Alcoholism is a complex disorder characterized by neuroadaptive changes in specific brain regions and circuits that promote adverse behavioral outcomes associated with alcohol dependence. Previous studies have focused on the role of the central amygdala (CeA) in the extended amygdala, however, CeA connections with other brain regions can also influence CeA responsivity to ultimately alter behavior. One region that forms reciprocal connections with the CeA is the Nucleus Tractus Solitarius (NTS). The NTS receives sensory input from the periphery and acts as an integrative autonomic center. The CeA confers emotional relevance to internal and external sensory input. Thus, the NTS ? CeA circuit represents a potential conduit by which peripheral state can influence emotional reactivity and emotional state can impact peripheral function. In that context, the NTS? CeA circuit may also represent an important target for acute and chronic ethanol and an understudied source of circuit dysfunction that alters drinking behavior. The overarching goal of this proposal is to employ a combined electrophysiological, molecular, and behavioral approach with functional circuit mapping using optogentics and chemogenetics to examine NTS microcircuitry, the sensitivity of NTS neurons to ethanol exposure, and the role of the NTS?CeA circuit in drinking behavior and the development of alcohol dependence. Molecular and electrophysiological studies will be used to identify distinct components of NTS microcircuitry and the impact of acute in vitro and chronic in vivo ethanol on synaptic transmission and activity in NTS circuit components. Retrograde tracing, electrophysiological, optogenetic, and chemogenetic studies will be used to identify specific components of the NTS? CeA circuit in the NTS and CeA to determine the impact of chronic ethanol on these specific components at a cellular and circuit level. Chemogenetic and behavioral studies of voluntary ethanol consumption will be used to assess the role of the NTS? CeA circuit in drinking. Collectively, these studies will provide new information on the role of the NTS and the NTS? CeA circuit in the cellular and circuit mechanisms underlying ethanol dependence.
Despite the prevalence and adverse biological and social effects of alcohol dependence, the neurobiological mechanisms mediating alcohol?s effects in critical brain regions such as the nucleus tractus solitarius (NTS) and NTS projections to the central amygdala (NTS? CeA circuit) remain unclear. A better understanding of the neuroadaptations produced by ethanol in the NTS and NTs? CeA circuit would provide important information on the increased vulnerability of certain individuals to the reinforcing properties of ethanol and identify possible therapeutic targets to treat and/or reverse the negative effects of ethanol on this critical brain circuit.
