A novel circuit underlying amotivation in a mouse model of 22q11DS

22q11DS 小鼠模型中潜在动机缺失的新型电路

• 批准号: 10592020
• 负责人: Mary H. Patton
• 金额: $ 8.84万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-12 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10592020
• 关键词: Animals; Behavior; Behavioral; Categories; Cell Nucleus; Cells; Cholinergic Receptors; Cognitive; Complex; Corpus striatum structure; Coupled; Data; DiGeorge Syndrome; Dopamine D1 Receptor; Dopamine D2 Receptor; Dorsal; Electrophysiology (science); Exhibits; Genetic; Genetic Diseases; Goals; Grant; Health Care Costs; Hyperactivity; Image; Implant; Individual; Interneurons; Investigation; Learning; Link; Location; Mental Depression; Mental disorders; Motivation; Mus; Muscarinic M2 Receptor; Neurodevelopmental Disorder; Neurons; Occupational; Parafascicular Nucleus; Pathogenicity; Pathway interactions; Patients; Phenotype; Positioning Attribute; Psychological reinforcement; Public Health; Quality of life; Receptor Activation; Research; Rewards; Role; Schizophrenia; Severities; Signal Transduction; Symptoms; Synapses; Synaptic Transmission; Thalamic Nuclei; Thalamic structure; Therapeutic; Training; Wild Type Mouse; addiction; career; cell type; cholinergic; effective therapy; experimental study; improved; in vivo; insight; lens; motivated behavior; mouse model; neural; neural circuit; neuropsychiatric disorder; novel; optogenetics; patch clamp; presynaptic; programs; social; transmission process

Project Summary Schizophrenia is a multifaceted neurodevelopmental disorder characterized by positive, cognitive, and negative symptom categories. One particular negative symptom, amotivation, generates a major impact on public health, yet the treatment options for this symptom remain sparse. This proposal seeks to investigate a novel circuit underlying the amotivation phenotype in a mouse model of 22q11 deletion syndrome (22q11DS), one of the most robust genetic contributors to schizophrenia. Data derived from this study stand to provide novel treatment options aimed at rectifying amotivation. Despite being implicated in motivational states, the dorsal striatum is largely overlooked when studying motivated behavior. Moreover, disruptions in thalamic nuclei are involved in all facets of schizophrenia symptomology, but the role of the thalamus in amotivation remains unknown. My preliminary results demonstrate amotivation in 22q11DS mice, as well as a deficit in synaptic transmission in the thalamostriatal pathway. Information flow through this circuit is modulated by intra-striatal cholinergic interneurons. In 22q11DS mice, I find that there is an increase in the number of spontaneously active cholinergic interneurons and that blocking cholinergic transmission rescues the thalamostriatal synaptic deficit. These findings are the first to implicate the thalamostriatal circuit and cholinergic signaling in motivated behaviors. To study this further, I propose to use cutting-edge approaches in three aims of investigation: 1) to determine the role of striatal cholinergic interneuron activity in amotivation, 2) to elucidate the cholinergic mechanism underlying weakened thalamostriatal synaptic transmission, and 3) to identify the contribution of distinct striatal microcircuits in amotivation. The results of this study stand to significantly enhance our understanding of the neural circuits underlying motivated behaviors and provide important insight into the disruption of motivation that occurs in neuropsychiatric disorders such as schizophrenia, depression, and addiction.

项目概要 精神分裂症是一种多方面的神经发育障碍，其特征为积极性、认知性和消极性 症状类别。一种特殊的负面症状，即缺乏积极性，会对公共健康产生重大影响， 然而，针对这种症状的治疗方案仍然很少。该提案旨在研究一种新颖的电路 22q11 缺失综合征 (22q11DS) 小鼠模型中缺乏动机表型的基础，22q11DS 是 精神分裂症最有力的遗传因素。这项研究得出的数据有望提供新的治疗方法 旨在纠正动机的选项。尽管与动机状态有关，背侧纹状体 在研究动机行为时很大程度上被忽视了。此外，丘脑核的破坏还涉及 精神分裂症症状的各个方面，但丘脑在动机缺失中的作用仍然未知。我的 初步结果表明 22q11DS 小鼠缺乏动机，以及突触传递缺陷 丘脑纹状体通路。通过该电路的信息流受到纹状体内胆碱能的调节 中间神经元。在 22q11DS 小鼠中，我发现自发活跃的胆碱能数量有所增加 中间神经元和阻断胆碱能传递可以挽救丘脑纹状体突触缺陷。这些 研究结果首次表明丘脑纹状体回路和胆碱能信号与动机行为有关。到 为了进一步研究这一点，我建议在三个研究目标中使用尖端方法：1）确定 纹状体胆碱能中间神经元活动在动机缺失中的作用，2）阐明潜在的胆碱能机制 丘脑纹状体突触传递减弱，3) 识别不同纹状体微电路的贡献 在无动力的情况下。这项研究的结果将显着增强我们对神经回路的理解 潜在的动机行为，并为发生在动机的破坏提供重要的见解 神经精神疾病，例如精神分裂症、抑郁症和成瘾症。