British journal of anaesthesia · 2026
Astrocytic α2A-adrenergic signalling in the hypothalamic paraventricular nucleus contributes to dexmedetomidine-induced sedation in mice.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Luo Rong, Hu Xiaojun, Luo Yuncheng, Liao Ping, Zhang Fan, Shen Yu, Tang Hao-Di, Li Qingran, Yu Yunqing, Yi Limei, Zuo Yunxia, Jiang Ruotian
Аннотация
BACKGROUND: Dexmedetomidine (Dex) is a selective α2-adrenergic receptor (α2-AR) agonist widely used for sedation, but its underlying mechanisms remain incompletely understood. We aimed to identify novel brain regions and cellular pathways mediating Dex-induced sedation in mice.
METHODS: Brain-wide α2A-ARs expression was mapped in adult male C57BL/6 mice using RNAscope in situ hybridisation with immunofluorescence. Functional expression was confirmed by intracellular Ca2+ imaging in astrocytes. Sedation was assessed by rotarod, open-field tests, and electroencephalography (EEG). Astrocyte-specific gene knockdown, chemogenetics, and electrophysiology were used to explore underlying mechanisms.
RESULTS: Expression of α2A-ARs was enriched in hypothalamic paraventricular nucleus (PVH) astrocytes, where Dex triggered α2A-AR-dependent Ca2+ elevations. Knockdown of astrocyte α2A-ARs reduced Dex-induced sedation, evidenced by increased rotarod fall latency (mean [standard deviation] 228 [52] vs 166 [62] s, P=0.026), increased open-field distance (3640 [950] vs 2680 [850] cm, P=0.029) and decreased EEG delta power (54.2 [11.0] vs 62.0 [5.9]%, P=0.024). Inhibition of astrocyte Ca2+ signalling produced similar effects. Mechanistically, Dex enhanced tonic gamma-aminobutyric acid (GABA) currents in local Vglut2+ neurones (15.5 [9.6] vs 7.8 [6.6] pA, P=0.035) and suppressed neuronal firing (0.5 [0.5] vs 1.8 [1.3] Hz, P<0.001); both effects were attenuated by inhibition of astrocyte Ca2+ levels. Furthermore, knockdown of the Ca2+-activated anion channel bestrophin-1 (BEST1) in PVH astrocytes reduced tonic GABA currents (3.5 [3.4] vs 7.5 [7.2] pA, P=0.024) and diminished sedation.
CONCLUSIONS: An astrocytic α2A-AR-Ca2+-BEST1 pathway in hypothalamic paraventricular nucleus neurones mediates Dex-induced sedation, which identifies a critical role for astrocytes in pharmacologically induced sedation.
METHODS: Brain-wide α2A-ARs expression was mapped in adult male C57BL/6 mice using RNAscope in situ hybridisation with immunofluorescence. Functional expression was confirmed by intracellular Ca2+ imaging in astrocytes. Sedation was assessed by rotarod, open-field tests, and electroencephalography (EEG). Astrocyte-specific gene knockdown, chemogenetics, and electrophysiology were used to explore underlying mechanisms.
RESULTS: Expression of α2A-ARs was enriched in hypothalamic paraventricular nucleus (PVH) astrocytes, where Dex triggered α2A-AR-dependent Ca2+ elevations. Knockdown of astrocyte α2A-ARs reduced Dex-induced sedation, evidenced by increased rotarod fall latency (mean [standard deviation] 228 [52] vs 166 [62] s, P=0.026), increased open-field distance (3640 [950] vs 2680 [850] cm, P=0.029) and decreased EEG delta power (54.2 [11.0] vs 62.0 [5.9]%, P=0.024). Inhibition of astrocyte Ca2+ signalling produced similar effects. Mechanistically, Dex enhanced tonic gamma-aminobutyric acid (GABA) currents in local Vglut2+ neurones (15.5 [9.6] vs 7.8 [6.6] pA, P=0.035) and suppressed neuronal firing (0.5 [0.5] vs 1.8 [1.3] Hz, P<0.001); both effects were attenuated by inhibition of astrocyte Ca2+ levels. Furthermore, knockdown of the Ca2+-activated anion channel bestrophin-1 (BEST1) in PVH astrocytes reduced tonic GABA currents (3.5 [3.4] vs 7.5 [7.2] pA, P=0.024) and diminished sedation.
CONCLUSIONS: An astrocytic α2A-AR-Ca2+-BEST1 pathway in hypothalamic paraventricular nucleus neurones mediates Dex-induced sedation, which identifies a critical role for astrocytes in pharmacologically induced sedation.