High density tetrode recording in freely behaving mouse models of mental disease

描述（由申请人提供）：我们的目标是探索一种新的实验方法来了解精神疾病。我们的长期目标是了解精神分裂症如何影响大脑中的信息处理。为此，我将应用高密度四极电生理技术，记录在多个精神分裂症动物模型中，自由活动期间的行为。最近精神分裂症的研究主要集中在增强默认模式网络的活动上：在休息期间特别活跃的大脑区域，包括海马体。这与我和其他人最近研究正常海马功能的工作相一致，特别是清醒重放现象，其中大量海马神经元以与正在进行的任务需求相关的顺序发射。例如，清醒重放可以沿着探索动物之前的空间轨迹“向前看”，以探索假设的结果。我们建议在两种不同的精神分裂症小鼠模型中研究运动和休息期间的神经活动，以便（1）确定是否存在特别是休息期活动的中断，让人想起默认模式网络的中断，以及（2）确定两种不同的精神分裂症遗传小鼠模型是否表现出共性，特别是在休息期活动方面。我们的初步数据表明，海马神经活动的影响，在前脑特异性钙调磷酸酶敲除小鼠模型，在特定的休息时间的方式。我们现在可以确定这些变化对清醒重放的影响。我们还将考虑一个转基因DISC1小鼠模型，表现出减少小清蛋白免疫反应，也是在精神分裂症患者。这是特别有趣的，因为含有小清蛋白的中间神经元在正常动物中启动和塑造清醒重放事件，并且这种抑制的丧失可能预期导致与在钙调磷酸酶小鼠中观察到的类似结果。确定休息期间的信息处理如何被中断是一个关键目标，这将使未来的研究有可能确定唤醒重放的中断如何影响正在进行的任务表现，异质性疾病机制如何导致类似的行为表型，以及最终如何治疗回路水平功能障碍。 公共卫生相关性：精神分裂症是一种精神疾病，影响着世界上近1%的人口，是社会第七大最昂贵的医疗疾病。该提案旨在探索一种新的实验方法来治疗这种疾病，寻找两种遗传上不同的动物模型之间的共性，并使用尖端的电生理技术在电路水平上专门针对神经活动，该技术允许同时记录数百个神经元在自由行为的动物中。这项工作将为更好地理解相似的回路水平表型如何从不同的遗传模型中产生铺平道路，并对精神现象的神经基础产生新的理解，这些理解可能在未来应用于人类患者的诊断和治疗。

DESCRIPTION (provided by applicant): We aim to explore a novel experimental approach to understanding mental disease. Our long-term goal is to understand how schizophrenia affects information processing in the brain. To this end, I will apply high-density tetrode electrophysiology techniques to record in multiple animal models of schizophrenia, during free behavior. Much recent work in schizophrenia has focused on enhanced activity of the default mode network: brain regions which are particularly co-active during rest periods, and which include the hippocampus. This converges with recent work by myself and others investigating normal hippocampal function, and particularly, the phenomenon of awake replay, in which large numbers of hippocampal neurons fire in sequences that relate to ongoing task demands. For example, awake replay can "look-ahead" along spatial trajectories ahead of an exploring animal to explore hypothetical outcomes. We propose to investigate neural activity during movement and rest, in two different mouse models of schizophrenia, in order to (1) determine whether there are disruptions to rest period activity in particular, reminiscent of disruption to the default mode network, and (2) determine whether two distinct genetic mouse models of schizophrenia exhibit commonalities, especially with respect to rest period activity. Our preliminary data show that hippocampal neural activity is affected in a forebrain-specific calcineurin knockout mouse model, in a manner specific to rest periods. We are now in a position to determine the effect of these changes on awake replay. We will also consider a transgenic DISC1 mouse model, which exhibits reduced parvalbumin-immunoreactivity, as is also seen in schizophrenia patients. This is particularly interesting because parvalbumin-containing interneurons initiate and sculpt awake replay events in normal animals, and loss of such inhibition might be expected to lead to a similar outcome as observed in the calcineurin mouse. Determining how information processing in rest periods is disrupted is a key goal, which will make possible future studies to determine how disruptions to awake replay affect ongoing task performance, how heterogeneous disease mechanisms may lead to similar behavioral phenotypes, and ultimately how circuit level dysfunction may be treated therapeutically. PUBLIC HEALTH RELEVANCE: Schizophrenia is a psychiatric disorder that affects almost 1% of the world population, and represents the seventh most costly medical illness to society. This proposal seeks to explore a novel experimental approach to the disease, looking for commonalities between two genetically distinct animal models, and specifically targeting neural activity at the level of circuits using a cutting edge electrophysiological technique that allows for the simultaneous recording of hundreds of neurons in freely behaving animals. This work will pave the way for a better understanding of how similar circuit level phenotypes might arise out of diverse genetic models, and generate a novel understanding of the neural basis of mental phenomena that might be applied in the future to the diagnosis and treatment of human patients.