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

项目摘要 精神分裂症是一种多方面的神经发育障碍，以积极、认知和消极为特征。 症状类别。一种特殊的消极症状，激动症，会对公共健康产生重大影响， 然而，针对这种症状的治疗选择仍然很少。这项提议旨在研究一种新的电路 在22q11缺失综合征(22q11DS)小鼠模型中的非激活表型，其中之一 精神分裂症最强大的基因贡献者。从这项研究中得出的数据将提供新的治疗方法 旨在纠正动机的选项。尽管与动机状态有关，但背侧纹状体 在研究动机行为时很大程度上被忽视了。此外，丘脑核团的破坏参与了 精神分裂症症状的所有方面，但丘脑在运动中的作用仍不清楚。我的 初步结果显示，在22q11DS小鼠中存在运动障碍，以及在突触传递方面的缺陷 丘脑纹状体通路。通过这个回路的信息流是由纹状体内胆碱能 中间神经元。在22q11DS小鼠中，我发现自发活跃的胆碱能神经元的数量增加 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 这一发现首次将丘脑纹状体回路和胆碱能信号与动机行为联系起来。至 进一步研究这一点，我建议在三个调查目标中使用尖端方法：1)确定 纹状体胆碱能中间神经元活性在运动中的作用，2)阐明纹状体胆碱能机制 丘脑-纹状体突触传递减弱，以及3)识别不同纹状体微回路的贡献 作为一种激励。这项研究的结果将极大地增强我们对神经回路的理解 潜在的动机行为，并为以下情况提供了重要的洞察 神经精神障碍，如精神分裂症、抑郁症和成瘾。

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.