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

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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.