A body of evidence assembled over the past several years indicates persuasively that GABAergic circuits in the nucleus accumbens shell (AcbSh) play an important role in the control of food intake. For example, injections of GABA agonists into the AcbSh result in a large and very specific increase in feeding, a surprising result given that the AcbSh is often assumed to exert a generalized influence on motivational or reward mechanisms. The magnitude and specificity of the effects produced by AcbSh manipulations suggest both that pathology of the neural circuitry underlying the AcbSh feeding effects may play a role in some human eating disorders, and that this circuit may be a promising target for the development of novel approaches to the treatment of disturbances in food intake and body weight. The long-term goal of the proposed research project is to identify and characterize the neural circuits through which the AcbSh produces changes in Feeding behavior. Our fundamental working hypothesis is that the AcbSh affects feeding by potently regulating neural activity in a distributed, but lateralized, network of structures that includes the medial ventral pallidum (VPm), and the lateral (LH), arcuate (Arc), and paraventricular (PVN) hypothalamic regions. The proposed experiments involve the use of complementary neuroanatomical, behavioral, pharmacological, and molecular techniques to better understand the flow of information through the circuit and the functional contribution of each structure to the expression of AcbSh-mediated feeding. Specifically, we propose to examine the ability of excitotoxic lesions of each of these structures to modify the amount and pattern of food intake elicited by unilateral intra-AcbSh injections of muscimol. These studies will be carried out using an """"""""ipsilateral-contralateral disruption"""""""" (ICD) design which will allow us to avoid many of the interpretative difficulties usually encountered in studies of this type. Because intra-AcbSh injections of muscimol induce intense Fos expression in all of the structures listed above, we will also use the ICD design to determine the manner in which lesions of these structures alter the patterns of neuronal activation produced by the intra- AcbSh injections. We will also establish whether LH neurons activated by intra-AcbSh muscimol project directly to the Arc or PVN. Additional studies will examine whether the feeding response can be altered by intracerebral injections of orexin and neuropeptide Y antagonists, and whether bicuculline injections into the VPm induce Fos expression and feeding similar to that seen after muscimol injections in the AcbSh. The prevalence of obesity and eating disorders has made these conditions a major public health concern and progress in treating them depends on our having a detailed understanding of the brain mechanisms controlling feeding. The results of these investigations will allow us to understand more clearly the functional organization of brain mechanisms that regulate feeding behavior and may provide information critical to the effort to discover effective treatments to reduce the suffering caused by dysregulation of feeding in humans. ? ? ? ?
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