Translational approaches to influence sleep and arousal

Brown, Ritchie E.; Spratt, Tristan J; Kaplan, Gary B.

doi:10.1016/j.brainresbull.2022.05.002

Cited by 14 publications

(16 citation statements)

References 346 publications

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“…In summary, chemogenetic activation of BF Npas1 + neurons strongly increased wakefulness, delayed the onset of sleep and disrupted NREM sleep oscillations, features reminiscent of sleep disruption in a variety of psychiatric and neurodegenerative disorders (Brown et al, 2022; Fernandez & Luthi, 2020).…”

Section: Resultsmentioning

confidence: 93%

“…Sleep is one of the three pillars of health alongside diet and exercise, and disrupted sleep has been linked to a wide variety of physical and neuropsychiatric consequences (Brown et al, 2022). Sleep disturbances are common among the general public, with higher prevalence among current and former military personnel, the elderly, and those suffering with psychiatric disorders, neurodegenerative disease, or traumatic brain injury (Brown et al, 2022). Precise delineation of the brain circuits which control sleep and wakefulness is essential for the development of new treatments but is hampered by the lack of markers to identify the key neuronal subpopulations in evolutionarily conserved brain regions.…”

Section: Introductionmentioning

confidence: 99%

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

Troppoli,

Yang,

Katsuki

et al. 2023

Preprint

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Here we describe a novel group of basal forebrain (BF) neurons expressing neuronal PAS domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. Immunohistochemical staining in Npas1-cre-2A-TdTomato mice revealed BF Npas1+neurons are distinct from well-studied parvalbumin or cholinergic neurons. Npas1 staining in GAD67-GFP knock-in mice confirmed that the vast majority of Npas1+neurons are GABAergic, with minimal colocalization with glutamatergic neurons in vGlut1-cre-tdTomato or vGlut2-cre-tdTomato mice. The density of Npas1+neurons was high, 5-6 times that of neighboring cholinergic, parvalbumin or glutamatergic neurons. Anterograde tracing identified prominent projections of BF Npas1+neurons to brain regions involved in sleep-wake control, motivated behaviors and olfaction such as the lateral hypothalamus, lateral habenula, nucleus accumbens shell, ventral tegmental area and olfactory bulb. Chemogenetic activation of BF Npas1+neurons in the light (inactive) period increased the amount of wakefulness and the latency to sleep for 2-3 hr, due to an increase in long wake bouts and short NREM sleep bouts. Non-REM slow-wave (0-1.5 Hz) and sigma (9-15 Hz) power, as well as sleep spindle density, amplitude and duration, were reduced, reminiscent of findings in several neuropsychiatric disorders. Together with previous findings implicating BF Npas1+neurons in stress responsiveness, the anatomical projections of BF Npas1+neurons and the effect of activating them suggest a possible role for BF Npas1+neurons in motivationally-driven wakefulness and stress-induced insomnia. Identification of this major subpopulation of BF GABAergic neurons will facilitate studies of their role in sleep disorders, dementia and other neuropsychiatric conditions involving BF.SIGNIFICANCE STATEMENTWe characterize a group of basal forebrain (BF) neurons in the mouse expressing neuronal PAS domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. BF Npas1+neurons are a major subset of GABAergic neurons distinct and more numerous than cholinergic, parvalbumin or glutamate neurons. BF Npas1+neurons target brain areas involved in arousal, motivation and olfaction. Activation of BF Npas1+neurons in the light (inactive) period increased wakefulness and the latency to sleep due to increased long wake bouts. Non-REM sleep slow waves and spindles were reduced reminiscent of findings in several neuropsychiatric disorders. Identification of this major subpopulation of BF GABAergic wake-promoting neurons will allow studies of their role in insomnia, dementia and other conditions involving BF.

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Section: Resultsmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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

Troppoli,

Yang,

Katsuki

et al. 2023

Preprint

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“…The involvement of TDP-43 in the complex reticular formation in MMC residents must be pursued further, given the complexity of the brainstem reticular nuclei and their connections with supra- and infra-cortical structures involving major integration and relay centers coordinating survival functions and key connections between the cerebral cortex, the cerebellum and the spinal cord [ 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 ]. We are particularly concerned about the associations between reticular brainstem-impaired connectivity and isolated sleep behavior disorder (iRBD) [ 88 ], one of the earliest manifestations of α synucleinopathies, which is present in MMC young adults [ 46 ], as well as the higher risk of falls [ 90 , 94 ] in young MMC adults [ 69 , 97 ].…”

Section: Discussionmentioning

confidence: 99%

TDP-43 CSF Concentrations Increase Exponentially with Age in Metropolitan Mexico City Young Urbanites Highly Exposed to PM2.5 and Ultrafine Particles and Historically Showing Alzheimer and Parkinson’s Hallmarks. Brain TDP-43 Pathology in MMC Residents Is Associated with High Cisternal CSF TDP-43 Concentrations

Calderón‐Garcidueñas

Stommel

Lachmann³

et al. 2022

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Environmental exposures to fine particulate matter (PM2.5) and ultrafine particle matter (UFPM) are associated with overlapping Alzheimer’s, Parkinson’s and TAR DNA-binding protein 43 (TDP-43) hallmark protein pathologies in young Metropolitan Mexico City (MMC) urbanites. We measured CSF concentrations of TDP-43 in 194 urban residents, including 92 MMC children aged 10.2 ± 4.7 y exposed to PM2.5 levels above the USEPA annual standard and to high UFPM and 26 low pollution controls (11.5 ± 4.4 y); 43 MMC adults (42.3 ± 15.9 y) and 14 low pollution adult controls (33.1 ± 12.0 y); and 19 amyotrophic lateral sclerosis (ALS) patients (52.4 ± 14.1 y). TDP-43 neuropathology and cisternal CSF data from 20 subjects—15 MMC (41.1 ± 18.9 y) and 5 low pollution controls (46 ± 16.01 y)—were included. CSF TDP-43 exponentially increased with age (p < 0.0001) and it was higher for MMC residents. TDP-43 cisternal CSF levels of 572 ± 208 pg/mL in 6/15 MMC autopsy cases forecasted TDP-43 in the olfactory bulb, medulla and pons, reticular formation and motor nuclei neurons. A 16 y old with TDP-43 cisternal levels of 1030 pg/mL exhibited TDP-43 pathology and all 15 MMC autopsy cases exhibited AD and PD hallmarks. Overlapping TDP-43, AD and PD pathologies start in childhood in urbanites with high exposures to PM2.5 and UFPM. Early, sustained exposures to PM air pollution represent a high risk for developing brains and MMC UFPM emissions sources ought to be clearly identified, regulated, monitored and controlled. Prevention of deadly neurologic diseases associated with air pollution ought to be a public health priority and preventive medicine is key.

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“…We are pleased to introduce this Research Topic of the Sleep and Circadian Rhythms section of Frontiers in Neuroscience entitled “ Insight in Sleep and Circadian Rhythms: 2021 .” Recent years have seen increased recognition that impaired sleep and circadian rhythms can lead to a wide range of deleterious effects for the body and the brain. Conversely, our improved understanding of the basic neurobiology of these processes allows novel targeted translational approaches to improve sleep and arousal (Brown et al, 2022 ). This collection of articles focuses on the basic neurobiology of sleep and circadian rhythms and the application of that knowledge to coma, sleep disorders, fatigue, psychiatric disorders, pain, and epilepsy.…”

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confidence: 99%