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.

Public Health Relevance

Stress plays a major role in the etiology of mental illness, especially depression and anxiety disorders. Stimulation of the neuroendocrine stress axis results in an increase in the blood levels of glucocorticoid hormones, which can have profound return effects on the brain, including profound changes in brain circuit signaling. This study will determine the cellular and neural circuit mechanisms in the basolateral complex of the amygdala that are responsible for the enhancing effects of stress on anxiety and fear memory formation. Upon completion of the study, we will know how stress and stress hormones enhance fear memory formation and anxiety by suppressing synaptic inhibition in the basolateral amygdala. This knowledge will contribute to our understanding of the etiology of stress-associated psychiatric disorders, and will provide pharmaceutical targets for therapeutic intervention for the treatment of posttraumatic stress disorder after exposure to traumatic events.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Winsky, Lois M
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Tulane University
Anatomy/Cell Biology
Schools of Arts and Sciences
New Orleans
United States
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Russell, Ashley L; Tasker, Jeffrey G; Lucion, Aldo B et al. (2018) Factors promoting vulnerability to dysregulated stress reactivity and stress-related disease. J Neuroendocrinol 30:e12641
Rainville, Jennifer R; Weiss, Grant L; Evanson, Nathan et al. (2017) Membrane-initiated nuclear trafficking of the glucocorticoid receptor in hypothalamic neurons. Steroids :
Weiss, Grant L; Rainville, Jennifer R; Zhao, Qi et al. (2017) Purity and stability of the membrane-limited glucocorticoid receptor agonist dexamethasone-BSA. Steroids :
Di, Shi; Itoga, Christy A; Fisher, Marc O et al. (2016) Acute Stress Suppresses Synaptic Inhibition and Increases Anxiety via Endocannabinoid Release in the Basolateral Amygdala. J Neurosci 36:8461-70