Dissecting the Role of Prefrontal Circuitry in Basolateral Amygdala Physiology and Regulation of Anxiety Following Chronic Ethanol Exposure and Withdrawal

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PROJECT SUMMARY Increased anxiety during alcohol withdrawal is a central characteristic of alcohol dependence and has been reported as a common, underlying cause of relapse in those with alcohol dependence, which is a critical barrier to their treatment. Animal models of alcohol dependence likewise show increased anxiety-like behaviors during alcohol withdrawal, suggesting they are a valid translational model. The lateral/basolateral amygdala (BLA) has been identified as a critical component of the neural circuitry that regulates many emotional behaviors, including anxiety. Our laboratory has recently shown that chronic ethanol exposure and withdrawal produce distinct synaptic alterations in the BLA that are input- and timing-specific. For example, glutamatergic afferents arriving within the stria terminalis (ST) along the medial BLA boundary express a presynaptic form of plasticity that develops early during alcohol exposure, whereas inputs arriving via the external capsule (EC) along the lateral boarder of the BLA express postsynaptic potentiation later in alcohol exposure. These data suggest that this initial presynaptic facilitation of ST inputs may be crucial for development of the behavioral and physiologic characteristics that develop during prolonged ethanol exposure. However, little is known about how specific inputs from distinct upstream brain regions are affected by chronic ethanol exposure or how these might independently influence anxiety during alcohol withdrawal. In the current NRSA proposal, we will examine inputs to the BLA from the medial prefrontal cortex (mPFC) and the agranular insular cortex (AI), which project to the BLA via these two anatomically distinct pathways. Thus, the overall goal of this training proposal is to understand whether the mPFC and/or AI inputs to the BLA undergo similar or unique synaptic alterations following chronic ethanol exposure/withdrawal, and whether they are necessary for the expression of withdrawal-induced anxiety-like behavior. Our central hypothesis is that early presynaptic facilitation of the ST- BLA from mPFC inputs is necessary for the subsequent neurophysiologic and behavioral consequences of chronic ethanol exposure and withdrawal. We will address this hypothesis through two Specific Aims. In Aim 1, we will use DREADD technology to manipulate these BLA inputs at different times during chronic ethanol exposure and use a variety of anxiety assays including the elevated plus maze and light/dark box. Our hypothesis is that early facilitation of mPFC-BLA inputs during chronic ethanol exposure mediate withdrawal- induced anxiety-like behavior. Using these same animals, in Aim 2, we will employ whole-cell patch clamp electrophysiology and optogenetics to characterize the temporal physiological relationships between pre- and postsynaptic potentiation of ST- and EC-BLA synapses following chronic ethanol exposure and withdrawal. The identification of specific brain regions might lead to potential novel targets for more effective treatments of alcohol withdrawal-induced anxiety in the clinical setting.