Examining Neurocircuit and Behavioral Effects in a Developmental Model for Indirect Pathway Hypofunction

检查间接通路功能障碍发育模型中的神经回路和行为效应

• 批准号: 10687115
• 负责人: Pedro Rabelo Olivetti
• 金额: $ 19.55万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-09-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687115
• 关键词: ADORA2A gene; Academic Medical Centers; Address; Adult; Affect; Agonist; Animals; Antipsychotic Agents; Attention; Balsams; Basal Ganglia; Behavior; Behavioral; Binding; Biological Models; Clozapine; Cognition; Cognitive; Cognitive deficits; Computer Analysis; Corpus striatum structure; Coupled; Cre driver; Data; Data Set; Development; Development Plans; Devices; Disease; Doctor of Philosophy; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dorsal; Early Intervention; Etiology; Fiber; Foundations; Functional disorder; Future; Ganglia; Genetic; Globus Pallidus; Goals; Head; Human; Image; Impaired cognition; Impairment; Injections; K-Series Research Career Programs; Laboratory Research; Lead; Life; Ligands; Link; Measurement; Measures; Medial; Mental disorders; Mentorship; Methods; Midbrain structure; Modeling; Motivation; Mus; Neonatal; Neurodevelopmental Disorder; Neurons; Neurosciences; New York; Nucleus Accumbens; Oxides; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Photometry; Physicians; Play; Prefrontal Cortex; Preventive; Psychiatry; Psychoses; Psychotic Disorders; Receptor Signaling; Receptor Up-Regulation; Research; Research Personnel; Resistance; Rewards; Risk; Risk Assessment; Risk Factors; Role; Schizophrenia; Scientist; Shapes; Short-Term Memory; Signal Transduction; Stimulus; Substantia nigra structure; Symptoms; Synapses; System; Testing; Thinking; Time; Training; Universities; Up-Regulation; Ventral Tegmental Area; Viral; Viral Vector; Virus; Work; antagonist; base; burden of illness; calcium indicator; career; career development; cognitive performance; cognitive testing; complex data; design; dopamine system; dopaminergic neuron; experimental study; genetic approach; human imaging; imaging study; improved; in vivo; insight; mature animal; microendoscopy; motivated behavior; neonatal brain; neonatal mice; neuropsychiatric disorder; neurotransmitter release; novel; overexpression; pars compacta; postnatal; receptor; receptor function; receptor upregulation; response; sensor; willingness

Project Summary I am an MD/PhD physician-scientist trained in psychiatry and neuroscience. My career goal is to become an independent neuroscience investigator devoted to a mechanistic understanding the long-term contributions of altered neurodevelopmental trajectories to neuropsychiatric disorders. I ultimately hope that discoveries made in my lab will generate new ways to assess risk factors during early life, as well as spur novel treatment and preventive approaches to neuropsychiatric disorders—in particular schizophrenia (SCZ), a devastating disorder in which development is thought to play an important but poorly understood role. I have designed a research plan that is integrated with my training objectives and career development plan, and will propel me towards scientific independence. Using the mouse as my model system, the questions I intend to address in this K08 proposal are centered on how striatal pathway-specific perturbations during basal ganglia (BG) circuit formation can shape developmental trajectories and alter the character of BG circuit computations with lasting behavioral consequences. Dysfunctions in dopamine (DA) signaling in the striatum and prefrontal cortex have long been associated with motivational and cognitive deficits in humans. In the striatum, increased expression of dopamine D2 receptors (D2Rs) in indirect pathway neurons have been implicated in the etiology of SCZ, but developmental mechanisms remain limited4-7. Mouse studies have shown that a non-pathway-specific developmental D2R overexpression led to behavioral deficits that were associated with altered DA signaling from the midbrain on striatum and prefrontal cortex16, 17, 20, 47. Meanwhile, early postnatal chemogenetic inhibition (with hM4D activation) of indirect pathway resulted in restructuring of corticostriatal synapses lasting for at least ten days19— suggesting a developmental window for corticostriatal wiring that may shape behaviors dependent on this circuitry. In this K08 proposal, I will address these questions with two Specific Aims. In Aim 1, I will test the hypothesis that transiently inhibiting striatal indirect pathway neurons during an early postnatal developmental window will result in decreased motivation and impaired cognitive performance in adult mice. I have developed a stereotaxic neonatal adaptor that improves regional targeting with viral vectors1. Preliminary data suggest a developmental effect on motivated behavior. In Aim 2, I will test the hypothesis that the developmental manipulation leads to persistent circuit-level changes affecting long-term DA release in adults, possibly by altering midbrain neuronal activity. I will record real-time striatal DA release dynamics in freely behaving mice by fiberphotometry (FP). To examine midbrain neuronal activity in vivo, I propose Ca2+ imaging experiments in freely behaving animals, using a virally-encoded Ca2+ indicator, GCaMP6f, in midbrain neurons. I will conduct this project at the New York State Psychiatric Institute and Columbia University under the mentorship team of Drs. Christoph Kellendonk, Peter Balsam, Mark Ansorge, René Hen, Joshua Berke, and Jonathan Javitch. Through the completion of the training goals delineated in this career development award proposal, I will be prepared to transition into scientific independence leading a research laboratory in an academic medical center.

