Alcohol and Interneurons in the Prefrontal Cortex

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The prefrontal cortex (PFC) mediates control over goal-directed behaviors and dysfunction of the PFC is thought to underlie compulsive drug-taking and relapse in substance abusers. The PFC has been implicated in behavioral effects that occur at levels of alcohol associated with social drinking. There are few detailed studies on the actions of alcohol in PFC, or specifically on the sensitivity of three major subtypes of interneurons (INTs) that augment and control the activity of pyramidal (PYR) neurons. We recently reported the stimulatory effects of alcohol on PYR and its inhibitory effect on somatostatin (SST+)-expressing INTs. We now propose to examine the sensitivity to alcohol of two additional major subtypes of INTs: parvalbumin (PV+)-, and vasoactive intestinal polypeptide (VIP+) expressing subtypes. The overarching hypothesis of the proposal is that one or more specific sub-populations of INTs are sensitive to alcohol, that modulation of INT activity by alcohol is mediated by ascending dopaminergic inputs from the ventral tegmental area (VTA) and leads to disinhibition within the PFC. We will study the effects of alcohol on the activity of PV+ and VIP+ INT using 2-photon imaging techniques to probe the actions and mechanisms of alcohol in the PFC. We will study the effects of alcohol on activity in PYR and INT in the PFC in vivo in the mouse pre-limbic area (PL) using the genetically-encoded calcium indicator GCaMP. We hypothesize that ethanol increases activity in PYR and certain INTs via the activation of a disinhibitory local circuit, and that these effects on PYR result from decreases in activity in a subgroup of SST+ INTs, perhaps via activation of VIP+ INTs. We will also study the effect of alcohol on activity in dopaminergic afferents within the PFC, imaging GCaMP under the control of the tyrosine hydroxylase promoter and measure the effects of activating Gi DREADDs within the ventral VTA to block the effects of alcohol on PYR and INT activity in the PFC in vivo. We hypothesize that activity within DA afferents in the PFC releases DA and modulate INTs in PFC, and that this may be prevented by silencing dopaminergic inputs from the VTA. We will examine the mechanisms of alcohol sensitivity of PYR and INT subtypes in PFC in vivo using specific dopamine receptor antagonists, in order to establish the mechanisms by which PYR and INTs are disinhibited by low dose alcohol and how specific INT sub-classes are modulated by alcohol in vivo and in vitro. We hypothesize that alcohol disinhibits PYR and that this occurs via indirect effects of alcohol that are mediated by ascending dopaminergic inputs from the VTA, acting on DA receptors in the PFC.