Basal forebrain parvalbumin neurons mediate arousals from sleep induced by hypercarbia or auditory stimuli

Abstract

<jats:title>SUMMARY</jats:title><jats:p>Brief arousals from sleep in patients with sleep apnea and other disorders prevent restful sleep, and contribute to cognitive, metabolic and physiologic dysfunction. Little is currently known about which neural systems mediate these brief arousals, hindering the development of treatments. The basal forebrain (BF) receives inputs from many nuclei of the ascending arousal system. These inputs include the brainstem parabrachial neurons which promote arousal in response to elevated blood carbon dioxide levels, as seen in sleep apnea. Optical inhibition of the terminals of parabrachial neurons in the BF impairs cortical arousals to hypercarbia, but which cell types within the BF mediate cortical arousals in response to hypercarbia or other sensory stimuli is unknown. Here using optogenetic techniques in mice, we show that BF parvalbumin (PV) neurons fulfill several criteria for a system mediating brief arousals from sleep. Optical stimulation of BF PV neurons during the light period, when mice normally sleep, caused rapid transitions to wakefulness and increased wake bout durations. Unlike many other ascending arousal systems, arousals induced by stimulation of BF PV neurons were brief, resulting in only a small (13.6%) increase in the total amount of wakefulness. Bilateral optical inhibition of BF PV neurons increased the latency to arousal produced by hypercarbia or auditory stimuli. Thus, BF PV neurons are an important component of the brain circuitry which generates brief arousals from sleep in response to internal and external sensory stimuli.</jats:p>

Glutamatergic Neurons in the Preoptic Hypothalamus Promote Wakefulness, Destabilize NREM Sleep, Suppress REM Sleep, and Regulate Cortical Dynamics

“…Additionally, there was a robust, long-lasting NREM sleep fragmentation and state instability resembling the disrupted sleep pattern observed in sleep apnea (Guilleminault et al, 1976;Kimoff, 1996), Alzheimer's disease (Lim et al, 2014), and aging (Lim et al, 2014;Li et al, 2018). Similarly, chemogenetic stimulation of cholinergic neurons in the basal forebrain, lateral to the preoptic area, increases wakefulness and fragments sleep (Anaclet et al, 2015) and optical stimulation of basal forebrain parvalbumin neurons induces brief, rapid arousals from sleep (McKenna et al, 2020). Relative to basal forebrain glutamatergic neurons, optogenetic stimulation increases wakefulness (Xu et al, 2015), whereas activation of these neurons using chemogenetic strategies did not significantly alter sleep-wake states (Anaclet et al, 2015).…”

Basal forebrain parvalbumin neurons modulate vigilant attention

“…In a previous study we showed that BF-PV neurons fulfil the criteria for a system which responds to danger signals during sleep by transiently enhancing alertness to support appropriate responses to threat 19,54 . Our results here show that during wake BF-PV neurons are important for vigilant attention in a food-motivated signal detection task.…”

“…However, the role of other neurochemically defined BF subtypes is unknown. Recent work has shown that one population of BF GABAergic neurons containing the calcium-binding protein parvalbumin (PV) control cortical fast oscillations and arousals from sleep [16][17][18][19] but their role in awake behavior is unclear. Thus, here we test the hypothesis that BF-PV neurons modulate vigilant attention in mice.…”

“…BF-PV neurons are large neurons which project to cortex and thalamic reticular nucleus and discharge at high rates (20-60 Hz) during wake 16,24,38 , similar to the discharge rates of a subset of non-cholinergic BF neurons identified in macaques and mice, whose activity ramps up in anticipation of uncertain or unpredictable events 36,37 and correlates with fast reaction times 36 . Optogenetic excitation of BF-PV neurons rapidly and briefly wakes animals from sleep 19 and potently enhances fast cortical gamma oscillations [16][17][18] which have been linked to successful performance in attention tasks 39 . Furthermore, appropriately timed excitation of BF-PV neurons modulates the cortical topography of sensory stimuli-induced gamma oscillations in a manner reminiscent of the effects of attention 17 .…”

Chemoreceptor mechanisms regulating CO2‐induced arousal from sleep

“…2017; McKenna et al . 2020). BF inhibition impairs arousal not only to CO 2 , but also to an auditory stimulus, which is consistent with the regulation of cortical excitability in general (McKenna et al .…”