Alcohol abuse and dependence affect an estimated 8.5% of the U.S. population and are responsible for substantial health and societal costs. The overarching goal of the Alcohol Research Center at The Scripps Research Institute (TSRI-ARC) is to understand the molecular and cellular mechanisms of vulnerability to alcohol dependence, with a focus on dysregulation of excitatory neurotransmission in stress-responsive brain regions, such as the basolateral amygdala (BLA) and the bed nucleus of the stria terminalis (BNST). In addition, adult neurogenesis will be examined during withdrawal. The Viral Vector Core will be instrumental in the realization of experiments proposed in TSRI-ARC Research Components by providing validated tools to manipulate gene expression locally and to label newborn neurons in adult rats exposed to models of binge drinking or alcohol dependence.
Specific Aim 1 is to characterize the ability of seven adeno-associated virus (AAV) pseudotypes to transduce glutamatergic cells in the BLA and the ventromedial prefrontal cortex (vmPFC), which send excitatory projections to the BLA and BNST. Results from this Aim will be used to select the best-suited AAV pseudotype for the production of custom AAV vectors in Specific Aims 2 and 3.
Specific Aim 2 is to provide AAV vectors for local silencing of monoacylglycerol lipase expression in BLA and vmPFC, and for knockdown of corticotropin-releasing factor receptor type 1 selectively in BLA glutamatergic neurons.
Specific Aim 3 is to provide AAV vectors for functional knockdown or glutamatergic neuron-specific overexpression of neuronal pentraxin 2 in the BLA.
Specific Aim 4 is to provide a retroviral vector expressing EGFP. This vector will label newborn neurons in the adult rat brain and enable characterization of their morphology and physiology. For each viral vector, we propose to design and clone DNA constructs, obtain high-titer, purified viral stocks from an outside production facility and validate their silencing/overexpression efficiency in vivo. Altogether, we anticipate that the innovative molecular tools provided by the Viral Vector Core will assist in gaining novel insights into the neurobiological mechanisms of excessive alcohol drinking.
The Viral Vector Core will provide tools to manipulate excitatory neurotransmission and label birth of new neurons in the adult rat brain. Viral vectors are an innovative and efficient approach to examine the role of genes or cells of interest in rat models of binge drinking and alcoholism. Translational implications include the identification of novel targets for the development of a more efficient treatment of alcoholism
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