Accumbal Synaptic Regulation and Bistability In The WID Mouse Model

WID 小鼠模型中的累积突触调节和双稳定性

• 批准号: 7493332
• 负责人: RICHARD A MORRISETT
• 金额: $ 22万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7493332
• 关键词: Adopted; Affinity; Alcohol consumption; Alcohol dependence; Alcohols; Amygdaloid structure; Animal Model; Animals; Antibodies; Bioinformatics; Boutos; Brain; Cell physiology; Cells; Chemosensitization; Chronic; Cocaine; Communication; Computer information processing; Condition; Confocal Microscopy; Corpus striatum structure; Data; Dependency; Depth; Development; Dorsal; Ethanol; Ethanol dependence; Exhibits; Frequencies; Genotype; Glutamate Receptor; Glutamates; Heavy Drinking; Image Analysis; Immunofluorescence Immunologic; Life; Maps; Measures; Mediating; Membrane Potentials; Mental Depression; Modeling; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor A1; Neurobiology; Neurons; Neuropeptides; Nucleus Accumbens; Process; Receptor Activation; Regulation; Research Personnel; Resources; Response to stimulus physiology; Self Administration; Shipping; Ships; Slice; Specificity; Standards of Weights and Measures; Stimulus; Structure; Subgroup; Synapses; Synapsins; Synaptic Receptors; Synaptic Transmission; Synaptic plasticity; Thinking; Time; Validation; Videoconferences; Videoconferencing; Water consumption; Wild Type Mouse; Withdrawal; Wolves; Work; addiction; alcohol exposure; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; base; behavioral sensitization; conditioning; design; drinking; experience; in vivo; interest; mouse model; neuroadaptation; patch clamp; postsynaptic; presynaptic; receptor; reinforcer; success; synaptic depression; transmission process; vapor

DESCRIPTION (provided by applicant): Glutamatergic synaptic transmission in the nucleus accumbens (NAc) has been implicated in neuroadaptive alterations which underlie the development of addiction to alcohol. In an animal model adopted by the INIA-West consortium (Withdrawal-induced drinking mouse model, hereafter termed WID experience), C57/BL6J mice that experienced 3 intermittent 16 hrethanol vapor exposures displayed a 2-3 fold enhancement in both shell and core NAc cFos expression and a marked increase in their ethanol intake over mice that experienced constant ethanol exposure. Our preliminary data indicate conditioning stimuli which normally induces NMDA-receptor dependent synaptic depression in wild-type mouse shell Nac medium spiny neurons (MSNs) instead induces a remarkable conversion to synaptic potentiation in nondrinking mice that had undergone a single bout of WID experience. This form of synaptic plasticity in shell NAc MSNs has also been implicated in the expression of behavioral sensitization to cocaine and therefore may represent a fundamental cellular process involved in neuroadaptation to ethanol and other reinforcers. Changes in the level of excitatory drive onto MSNs have been implicated in sustained upstates of the membrane potential or bistability recorded under current clamp conditions. Such shifts in excitability of these neurons are thought to be critically involved in information processing in mesolimbic structures and thus we propose that MSN bistability is an important electrophysiological process altered by WID experience and therefore important to the development of ethanol dependence. Finally, alterations in AMPA and NMDA receptor synaptic drive are implicated in ethanol dependence, synaptic plasticity as well as membrane potential bistability. Therefore, our overarching hypothesis is that WID experience induces alterations in excitatory synaptic drive mediated by aberrant plasticity of AMPA/NMDA receptors and that these changes in plasticity impact MSN function (bistability). Thus, we propose to perform a comprehensive analysis of the alterations in synaptic plasticity, membrane potential bistability and AMPA/NMDA receptor mediated synaptic transmission and receptor levels induced by WID experience in medium spiny neurons of the shell of the NAc. This project uses electrophysiological, immunofluorescent, confocal microscopy and co-localization image analysis to investigate these hypotheses.

描述（由申请人提供）：伏隔核（NAC）中的谷氨酸能突触传播与神经适应性改变有关，这些改变是对酒精成瘾发展的基础。在Inia-West Consortium采用的动物模型（戒断诱导的饮用小鼠模型，以下称为WID经验）中，C57/BL6J小鼠经历了3种间歇性16 hrethanol蒸气的暴露，在壳中表现出2-3倍的增强，在壳中的表达和不断增加的乙醇乙醇的eThanol eThanol eThanol eThanol eThanol extanol eThanol的曝光不断增加。我们的初步数据表明调节刺激通常会诱导野生型小鼠壳壳NAC中棘神经元（MSN）中的NMDA受体依赖性突触抑制，而是引起了非牵引小鼠突触增强的显着转化，使无需单一的宽度经验。壳NAC MSN中这种突触可塑性的这种形式也与可卡因的行为敏化表达有关，因此可能代表与乙醇和其他增强剂有关神经适应的基本细胞过程。在当前夹具条件下记录的膜电位或双态性的持续上升的兴奋性驱动水平的变化与持续的上山有关。这些神经元的兴奋性的这种转变被认为与中溶液结构中的信息处理有关，因此我们建议MSN的双重性是一个重要的电生理过程，它因wid经验而改变，因此对乙醇依赖性的发展很重要。最后，AMPA和NMDA受体突触驱动的改变与乙醇依赖性，突触可塑性以及膜潜在双重性有关。因此，我们的总体假设是WID经验引起了由AMPA/NMDA受体异常可塑性介导的兴奋性突触驱动器的改变，并且这些可塑性的变化会影响MSN功能（BISTAIBLY）。因此，我们建议对突触可塑性，膜潜在双重性和AMPA/NMDA受体介导的突触传递和受体水平的变化进行全面分析。该项目使用电生理，免疫荧光，共聚焦显微镜和共定位图像分析来研究这些假设。