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 在精神障碍中，过量的黑质纹状体(NS)多巴胺信号与幻觉、妄想和 对抗精神病药物有反应的杂乱无章的阳性思维症状。相比之下，盛行的 这些疾病中的阴性和认知症状在很大程度上对治疗没有反应。抗精神病药物 被认为是通过阻断D2多巴胺受体(D2Rs)起作用的，D2Rs在纹状体中高度表达。这 增加全脑多巴胺(通过苯丙胺治疗)改善认知的观察和事实 助长了过量的多巴胺与认知和消极症状无关的教条。然而，在患者中 对于精神分裂症，多巴胺在纹状体(而不是整个大脑)选择性地增加。此外， 纹状体也表达D1多巴胺受体(D1Rs)，这是目前的抗精神病药物不针对的。 因此，多巴胺可能通过纹状体D1R信号导致阴性和认知症状，但这 这个想法从未被直接测试过。这项拟议研究的目标是确定纹状体D1R- 和D2R表达的棘突投射神经元(SPN)对多巴胺驱动的脑缺血有不同的作用 社会功能和认知功能。为了做到这一点，我开发了一种方法来模拟 选择性表达兴奋性阳离子通道TRPV1在精神分裂症中观察到的多巴胺 TRPV1基因敲除小鼠的多巴胺神经元。用TRPV1激动剂辣椒素系统治疗这些小鼠 增加背侧纹状体的多巴胺释放，但不增加前额叶皮质(PFC) 荧光法采用体内纤维光度法。以这种方式选择性地驱动NS多巴胺传递增加 运动，但也扰乱了社会互动和工作记忆，这是负面和 认知症状。在这里，我建议以以下具体目标来扩大这些调查结果： (1)在目标1中，我将使用基于TRPV1的方法和微型显微镜来成像 在正常和高多巴胺能条件下测定D_1或D_2-SPN的活性变化 类型会导致社交和认知行为的缺陷。(2)在目标2中，我将使用基于TRPV1的方法 通过对表达D1R或D2R的SPN进行化学遗传操作，将其活性与特定的 选择性地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的角色- 和D2-SPN在多巴胺驱动的与精神分裂症症状相关的行为结构的变化中， 我的实验有可能发现精神病的新治疗策略 全面对症下药。根据这一奖学金，我计划接受体内成像和 电生理记录技术、编码和数据分析、助学金和手稿写作、教学和 指导，以及对基底节相关功能障碍和精神疾病的进一步了解。我的训练 目标，致力于科学研究的进步和学术界的多样性，强大的导师团队，以及 西北大学充满活力的学术环境确保了我作为一名NRSA研究员取得成功。