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Fear extinction is impaired in neuropsychiatric disorders, including posttraumatic stress disorder. Identifying drugs that facilitate fear extinction in animal models provides leads for novel pharmacological treatments for these disorders. Zinc (Zn) is expressed in neurons in a cortico-amygdala circuit mediating fear extinction, and modulates neurotransmitter systems regulating extinction. We previously found that the 129S1/SvImJ mouse strain (S1) exhibited a profound impairment in fear extinction, coupled with abnormalities in the activation of the extinction circuit. Here, we tested the role of Zn in fear extinction in S1 and C57BL/6N reference strain (B6) by feeding the mice a Zn-restricted diet (ZnR) and testing for fear extinction, as well as neuronal activation of the extinction circuit via quantification of the immediate-early genes c-Fos and Zif268. Results showed that (preconditioning or postconditioning) ZnR completely rescued deficient extinction learning and long-term extinction retrieval in S1 and expedited extinction learning in B6, without affecting fear acquisition or fear expression. The extinction-facilitating effects of ZnR were associated with the normalization of Zif268 and/or c-Fos expression in cortico-amygdala regions of S1. Specifically, ZnR increased activity in infralimbic cortex, lateral and basolateral amygdala nuclei, and lateral central amygdala nucleus, and decreased activity in prelimbic and insular cortices and medial central amygdala nucleus. ZnR also increased activation in the main intercalated nucleus and decreased activation of the medial paracapsular intercalated mass in S1. Our findings reveal a novel role for Zn in fear extinction and further support the utility of the S1 model for identifying extinction facilitating drugs.

Rescue of Impaired Fear Extinction and Normalization of Cortico-Amygdala Circuit Dysfunction in a Genetic Mouse Model by Dietary Zinc Restriction