Theperioculomotor area (pili) is the main source of neuropeptide Urocortin 1 (Ucn1 lin the brain. Ucn1 is an endogenous peptide related to the corticotropin-releasing factor (CRF) that has higher affinity to CRF receptors than CRF itself. In addition to the Ucn1-containing cells of pili (plllu), theplll area also contains a population of dopaminergic neurons (pillda). Experiments perfornied in the previous years of this R01 have strongly confirmed the involvement of pili neurons in the regulation of alcohol consumption. Definitive evidence for this involvement accumulated across four lines of research: 1) the piliu neurons are preferentially activated following alcohol self-administration in mice and rats;2) Ucn1 immunoreactivity in piliu is positively correlated with alcohol intake in selectively-bred mouse and rat lines;3) electrolytic lesions of pili selectively block alcohol preference in C57BLl6J mice;4) microinjection of Ucn1 into the lateral septum, one of the target areas of plllu, selectively attenuates alcohol intake. Taken together these studies robustly implicate the pili neurons in the regulation of alcohol consumption. This application proposes to extend these studies to understand the mechanisms of this regulation. We hypothesize that pllldapromotes alcohol consumption, while plllu decreases alcohol consumption through their respective central projections. The main goal of this study is to address our hypothesis by characterizing the projectioTIs from pilida and plllu, and by testing the role of pilida in alcohol intake. To achieve thisgoal we prOpose three specific aims: 1) To characterize the distribution of prOjections from the piliu and pilida area of inbred C57BLl6J (C57) mice using neuroanatdrnical tracing approaches;2) To test whether the effects of pili lesions on alcohol intake are independent of the functions of Ucn1 using Ucn1 knockout mice;3) To test the importance of pilida in alcohol consumption using intracranial injections of dopamine agonists into pili of C57 mice. These studies will provide novel important information indicating how these recently identified neurons robustly regulate alcohol intake.
The neural mechanisms leading to alcoholism are still poorly understood. An increasing number of studies indicate that the perioculomotor area, a recently identified brain region, plays an important role in regulating of alcohol intake. This project uses rodent models to identify connections of neural cells in this brain area and test their involvement in regulation of alcohol intake. The success of these studies may provide new insights into mechanisms of alcoholism and suggest new therapeutic treatments of this disorder.
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