项目摘要 我是一名医学博士/博士，在精神病学和神经科学方面接受过培训。我的职业目标是成为一个独立的 神经科学研究者，致力于从机制上理解改变的长期贡献。 从神经发育轨迹到神经精神疾病我最终希望我实验室的发现 产生新的方法来评估生命早期的风险因素，以及刺激新的治疗和预防方法， 神经精神疾病-特别是精神分裂症（SCZ），一种破坏性的疾病，其中发展被认为是 扮演着一个重要但鲜为人知的角色。我已经设计了一个研究计划，与我的培训相结合 目标和职业发展计划，并将推动我走向科学独立。使用鼠标作为我的 模型系统，我打算在这个K 08建议中解决的问题集中在纹状体通路特异性 基底神经节（BG）回路形成过程中的扰动可以塑造发育轨迹，并改变神经元的特征。 BG电路计算与持久的行为后果。纹状体中多巴胺（DA）信号传导功能障碍 和前额叶皮层一直与人类的动机和认知缺陷有关。在纹状体， 间接通路神经元中多巴胺D2受体（D2 Rs）表达增加与病因学有关 的SCZ，但发展机制仍然有限4 -7。小鼠研究表明，非途径特异性 发育性D2 R过表达导致行为缺陷，这与来自发育期的DA信号改变有关。 中脑位于纹状体和前额叶皮质16，17，20，47.同时，出生后早期的化学发生抑制（用hM 4D 激活）的间接途径导致皮质纹状体突触的重建持续至少10天19- 这表明皮质纹状体布线的发育窗口可能会塑造依赖于此电路的行为。在这 K 08提案，我将以两个具体目标来解决这些问题。在目标1中，我将检验假设，即 在出生后早期发育窗期间抑制纹状体间接通路神经元将导致 动机和认知能力受损。我开发了一种立体定位新生儿适配器， 改善病毒载体的区域靶向1。初步数据表明，动机行为的发展效果。在 目的2，我将测试这一假设，即发展操纵导致持续的电路水平的变化，影响 成年人长期DA释放，可能通过改变中脑神经元活动。我会实时记录纹状体多巴胺的释放 通过纤维光度法（FP）测定自由行为小鼠中的动力学。为了研究体内中脑神经元的活动，我提出了Ca 2 + 在自由行为的动物中进行成像实验，使用病毒编码的Ca 2+指示剂GCaMP 6 f在中脑神经元中进行。 我将在导师团队的指导下在纽约州立精神病学研究所和哥伦比亚大学开展这个项目 Christoph Kellendonk博士、Peter Balsam博士、Mark Ansorge博士、René Hen博士、约书亚Berke博士和Jonathan Javitch博士。通过 完成本职业发展奖建议书中所划定的培训目标后，我将准备过渡到 在学术医学中心领导研究实验室的科学独立性。