Neural Circuitry of Wakefulness and Sleep

Wake-sleep circuitry: an overview.

The pedunculopontine tegmental nucleus (PPT) has long been implicated in the regulation of cortical activity and behavioral states, including rapid eye movement (REM) sleep. For example, electrical stimulation of the PPT region during sleep leads to rapid awakening, whereas lesions of the PPT in cats reduce REM sleep. Though these effects have been linked with the activity of cholinergic PPT neurons, the PPT also includes intermingled glutamatergic and GABAergic cell populations, and the precise roles of cholinergic, glutamatergic and GABAergic PPT cell groups in regulating cortical activity and behavioral state remains unknown. Using a chemogenetic approach in three cre-driver mouse lines, we found that selective activation of glutamatergic PPT neurons induced prolonged cortical activation and behavioral wakefulness, whereas inhibition reduced wakefulness and increased NREM sleep. Activation of cholinergic PPT neurons suppressed lower frequency electroencephalogram (EEG) rhythms during non-rapid eye movement (NREM) sleep. Lastly, activation of GABAergic PPT neurons slightly reduced REM sleep. These findings reveal that glutamatergic, cholinergic and GABAergic PPT neurons differentially influence cortical activity and sleep/wake states.

Statement of Significance 

More than 40 million Americans suffer from chronic sleep disruption, and the development of effective treatments requires a more detailed understanding of the neuronal mechanisms controlling sleep and arousal. The PPT, in particular cholinergic PPT neurons, has long been considered a key site for regulating wakefulness and REM sleep. However, the PPT also contains glutamatergic and GABAergic neurons that likely contribute to the regulation of cortical activity and sleep-wake states. The chemogenetic experiments in the present study reveal that cholinergic, glutamatergic and GABAergic PPT neurons each have distinct effects on sleep/wake behavior, improving our understanding of how the PPT regulates cortical activity and behavioral states.

https://www.jneurosci.org/content/jneuro/37/5/1352.full.pdf

Cholinergic, Glutamatergic, and GABAergic Neurons of the Pedunculopontine Tegmental Nucleus Have Distinct Effects on Sleep/Wake Behavior in Mice.

Neuronal Mechanisms for Sleep/Wake Regulation and Modulatory Drive

Nucleus accumbens (NAc) is involved in behaviors that depend on heightened wakefulness, but its impact on arousal remains unclear. Here, we demonstrate that NAc dopamine D1 receptor (D1R)-expressing neurons are essential for behavioral arousal. Using in vivo fiber photometry in mice, we find arousal-dependent increases in population activity of NAc D1R neurons. Optogenetic activation of NAc D1R neurons induces immediate transitions from non-rapid eye movement sleep to wakefulness, and chemogenetic stimulation prolongs arousal, with decreased food intake. Patch-clamp, tracing, immunohistochemistry, and electron microscopy reveal that NAc D1R neurons project to the midbrain and lateral hypothalamus, and might disinhibit midbrain dopamine neurons and lateral hypothalamus orexin neurons. Photoactivation of terminals in the midbrain and lateral hypothalamus is sufficient to induce wakefulness. Silencing of NAc D1R neurons suppresses arousal, with increased nest-building behaviors. Collectively, our data indicate that NAc D1R neuron circuits are essential for the induction and maintenance of wakefulness.

/pdf/nucleus-accumbens-controls-wakefulness-by-a-subpopulation-of-2ymy09pgxp.pdf

Nucleus accumbens controls wakefulness by a subpopulation of neurons expressing dopamine D 1 receptors

Basal Forebrain Cholinergic Neurons Primarily Contribute to Inhibition of Electroencephalogram Delta Activity, Rather Than Inducing Behavioral Wakefulness in Mice.

Tian Xiao Wang

Papers

Basal Forebrain Cholinergic Neurons Primarily Contribute to Inhibition of Electroencephalogram Delta Activity, Rather Than Inducing Behavioral Wakefulness in Mice.