Project Summary A hallmark of alcohol use disorder is continued seeking and consumption of alcohol despite negative consequences. Neuroadaptations in corticostriatal projections to nucleus accumbens are critical for the development of compulsive-like alcohol use behaviors, including in an aversion-resistant drinking model. Yet it remains unclear how potentiated activity in nucleus accumbens neurons alters sensitivity to aversive outcomes during consumption and seeking of alcohol. Pre-existing individual differences in aversion-related circuits have been shown to predict future compulsive-like alcohol consumption. Yet, we are not aware of any demonstrations of alcohol-induced neuroadaptations in aversion-related circuits that track the development of aversion-resistant drinking, and that account for the emergence of this compulsive phenotype after alcohol exposure. Our long-term goal is to identify dynamics changes in the activity of aversion-related neural circuits that drive the emergence of compulsive alcohol use. Here, we will examine glutamatergic basal forebrain neurons that project to the lateral habenula. These neurons are found in an anterior-posterior continuum from the ventral pallidum to the lateral hypothalamus and are targeted by nucleus accumbens inhibitory projection neurons. We hypothesize that the emergence of aversion-resistant drinking requires selective inhibition of these neurons during alcohol consumption. A crucial first step in our investigation of this circuit is to determine whether the emergence of aversion- resistant drinking is correlated with cell-type specific alterations in drinking-related neural activity in the glutamatergic basal forebrain. We will assess this question, and whether these neural correlates are downstream of nucleus accumbens mechanisms in Aim 1. Our second goal is to examine lateral habenula glutamate activity dynamics during aversion-resistant drinking. Therefore, our Aim 2 experiments will utilize a fluorescent glutamate sensor combined with fiber photometry to identify temporally-specific neural correlates of aversion-resistant drinking. Finally, in Aim 3 we will use chemogenetic approaches to assess the functional contributions of basal forebrain projections to lateral habenula in aversion-resistant drinking and determine which inputs to lateral habenula from regions of the glutamatergic basal forebrain most effectively modulate compulsive alcohol consumption. Together, these experiments will yield novel insights into the neural circuits mediating compulsive alcohol use, as well as aversion-related constraint of reward-seeking more broadly.

Project Narrative A major diagnostic feature of alcohol use disorder is compulsive alcohol use despite negative consequences. Our goal is to determine the brain mechanisms that drive compulsive drinking after long-term exposure to alcohol. Here we examine how alcohol exposure alters recruitment of a brain pathway that is normally involved in constraining reward-seeking behavior in the face of negative consequences.