The role of nigrostriatal and striatal cell subtype signaling in behavioral impairments related to schizophrenia

黑质纹状体和纹状体细胞亚型信号传导在精神分裂症相关行为障碍中的作用

• 批准号: 10751224
• 负责人: Nicolette A Moya
• 金额: $ 4.29万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751224
• 关键词: Academia; Address; Affect; Agonist; Amphetamines; Antipsychotic Agents; Automobile Driving; Basal Ganglia; Behavior; Behavioral; Brain; Capsaicin; Cations; Cells; Code; Cognition; Cognitive; Corpus striatum structure; Data Analyses; Dedications; Delusions; Disease; Dopamine; Dopamine Antagonists; Dopamine D1 Receptor; Dopamine D2 Receptor; Dorsal; Educational process of instructing; Electrophysiology (science); Ensure; Environment; Etiology; Fellowship; Fiber; Fluorescence; Functional disorder; Genetic; Goals; Grant; Hallucinations; Hyperactivity; Image; Impaired cognition; Knockout Mice; Knowledge; Link; Locomotion; Manuscripts; Measures; Memory impairment; Mental disorders; Mentorship; Methods; Microscope; Mus; National Research Service Awards; Neurobehavioral Manifestations; Neuronal Dysfunction; Neurons; Output; Pathway interactions; Patients; Pattern; Photometry; Process; Proxy; Psychoses; Psychotic Disorders; Receptor Signaling; Research; Resistance; Role; Schizophrenia; Science; Short-Term Memory; Signal Transduction; Social Functioning; Social Interaction; Substantia nigra structure; Symptoms; TRPV1 gene; Techniques; Testing; Therapeutic; Thinking; Training; Withdrawal; Work; Writing; behavioral construct; behavioral impairment; cognitive function; designer receptors exclusively activated by designer drugs; dopaminergic neuron; experimental study; genetic manipulation; improved; in vivo; in vivo imaging; neural; neural circuit; neuroimaging; nigrostriatal pathway; novel therapeutic intervention; receptor; receptor expression; selective expression; social; social deficits; success; transmission process

Project Summary/Abstract In psychotic disorders, excess nigrostriatal (NS) dopamine signaling is linked to hallucinations, delusions, and disorganized thought—positive symptoms that respond to antipsychotic drugs. By contrast, the prevalent negative and cognitive symptoms in these disorders are largely unresponsive to treatment. Antipsychotic drugs are thought to work by blocking D2 dopamine receptors (D2Rs), which are highly expressed in the striatum. This observation and the fact that increasing brain-wide dopamine (via amphetamine treatment) improves cognition fueled the dogma that excess dopamine is not involved in cognitive and negative symptoms. However, in patients with schizophrenia, dopamine is selectively increased in the striatum (not throughout the brain). Moreover, the striatum also expresses D1 dopamine receptors (D1Rs), which are not targeted by current antipsychotics. Therefore, dopamine may contribute to negative and cognitive symptoms through striatal D1R signaling, but this idea has never been directly tested. The goal of the proposed research is to determine whether striatal D1R- and D2R-expressing spiny projection neurons (SPNs) differentially contribute to dopamine-driven deficits in social and cognitive function. To do this, I developed an approach to mimic the pathway-specific excess in dopamine observed in schizophrenia by selectively expressing the excitatory cation channel TRPV1 in SNc dopamine neurons of Trpv1 knockout mice. Systemically treating these mice with the TRPV1 agonist capsaicin increases dopamine release in the dorsal striatum but not prefrontal cortex (PFC) as measured by dLight fluorescence using in vivo fiber photometry. Selectively driving NS dopamine transmission in this way increases locomotion, but also disrupts social interaction and working memory, behavioral proxies for negative and cognitive symptoms. Here I propose to expand on these findings with the following specific aims: (1) In Aim 1, I will use the TRPV1-based approach with miniature microscopes to image Ca2+ activity in D1- or D2-SPNs under normal and hyperdopaminergic conditions to determine how altered activity in each SPN type contributes to deficits in social and cognitive behavior. (2) In Aim 2, I will use the TRPV1-based approach with chemogenetic manipulations of D1R- or D2R-expressing SPNs to causally link their activity to specific changes in behavior caused by selectively driving striatal dopamine release. By defining the roles of striatal D1- and D2-SPNs in dopamine-driven changes in behavioral constructs related to the symptoms of schizophrenia, my experiments have the potential to identify novel therapeutic strategies for psychosis that more comprehensively address its symptoms. Under this fellowship, I plan to receive training in in vivo imaging and electrophysiology recording techniques, coding and data analysis, grant and manuscript writing, teaching and mentorship, and further knowledge of basal ganglia-related dysfunction and psychiatric disease. My training goals, dedication to progressing science research and diversity in academia, strong mentorship team, and the vibrant academic environment at Northwestern ensure I will reach success as an NRSA fellow.

项目摘要/摘要 在精神病中，多巴胺信号超过杂纹（NS）与幻觉，妄想和 混乱的思想 - 对抗精神病药反应的阳性症状。相比之下，普遍存在 这些疾病中的阴性和认知症状在很大程度上对治疗无反应。抗精神病药 被认为通过阻止D2多巴胺受体（D2R）来起作用，这些受体在纹状体中高度表达。这 观察和增加大脑多巴胺（通过苯丙胺治疗）的事实改善了认知 超过多巴胺的教条助长了认知和负面症状。但是，在患者中 对于精神分裂症，纹状体（不是在整个大脑）中有选择地增加了多巴胺。而且， 纹状体还表达D1多巴胺受体（D1RS），这些受体不受当前抗精神病药的靶向。 因此，多巴胺可能通过纹状体D1R信号导致负面和认知症状，但这 想法从未直接测试过。拟议的研究的目的是确定纹状体D1R-是否是否 表达D2R的棘刺影神经元（SPN）对多巴胺驱动的缺陷有所不同 社会和认知功能。为此，我开发了一种模仿特定路径的方法 在精神分裂症中观察到的多巴胺通过选择性地表达SNC中的兴奋性阳离子通道TRPV1 TRPV1敲除小鼠的多巴胺神经元。用TRPV1激动剂辣椒素系统地治疗这些小鼠 通过Dlight测得 使用体内纤维光度法荧光。以这种方式有选择地驱动NS多巴胺传输 运动，但也破坏了社会互动和工作记忆，负面行为代理 认知症状。在这里，我建议以以下具体目的扩展这些发现： （1）在AIM 1中，我将使用带有微型显微镜的基于TRPV1的方法来图像Ca2+活动 在正常和高多巴胺能条件下的D1或D2-SPN，以确定每个SPN的活性如何改变 类型有助于社会和认知行为定义。 （2）在AIM 2中，我将使用基于TRPV1的方法 用D1R-或D2R表达SPNS的化学发生操作，可将其活性与特定的活性联系起来 选择性驱动纹状体多巴胺释放引起的行为变化。通过定义纹状体D1-的作用 与精神分裂症症状有关的多巴胺驱动的变化中的D2-SPN， 我的实验有可能识别精神病的新型治疗策略，更多 总体上解决了其症状。在此奖学金下，我计划接受体内成像的培训 电生理记录技术，编码和数据分析，赠款和手稿写作，教学和 脑膜和基础神经节相关功能障碍和精神病的进一步了解。我的训练 目标，对进步的科学研究的奉献以及学术界的多样性，强大的精明训练团队以及 西北地区充满活力的学术环境可确保我成为NRSA研究员的成功。