Activation of the ventral tegmental area increased wakefulness in mice

Abstract

The ventral tegmental area (VTA) is crucial for brain functions, such as voluntary movement and cognition; however, the role of VTA in sleep-wake regulation when directly activated or inhibited remains unknown. In this study, we investigated the effects of activation or inhibition of VTA neurons on sleep-wake behavior using the pharmacogenetic “designer receptors exclusively activated by designer drugs (DREADD)” approach. Immunohistochemistry staining was performed to confirm the microinjection sites, and combined with electrophysiological experiments, to determine whether the VTA neurons were activated or inhibited. The hM3Dq-expressing VTA neurons were excited confirmed by clozapine-N-oxide (CNO)-driven c-Fos expression and firing in patch-clamp recordings; whereas the hM4Di-expressing VTA neurons inhibited by reduction of firing. Compared with controls, the activation of VTA neurons at 9:00 (inactive period) produced a 120.1% increase in the total wakefulness amount for 5 h, whereas NREM and REM sleep were decreased by 62.5 and 92.2%, respectively. Similarly, when VTA neurons were excited at 21:00 (active period), the total wakefulness amount increased 81.5%, while NREM and REM sleep decreased 64.6 and 93.8%, respectively, for 8 h. No difference of the amount and EEG power density of the NREM sleep was observed following the arousal effects of CNO. The inhibition of VTA neurons during active or inactive periods gave rise to no change in the time spent in the wakefulness, REM, and NREM sleep compared with control. The results indicated that VTA neurons activated pharmacogentically played important roles in promoting wakefulness.

Characterization of basal forebrain glutamate neurons suggests a role in control of arousal and avoidance behavior

“…Although largely implicated in reward system processing recent evidence suggests that the ventral tegmental area of Tsai (VTA) may also play a role in arousal and cortical activation (Eban-Rothschild et al, 2016;Oishi et al, 2017;Sun et al, 2017;Yu et al, 2019) and defensive responses (Barbano et al, 2020). We found particularly strong fiber labeling here in VTA, one of the strongest BF vGluT2+ projections.…”

Whole-Brain Mapping of Direct Inputs to and Axonal Projections from GABAergic Neurons in the Parafacial Zone

“…In addition, in the nuclei that connect to PZ GABAergic neurons, BF [37] and BG [38] also regulate NREM sleep. DR dopamine neurons [39], VTA [40] and LH [41] have been reported to regulate wakefulness.…”

Modulating Dopamine Signaling and Behavior with Chemogenetics: Concepts, Progress, and Challenges

“…Sleep-Wake Patterns and Arousal. Activation of VTA DAergic neurons by hM3Dq was shown to increase wakefulness periods while reducing sleep-associated behaviors, such as nest building, in both stages of the light/dark cycle in a D 2 R-dependent manner (Oishi et al, 2017a;Sun et al, 2017). Further investigations revealed that NAc D 1 R-and NAc core adenosine A2a receptorexpressing neurons also regulated these sleep-wake patterns (Oishi et al, 2017b;Luo et al, 2018).…”