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）对于高阶认知功能和复杂行为的组织（包括与成瘾有关的行为）至关重要。尽管有明确的临床证据表明慢性酒精消耗改变了PFC的活性和功能，但令人惊讶的是，对于分子和细胞水平下的基本变化知之甚少。尽管前额叶环路中谷氨酸能神经传递的改变已与成瘾的发展有关，但实际上，关于慢性酒精如何在PFC内诱导异常可塑性的几乎没有任何了解。对酒精诱导的PFC功能变化的理解需要了解兴奋性突触传播的性质变化，特别是NMDA受体功能。该应用的架构假设是，慢性乙醇暴露会诱导NMDA受体的稳态增加，这将影响反向传播的动作电位与峰值时间依赖性可变性所需的局部CA2+旋转之间的相互作用，这是一种与生理学相关的突触塑性模型。这种变化可以改变整合性和突触可塑性，并可能代表酒精依赖性的PFC锥体神经元的病理神经适应。因此，长时间乙醇暴露后的NM.D.AR活性增加可能会导致异常可塑性，这可能导致PFC中可能抑制饮酒行为的反应抑制。我们提供支持这一想法的初步数据。在当前的探索性R21应用中，我们将检查乙醇诱导的急性药物小鼠急性脑切片中PFC突触可塑性的变化，并长期暴露于酒精。小鼠的酒精消耗将以有限的范围范围进行测量，并通过以长期的期限将动物暴露于酒精蒸气来诱导依赖性。 AIM 1将使用电流钳记录来评估NMDA受体对突触可塑性的稳态变化的影响。因此，我们将研究依赖性可塑性（STDP；通过将EPSP与反向传播的动作电位配对引起的可塑性）以研究长期增强（LTP）或抑郁（LTD）的幅度和诱导阈值的变化。 AIM 1.1将建立主要效果（即酒精暴露的动物中STDP的改变）及其在退出1周内的持久性。 AIM 1.2将测试NMDA受体的变化是否会改变STDP诱导的频率依赖性。在AIM 2中，我们将使用当前的夹具记录和高分辨率Ca2+成像的组合来研究基础树突中NMDA受体（树突状CA2+ SPIKES）是否通过NMDA受体的变化，为STDP的假设变化提供了一种机制。 AIM 2.2测试是替代假设，即电压门控Ca2+通道是饮酒的主要目标，负责AIM 1中STDP的假设变化。 公共卫生相关性：前额叶皮层与这些过程中高阶认知功能和干扰的调节有关，这可能是失去对饮酒行为的控制的基础。该项目中的实验将使用酒精成瘾的动物模型来研究前额叶皮层中谷氨酸能突触传播和NMDA受体功能的变化。这些研究将提供有关在对酒精成瘾的发展和维持过程中突触可塑性基础的机制的见解。