Controlled Cortical Impact Traumatic Brain Injury Acutely Disrupts Wakefulness and Extracellular Orexin Dynamics as Determined by Intracerebral Microdialysis in Mice
Open accessAbstract
Among other deficits, traumatic brain injury (TBI) causes impaired arousal and cognitive dysfunction. Hypothalamic orexin neuropeptides (also called hypocretins) regulate levels of arousal, and cerebrospinal fluid orexin levels are reportedly low in TBI patients. We hypothesized that TBI acutely impairs the dynamics of orexin release into brain interstitial fluid, and that these extracellular orexin levels correlate with wakefulness and motor activity. To test this in mice, we combined an electromagnetic controlled cortical impact (CCI) model of experimental TBI with dual intracerebral microdialysis using one catheter in the hypothalamus and one catheter in the hippocampus, plus electroencephalography/electromyography (EEG/EMG), and motor activity monitoring. Baseline data were continuously collected in tethered but relatively freely moving mice for 2 days. Then, ipsilateral CCI or sham surgery was performed, and data collection was continued for 3 additional days. At baseline, extracellular orexin levels in the hypothalamus showed a circadian rhythm, with peak levels during the dark (wake) phase, and a nadir during the light (rest) phase. Following CCI but not sham surgery, orexin levels were depressed in both the hypothalamus and hippocampus, and diurnal fluctuation amplitudes were blunted in the hypothalamus. At baseline, correlations of orexin with wakefulness and motor activity were positive and highly significant. Following CCI but not sham surgery, the mice exhibited reduced wakefulness and motor activity, and correlations between orexin and these measures were diminished. These abnormal orexin dynamics were associated with hypothalamic astrogliosis, but not acute loss of orexin neurons, as assessed by immunohistochemistry 3 days after injury. Future studies involving experimental manipulations of the orexin system will be required to determine its contribution to neurological outcomes following injury.
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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 [49]
The Discussion describes hypersomnia and impaired arousal after human TBI, while “Effects of TBI on wakefulness” reports shorter, more fragmented wake bouts in brain-injured mice during their active (dark) phase. This supports a parallel in impaired wakefulness, but the paper does not demonstrate excessive daytime sleepiness in mice or establish that animal models generally recapitulate human sleep disorders. The section “Are brain-injured mice narcoleptic?” also cautions that these mice show only some features of narcolepsy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn the authors' previous study, there was an increase in orexin neurons after injury.
“In our previous study, there was an increase in orexin neurons after injury.49”
From Effects of Traumatic Brain Injury on the Orexin/Hypocretin System (2025) · cites this paper as [49]
The Immunohistochemistry for orexin section reports more orexin-positive cells after injury than in sham controls. But the Effects of injury on orexin-immunoreactive cell counts section cautions that increased staining may have made cell counts appear higher; it does not establish an increase in the actual number of neurons. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn the authors' study, orexin was measured over time and only decreased expression after injury was seen, but all measurements were taken after 24 h post-injury.
“In our study,49 we measured orexin over time and only saw decreased expression after injury, but all of our measurements were taken after 24 h post-injury.”
From Effects of Traumatic Brain Injury on the Orexin/Hypocretin System (2025) · cites this paper as [49]
The ‘Effect of TBI on orexin dynamics’ section reports lower extracellular orexin levels after injury. But the ‘Experimental overview’ says sampling resumed following injury and continued for 72 hours, not that all measurements were taken after 24 hours. The paper also reports increased orexin-positive cell counts, so ‘only decreased expression’ does not describe all its orexin findings. Page numbers were unavailable in our copy. (LLM, conf=0.91)
Experimental — accuracy not yet measuredSeveral other studies, including the authors' own, found a decrease in orexin after TBI.
“In several other studies, including ours, there was a decrease in orexin after TBI.49,77,78”
From Effects of Traumatic Brain Injury on the Orexin/Hypocretin System (2025) · cites this paper as [49]
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Cites
Neurons containing hypocretin (orexin) project to multiple neuronal systems
Peyron, C., Tighe, D. K., van den Pol, A. N., de Lecea, L., Heller, H. C., Sutcliffe, J. G., & Kilduff, T. S. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-23-09996.1998 · Cited by 3,466 · see citing works
Sleep-wake disturbances 6 months after traumatic brain injury: a prospective study
Baumann, C. R., Werth, E., Stocker, R., Ludwig, S., & Bassetti, C. L. (2007) · Brain · doi:10.1093/brain/awm109 · Cited by 380 · see citing works
Experimental models of traumatic brain injury: do we really need to build a better mousetrap?
Morales, D. M., Marklund, N., Lebold, D., Thompson, H. J., Pitkanen, A., Maxwell, W. L., Longhi, L., Laurer, H., Maegele, M., Neugebauer, E., et al. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2005.08.030 · Cited by 339 · see citing works
Prevalence and Consequences of Sleep Disorders in Traumatic Brain Injury
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Hypothalamic lesions following closed head injury
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Loss of hypocretin (orexin) neurons with traumatic brain injury
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“Furthermore, an autopsy study demonstrated significant reduction of orexin neurons in brains obtained following lethal TBI compared with control brains (Baumann et al., 2009).”
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Research works printed but not linked: 2
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Sleep-Wake Disturbances After Traumatic Brain Injury: Synthesis of Human and Animal Studies
Sandsmark, D. K., Elliott, J. E., & Lim, M. M. (2017) · Sleep · doi:10.1093/sleep/zsx044 · Cited by 183 · see citing works
Self-citationSaber, M., Giordano, K. R., Hur, Y., Ortiz, J. B., Morrison, H., Godbout, J. P., Murphy, S. M., Lifshitz, J., & Rowe, R. K. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.14611 · Cited by 46 · see citing works
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Self-citationEffects of Traumatic Brain Injury on the Orexin/Hypocretin System
Somach, R. T., Lim, M. M., & Cohen, A. S. (2025) · Neurotrauma Reports · doi:10.1089/neur.2024.0111 · Cited by 2 · see citing works
Self-citation
- Authors
- Willie, J. T., Lim, M. M., Bennett, R. E., Azarion, A. A., Schwetye, K. E., & Brody, D. L.
- Affiliations
- Emory University (US)
- University of Pennsylvania (US)
- Corresponding author
- Brody, David L.
- Venue
- Journal of Neurotrauma
- Publisher
- SAGE Publications
- Published
- 2012-07
- Volume
- 29
- Issue
- 10
- Pages
- 1908-1921
- ISSN
- 0897-7151 (ISSN-L)
- 1557-9042
- PMC
- PMC3390985
- OpenAlex
- W2135623011
- Cited by
- 79
- References
- 6
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 2 · 2023: 6 · 2022: 6 · 2021: 5 · 2020: 5 · 2019: 5 · 2018: 10 · 2017: 4 · 2016: 7 · 2015: 9 · 2014: 4 · 2013: 6
- FWCI
- 3.11
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Neurotrauma (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (NS065069, R01NS065069)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Keywords
- traumatic brain injury, controlled cortical impact, orexin, wakefulness, arousal, hypothalamus, hippocampus, circadian rhythm, motor activity, astrocyte activation, cerebrospinal fluid
- MeSH terms
- Orexins, Acute Disease, Animals, Brain Injuries, Cerebral Cortex, Consciousness Disorders, Disease Models, Animal, Male, Mice, Inbred C57BL, Neuropeptides, Wakefulness, Microdialysis, Intracellular Signaling Peptides and Proteins, Mice
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