Characterizing thalamocortical prefrontal network dynamics underlying cognitive control in a model of schizophrenia

 描述（由申请人提供）：该提案旨在促进我们对丘脑皮质网络在认知控制行为产生中的作用的理解，具体而言，了解该网络如何在精神分裂症（一种影响约1%人口的精神疾病）中受到干扰，从而在疾病中产生认知控制缺陷。前额叶皮层（PFC）和丘脑的内侧背核（MD）都被认为在涉及工作记忆和上下文处理的认知控制任务中发挥作用，这些区域在精神分裂症患者中功能被破坏。这些实验将探讨丘脑皮层网络连接MD的背外侧PFC如何运作，以实现认知控制，在这个网络中的神经动力学的选择几个替代反应相同的刺激。该方法将结合联合收割机大规模的神经记录，突触功能的药理学操作和突触相互作用的计算建模，以研究丘脑和PFC中的神经元之间的通信如何允许前额叶网络在对相同刺激的替代反应之间切换。然后，我们将用NMDA受体拮抗剂操纵突触功能，这会诱导认知控制中的特定模式的错误，如在精神分裂症患者中所见。这将使我们能够将局部PFC和MD-PFC网络的生理动力学变化与观察到的行为表现缺陷联系起来。我们将实现以下两个目标：（1）提供一个最好的功能解剖丘脑皮质前额叶网络在信息处理中的作用，（2）揭示这些网络的功能中断如何导致典型的人类神经精神疾病的认知缺陷。此外，在拟议的实验中，单细胞记录的时间和空间分辨率允许通过揭示信息处理如何在精神分裂症的细胞水平上被破坏来补充成像研究的数据。最终，这项工作将为新疗法的开发和测试铺平道路，如新药，神经调节干预和基因疗法。

 DESCRIPTION (provided by applicant): This proposal seeks to advance our understanding of the role of thalamocortical networks in the production of cognitive control behaviors, and specifically, to understand how this network is perturbed in schizophrenia, a psychiatric illness affecting about 1% of the population, to produce cognitive control deficits in the disease. Both the prefrontal cortex (PFC) and the mediodorsal nucleus of the thalamus (MD) have been implicated to play a role in cognitive control tasks that involve working memory and context processing, areas that are functionally disrupted in patients with schizophrenia. These experiments will investigate how the thalamocortical network linking the MD to the dorsolateral PFC operates to implement cognitive control by relating neural dynamics in this network to the selection of one out of several alternative responses to the same stimulus. The approach will combine large-scale neural recording, pharmacological manipulation of synaptic function, and computational modeling of synaptic interactions to investigate how communication between neurons in the thalamus and the PFC allows prefrontal networks to switch between alternative responses to the same stimulus. We will then manipulate synaptic function with an NMDA receptor antagonist, which induces the specific pattern of errors in cognitive control as is seen in patients with schizophrenia. This will allow us to relate changes in physiological dynamics of local PFC and MD-PFC network to the observed deficit in behavioral performance. We will achieve the following two objectives: (1) provide one of the best available functional dissections of the role of thalamocortical prefrontal networks in information processing, and (2) reveal how disruption of the function of these networks could lead to cognitive deficits that typify human neuropsychiatric disease. Additionally, the temporal and spatial resolution of the single cell recordings in the proposed experiments allow for the potential to complement data from imaging studies by revealing how information processing is disrupted at a cellular level in schizophrenia. Eventually, this work will pave the way for the development and testing of new therapeutics such as new drugs, neuromodulation interventions, and gene therapies.