Neuroplasticity of the Extended Amygdala CRF circuitry in alcohol dependence

酒精依赖中扩展杏仁核 CRF 回路的神经可塑性

基本信息

批准号：
8690687
负责人：
MARISA ROBERTO
金额：
$ 36.76万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8690687
关键词：
Acute Alcohol consumption Alcohol dependence Alcohol withdrawal syndrome Alcoholism Alcohols Amygdaloid structure Anxiety Area Brain Brain region Breathing CRF receptor type 1 Calcium-Binding Proteins Cell Nucleus Cells Characteristics Chronic Complex Corticotropin-Releasing Hormone Dependence Development Electrophysiology (science)Environment Ethanol Ethanol dependence Exhibits Glutamate Decarboxylase Glutamates Green Fluorescent Proteins Heterogeneity Human Resources Immunohistochemistry In Situ Hybridization Investigation Knowledge Mediating Mediator of activation protein Membrane Methodology Methods Microspheres Molecular Mus Neuronal Plasticity Neurons Neuropeptides Neurotransmitter Receptor Nucleus Accumbens Output Population Process Property Rattus Research Research Personnel Research Proposals Role Self Administration Sensory Shapes Sorting - Cell Movement Stress Structure of terminal stria nuclei of preoptic region Synapses Synaptic Transmission System Testing Thalamic structure Therapeutic Agents Transgenic Mice Vertebral column addiction alcohol effect alcohol exposure alcoholism therapy base biocytin cell type density gamma-Aminobutyric Acid innovation insight mouse model multidisciplinary negative emotional state neuroadaptation neurochemistry neuronal cell body neuronal circuitry novel novel therapeutics presynaptic public health relevance receptor stressor transmission process voltage

项目摘要

DESCRIPTION (provided by applicant): Recent research has highlighted the role of the central nucleus of the amygdala (CeA) and the recruitment of the corticotropin-releasing factor (CRF) system in the development of ethanol dependence. Particularly, CRF type 1 receptor (CRF1) antagonists block the anxiogenic effects and the increase in ethanol self-administration produced by stressors and ethanol withdrawal. Notably, chronic CRF1 antagonism abolishes dependence-induced escalation of ethanol drinking in rats exposed to chronic intermittent ethanol. We demonstrated that acute ethanol and CRF increase GABAergic transmission in mouse and rat CeA via CRF1 activation, and the effects of CRF and CRF1 antagonists on GABAergic transmission are enhanced in CeA neurons from ethanol-dependent rats. However, the CeA is comprised of heterogeneous cell types and technical limitations have precluded the identification and further characterization of neurons from which recordings were obtained. Thus, despite the vast knowledge accumulated on the CRF1-mediated effects of acute and chronic ethanol in this brain region, the underlying local neuronal microcircuitry needs to be delineated. Thus, in this research proposal we will use an innovative transgenic mouse model expressing green fluorescent protein (GFP) in neurons expressing CRF1 (CRF1:GFP mice) to compare the electrophysiological, neurochemical, morphological and hodological properties of CeA CRF1-expressing neurons to those of unlabeled neurons. Using electrophysiology in combination with histochemical and neurotracing methods, we will obtain novel information on functionality and connectivity of these neurons, thereby providing mechanistic insights into the role of the CRF system in the development of alcohol dependence. Drs. Contet and Mandyam, key personnel involved in the present study, possess all the necessary expertise needed to accomplish such a multidisciplinary project. A better understanding of the molecular mechanisms underlying ethanol effects and the neuroadaptations shaping the CRF neurocircuitry involved in ethanol-dependence represent a challenge to alcohol researchers and will be useful toward uncovering new therapeutic agents to alleviate alcoholism.

描述（由申请人提供）：最近的研究强调了杏仁核（CEA）中心核的作用以及促脂蛋白释放因子（CRF）系统在乙醇依赖性发展中的作用。特别是，CRF 1型受体（CRF1）拮抗剂阻止了压力源和退出乙醇产生的乙醇自我给药的焦虑作用和增加。值得注意的是，慢性CRF1拮抗作用消除了暴露于慢性间歇性乙醇的大鼠乙醇饮用的依赖性升级。我们证明，通过CRF1激活，急性乙醇和CRF增加了小鼠和大鼠CEA的GABA能传播，并且CRF和CRF1拮抗剂对乙醇依赖性大鼠的CEA神经元的CRF和CRF1拮抗剂对GABAERGIC传播的影响增强了。但是，CEA由异质细胞类型组成，技术局限性排除了获得记录的神经元的识别和进一步表征。因此，尽管在该大脑区域急性和慢性乙醇的CRF1介导的作用上积累了广泛的知识，但仍需要描述潜在的局部神经元微电路。因此，在这项研究建议中，我们将使用一种创新的转基因小鼠模型，该模型表达CRF1（CRF1：GFP小鼠）的神经元中表达绿色荧光蛋白（GFP），以比较这些表达CRF1神经元的电生理，神经化学，神经化学，形态学和HODOLOGITION未标记的神经元。使用电生理学与组织化学和神经接触方法结合使用，我们将获得有关这些神经元功能和连通性的新信息，从而为CRF系统在酒精依赖性发展中的作用提供了机械见解。博士。参与本研究的关键人员Contet和Mandyam拥有完成此类多学科项目所需的所有必要专业知识。更好地理解乙醇作用的分子机制以及构成乙醇依赖性涉及的CRF神经记录的神经适应性对酒精研究人员的挑战，并将有助于发现新的治疗药物来减轻酒精中毒。