我们将区分糖皮质激素和内源性大麻素的机制，负责这种压力诱导的LTDi使用药理学和遗传学的方法，我们将确定是否压力诱导的LTDi eliminating焦虑行为，并促进恐惧记忆的形成，通过促进LTP兴奋性突触电路在BLA。我们将确定参与应激和糖皮质激素促进焦虑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的压力如何促进焦虑和恐惧记忆的形成，通过诱导突触可塑性的抑制回路在BLA的基本理解，并将提供可能的细胞和分子targts为未来的治疗干预，预防和/或治疗焦虑症。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，确定大麻素和/或去甲肾上腺素能药物靶点，用于预防创伤后恐惧记忆的形成。

 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.