Circadian and Homeostatic Modulation of Multi-Unit Activity in Midbrain Dopaminergic Structures

Abstract

Although the link between sleep disturbances and dopamine (DA)-related neurological and neuropsychiatric disorders is well established, the impact of sleep alterations on neuronal activity of midbrain DA-ergic structures is currently unknown. Here, using wildtype C57Bl mice, we investigated the circadian- and sleep-related modulation of electrical neuronal activity in midbrain ventral-tegmental-area (VTA) and substantia nigra (SN). We found no significant circadian modulation of activity in SN while VTA displayed a low amplitude but significant circadian modulation with increased firing rates during the active phase. Combining neural activity recordings with electroencephalogram (EEG) recordings revealed a strong vigilance state dependent modulation of neuronal activity with increased activity during wakefulness and rapid eye movement sleep relative to non-rapid eye movement sleep in both SN and VTA. Six-hours of sleep deprivation induced a significant depression of neuronal activity in both areas. Surprisingly, these alterations lasted for up to 48 hours and persisted even after the normalization of cortical EEG waves. Our results show that sleep and sleep disturbances significantly affect neuronal activity in midbrain DA structures. We propose that these changes in neuronal activity underlie the well-known relationship between sleep alterations and several disorders involving dysfunction of the DA circuitry such as addiction and depression.

Circadian regulation of membrane physiology in neural oscillators throughout the brain

“…Interestingly, an earlier study of glucose utilization in mice reported no day/night difference in either SN region (Jay et al., ). Similarly, MUA in SN of freely moving mice across all vigilance states does not appear to vary across the 24‐hr cycle (Fifel et al., ). However, when MUA during NREM sleep was examined separately, lateral SN showed a day/night difference in LD—with peak activity occurring during the night (Fifel et al., ).…”

“…Similarly, MUA in SN of freely moving mice across all vigilance states does not appear to vary across the 24‐hr cycle (Fifel et al., ). However, when MUA during NREM sleep was examined separately, lateral SN showed a day/night difference in LD—with peak activity occurring during the night (Fifel et al., ). Given that DA release in the dorsal striatum exhibits a clear 24‐hr rhythm (Hood et al., ) and receives input from DA neurons of the SN, future work should examine if daily rhythms are present in the different nigral cell types (i.e., DA and GABA).…”

“…Yet the rate of DA neuronal activity in freely moving mice during spontaneous REM sleep across the 24‐hr cycle showed no rhythm (Sidor et al., ). Conversely, multiunit activity (MUA) in the VTA of freely moving mice across all vigilance states shows a 24‐hr rhythm—with peak activity at night—that persists in LD and DD (Fifel, Meijer, & Deboer, ); however, when the MUA rhythms for different vigilance states were examined separately, only activity during NREM sleep remained rhythmic (Fifel et al., ). Altogether, these issues raise the importance of considering cell‐type, vigilance state, and temporal resolution when assessing rhythmic electrical properties within the VTA.…”

Cell-type specialization in the brain is encoded by specific long-range chromatin topologies

“…DNspecific borders also contained cell specialization related genes, such as genes related to circadian regulation. Midbrain DNs have an important role in the homeostatic circadian and sleep-related modulation of neuronal activity 48 .…”

Arousal State-Dependent Alterations in VTA-GABAergic Neuronal Activity

“…Neuronal activity in the VTA exhibits arousal-state-dependent alterations, with increased activity during wakefulness and REM sleep compared to NREM sleep (Miller et al, 1983;Fifel et al, 2018). Although initial studies suggested that VTA-dopaminergic neurons do not change their mean firing rate across sleep/wake states (Miller et al, 1983;Steinfels et al, 1983), more recent examinations revealed marked arousal statedependent alterations in both firing rate and firing pattern (Dahan et al, 2007;Gomperts et al, 2015).…”