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.

项目概要 我是一名医学博士/博士，接受过精神病学和神经科学方面的培训，我的职业目标是成为一名独立的人。 神经科学研究者致力于机械地理解长期贡献 我最终希望我的实验室的发现能够揭示神经精神疾病的神经发育轨迹。 产生评估生命早期风险因素的新方法，并刺激新的治疗和预防方法 神经精神疾病，尤其是精神分裂症 (SCZ)，这是一种破坏性的疾病，人们认为，在这种疾病中，发育会影响 发挥着重要但鲜为人知的作用，我设计了一个与我的培训相结合的研究计划。 目标和职业发展计划，并将推动我走向科学独立。 模型系统，我打算在这个 K08 提案中解决的问题集中在纹状体通路特异性如何 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其特征 纹状体多巴胺 (DA) 信号功能障碍的 BG 电路计算。 长期以来，前额皮质与人类的动机和认知缺陷有关。 间接通路神经元中多巴胺 D2 受体 (D2R) 表达增加与病因有关 SCZ，但发育机制仍然有限4-7。 发育性 D2R 过度表达导致行为缺陷，这与 DA 信号的改变有关 中脑纹状体和前额皮质16, 17, 20, 47。同时，出生后早期化学遗传学抑制（使用 hM4D 间接途径的激活）导致皮质纹状体突触的重组，持续至少十天19- 表明皮质纹状体接线的发育窗口可能会塑造依赖于该电路的行为。 K08 提案中，我将通过两个具体目标来解决这些问题。在目标 1 中，我将暂时检验假设。 在出生后早期发育窗口期间抑制纹状体间接通路神经元将导致 成年小鼠的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。 初步数据表明，病毒载体可改善区域靶向性。 目标 2，我将检验以下假设：发育操纵会导致持续的电路级变化影响 成人的长期 DA 释放，可能通过改变中脑神经活动，我将记录实时纹状体 DA 释放。 为了检查体内中脑神经元活动，我建议使用 Ca2+ 来观察自由行为小鼠的动态。 在自由行为的动物中进行成像实验，在中脑神经元中使用病毒编码的 Ca2+ 指示剂 GCaMP6f。 我将在纽约州精神病学研究所和哥伦比亚大学的导师团队的指导下进行这个项目 Christoph Kellendonk、Peter Balsam、Mark Ansorge、René Hen、Joshua Berke 和 Jonathan Javitch 博士。 完成本职业发展奖提案中规定的培训目标后，我将准备过渡到 科学独立，领导学术医疗中心的研究实验室。