DA-GABA modulation of cortical ACh release

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DESCRIPTION (provided by applicant): The nucleus accumbens (NAC) is a key region in a distributed neural system that integrates essential information underlying goal-directed behavior. Attentional functions, including the detection and selection of stimuli, and the appropriate processing of selected stimuli are instrumental for goal-directed behavior. In this renewal application, we propose that the integration between motivational and attentional processes is mediated by interactions between glutamatergic and dopaminergic inputs to NAC and the subsequent recruitment of NAC neuronal ensembles and their projections to the basal forebrain cortical cholinergic system (BFCS). The BFCS innervates all cortical areas and generally gates cortical information processing. Behaviorally, the BFCS has been demonstrated to mediate essential aspects of attentional functions. The proposed studies will utilize a combination of in vivo microdialysis, intracerebral injections, and operant behavior to reveal the coordinated neurochemical activity within the prefrontal cortex (RFC), NAC, and basal forebrain (BF) of the same animal. We will determine the functional consequences of interactions between glutamate (Glu) and dopamine (DA) in NAC for the release of acetylcholine (ACh) in RFC and attentional performance. We propose that attentional performance, as opposed to when the animal is at rest, specifically challenges on attentional performance which trigger the motivated enhancement of attentional capacities, will selectively recruit this PFC-NAC-BF circuit. Finally, we will determine how these functional interactions between NAC Glu and DA and cortical ACh are altered in animals sustaining lesions of the ventral hippocampus as neonates or as adults. Lesions of the ventral hippocampus during early development are a widely used animal model of schizophrenia and the documentation of dysregulations in Glu/DA in NAC and ACh in RFC, as well as impairments in attentional processing, will further validate this important model. Collectively, these studies have relevance to important public health implications. Several neuropsychiatric disorders are believed to reflect dysregulations in this distributed neural circuit that manifest themselves cognitively in impairments in attentional and related executive functions. These disorders include drug addiction, ADHD, and schizophrenia. The proposed research should further the development and validation of animal models that form the foundation of translational research in these health-related areas.