The inclusion of an Animal & Resource Core (C001) in this Center renewal reflects the emergent needs of a research enterprise with an augmented focus on shared genetic mouse models and demands for integrated behavioral phenotyping and high-throughput sequencing services. To address these requirements, C001 will 1) establish and maintain colonies of genetic mouse models; 2) conduct standard operating procedures (SOPs) for: short-term selective breeding based on level of ethanol preference, chronic ethanol consumption via a two- bottle choice (2BC) procedure, and the evaluation of cognitive flexibility with a set-shifting procedure; and 3) provide a streamlined process for the submission and processing of RNA/DNA samples for sequencing by the Massively Parallel Sequencing Shared Resource (MPSSR) via the Sequencing Division of C001. Centralizing these roles and responsibilities within C001 will relieve project investigators from the burden of developing separate sets of resources and procedures, thereby providing greater latitude to address pertinent experimental manipulations and perform cutting-edge analyses to address specific hypotheses. Animal & Resource Core initiatives will offer multiple Center-wide advantages, including reduction of research costs through an economy of scale, enhanced scientific rigor and experimental reproducibility through standardized husbandry and colony maintenance practices, and implementation of optimized SOPs by dedicated staff in a constant and controlled environment. C001 will collaborate with the Research Projects in the completion of four Specific Aims.
In Aim 1, the Core will establish, maintain and distribute genetic mouse models to support the Center Research Projects. The models are the Heterogeneous Stock Collaborative Cross (HS-CC) mice, selectively bred mouse lines for high (HP) and low (LP) ethanol preference, and Aldh1l1-EGFP-Rpl10a transgenic mice.
In Aim 2, the Core will perform behavioral phenotyping services, including those SOPs mentioned above, but also for traits that aid in the interpretation of significant effects of genomic and pharmacological manipulations on ethanol drinking, such as tastant preference, locomotor activity, and ethanol clearance.
In Aim 3, a set-shifting procedure will be optimized in HS-CC mice that closely parallels cognitive testing performed in rhesus macaques, thereby enhancing cross-species translation between Center projects. This SOP will be used to perform studies for P001 in HP and LP mice that address the relationship of cognitive flexibility with risk for ethanol intake and for P001 and P004 to address the dose-dependent consequences of chronic ethanol intake.
In Aim 4, the Sequencing Division of the Animal & Resource Core will perform next- generation sequencing services for all Research Projects, and will work in conjunction with the Bioinformatics Core (C002) for the alignment and analysis of RNA-seq and genome-wide DNAm-seq data.
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