CORE 2/2: INIA Stress and Chronic Alcohol Interactions: CIE-Stress Mouse Brain Activity Mapping Core (BAMC)

SUMMARY Stressful life experiences are risk factors that play considerable roles in the development and maintenance of alcohol (ethanol) abuse, excessive drinking, and relapse. Preclinical studies from the INIAstress Consortium that examined chronic ethanol-stress interactions in mice have demonstrated elevations in ethanol drinking, cognitive deficits, metaplastic adaptations, and emergence of negative affective behaviors. The INIAstress investigators also performed mechanistic and pharmacological studies that revealed key biological targets that are responsible for driving these aberrant behaviors in stressed, chronic intermittent ethanol (CIE) exposed mice. However, the brain-wide neural adaptations produced by ethanol-stress interactions are unknown, and a better understanding of the brain-wide activity patterns that underlie alcohol and stress interactions will lead to effective strategies for treating individuals with alcohol use disorder. Recent advancements in brain-wide mapping and innovative network neuroscience statistical approaches prompted the formation of the CIE-Stress Mouse Brain Activity Mapping Core (BAMC). In this application, we provide preliminary data showing whole-brain light sheet imaging of c-Fos expression and functional connectivity mapping in CIE-FSS treated mice and in mice drinking in the intermittent access model. Thus, the primary goals of the BAMC are to 1) apply cutting-edge technology in whole- brain light sheet imaging and expertise in network analyses to provide investigators in the INIAstress Consortium and the scientific community with novel brain regions, circuits, and networks that drive increased drinking in mice with a history of forced swim stress (FSS) and CIE exposure, and 2) provide brain-wide signatures of immediate early gene (IEG) activity in response to pharmacological agents that are known to reduce the excessive drinking phenotype in stress, ethanol dependent mice. The secondary goals of the BAMC are to 1) provide the whole- brain mapping data to the Computational and Statistical Analysis Core (CSAC) for integration with additional neural and behavioral data collected across all components, and 2) perform cross-INIA Consortia analyses of whole-brain IEG expression. In Aim 1, the BAMC will generate whole-brain IEG mapping data using the standard INIAstress Consortium model of stress-induced excessive drinking for INIAstress investigators and the scientific community. Studies in Aim 2 will determine brain-wide IEG signatures after pharmacological treatment of drugs that reduce drinking in the CIE-FSS model. By applying cutting-edge light sheet imaging, advanced network analysis, and pharmacological interrogation of IEG expression across the whole mouse brain using a reliable model that results in escalated voluntary ethanol intake in stressed, ethanol dependent mice, the BAMC will help to generate new hypotheses and unbiased insights into systems and circuitry underlying alcohol-stress interactions. Finally, through its interactions with the CSAC and BRAIN Initiative investigators, the Brain Activity Mapping Core will contribute to Open Science practices that will provide the greater scientific community with whole-brain IEG mapping data from excessively drinking mice.