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.
NIH ExPorter
NIH ExPorter