AMPK-dependent brain-wide norepinephrine release promotes recovery from metabolic coma in mice
- 1National Institute of Biological Sciences, Beijing
Abstract
Coma is a pathological brain state characterized by loss of consciousness. How the brain recovers from coma remains largely unknown. Using mouse models of metabolic coma, we identified an endogenous neuromodulatory pathway that actively promotes coma recovery. In mice subjected to hypoglycemic coma, hypoglycemia triggered AMPK-dependent excitation of nucleus tractus solitarius (NTS) neurons, which activated locus coeruleus (LC) norepinephrine neurons through a glutamatergic NTS-LC circuit. LC activation drives widespread norepinephrine release across cortical and subcortical regions, thereby promoting post-coma arousal. Notably, coma-associated brain-wide norepinephrine release was unconventional in both scale and duration, with a magnitude approximately 10-fold higher than physiological norepinephrine release during sleep-wake cycles. This neuromodulatory process also operated during hypercapnic coma. Vagus nerve stimulation accelerated coma recovery by engaging this endogenous anti-coma mechanism. Our findings uncover an AMPK-dependent brainstem circuit that actively restores arousal from metabolic coma, revealing a neural defense strategy against profound metabolic stress.
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BibTeX
@misc{wu2026ampkdependent,
title = {{AMPK-dependent brain-wide norepinephrine release promotes recovery from metabolic coma in mice}},
author = {M. Wu and L. Zhang and Y. Li and G. Chen and D. Li and M. Zhao and H. Gu and H. Song and Y. Cao and Z. Yang and Z. Liu and F. Zhang and T.-Z. Li and H.-H. Miao and P. Cao},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.07.757341},
url = {https://www.biorxiv.org/content/10.64898/2026.10.07.757341v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - AMPK-dependent brain-wide norepinephrine release promotes recovery from metabolic coma in mice
AU - M. Wu
AU - L. Zhang
AU - Y. Li
AU - G. Chen
AU - D. Li
AU - M. Zhao
AU - H. Gu
AU - H. Song
AU - Y. Cao
AU - Z. Yang
AU - Z. Liu
AU - F. Zhang
AU - T.-Z. Li
AU - H.-H. Miao
AU - P. Cao
PY - 2026
DA - 2026/10/07
PB - bioRxiv
DO - 10.64898/2026.10.07.757341
UR - https://www.biorxiv.org/content/10.64898/2026.10.07.757341v1
AB - Coma is a pathological brain state characterized by loss of consciousness. How the brain recovers from coma remains largely unknown. Using mouse models of metabolic coma, we identified an endogenous neuromodulatory pathway that actively promotes coma recovery. In mice subjected to hypoglycemic coma, hypoglycemia triggered AMPK-dependent excitation of nucleus tractus solitarius (NTS) neurons, which activated locus coeruleus (LC) norepinephrine neurons through a glutamatergic NTS-LC circuit. LC activation drives widespread norepinephrine release across cortical and subcortical regions, thereby promoting post-coma arousal. Notably, coma-associated brain-wide norepinephrine release was unconventional in both scale and duration, with a magnitude approximately 10-fold higher than physiological norepinephrine release during sleep-wake cycles. This neuromodulatory process also operated during hypercapnic coma. Vagus nerve stimulation accelerated coma recovery by engaging this endogenous anti-coma mechanism. Our findings uncover an AMPK-dependent brainstem circuit that actively restores arousal from metabolic coma, revealing a neural defense strategy against profound metabolic stress.
ER -