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

摘要 哺乳动物的行为模式有明显的昼夜节律，而昼夜节律紊乱是 神经精神障碍中最常见的共病。行为本身通过 电生理活动，如神经元动作电位或“尖峰”和振荡。然而，我们并没有 了解电生理变化是如何引起昼夜节律的。为了研究 脑电生理的昼夜节律，以啮齿动物为基础的神经科学方法提供了强大的 平台，因为它们包括长期探测和记录神经回路的电活动的工具，并且在 非常详细。不幸的是，虽然人类是昼夜活动的，但神经科学中使用的动物模型往往是 它们是夜间活动的，因此不允许我们轻易地将发现转化为人类。这是因为夜间活动 动物并不简单地代表了昼夜动物的反相版本--存在着非线性差异 夜间活动和白天活动的动物之间的关系，以及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24小时的大脑周期中进行调制的，我们 建议在一种昼夜啮齿动物身上进行昼夜时间尺度电生理记录。我们将从 内侧前额叶皮质(MPFC)，这是一个已知在啮齿动物行为中的重要区域，也与人类有关 精神状况，包括季节性情感障碍(SAD)，它受到 昼夜节律的灯光模式。对于这些长时间的问题，我们将使用非传统的电生理学 适用于慢性和非刺激锁定量化的分析--我们称之为“电生理学” 背景状态“(EBS)。此EBS方法将包括详细的峰值动态的多个指标 MPFC适合在持续的时期内进行分析。包括兴奋性-抑制性平衡和棘波。 在文献中或在我们的初步研究中，我们被认为是昼夜节律调制的速率变化 数据。我们的假设是，在白天的物种中，包括种群在内的内侧前额叶皮质的EBS指标 尖峰速率变异性和EI平衡显示出预测行为模式的每日节律。为了检验这一假设， 我们计划利用我们的技术建立第一个昼夜啮齿动物的慢性高密度电生理学 结合了昼夜尼罗河草大鼠神经生物学(Yen)和啮齿动物电生理学(Watson)的专业知识。 我们建议将通道探头植入mPFC，然后在白天的草地上记录96小时的周期 老鼠。我们将测量尖峰频率的方差和兴奋抑制比来确定昼夜节律 这些措施。在第一个目标中，我们将确定任何观察到的EBS的光与昼夜节律的调制 节奏。在第二个目标中，我们将使用减少的日光来诱导行为变化，就像在SAD患者和 然后会将行为变化与同一动物体内的EBS变化联系起来。这项工作将在体内进行研究 首次报道了昼夜啮齿动物神经网络的电生理调制。未来的工作可以探索 更详细地说，白天啮齿动物的健康电生理学和病理电生理学。

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.