The ventral tegmental area (VTA) reportedly regulates sleep and wakefulness through communication with the lateral hypothalamus (LH). It has also been suggested that adequate anesthesia produced by administration of chloral hydrate, ketamine, or halothane significantly reduces the GABAergic neuronal firing rate within the VTA. However, the exact effects on GABAergic neurons in the VTA and the mechanisms through which these neurons modulate anesthesia through associated neural circuits is still unclear. Here, we used optogenetic and chemogenetic methods to specifically activate or inhibit GABAergic neuronal perikarya in the VTA or their projections to the LH in Vgat-Cre mice. Electroencephalogram (EEG) spectral analyses and burst suppression ratio (BSR) calculations were conducted following administration of 0.8 or 1.0% isoflurane, respectively; and loss of righting reflex (LORR), recovery of righting reflex (RORR), and anesthesia sensitivity were assessed under 1.4% isoflurane anesthesia. The results showed that activation of GABAergic neurons in the VTA increased delta wave power from 40.0 to 46.4% (P = 0.006) and decreased gamma wave power from 15.2 to 11.5% (P = 0.017) during anesthesia maintenance. BSR was increased from 51.8 to 68.3% (P = 0.017). Induction time (LORR) was reduced from 333 to 290 s (P = 0.019), whereas arousal time (RORR) was prolonged from 498 to 661 s (P = 0.007). Conversely, inhibition of VTA GABAergic neurons led to opposite effects. In contrast, optical activation of VTA-LH GABAergic projection neurons increased power of slow delta waves from 44.2 to 48.8% (P = 0.014) and decreased that of gamma oscillations from 10.2 to 8.0%. BSR was increased from 39.9 to 60.2% (P = 0.0002). LORR was reduced from 330 to 232 s (P = 0.002), and RORR increased from 396 to 565 s (P = 0.007). Optical inhibition of the projection neurons caused opposite effects in terms of both the EEG spectrum and the BSR, except that inhibition of this projection did not accelerate arousal time. These results indicate that VTA GABAergic neurons could facilitate the anesthetic effects of isoflurane during induction and maintenance while postponing anesthetic recovery, at least partially, through modulation of their projections to the LH.

中文翻译：

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腹侧被盖区中的GABA能神经元的光遗传/化学遗传激活可通过投射至小鼠下丘脑的侧面来促进全身麻醉。

据报道，腹侧被盖区（VTA）通过与下丘脑外侧（LH）的交流来调节睡眠和清醒状态。还已经提出，通过施用水合氯醛，氯胺酮或氟烷产生的充分麻醉显着降低了VTA内的GABA能神经元放电速率。但是，尚不清楚VTA对GABA能神经元的确切作用以及这些神经元通过相关神经回路调节麻醉的机制尚不清楚。在这里，我们使用了光遗传学和化学遗传学方法来特异性激活或抑制VTA中的GABA能神经元周围核或在Vgat-Cre小鼠中向LH的投射。分别给予0.8％或1.0％的异氟烷​​后，进行脑电图（EEG）频谱分析和猝发抑制率（BSR）计算。在1.4％异氟烷麻醉下评估了恢复力和恢复力丧失（LORR），恢复力恢复能力（RORR）和麻醉敏感性。结果表明，在麻醉维持过程中，VTA中GABA能神经元的激活将三角波功率从40.0％提高到46.4％（P = 0.006），并将伽马波功率从15.2降低到11.5％（P = 0.017）。BSR从51.8％增加到68.3％（P = 0.017）。诱导时间（LORR）从333减少到290 s（P = 0.019），而唤醒时间（RORR）从498延长到661 s（P = 0.007）。相反，抑制VTA GABA能神经元会产生相反的作用。相比之下，VTA-LH GABA能投射神经元的光学激活将慢三角波的功率从44.2提高到48.8％（P = 0.014），并将伽马振荡的功率从10.2降低到8.0％。BSR从39.9增加到60 2％（P = 0.0002）。LORR从330减少到232 s（P = 0.002），RORR从396增加到565 s（P = 0.007）。投射神经元的光学抑制在脑电图谱和BSR方面均产生相反的作用，除了抑制投射不会加速唤醒时间。这些结果表明，VTA GABA能神经元可以在诱导和维持过程中促进异氟烷的麻醉作用，同时至少部分地通过调节其向LH的投射来推迟麻醉剂的恢复。