Neural circuits for stress-impaired extinction learning
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Project SummaryClinical disorders of fear and anxiety, including trauma- and stressor-related disorders, represent an enormouspublic health burden. Cognitive-behavioral therapies, such as prolonged exposure therapy, have proven to beremarkably effective in reducing pathological fear in patients with these disorders. Nonetheless, there are anumber of factors that limit the efficacy of exposure therapy. In particular, stress undermines exposure-basedtherapies by impairing extinction learning and promoting fear relapse. Despite years of work elucidating theneural circuitry for extinction, the neural mechanisms responsible for stress-induced extinction impairmentsremain poorly understood. One possibility is that stress dysregulates neuronal activity in the medial prefrontalcortex (mPFC), a brain area that is critical for extinction learning. In support of this possibility, we haverecently shown that footshock stress causes lasting decreases in the spontaneous firing of neurons in theinfralimbic (IL) division of the mPFC in rats. Decreases in IL firing were associated with an â€œimmediateextinction deficitâ€ (IED), an extinction impairment that occurs when extinction is performed soon after fearconditioning (a stressor). Importantly, systemic administration of propranolol, a ÃŸ-noradrenergic receptorantagonist, prevented both the stress-induced depression of IL firing and the IED, suggesting a role for locuscoeruleus norepinephrine (LC-NE) in this phenomenon. Although these data reveal that noradrenergictransmission is involved in the stress-induced depression of mPFC firing, the neural circuit by which stressperturbs mPFC firing is unknown. Interestingly, we have found that propranolol rescues the IED whendelivered to the basolateral amygdala (BLA), but not the IL. Based on this work, we propose a novel hypothesisthat stress-induced NE release from the LC recruits an inhibitory BLA->IL circuit that dampens activity in ILprincipal neurons to impair the acquisition and retention of long-term extinction memories. We propose threespecific aims to test this hypothesis using a combination of in vivo electrophysiology, functional circuit tracing,and pharmacogenetic manipulations (e.g., `designer receptors exclusively activated by designer drugs'' orDREADDs). The first specific aim of the project examines whether LC-NE projections to the IL or BLA arenecessary and sufficient for stress-induced changes in mPFC firing and extinction learning deficits. The secondspecific aim examines explores whether BLA neurons projecting to the IL or PL mediate these effects. Thethird specific aim determines whether parvalbumin interneurons (PV-INs) in the mPFC are recruited by LC-NE activation and mediate the immediate extinction deficit through feed forward inhibition by BLA afferents.The outcomes of these aims will advance a novel circuit mechanism for stress-induced extinction impairments.Understanding this mechanism will facilitate the development of novel pharmacotherapeutic approaches thatoptimally engage mPFC circuits to facilitate extinction learning under stress.