Corticostriatal networks and NMDAR mediation of habitual and flexible action

皮质纹状体网络和 NMDAR 对习惯性和灵活行动的调节

• 批准号: 8325063
• 负责人: Jonathan L Brigman
• 金额: $ 16.57万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8325063
• 关键词: Acute; Adult; Alcohol abuse; Alcohol dependence; Alcohols; Animals; Area; Association Learning; Behavior; Behavioral; Behavioral Paradigm; Brain; Cannulas; Chronic; Clinical; Clinical Research; Complex; Corpus striatum structure; Dependence; Development; Discrimination; Discrimination Learning; Disease; Dissection; Drug Addiction; Drug abuse; Educational workshop; Electrophysiology (science); Environment; Environmental Risk Factor; Equilibrium; Fellowship; Foundations; Functional disorder; Future; Genetic; Genetic Techniques; Glutamates; Goals; Habits; Health; High Pressure Liquid Chromatography; Histological Techniques; Infusion procedures; Intramural Research Program; Knowledge; Laboratories; Learning; Lesion; Maps; Measures; Mediating; Mediation; Mentors; Mentorship; Modeling; Molecular; Molecular Genetics; Mus; Mutant Strains Mice; N-Methyl-D-Aspartate Receptors; National Institute on Alcohol Abuse and Alcoholism; Neurons; Neurosciences; Neurosciences Research; Operative Surgical Procedures; Pattern; Performance; Pharmaceutical Preparations; Phase; Play; Population; Process; Recruitment Activity; Research; Resources; Reversal Learning; Role; Scientist; Series; Staging; Surgical Equipment; Synapses; System; Taxes; Techniques; Testing; Tissues; Training; Transgenic Organisms; United States; Visual; Western Blotting; Work; addiction; alcohol research; alcohol seeking behavior; animal care; awake; behavior measurement; behavioral impairment; biological research; career development; design; drug of abuse; executive function; experience; flexibility; genetic manipulation; graduate student; habit learning; implantation; in vivo; loss of function; meetings; memory process; mouse model; mutant; mutant mouse model; neuropathology; novel; programs; research study; responsible research conduct; theories; tool

DESCRIPTION (provided by applicant): Corticostriatal networks and NMDAR mediation of habitual and flexible action in the mouse. The objective of the proposed research is to investigate the neurocircuitry modulating the balance of habitual and flexible action that is thought to be dysfunctionally altered in alcohol dependence. Although studies in other species have provided strong evidence that these behaviors are mediated by networks connecting cortical and striatal subregions, this has not been well established in the mouse. In order for alcohol research to take full advantage of the molecular and genetic techniques that mouse models permit it is essential to first establish the role of these circuits in that species. I propose to elucidate the networks and molecular mechanism underlying habitual and flexible action in the mouse by using an integrative approach that combines traditional techniques (lesion and microinfusion) with emerging genetic and electrophysiological techniques. In order to do this, I propose three specific aims 1) Determine the involvement of corticostriatal networks and NMDAR mediation of well-learned and flexible behavior in the mouse. To accomplish this aim I propose to map endogenous activation patterns and examine the effects of subregion specific lesions in mice performing a task that requires both habitual and flexible action: visual discrimination and reversal. Further, the effects of NMDAR subunit loss in corticostriatal subregions on habitual and flexible performance will be tested using a conditional GluN2B mutant mouse model. 2. Examine in vivo electrophysiological activity of corticostriatal networks and the role of NMDAR during well- learned and flexible behavior. To accomplish this aim I propose to perform in vivo recording of neuronal activity in cortical and striatal subregions during performance of the discrimination-reversal task in both non-mutant mice and the GluN2B conditional mutant model. 3. Examine in vivo electrophysiological activity of corticostriatal networks during higher-order measures of executive control. In order to complete this aim I propose to perform electrophysiological recording in non-mutant and GluN2B mutant mice performing an operant task directly adapted from those used to measure executive control in clinical populations: visual set-shifting. Taken together, the completion of these specific aims will provide strong evidence for the role of corticostriatal networks and NMDAR in the mediation of flexible and habitual actions and provide a strong foundation for future studies investigating how these systems are dysregulated in alcohol abuse and dependence. During my graduate training and fellowship I developed the knowledge of scientific design and conduct necessary to complete the mentored training and development necessary to succeed in the proposed experiments. As a graduate student in the laboratory of Dr. Lawrence Rothblat I was trained in the fundamentals of design and conduct of neuroscience research using operant behavioral tasks with transgenic and mutant mouse models and gained experience in stereotaxic surgical procedures and histological techniques. During my fellowship at NIAAA under the mentorship of Dr. Andrew Holmes I have received extensive hands-on training in a broad range of behavioral measures and a variety of techniques for acute and chronic systemic drug administration as well as tissue micro-dissection for western blotting and high pressure liquid chromatography. In addition I have expanded his surgical techniques to include implantation of indwelling guide cannulae and micro-infusion of bioactive drugs in awake behaving animals. The mentored phase of the proposal will be conducted in the Division of Intramural Clinical and Biological Research at NIAAA under the mentorship of Dr. Andrew Holmes and the co-mentorship of Dr. David Lovinger. Dr. Holmes has extensive expertise in behavioral neuroscience techniques and a well-established research program using behavioral paradigms to investigate genetic and environmental factors underlying addiction and neuropathology using mouse models. Dr. Lovinger is a leader in studying the targets of alcohol and drugs of abuse using in vivo and ex vivo electrophysiology. This environment will provide all the necessary resources necessary to complete the research goals including, but not limited to behavioral apparatus, surgical equipment and animal care, histological resources and multi-channel acquisition systems for in vivo recording. The training and career development resources in the intramural program such as weekly laboratory meetings, seminar series conducted by leading scientists in the field, career development workshops, and training in the responsible conduct of research, make NIAAA an excellent scientific environment for conducting the mentored phase of the proposal.

