Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY Clinical disorders of fear and anxiety, including trauma- and stressor-related disorders, represent an enormous public health burden. Unfortunately, cognitive-behavioral therapies, such as exposure therapy, that are aimed at reducing pathological fear are vulnerable to relapse. This is particularly problematic for patients under high levels of stress, which undermines exposure-based therapies by impairing extinction learning and promoting fear relapse. Despite years of work elucidating the neural circuitry for extinction, the neural mechanisms responsible for stress-induced extinction impairments remain poorly understood. In previous work on this project, we established that stress recruits bottom-up neuromodulatory circuits that inhibit the medial prefrontal cortex (mPFC), a brain area that is critical for extinction learning. We have now shown that that noradrenergic neurons in the locus coeruleus (LC) are critical for stress-induced extinction impairments, such as the immediate shock deficit. Critically, chemogenetic activation of noradrenergic LC neurons induces basolateral amygdala (BLA) hyperexcitability, which in turn drives feed-forward inhibition of the mPFC. Preliminary data indicate that stress-sensitive corticotropin-releasing factor (CRF) neurons in the central nucleus of the amygdala (CEA) drive extinction learning deficits. Based on this, we propose a novel hypothesis that CEA-CRF+ neurons drive LC-NE projections to the BLA, which results in both BLA hyperexcitability and impaired extinction learning. We propose three specific aims to test this hypothesis using a combination of in vivo electrophysiology, calcium imaging, and intersectional opt0genetic manipulations in male and female rats. The first specific aim examines whether CEA-CRF+ projections to the LC are necessary and sufficient for stress- induced increases in BLA hyperexcitability and extinction learning deficits. The second specific aim examines explores whether noradrenergic modulation of parvalbumin (PV) interneurons in the BLA regulates stress- induced hyperexcitability and extinction deficits. Lastly, the third specific aim examines whether the BLA is critical for transducing stress-induced activation of CEA-CRF+ and LC➙BLA circuits to undermine mPFC activity and extinction learning. 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 that optimally engage mPFC circuits to promote extinction learning under stress.
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