Motivational and Valence‐Related Modulation of Sleep/Wake Behavior are Mediated by Midbrain Dopamine and Uncoupled from the Homeostatic and Circadian Processes

Abstract

Motivation and its hedonic valence are powerful modulators of sleep/wake behavior, yet its underlying mechanism is still poorly understood. Given the well-established role of midbrain dopamine (mDA) neurons in encoding motivation and emotional valence, here, neuronal mechanisms mediating sleep/wake regulation are systematically investigated by DA neurotransmission. It is discovered that mDA mediates the strong modulation of sleep/wake states by motivational valence. Surprisingly, this modulation can be uncoupled from the classically employed measures of circadian and homeostatic processes of sleep regulation. These results establish the experimental foundation for an additional new factor of sleep regulation. Furthermore, an electroencephalographic marker during wakefulness at the theta range is identified that can be used to reliably track valence-related modulation of sleep. Taken together, this study identifies mDA signaling as an important neural substrate mediating sleep modulation by motivational valence.

Neuronal PAS domain 1 identifies a major subpopulation of wakefulness-promoting GABAergic neurons in basal forebrain

“…Overall, these results are consistent with BF Npas1 + neurons being involved in limbic basal ganglia circuits related to motivation, reward, stress and sleep-wake control (Luo et al, 2018;Li et al, 2021;Fifel et al, 2022;Morais-Silva et al, 2023;Soares-Cunha & Heinsbroek, 2023).…”

“…Overall, BF Npas1 + neurons appear to be part of subcortical circuits involved in motivationally driven wakefulness (Li et al, 2021). Consistent with that interpretation, chemogenetic activation of Npas1 + neurons increased EEG power in the high theta/alpha EEG band which has been linked to goal-directed behavior during wakefulness (Vassali & Franken, 2017;Fifel et al, 2022).…”

Mechanisms of Sleep/Wake Regulation under Hypodopaminergic State: Insights from MitoPark Mouse Model of Parkinson's Disease

“…[5,6] While it is clear that several factors, including intrinsic neuronal pathology, secondary impact of motor and NMS, and medication, are implicated in the etiology of sleep problems in PD, the relative contribution of DA dysfunction is still not fully appreciated. [65] Ever since the discovery of DA as an independent neurotransmitter in the brain, [66,67] lesional, [8,9] pharmacological [8,9] and more specific chemo/optogenetic [10][11][12][13][14][15][16][17] preclinical manipulations, that up or down-regulate DA neurotransmission have revealed the potent role of DA in regulating arousal and motivational wakefulness. In the clinic, however, the consequences of dopaminomimetic drugs on sleep/wake state unravel more complex dose-and targeted receptors-dependent effects.…”

“…Ever since the discovery of DA as an independent neurotransmitter in the brain, [ 66 , 67 ] lesional, [ 8 , 9 ] pharmacological [ 8 , 9 ] and more specific chemo/optogenetic [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ] preclinical manipulations, that up or down‐regulate DA neurotransmission have revealed the potent role of DA in regulating arousal and motivational wakefulness. In the clinic, however, the consequences of dopaminomimetic drugs on sleep/wake state unravel more complex dose‐ and targeted receptors‐dependent effects.…”

“…Classical lesional and pharmacological manipulations as well as recent chemo‐ and optogenetic studies have firmly implicated midbrain DA signaling in the modulation of both sleep/wake cycle [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ] and electroencephalogram (EEG)/local field potential brain rhythms. [ 18 ] Dysfunctional DA neurotransmission is therefore expected to precipitate qualitative and quantitative alterations of sleep/wake behavior.…”