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Cited by 37Sleep and Wakefulness ResearchTraumatic Brain Injury and Neurovascular DisturbancesNeuroscience of respiration and sleep

Hypocretinergic and cholinergic contributions to sleep-wake disturbances in a mouse model of traumatic brain injury

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Thomasy, Hannah E., Febinger, Heidi Y., Ringgold, Kristyn M., Gemma, Carmelina, Opp, Mark R.·2017·Neurobiology of Sleep and Circadian Rhythms
DOI 10.1016/j.nbscr.2016.03.001PMC PMC6575582
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Abstract

Disorders of sleep and wakefulness occur in the majority of individuals who have experienced traumatic brain injury (TBI), with increased sleep need and excessive daytime sleepiness often reported. Behavioral and pharmacological therapies have limited efficacy, in part, because the etiology of post-TBI sleep disturbances is not well understood. Severity of injuries resulting from head trauma in humans is highly variable, and as a consequence so are their sequelae. Here, we use a controlled laboratory model to investigate the effects of TBI on sleep-wake behavior and on candidate neurotransmitter systems as potential mediators. We focus on hypocretin and melanin-concentrating hormone (MCH), hypothalamic neuropeptides important for regulating sleep and wakefulness, and two potential downstream effectors of hypocretin actions, histamine and acetylcholine. Adult male C57BL/6 mice ( n =6–10/group) were implanted with EEG recording electrodes and baseline recordings were obtained. After baseline recordings, controlled cortical impact was used to induce mild or moderate TBI. EEG recordings were obtained from the same animals at 7 and 15 days post-surgery. Separate groups of animals ( n =6–8/group) were used to determine effects of TBI on the numbers of hypocretin and MCH-producing neurons in the hypothalamus, histaminergic neurons in the tuberomammillary nucleus, and cholinergic neurons in the basal forebrain. At 15 days post-TBI, wakefulness was decreased and NREM sleep was increased during the dark period in moderately injured animals. There were no differences between groups in REM sleep time, nor were there differences between groups in sleep during the light period. TBI effects on hypocretin and cholinergic neurons were such that more severe injury resulted in fewer cells. Numbers of MCH neurons and histaminergic neurons were not altered under the conditions of this study. Thus, we conclude that moderate TBI in mice reduces wakefulness and increases NREM sleep during the dark period, effects that may be mediated by hypocretin-producing neurons and/or downstream cholinergic effectors in the basal forebrain.

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  • Some studies report a significant reduction of orexin neurons after injury.

    “Some studies report a significant reduction of orexin neurons after injury.45,48,73”

    From Effects of Traumatic Brain Injury on the Orexin/Hypocretin System (2025) · cites this paper as [45]

  • At the same injury severity, orexin neurons may be more vulnerable to the effects of TBI compared to MCH neurons.

    “This suggests that at the same injury severity, orexin neurons may be more vulnerable to the effects of the TBI as compared to MCH neurons.”

    From Effects of Traumatic Brain Injury on the Orexin/Hypocretin System (2025) · cites this paper as [45]

  • Animal models recapitulate sleep phenotypes of disordered sleep in humans, especially excessive daytime sleepiness.

    “Animal models recapitulate sleep phenotypes of disordered sleep in humans, especially that of EDS.22,44,45,48,49,64–73”

    From Effects of Traumatic Brain Injury on the Orexin/Hypocretin System (2025) · cites this paper as [45]

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Cited by

Sorted by citations

Authors
Thomasy, H. E., Febinger, H. Y., Ringgold, K. M., Gemma, C., & Opp, M. R.
Affiliations
University of Washington (US)
Corresponding author
Opp, Mark R.
ORCID
Venue
Neurobiology of Sleep and Circadian Rhythms
Publisher
Elsevier BV
Published
2017-01
Volume
2
Pages
71-84
ISSN
2451-9944 (ISSN-L)
DOI
10.1016/j.nbscr.2016.03.001
PMC
PMC6575582
OpenAlex
W2403859622
Cited by
37
References
7
Citations by year
2026: 4 · 2025: 6 · 2024: 2 · 2023: 4 · 2022: 7 · 2021: 3 · 2020: 3 · 2019: 1 · 2018: 5 · 2017: 2
FWCI
1.70
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Sleep and Circadian Rhythms (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Department of Anesthesiology & Pain Medicine
  • Graduate Program in Neuroscience of the University of Washington
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
Keywords
traumatic brain injury, sleep-wake disturbances, orexin, melanin-concentrating hormone, acetylcholine, histamine, tuberomammillary nucleus, basal forebrain cholinergic neurons, NREM sleep, wakefulness, controlled cortical impact, hypothalamic neuropeptides, excessive daytime sleepiness

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