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理解精神疾病的新的实验方法。我们的长期目标是了解精神分裂症如何影响大脑的信息处理。为此，我将应用高密度四极管电生理学技术来记录精神分裂症的多个动物模型，在自由行为期间。精神分裂症最近的研究主要集中在增强默认模式网络的活动：在休息期间特别活跃的大脑区域，其中包括海马体。这与我和其他研究正常海马体功能的人最近的工作一致，特别是清醒重放现象，在这种现象中，海马神经元以与正在进行的任务需求相关的序列发射。例如，觉醒重播可以沿着空间轨迹向前看，在探索中的动物之前探索假设的结果。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(1)确定是否存在特别的休息期间活动的中断，这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同点，特别是关于休息期间的活动。我们的初步数据显示，在前脑特异的钙调神经磷酸酶基因敲除小鼠模型中，海马神经活动受到影响，这种方式特定于休息期。我们现在可以确定这些变化对唤醒重播的影响。我们还将考虑转基因DISC1小鼠模型，该模型显示出小白蛋白免疫反应性降低，这在精神分裂症患者中也可以看到。这一点特别有趣，因为在正常动物中，含有小白蛋白的中间神经元启动并塑造清醒的重放事件，而这种抑制的丧失可能会导致类似于在钙调神经磷酸酶小鼠中观察到的结果。确定休息期间的信息处理是如何被干扰的是一个关键目标，这将使未来的研究成为可能，以确定清醒重放的干扰如何影响正在进行的任务表现，不同的疾病机制可能如何导致相似的行为表型，以及最终如何从治疗的角度治疗电路水平的功能障碍。 与公共卫生相关：精神分裂症是一种精神疾病，影响着世界近1%的人口，是社会第七大最昂贵的医疗疾病。这项提议旨在探索一种治疗这种疾病的新的实验方法，寻找两个遗传上不同的动物模型之间的共同点，并使用一种尖端的电生理技术，特别针对电路水平的神经活动，该技术允许同时记录自由行为动物的数百个神经元。这项工作将为更好地理解相似的电路水平表型如何从不同的遗传模型中产生铺平道路，并对未来可能应用于人类患者诊断和治疗的精神现象的神经基础产生一种新的理解。

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.