Regulation of Cocaine Reward and Reinforcement by MeCP2

MeCP2 对可卡因奖励和强化的监管

• 批准号: 8996558
• 负责人: Anne Elizabeth West
• 金额: $ 34.71万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8996558
• 关键词: Address; Adult; Amphetamines; Behavior; Behavioral; Biological Testing; Brain; Cells; Chromatin; Chronic; Cocaine; Cocaine Abuse; Cocaine Dependence; Complex; Corpus striatum structure; DNA-Binding Proteins; Data; Development; Disease; Dose; Drug Addiction; Equilibrium; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Health; Immediate-Early Genes; Interneuron function; Interneurons; Knock-in Mouse; Lead; Left; Link; Methyl-CpG-Binding Protein 2; Molecular; Motivation; Mus; Mutant Strains Mice; Mutation; Neuronal Plasticity; Neurons; Nucleus Accumbens; Outcome; Output; Parvalbumins; Phosphorylation; Population; Predisposition; Process; Property; Psychological reinforcement; Regulation; Rewards; Rodent; Role; Schedule; Self Administration; Site; Societies; Synapses; Testing; Transgenic Organisms; Virus; addiction; base; cell type; cocaine exposure; combat; cost; gene induction; gene product; genetic regulatory protein; insight; knock-down; neural circuit; neurobiological mechanism; neuronal circuitry; neuronal excitability; novel; novel therapeutics; programs; psychostimulant; recombinase; research study; response; synaptic function

DESCRIPTION (provided by applicant): Chronic cocaine abuse arises as a result of persistent cocaine-induced adaptations in the function of neurons within mesolimbocortical brain reward circuits. An understanding of the molecular mechanisms by which cocaine alters the function of these neural circuits may lead to development of novel therapies for the treatment of cocaine addiction. The overall hypothesis of this proposal is that cocaine exerts long-lasting effects on behavior by inducing the transcription of new gene products in the nucleus accumbens (NAc) that change the excitability and/or synaptic connectivity of NAc neurons. We have shown that genetically manipulating the expression of the methyl-DNA binding protein MeCP2 in specific regions of the adult striatum modulates the ability of cocaine and the related psychostimulant amphetamine to induce addictive-like behaviors in rodents. Furthermore, we find that cocaine induces phosphorylation of MeCP2 at Ser421 (pMeCP2) selectively in parvalbumin (Pv)-positive fast-spiking GABAergic interneurons (FSIs) in the NAc. The objective of this proposal is to test the novel hypothesis that phosphorylation of MeCP2 in FSIs provides a mechanism to link cocaine exposure with transcription-dependent changes in striatal circuit function that limit the rewarding properties of cocaine. To address this hypothesis, in Aim 1 we will test the consequences of MeCP2 phosphorylation on the rewarding and reinforcing properties of cocaine by assessing cocaine self-administration (SA) in mice bearing a mutation knocked into the Mecp2 gene that changes Ser421 to Ala, rendering MeCP2 non-phosphorylatable at this site. In Aim 2 we will test the hypothesis that MeCP2 acts in FSIs in the NAc to limit cocaine SA. We will achieve this goal by stereotaxically injecting LoxP-conditional viruses into the NAc of adult mice from a transgenic strain that expresses the Cre recombinase in Pv-positive neurons. We will use these viruses to manipulate MeCP2 expression and phosphorylation in these cells as a means to alter FSI function and we will determine the effects of these manipulations on cocaine SA. Finally in Aim 3 we will test the hypothesis that pMeCP2 regulates a striatal plasticity that limits cocaine SA by modulating the inducibility of immediate-early genes in FSIs of the NAc. The outcome of our study will be the experimental demonstration of a specific circuit-based mechanism by which the chromatin regulatory protein MeCP2 limits cocaine reward. These studies promise to yield significant new insights into the neurobiological mechanisms that impact susceptibility to cocaine addiction.

描述（由申请人提供）：由于可卡因诱导的适应性可卡因滥用，因此在中脂型脑中脑奖励电路中神经元的功能进行了适应。对可卡因改变这些神经回路功能的分子机制的理解可能导致开发可卡因成瘾治疗的新型疗法。该提议的总体假设是可卡因通过在伏隔核（NAC）中诱导新基因产物的转录来改变NAC神经元的兴奋性和/或突触连接性，从而对行为产生持久影响。我们已经表明，遗传操纵成年纹状体特定区域中甲基-DNA结合蛋白MECP2的表达调节可卡因和相关的心理刺激二苯丙胺在啮齿动物中诱导成瘾性行为的能力。此外，我们发现可卡因在白细胞蛋白（PV）中有选择地诱导MECP2在SER421（PMECP2）上磷酸化 - NAC中的阳性快速加速GABA能中间神经元（FSIS）。该提案的目的是检验新的假设，即FSIS中MECP2的磷酸化提供了一种将可卡因暴露与纹状体电路功能的转录依赖性变化联系起来的机制，从而限制了可卡因的奖励性质。为了解决这一假设，在目标1中，我们将测试MECP2磷酸化对可卡因的奖励和增强可卡因特性的后果，通过评估可卡因自我给药（SA）中的MICE中的可卡因自我给药（SA），该突变撞击了MECP2基因中的MeCP2基因，该基因将Ser421变化为ALA，将MECP2 Nor-P2 norphopp2 norphosp2 artopphorpations at phospapp2 phosstim phosstim phostopticalloseptim phospp2。在AIM 2中，我们将检验以下假设：MECP2在NAC中起作用FSI以限制可卡因SA。我们将通过立体定义地将LOXP条件病毒从转基因菌株中表达为PV阳性神经元中的CRE重组酶的成年小鼠NAC来实现这一目标。我们将使用这些病毒在这些细胞中操纵MECP2表达和磷酸化，以改变FSI功能，我们将确定这些操纵对可卡因SA的影响。最后，在AIM 3中，我们将测试以下假设：PMECP2调节纹状体可塑性，该纹状体可卡因SA通过调节NAC FSIS中立即呈现基因的诱导性来限制可卡因SA。我们研究的结果将是一种基于特定电路的机制的实验证明，染色质调节蛋白MECP2限制了可卡因奖励。这些研究有望对影响可卡因成瘾易感性的神经生物学机制产生重大的新见解。