Perioculomotor area and alcohol

眼周区（皮利）是脑内神经肽Urocortin 1（Ucn 1）的主要来源。Ucn 1是一种与促肾上腺皮质激素释放因子（CRF）相关的内源性肽，与CRF受体的亲和力高于CRF本身。除了含有Ucn 1的皮利细胞（plllu）外，plll区还含有多巴胺能神经元（pillda）。在前几年的R 01中进行的实验已经有力地证实了皮利神经元参与酒精消耗的调节。在四个方面的研究中积累了这一参与的连续证据：1）在小鼠和大鼠中，酒精自我给药后，纤毛神经元优先被激活; 2）在选择性繁殖的小鼠和大鼠品系中，纤毛中的Ucn 1免疫反应性与酒精摄入量呈正相关; 3）在C57 BL 16 J小鼠中，皮利的电解损伤选择性地阻断酒精偏好; 4）将Ucn 1微量注射到plllu的靶区域之一的侧隔中，选择性地减弱酒精摄入。综合这些研究，强烈暗示皮利神经元在酒精消耗的调节。本申请建议扩展这些研究，以了解这种调节的机制。我们假设plllda促进酒精消费，而plllu通过各自的中枢投射减少酒精消费。本研究的主要目的是通过描述纤毛和plllu的projectioTI，并通过测试纤毛在酒精摄入中的作用来解决我们的假设。为了达到这一目的，我们提出了三个具体的目标：1）用神经解剖学示踪方法来表征来自近交系C57 BL 16 J（C57）小鼠的纤毛和纤毛区的投射物的分布：2）用Ucn 1基因敲除小鼠来检验皮利损伤对酒精摄入的影响是否与Ucn 1的功能无关; 3）通过向C57小鼠的皮利颅内注射多巴胺激动剂来测试毛在饮酒中的重要性。这些研究将提供新的重要信息，表明这些最近发现的神经元如何有力地调节酒精摄入。

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.