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

摘要 精神分裂症是一种神经精神障碍，会导致认知缺陷和基本感觉障碍。 正在处理。精神分裂症患者的结构和功能成像研究表明，主要的结构 然而，精神分裂症的特征是大脑区域之间的远程连接和断开 这种降低的连接性如何影响特定的电路组件和皮质功能在很大程度上仍不清楚。 在这个项目中，我们将把在体线性探测记录与视觉系统中的光遗传调制结合起来 22q11缺失综合征小鼠模型研究自下而上和自上而下感觉调制的改变 正在处理。此外，最近的转录学研究发现，神经胶质样细胞是一类独特的 GABA能抑制神经元是精神分裂症中受影响最大的一类神经元。神经网状细胞 主要驻留在皮质的浅层1，接受皮质轴突的输入，包括 前额叶皮质区域、丘脑和高级丘脑核团以及皮质下核团 然而，神经胶质样细胞在健康中的体内功能及其功能障碍 由于缺乏专门针对疾病的工具，疾病在很大程度上仍然未知。澄清……的作用 神经胶质细胞在自下而上和自上而下的处理中，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，并测量它们对感觉加工的影响。这项研究 在本申请中提出的建议在概念上具有创新性和重要意义，因为它将为我们提供更好的 了解自下而上和自上而下的皮质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，因为有了专门针对神经胶质细胞的新方法 并在22q11.2的背景下调查它们在健康的感觉处理中的作用。最终，这样的 知识有可能为识别疾病的生物标记物和 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.