Dietary therapy restores glutamatergic input to orexin/hypocretin neurons after traumatic brain injury in mice

Jonathan E. Elliott, Samuel E. De Luche, Madeline J. Churchill, Cindy Moore, Akiva S. Cohen, Charles K. Meshul, Miranda Lim

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Study Objectives In previous work, dietary branched-chain amino acid (BCAA) supplementation, precursors to de novo glutamate and γ 3-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 terminals contacting orexin-positive hypothalamic neurons. BCAA supplementation did not change relative glutamate density in presynaptic terminals making axosomatic contacts, or relative GABA density in presynaptic terminals making axosomatic or axodendritic contacts, within either the hypothalamus or cortex. Conclusions These results suggest TBI compromises orexin neuron function via decreased glutamate density and highlight BCAA supplementation as a potential therapy to restore glutamate density to orexin neurons.

Original languageEnglish (US)
JournalSleep
Volume41
Issue number3
DOIs
StatePublished - Mar 1 2018

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Glutamic Acid
Neurons
Branched Chain Amino Acids
Presynaptic Terminals
Therapeutics
Specific Gravity
Traumatic Brain Injury
Orexins
Hypothalamus
3-aminobutyric acid
Electron Microscopy
Sleep

Keywords

  • branched-chain amino acids
  • electron microscopy
  • hypocretin
  • sleep
  • wakefulness

ASJC Scopus subject areas

  • Clinical Neurology
  • Physiology (medical)

Cite this

Elliott, J. E., De Luche, S. E., Churchill, M. J., Moore, C., Cohen, A. S., Meshul, C. K., & Lim, M. (2018). Dietary therapy restores glutamatergic input to orexin/hypocretin neurons after traumatic brain injury in mice. Sleep, 41(3). https://doi.org/10.1093/sleep/zsx212

Dietary therapy restores glutamatergic input to orexin/hypocretin neurons after traumatic brain injury in mice. / Elliott, Jonathan E.; De Luche, Samuel E.; Churchill, Madeline J.; Moore, Cindy; Cohen, Akiva S.; Meshul, Charles K.; Lim, Miranda.

In: Sleep, Vol. 41, No. 3, 01.03.2018.

Research output: Contribution to journalArticle

Elliott, Jonathan E. ; De Luche, Samuel E. ; Churchill, Madeline J. ; Moore, Cindy ; Cohen, Akiva S. ; Meshul, Charles K. ; Lim, Miranda. / Dietary therapy restores glutamatergic input to orexin/hypocretin neurons after traumatic brain injury in mice. In: Sleep. 2018 ; Vol. 41, No. 3.
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AU - Elliott, Jonathan E.

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AU - Moore, Cindy

AU - Cohen, Akiva S.

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AB - Study Objectives In previous work, dietary branched-chain amino acid (BCAA) supplementation, precursors to de novo glutamate and γ 3-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 terminals contacting orexin-positive hypothalamic neurons. BCAA supplementation did not change relative glutamate density in presynaptic terminals making axosomatic contacts, or relative GABA density in presynaptic terminals making axosomatic or axodendritic contacts, within either the hypothalamus or cortex. Conclusions These results suggest TBI compromises orexin neuron function via decreased glutamate density and highlight BCAA supplementation as a potential therapy to restore glutamate density to orexin neurons.

KW - branched-chain amino acids

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KW - hypocretin

KW - sleep

KW - wakefulness

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