Dietary therapy restores glutamatergic input to orexin/hypocretin neurons after traumatic brain injury in mice
Open accessAbstract
Study objectives In previous work, dietary branched-chain amino acid (BCAA) supplementation, precursors to de novo glutamate and γ-aminobutyric acid (GABA) synthesis, restored impaired sleep-wake regulation and orexin neuronal activity following traumatic brain injury (TBI) in mice. TBI was speculated to reduce orexin neuronal activity through decreased regional excitatory (glutamate) and/or increased inhibitory (GABA) input. Therefore, we hypothesized that TBI would decrease synaptic glutamate and/or increase synaptic GABA in nerve terminals contacting orexin neurons, and BCAA supplementation would restore TBI-induced changes in synaptic glutamate and/or GABA. Methods Brain tissue was processed for orexin pre-embed diaminobenzidine labeling and glutamate or GABA postembed immunogold labeling. The density of glutamate and GABA immunogold within presynaptic nerve terminals contacting orexin-positive lateral hypothalamic neurons was quantified using electron microscopy in three groups of mice (n = 8 per group): Sham/noninjured controls, TBI without BCAA supplementation, and TBI with BCAA supplementation (given for 5 days, 48 hr post-TBI). Glutamate and GABA were also quantified within the cortical penumbral region (layer VIb) adjacent to the TBI lesion. Results In the hypothalamus and cortex, TBI decreased relative glutamate density in presynaptic terminals making axodendritic contacts. However, BCAA supplementation only restored relative glutamate density within presynaptic te…
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There was a decrease in the density of glutamate in the synapses on the dendrites of orexin neurons after TBI.
“We found that there was a decrease in the density of glutamate in the synapses on the dendrites of orexin neurons after TBI.”
From Effects of Traumatic Brain Injury on the Orexin/Hypocretin System (2025) · cites this paper as [82]
Cites
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“compared with noninjured control brains [41].”
Sleep-Wake Disturbances After Traumatic Brain Injury: Synthesis of Human and Animal Studies
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Self-citationAdaptation of the fluid percussion injury model to the mouse
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“Importantly, based on a significant body of work over the past 3 decades [47], this fluid pressure pulse has previously been shown to generate a mild brain injury, given the short latency to righting reflex [48, 49] and lack significant cell death and cavitation of the ventricles [50].”
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Self-citationBRAINSTEM LESIONS DUE TO CLOSED HEAD INJURY
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Lin, J., Jiang, Y., Wang, G., Meng, M., Zhu, Q., Mei, H., Liu, S., & Jiang, F. (2020) · Obesity Reviews · doi:10.1111/obr.13051 · Cited by 126 · 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
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- Authors
- Elliott, J. E., De Luche, S. E., Churchill, M. J., Moore, C., Cohen, A. S., Meshul, C. K., & Lim, M. M.
- Affiliations
- Oregon Health & Science University (US)
- VA Portland Health Care System, Portland, OR
- VA Portland Health Care System (US)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Lim, Miranda M
- ORCID
- Venue
- Sleep
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-01-05
- Volume
- 41
- Issue
- 3
- ISSN
- 0161-8105 (ISSN-L)
- 1550-9109
- PMC
- PMC6454530
- OpenAlex
- W2782347462
- Cited by
- 63
- References
- 9
- Citations by year
- 2026: 28 · 2025: 9 · 2024: 4 · 2023: 7 · 2022: 8 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 2
- FWCI
- 1.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- public-domain
- Locations
- SLEEP (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Funders
- American Sleep Medicine Foundation (#105-JF-14, #110-BK-14)
- VA Portland Health Care System (#IK2 BX002712)
- Portland VA Research Foundation (#I01 BX001643A)
- Topics
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Keywords
- traumatic brain injury, orexin neurons, orexin, branched-chain amino acids, dietary supplementation, glutamate, GABA, presynaptic terminals, lateral hypothalamus, sleep-wake regulation, axodendritic synapses
- MeSH terms
- Orexins, Brain Injuries, Traumatic, Animals, Diet Therapy, Hypothalamic Area, Lateral, Hypothalamus, Male, Mice, Inbred C57BL, Neurons, Sleep, Presynaptic Terminals, Glutamic Acid, Mice
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