Optogenetic/Chemogenetic Activation of GABAergic Neurons in the Ventral Tegmental Area Facilitates General Anesthesia via Projections to the Lateral Hypothalamus in Mice
Optogenetic/Chemogenetic Activation of GABAergic Neurons in the Ventral Tegmental Area Facilitates General Anesthesia via Projections to the Lateral Hypothalamus in Mice
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DOI：
10.3389/fncir.2019.00073
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发表时间：
2019-11-19
影响因子：
3.5
通讯作者：
Dong, HaiLong
中科院分区：
文献类型：
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作者：
Yin, Lu;Li, Long;Dong, HaiLong
据报道，腹侧被盖区(VTA)通过与外侧下丘脑(LH)的通讯来调节睡眠和觉醒。也有研究表明，通过给予水合氯醛、氯胺酮或氟烷产生足够的麻醉可显著降低VTA内GABA能神经元的放电率。然而，对VTA内GABA能神经元的确切影响以及这些神经元通过相关神经回路调节麻醉的机制仍不清楚。在这里，我们使用光遗传学和化学遗传学的方法来特异性地激活或抑制Vgat-CRE小鼠VTA中的GABA能神经元周围膜或它们向LH的投射。分别在0.8%和1.0%异氟醚麻醉下进行脑电(EEG)频谱分析和猝发抑制比(BSR)计算，并在1.4%异氟醚麻醉下测定翻正反射消失(LOR)、翻正反射恢复(RORR)和麻醉敏感性。结果表明，麻醉维持期间，激活下丘脑室旁核GABA能神经元，可使Delta波功率从40.0%增加到46.4%(P=0.006)，使伽玛波功率从15.2%降低到11.5%(P=0.017)。血肌率由治疗前的51.8%提高到治疗后的68.3%(P=0.017)。苏醒时间S由333缩短至290(P=0.019)，苏醒时间由498延长至661 S(P=0.007)。相反，抑制VTA GABA能神经元则产生相反的效应。而激活VTA-LHGABA能投射神经元，慢增量波的功率从44.2%增加到48.8%(P=0.014)，伽马振荡的功率从10.2%降低到8.0%。血肌率由治疗前的39.9%上升至60.2%(P=0.0002)。LOR从330降至232 S(P=0.002)，RORR由396升至565 S(P=0.007)。视觉抑制投射神经元在脑电频谱和脑干听觉诱发电位上都产生相反的影响，除了抑制这一投射并不能加快觉醒时间。这些结果表明，VTA GABA能神经元在异氟醚诱导和维持过程中可促进异氟醚的麻醉效应，而延迟麻醉恢复，至少部分是通过调节其向黄体生成素的投射来实现的。
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.