This Integrative Neuroscience Initiative on Alcoholism (INIA-Neuroimmune [INIA-N]) consortium application is for a U24 Research Resource that will act as a service core to provide electrophysiological evaluation of targets identified or developed by INIA-N investigators. The guiding hypothesis of INIA-N is that genetic differences and neuroadaptations in immune-related pathways contribute to the vulnerability to excessive alcohol consumption. In addition to validating neuroimmune signaling pathways already identified during the prior funding period, this consortium will use genomic datasets and computational approaches to predict novel compounds that may be efficacious in reducing excessive alcohol consumption. This core resource will provide essential services to INIA-N investigators by performing studies that examine the cellular electrophysiological functions of brain immune signaling systems and their causal or therapeutic role(s) in excessive alcohol consumption. These studies will be divided among three major subgroups of INIA-N target identification and investigation.
In Specific Aim 1, novel INIA-N compounds that are efficacious in reducing excessive alcohol consumption will be evaluated.
In Specific Aim 2, the focus will be on genetic targets, of which the majority will be long non-coding RNAs shown to influence drinking.
Specific Aim 3 will focus on studies in animal models of hereditary excessive drinking. Electrophysiological experiments, designed in collaboration with the relevant INIA-N investigators, will use new technologies to study neural circuits involved in excessive drinking, and, in cases of wholly novel targets, will employ an unbiased approach of measuring basic membrane properties along with excitatory and/or inhibitory synaptic transmission to screen for mechanisms of action in mesolimbic brain structures. The results of these studies will provide basic information on the role of brain neuroimmune systems in excessive ethanol consumption and help prioritize novel targets for further development.
This Research Resource will provide an essential service to the multi-disciplinary INIA-Neuroimmune research consortium. It will do this by performing electrophysiology experiments in key brain regions. The results of these experiments will uncover mechanisms by which neuroimmune manipulations influence the functioning of brain circuits involved in excessive alcohol consumption.
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