描述(由申请人提供)：皮质纹状体网络和NMDAR调节小鼠习惯性和灵活的行动。这项拟议的研究的目的是调查调节习惯性和灵活性动作平衡的神经回路，这些动作被认为在酒精依赖中发生了功能障碍的改变。尽管对其他物种的研究提供了强有力的证据表明，这些行为是通过连接皮质和纹状体亚区的网络来调节的，但这一点在小鼠身上还没有得到很好的证实。为了让酒精研究充分利用小鼠模型允许的分子和遗传技术，首先确定这些回路在该物种中的作用是至关重要的。我建议使用一种结合传统技术(损伤和显微输注)与新兴的遗传和电生理技术的综合方法来阐明小鼠习惯性和灵活性行为背后的网络和分子机制。为此，我提出了三个具体目标：1)确定皮质纹状体网络和NMDAR对小鼠习得性和灵活性行为的调节作用。为了实现这一目标，我建议绘制内源性激活模式图，并在执行一项既需要习惯性动作又需要灵活动作的小鼠身上检查次区域特定病变的影响：视觉辨别和反转。此外，将使用条件性GluN2B突变小鼠模型来测试皮质纹状体亚区NMDAR亚单位丢失对习惯性和灵活性表现的影响。2.在体内检测皮质纹状体网络的电生理活动，以及NMDAR在良好学习和灵活行为中的作用。为了实现这一目标，我建议在非突变小鼠和GluN2B条件突变模型中，在执行辨别-逆转任务期间，对皮质和纹状体亚区的神经元活动进行活体记录。3.在执行控制的高阶措施中，检查体内皮质纹状体网络的电生理活动。为了实现这一目标，我建议在非突变和GluN2B突变小鼠中进行电生理记录，执行一项直接适用于临床人群中用于测量执行控制的可操作性任务：视觉定势转移。综上所述，这些特定目标的完成将为皮质纹状体网络和NMDAR在调节灵活和习惯性行为中的作用提供强有力的证据，并为未来研究这些系统在酒精滥用和依赖中是如何失调的提供了坚实的基础。在我的研究生培训和奖学金期间，我发展了必要的科学设计和指导知识，以完成在拟议的实验中取得成功所必需的指导培训和发展。作为劳伦斯·罗斯布拉特博士实验室的一名研究生，我接受了神经科学研究的基础知识培训，使用转基因和突变小鼠模型进行操作行为任务，并在立体定向手术程序和组织学技术方面积累了经验。在我担任NIAAA研究员期间，在安德鲁·霍姆斯博士的指导下，我接受了广泛的实践培训，内容涉及广泛的行为测量和各种急性和慢性全身给药技术，以及用于蛋白质印迹和高压液相色谱的组织显微解剖。此外，我还扩展了他的外科技术，包括植入留置导尿管和在清醒行为的动物身上微量输注生物活性药物。该提案的指导阶段将在NIAAA的内科临床和生物研究部进行，由安德鲁·霍姆斯博士指导和大卫·洛文格博士共同指导。霍姆斯博士在行为神经科学技术方面拥有广泛的专业知识，并有一个成熟的研究项目，使用行为范式，利用小鼠模型研究成瘾的遗传和环境因素以及神经病理学。洛文格博士是利用体内和体外电生理学研究酒精和药物滥用目标的领先者。这种环境将提供完成研究目标所需的所有必要资源，包括但不限于行为仪器、手术设备和动物护理、组织学资源和用于活体记录的多渠道采集系统。NIAAA内部计划中的培训和职业发展资源，如每周一次的实验室会议、该领域领先科学家举办的系列研讨会、职业发展研讨会和负责任的研究指导培训，使NIAAA成为实施提案指导阶段的良好科学环境。