Investigating abnormalities in top-down cortical processing and behavior in a model of the 22q11.2 deletion

总结 精神分裂症是一种神经精神疾病，导致认知缺陷和基本感觉障碍， 处理.精神分裂症患者的结构和功能成像研究表明， 然而，精神分裂症的特征是大脑区域之间的长距离连接减少和断开， 这种降低的连通性如何影响特定的电路组件和皮质功能仍然是未知的。 在本计画中，我们将结合联合收割机在活体线性探针记录与视觉系统中的光遗传学调控 22q11缺失综合征的小鼠模型，以研究感觉神经元自下而上和自上而下的调节改变， 处理.此外，最近的转录组学研究发现，神经胶质样细胞，一种独特的神经胶质样细胞， GABA能抑制性神经元是精神分裂症中受影响最严重的一类神经元。神经胶质样细胞 主要位于皮层的浅层1，并接收来自皮层轴突的输入，包括 前额叶皮质区，从丘脑和高级丘脑核，并从皮质下 神经调节群体，然而，神经胶质样细胞在健康和它们的功能障碍中的体内功能 由于缺乏专门针对这些疾病的工具，这些疾病在很大程度上仍然未知。澄清的作用 神经胶质细胞自下而上和自上而下的处理，我们将操纵神经胶质细胞的活动 在野生型和22q11.2小鼠中进行光遗传学研究，并测量它们对感觉处理的影响。研究 在这个应用中提出的是概念上的创新和意义，因为它将给我们一个更好的 理解自下而上和自上而下的皮层处理和神经回路如何参与精神分裂症。 这项工作在技术上也是创新的，因为新的方法专门针对神经胶质细胞 并调查其在健康和22q11.2的背景下感觉处理中的作用。最终，这样的 知识有可能为识别疾病的生物标志物和 针对特定回路的治疗干预。

SUMMARY Schizophrenia is a neuropsychiatric disorder that causes cognitive deficits and impairments in basic sensory processing. Structural and functional imaging studies in schizophrenia patients suggest that a main structural signature of schizophrenia is reduced long-range connectivity and disconnection between brain areas, however how such reduced connectivity affects specific circuit components and cortical function remains largely unknown. In this project, we will combine in vivo linear probe recordings with optogenetic modulation in the visual system of the mouse model of 22q11 deletion syndrome to study altered bottom-up and top-down modulation of sensory processing. In addition, recent transcriptomics studies have found that neurogliaform cells, a distinct class of GABAergic inhibitory neurons, are the most affected class of neurons in schizophrenia. Neurogliaform cells primarily reside in superficial layer 1 of the cortex and receive inputs from corticocortical axons, including prefrontal cortical regions, from the thalamus and higher-order thalamic nuclei, and from subcortical neuromodulatory populations, however the in vivo function of neurogliaform cells in health and their dysfunction disease remains largely unknown due to lack of tools to specifically target them. To clarify the role of neurogliaform cells in bottom-up and top-down processing, we will manipulate activity in neurogliaform cells optogenetically in wild type and 22q11.2 mice and measure their effect on sensory processing. The research proposed in this application is conceptually innovative and significant because it will give us a better understanding of how bottom-up and top-down cortical processing and neural circuits involved in schizophrenia. This work is also technically innovative because of the novel approaches to specifically target neurogliaform cells and investigating their role in sensory processing in health and in the context of 22q11.2. Ultimately, such knowledge has the potential to offer new opportunities for identification of biomarkers of disease and for therapeutic interventions that target specific circuits.