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: 8088489
• 负责人: Jonathan L Brigman
• 金额: $ 16.68万
• 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/8088489
• 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. PUBLIC HEALTH RELEVANCE: Alcohol disorders represent a major health issue in the United States as 17.6 million people (H 1 in every 12 adults) abuse alcohol or are alcohol dependent. Current theories of dependence suggest that increases in habitual drug and alcohol seeking during the cycle of dependence may be caused by dysfunction in circuits connecting cortical and striatal brain areas. This project seeks to understand how these systems mediate behavior in the mouse, in order to provide a unique model for investigating the genetic and environmental factors underlying alcohol abuse and dependence.

描述（由申请人提供）：皮质纹状体网络和 NMDAR 对小鼠习惯性和灵活动作的调节。 拟议研究的目的是调查调节习惯性和灵活行动平衡的神经回路，这种平衡被认为在酒精依赖中会发生功能障碍。尽管对其他物种的研究提供了强有力的证据，表明这些行为是由连接皮质和纹状体亚区域的网络介导的，但这一点在小鼠中尚未得到很好的证实。为了让酒精研究充分利用小鼠模型所允许的分子和遗传技术，必须首先确定这些回路在该物种中的作用。我建议通过使用将传统技术（损伤和微输注）与新兴遗传和电生理学技术相结合的综合方法来阐明小鼠习惯性和灵活动作背后的网络和分子机制。为了做到这一点，我提出了三个具体目标 1) 确定皮质纹状体网络的参与和 NMDAR 对小鼠良好学习和灵活行为的调节。为了实现这一目标，我建议绘制内源性激活模式图，并检查小鼠执行一项需要习惯性和灵活动作的任务（视觉辨别和逆转）时子区域特定病变的影响。此外，将使用条件 GluN2B 突变小鼠模型测试皮质纹状体亚区 NMDAR 亚基缺失对习惯性和灵活性表现的影响。 2. 检查皮质纹状体网络的体内电生理活动以及 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 条件突变模型中执行辨别逆转任务期间，对皮质和纹状体亚区域的神经元活动进行体内记录。 3. 检查执行控制的高阶测量期间皮质纹状体网络的体内电生理活动。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，执行直接改编自用于测量临床人群执行控制的操作任务：视觉设定转换。总而言之，这些具体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如何在酒精滥用和依赖中失调提供坚实的基础。 在我的研究生培训和进修期间，我发展了必要的科学设计和行为知识，以完成所提议的实验取得成功所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研究生，我接受了使用转基因和突变小鼠模型的操作行为任务进行神经科学研究的设计和实施基础知识的培训，并获得了立体定位外科手术和组织学技术的经验。在 NIAAA 期间，在 Andrew Holmes 博士的指导下，我接受了广泛的实践培训，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，包括在清醒的行为动物中植入留置引导插管和微量输注生物活性药物。 该提案的指导阶段将在 NIAAA 的校内临床和生物学研究部门进行，由 Andrew Holmes 博士和 David Lovinger 博士共同指导。 Holmes 博士在行为神经科学技术方面拥有丰富的专业知识，并拥有完善的研究计划，利用行为范式利用小鼠模型研究成瘾和神经病理学背后的遗传和环境因素。 Lovinger 博士是利用体内和离体电生理学研究酒精和药物滥用目标的领导者。该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、组织学资源和用于体内记录的多通道采集系统。校内项目中的培训和职业发展资源，例如每周实验室会议、由该领域领先科学家举办的系列研讨会、职业发展研讨会以及负责任的研究培训，使 NIAAA 成为进行提案指导阶段的绝佳科学环境。 公共健康相关性：酒精障碍是美国的一个主要健康问题，因为有 1760 万人（每 12 名成年人中就有 1 人）滥用酒精或酒精依赖。目前的依赖理论表明，在依赖周期期间习惯性吸毒和酗酒的增加可能是由于连接皮质和纹状体大脑区域的回路功能障碍引起的。该项目旨在了解这些系统如何介导小鼠的行为，以便为研究酒精滥用和依赖背后的遗传和环境因素提供独特的模型。