Anatomy of neuroendocrine peptide pathways in brain

促肾上腺皮质激素释放因子(CRF)家族信号分子由四个配体(CRF和UCNs 1-3)、两个受体(CRFR1和-R2)和一个结合蛋白(CRFBP)组成。这个家族被认为在整合内分泌、自主神经和行为对压力的反应中扮演着关键和互动的角色。中枢自主神经系统(CAS)是一个相互联系的大脑结构网络，它含有与应激相关的CRF/UCN活动的敏感部位，但其组成部分通常缺乏或缺乏相关的配体和/或受体表达。我们的目标是阐明为应激诱导的CAS激活提供功能解剖组织，通过确定处置和 特定位置的特定信号分子的作用，为该回路在一系列挑战范例中的招募提供了条件。将在光学和电子显微镜水平上使用免疫定位方法来确定CRFR如何在CAS组分中分布，以及它们与含有配体的末端区域的关系。我们将与该计划的其他组成部分合作，寻找富含CAS的新型CRFR的证据，如果成功，将确定其在CAS电路中的分布和作用。组织化学和解剖学方法将被用来确定CAS中CRFR1和R2机制相互作用以塑造应激反应的分子靶点和位置，并确定潜在的回路。在基因操纵的小鼠模型中的药物操纵将被用来追踪意外的 CRFBP在中科院信令中的作用。解剖学和功能研究将寻求为新发现的可溶性CRFR2变异体提供背景。最后，我们将探索最近发现的CRFR2选择性配体UCN 2和UCN 3未能激活同源受体表达位点的一系列可能的解释。我们将比较表达UCN1、UCN2和UCN3的细胞组对一系列挑战范例的差异反应程度，并使用零突变系来探索每个肽系统在CAS对压力的反应中的作用。研究中的CMS系统在应激适应中起着重要的生理作用，其功能障碍与自身免疫性疾病、高血压和年龄相关的学习和记忆障碍等多种病理机制有关，并与一系列情感障碍的病因有关，包括神经性厌食症和严重抑郁症。

The corticotropin-releasing factor (CRF) family of signaling molecules comprises four ligands (CRF, and urocortins (Ucns) 1-3), two receptors (CRFR1 and -R2) and a binding protein (CRFBP). This family is thought to play critical and interactive roles in the integration of endocrine, autonomic and behavioral responses to stress. An interconnected network of brain structures, termed the central autonomic system (CAS), harbors sensitive sites of stress-related CRF/Ucn action, but its components are generally lacking or impoverished in relevant ligand and/or receptor expression. Our goal is to clarify the functional anatomical organization that provides for generalized stress-induced CAS activation, by ascertaining the disposition and role of specific signaling molecules in specific locations that provide for recruitment of this circuitry in a range of challenge paradigms. Immunolocalization methods will be used at the light and electron microscopic levels to determine how CRFRs are distributed in CAS components, and their relation to ligand-containing terminal fields. We will work with other components of the program to pursue evidence of a novel CRFR enriched in CAS, and if successful, determine its distribution and role in CAS circuitry. Histochemical and anatomical methods will be used to identify molecular targets and sites within the CAS at which CRFR1 and R2 mechanisms interact to sculpt stress responses, and to identify the underlying circuitry. Pharmacologic manipulations in genetically manipulated mouse models will be used to pursue indications of an unexpected role for the CRFBP in signaling in the CAS. Anatomical and functional studies will seek to provide a context for a newly discovered soluble CRFR2 variant. Finally, we will explore a range of possible explanations for the failure of recently discovered CRFR2-selective ligands, Ucn 2 and 3, to activate sites of cognate receptor expression. We will compare the extent to which Ucn 1, 2 and 3-expressing cell groups may be differentially responsive to a range of challenge paradigms, and employ null mutant lines to probe the roles of each peptide system in CAS responses to stress. The CMS systems under scrutiny here play essential physiologic roles in stress adaptation, dysfunction of which has been linked to such diverse pathologies as autoimmune disease, hypertension and age-related deficits in learning and memory, and have been implicated in the etiology of a range of affective disorders, including anorexia nervosa and major depression.