Electrophysiologic characterization of circadian rhythms of prefrontal cortical network states in a diurnal rodent

摘要 在哺乳动物的行为模式中有明显的昼夜节律，昼夜节律紊乱是其中一种 神经精神疾病中最常见的合并症。行为本身是通过 电生理活动，如神经元动作电位或“尖峰”和振荡。但我们不 了解电生理学变化如何引起昼夜行为节律。研究 脑电生理学的昼夜节律调节，基于啮齿动物的神经科学方法提供了一个强大的 平台，因为它们包括长期探测和记录神经回路电活动的工具， 很详细。不幸的是，虽然人类是白天活动的，但神经科学中使用的动物模型往往是 夜间活动，因此不允许我们轻易地将发现翻译给人类。这是因为夜间 动物并不简单地代表昼夜活动动物的相位反转版本-存在非线性差异 夜间活动和白天活动的动物之间在全脑神经回路如何耦合到昼夜节律起搏器。 因此，为了了解神经回路是如何在昼夜循环的大脑中调节的，我们 建议进行昼夜节律的时间尺度的电生理记录在一个昼夜啮齿动物。我们将记录从 内侧前额叶皮层（mPFC），一个已知在啮齿动物行为中起重要作用并与人类有关的区域 精神疾病，包括季节性情感障碍（SAD），这是严重影响的改变， 昼夜光模式对于这些长时间的问题，我们将使用非传统的电生理学 分析适合慢性和非刺激锁定量化-我们称之为“电生理学”的方法 背景状态”（EBS）。这种EBS方法将包括许多详细的尖峰动态指标， mPFC可以在持续的时间内进行分析。这些包括兴奋抑制平衡和尖峰 速率方差，我们已经建议是昼夜节律调制无论是在文献或我们的初步研究， 数据我们的假设是，在白天活动的物种中，包括种群在内的内侧前额叶皮层的EBS指标 峰频率变异性和EI平衡显示了预测行为模式的每日节律。为了验证这个假设， 我们建议在白天活动的啮齿动物中开发第一个慢性高密度电生理学， 结合昼夜尼罗河草鼠神经生物学（Yan）和啮齿动物电生理学（沃森）的专业知识。 我们建议将64通道探头植入mPFC，然后在昼夜草中记录96小时 大鼠我们将测量尖峰频率方差和兴奋抑制比来确定昼夜节律调节 这些措施。在第一个目标中，我们将确定任何观察到的EBS的光与昼夜节律调制 节奏在第二个目标中，我们将使用减少的日光来诱导SAD患者的行为变化， 然后将行为变化与相同动物的EBS变化相关联。这项工作将在体内进行研究 电生理调制的神经网络在白天啮齿动物的第一次。未来的工作可以探索 更详细地描述了白天活动啮齿动物的健康和病理电生理学。

ABSTRACT There are clear circadian rhythms in the behavioral patterns of mammals and circadian disruption is one of the most common co-morbidities in neuropsychiatric disorders. Behaviors themselves are instantiated via electrophysiologic activity, such as neuronal action potentials or “spiking” and oscillations. However, we do not know how circadian behavioral rhythms are brought about by electrophysiologic changes. To study the circadian modulation of brain electrophysiology, rodent-based neuroscientific methods offer a powerful platform, since they include tools to probe and record the electrical activity of neural circuits chronically, and in great detail. Unfortunately, while humans are diurnal, the animal models used in neuroscience tend to be nocturnal and therefore do not allow us to easily translate findings to humans. This is because nocturnal animals do not simply represent phase-reversed versions of diurnal animals – there are non-linear differences between nocturnal and diurnal animals in how brainwide neural circuits couple to the circadian pacemaker. Therefore, to understand how neural circuits are modulated over the 24-hour cycle in a diurnal brain, we propose to perform circadian timescale electrophysiologic recordings in a diurnal rodent. We will record from the medial prefrontal cortex (mPFC), a region with both known import in rodent behavior and relation to human psychiatric conditions including seasonal affective disorder (SAD) which is heavily affected by alterations in circadian light patterns. For these long-timescale questions we will use non-traditional electrophysiologic analytics amenable to chronic and non-stimulus locked quantification – an approach we call “Electrophysiologic Background State” (EBS). This EBS approach will include a number of metrics of detailed spiking dynamics in the mPFC amenable to analysis over sustained periods. These include excitatory-inhibitory balance and spike rate variance which we have been suggested to be circadian modulated either in literature or our preliminary data. Our hypothesis is that in diurnal species, EBS metrics in medial prefrontal cortex including population spike rate variability and EI balance show daily rhythms that predict behavioral patterns. To test this hypothesis, we propose to develop the first-ever chronic high-density electrophysiology in diurnal rodents using our combination of expertise with diurnal Nile grass rat neurobiology (Yan) and rodent electrophysiology (Watson). We propose to implant a 64-channel probe into the mPFC and then record for 96-hour periods in diurnal grass rats. We will measure the spike rate variance and excitatory-inhibitory ratio to determine circadian modulation of these measures. In the first aim we will determine light versus circadian modulation of any observed EBS rhythms. In the second aim we will use reduced daylight to induce behavioral changes as in SAD patients and will then correlate behavioral changes with EBS changes within the same animals. This work will study in vivo electrophysiologic modulation of neural networks in diurnal rodents for the first time. Future work can explore in more detail both healthy and pathological electrophysiology of diurnal rodents.