Effects of Chronic Alcohol Exposure on Synaptic Plasticity in the Prefrontal Cort

长期酒精暴露对前额皮质突触可塑性的影响

• 批准号: 7923710
• 负责人: SVEN KROENER
• 金额: $ 18.93万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7923710
• 关键词: Action Potentials; Acute; Adult; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Animals; Behavior; Behavioral; Biological; Brain; Breathing; Calcium Channel; Characteristics; Chronic; Clinical; Complex; Data; Decision Making; Dendrites; Dependence; Development; Disease; Ethanol; Ethanol dependence; Excitatory Postsynaptic Potentials; Frequencies; Functional disorder; Glutamate Receptor; Glutamates; Health; Image; Impulsive Behavior; Knowledge; Lead; Long-Term Potentiation; Maintenance; Measures; Mediating; Mental Depression; Modeling; Molecular; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Outcome; Pharmaceutical Preparations; Plastics; Play; Prefrontal Cortex; Process; Property; Regulation; Relapse; Resolution; Role; Slice; Social Problems; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Therapeutic; Time; Withdrawal; addiction; alcohol effect; alcohol exposure; base; chronic alcohol ingestion; cognitive function; detector; drinking; drinking behavior; drug of abuse; executive function; experience; hippocampal pyramidal neuron; insight; neuroadaptation; neurotransmission; problem drinker; public health relevance; receptor function; research study; response; social; transmission process; vapor; voltage

DESCRIPTION (provided by applicant): The prefrontal cortex (PFC) is of critical importance for higher order cognitive functions and the organization of complex behaviors, including those related to addiction. In spite of clear clinical evidence that chronic alcohol consumption alters the activity and function of the PFC, surprisingly little is known about the underlying changes at the molecular and cellular level. Although altered glutamatergic neurotransmission in prefrontal- limbic circuits has been implicated in the development of addiction, virtually nothing is known regarding how chronic alcohol may induce aberrant plasticity within the PFC. An understanding of the alcohol-induced changes in PFC function requires knowledge of the changes in the properties of excitatory synaptic transmission and specifically NMDA receptor function. The over-arching hypothesis of this application is that chronic ethanol exposure induces homeostatic increases in NMDA receptors, which will affect the interplay between backpropagating action potentials and localized Ca2+-spikes that are required for spike timing-dependent plasticity, a physiologically relevant model of synaptic plasticity. Such changes could alter integrative properties and synaptic plasticity and may represent pathological neuroadaptations of PFC pyramidal neurons underlying alcohol dependence. Thus, the increased NM.D.AR activity after prolonged ethanol exposure may result in aberrant plasticity, which could contribute to a loss of response inhibition in the PFC that may underlie alcohol drinking behavior. We provide preliminary data that supports this idea. In the current exploratory R21 application, we will examine ethanol-induced changes in the synaptic plasticity of the PFC in acute brain slices from adult drug-naive mice and mice chronically exposed to alcohol. Alcohol consumption of mice will be measured in a limited-access paradigm and dependence will be induced by exposing animals to alcohol vapor in a chronic-intermittent fashion. Aim 1 will use current-clamp recordings to assess the effects of the homeostatic changes at the NMDA receptor on synaptic plasticity. Therefore, we will study spike-timing dependent plasticity (STDP; plasticity induced by pairing EPSPs with backpropagating action potentials) to study changes in the magnitude and induction threshold of long term potentiation (LTP) or depression (LTD). Aim 1.1 will establish the main effect (i.e., alterations in STDP in alcohol exposed animals) and its persistence over 1 week of withdrawal. Aim 1.2 will test whether changes at NMDA receptors shift the frequency dependence of the induction of STDP. In Aim 2 we will use a combination of current clamp recordings and high resolution Ca2+ imaging to investigate whether altered Ca2+ influx through NMDA receptors in basal dendrites (dendritic Ca2+ spikes) provides a mechanism for the hypothesized changes in STDP. Aim 2.2 tests the alternative hypothesis that voltage-gated Ca2+ channels are a main target of alcohol responsible for the hypothesized changes in STDP in Aim 1. PUBLIC HEALTH RELEVANCE: The prefrontal cortex is critically involved in the regulation of higher order cognitive functions and disturbances in these processes may underlie a loss of control over alcohol drinking behavior. The experiments in this project will use an animal model of alcohol addiction to study changes in glutamatergic synaptic transmission and NMDA receptor function in the prefrontal cortex. These studies will provide insights into the mechanisms that underlie synaptic plasticity during the development and maintenance of addiction to alcohol.

描述（由申请人提供）：前额叶皮层（PFC）对于高级认知功能和复杂行为的组织至关重要，包括与成瘾相关的行为。尽管有明确的临床证据表明，长期饮酒会改变PFC的活性和功能，但令人惊讶的是，人们对分子和细胞水平的潜在变化知之甚少。虽然改变了前额叶-边缘系统回路的多巴胺能神经传递已被牵连在成瘾的发展，几乎没有什么是已知的慢性酒精如何可能会引起异常可塑性PFC内。了解酒精诱导的PFC功能的变化需要知识的兴奋性突触传递的特性，特别是NMDA受体功能的变化。本申请的过度假设是，慢性乙醇暴露诱导NMDA受体的稳态增加，这将影响反向传播动作电位和局部Ca 2+尖峰之间的相互作用，这是尖峰时间依赖性可塑性（突触可塑性的生理相关模型）所需的。这种变化可能会改变整合特性和突触可塑性，并可能代表病理性神经适应PFC锥体神经元的酒精依赖。因此，增加NM.D.AR活性后，长期乙醇暴露可能会导致异常的可塑性，这可能有助于在PFC的反应抑制，可能是饮酒行为的基础损失。我们提供的初步数据支持这一想法。在目前的探索性R21应用中，我们将研究酒精诱导的PFC突触可塑性变化，在急性脑切片从成年药物幼稚小鼠和小鼠长期暴露于酒精。将在有限进入模式中测量小鼠的酒精消耗，并通过以慢性-间歇方式将动物暴露于酒精蒸汽来诱导依赖性。目的1将使用电流钳记录来评估NMDA受体的稳态变化对突触可塑性的影响。因此，我们将研究尖峰时间依赖性可塑性（STDP;通过配对EPSP与反向传播动作电位诱导的可塑性），以研究长时程增强（LTP）或抑郁（LTD）的幅度和诱导阈值的变化。目标1.1将确定主效应（即，酒精暴露动物中STDP的改变）及其在1周内的持续性。目的1.2将测试NMDA受体的变化是否改变STDP诱导的频率依赖性。在目的2中，我们将使用电流钳记录和高分辨率钙离子成像的组合，以调查是否改变钙离子通过NMDA受体在基底树突（树突钙离子峰）流入STDP的假设变化提供了一种机制。目的2.2检验备择假设，即电压门控性Ca 2+通道是负责目的1中STDP假设变化的酒精的主要靶点。 公共卫生相关性：前额叶皮层是重要的参与调节高级认知功能和干扰，在这些过程中可能会失去控制的饮酒行为。本项目的实验将使用酒精成瘾的动物模型来研究前额叶皮层中的谷氨酸能突触传递和NMDA受体功能的变化。这些研究将为酒精成瘾的发展和维持过程中突触可塑性的基础机制提供见解。