TY - JOUR T1 - Chemogenetic Inhibition of Infralimbic Prefrontal Cortex GABAergic Parvalbumin Interneurons Attenuates the Impact of Chronic Stress in Male Mice JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0423-19.2020 SP - ENEURO.0423-19.2020 AU - Nawshaba Nawreen AU - Evelin M. Cotella AU - Rachel Morano AU - Parinaz Mahbod AU - Khushali Dalal AU - Maureen Fitzgerald AU - Susan Martelle AU - Benjamin A. Packard AU - Ana Franco-Villanueva AU - Rachel D. Moloney AU - James P. Herman Y1 - 2020/10/14 UR - http://www.eneuro.org/content/early/2020/10/14/ENEURO.0423-19.2020.abstract N2 - Hypofunction of the prefrontal cortex (PFC) contributes to stress-related neuropsychiatric illnesses. Mechanisms leading to prefrontal hypoactivity remain to be determined. Prior evidence suggests that chronic stress leads to an increase in activity of parvalbumin (PV) expressing GABAergic interneurons (INs) in the PFC. The purpose of the study was to determine whether reducing PV IN activity in the Infralimbic (IL) PFC would prevent stress-related phenotypes. We used a chemogenetic approach to inhibit IL PFC PV INs during stress. Mice were first tested in the tail suspension test (TST) to determine the impact of PV IN inhibition on behavioral responses to acute stress. The long-term impact of PV IN inhibition during a modified chronic variable stress (CVS) was tested in the forced swim test (FST). Acute PV IN inhibition reduced active (struggling) and increased passive coping behaviors (immobility) in the TST. In contrast, inhibition of PV INs during CVS increased active and reduced passive coping behaviors in the FST. Moreover, chronic inhibition of PV INs attenuated CVS-induced changes in Fos expression in the prelimbic cortex (PrL), basolateral amygdala (BLA), and ventrolateral periaqueductal gray (vlPAG) and also attenuated adrenal hypertrophy and body weight loss associated with chronic stress. Our results suggest differential roles of PV INs to acute versus chronic stress, indicative of distinct biological mechanisms underlying acute versus chronic stress responses. Our results also indicate a role for PV INs in driving chronic stress adaptation and support literature evidence suggesting cortical GABAergic INs as a therapeutic target in stress-related illnesses.Significance Stress-related diseases are associated with prefrontal hypoactivity, the mechanism of which is currently not known. In this study we showed that by inhibiting prefrontal GABAergic parvalbumin interneurons (PV INs), we can attenuate some of chronic stress-related phenotypes. Additionally, we showed that modulation of PV IN activity during acute stress had opposing effects on stress coping strategies, suggesting different plasticity mechanisms in PV INs following acute versus chronic stress. Our findings indicate that GABAergic PV INs may be involved in driving stress-related phenotypes and may therefore be an important target for treatment of stress-related illnesses. Our data suggest that reducing PV IN activity to promote prefrontal output may be a potential treatment strategy for stress-related disorders. ER -