TY - JOUR T1 - Chronic Ethanol Differentially Modulates Glutamate Release from Dorsal and Ventral Prefrontal Cortical Inputs onto Rat Basolateral Amygdala Principal Neurons JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0132-19.2019 SP - ENEURO.0132-19.2019 AU - Molly M. McGinnis AU - Brian C. Parrish AU - Ann M. Chappell AU - Nancy J. Alexander AU - Brian A. McCool Y1 - 2019/09/23 UR - http://www.eneuro.org/content/early/2019/09/23/ENEURO.0132-19.2019.abstract N2 - The medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA) have strong reciprocal connectivity. Projections from the BLA to the mPFC can drive innate, anxiety-related behaviors but it is unclear if reciprocal projections from the mPFC to BLA have similar roles. Here, we use optogenetics and chemogenetics to characterize the neurophysiological and behavioral alterations produced by chronic ethanol exposure and withdrawal on dorsal (dmPFC) and ventral (vmPFC) medial prefrontal cortical terminals in the BLA. We exposed adult male Sprague-Dawley rats to chronic intermittent ethanol (CIE) using vapor chambers, measured anxiety-like behavior on the elevated zero maze (EZM), and used electrophysiology to record glutamatergic and GABAergic responses in BLA principal neurons. We found that withdrawal from a 7-day CIE exposure produced opposing effects at dmPFC (increased glutamate release) and vmPFC (decreased glutamate release) terminals in the BLA. Chemogenetic inhibition of dmPFC terminals in the BLA attenuated the increased anxiety-like behavior we observed during withdrawal. These data demonstrate that chronic ethanol exposure and withdrawal strengthens the synaptic connections between the dmPFC – BLA but weakens the vmPFC– BLA pathway. Moreover, facilitation of the dmPFC – BLA pathway during withdrawal contributes to anxiety-like behavior. Given the opposing roles of dmPFC- and vmPFC-BLA pathways in fear conditioning, our results suggest that chronic ethanol exposure simultaneously facilitates circuits involved in the acquisition of, and diminishes circuits involved with the extinction of, withdrawal-related aversive behaviors.Significance Statement Accumulating evidence suggests that the medial prefrontal cortex (mPFC) and its projections to the basolateral amygdala (BLA) bidirectionally modulate fear-related behaviors. Since the neuronal circuits for fear and anxiety are thought to overlap, we sought to examine the role of dorsal and ventral subdivisions of the mPFC and their inputs to the BLA in regulating anxiety. Specifically, we focused on alcohol withdrawal-induced anxiety-like behavior, which is a commonly reported cause of relapse in human alcoholics. In our study, we used optogenetics and chemogenetics to demonstrate, for the first time, that withdrawal from chronic ethanol exposure strengthens dmPFC synapses, but weakens vmPFC synapses in the BLA and that inhibiting glutamate release from dmPFC terminals in the BLA reduces anxiety-like behavior. ER -