Department of Radiology, Zhongnan Hospital of Wuhan University, Wuchang District, Wuhan City, Hubei Province, 430071, China.
Neurochem Res. 2023 Aug;48(8):2463-2475. doi: 10.1007/s11064-023-03925-9. Epub 2023 Apr 4.
Insomnia and anxiety are two common and closely related clinical problems that pose a threat to individuals' physical and mental well-being. There is a possibility that some nuclei and neural circuits in the brain are shared by both insomnia and anxiety. In the present study, using a combination of chemogenetics, optogenetics, polysomnographic recordings and the classic tests of anxiety-like behaviors, we verified that the calmodulin-dependent protein kinase II alpha (CaMKIIa) neurons of the ventromedial hypothalamus (VMH) are involved in the regulation of both wakefulness and anxiety. Chemogenetic manipulation of the VMH CaMKIIa neurons elicited an apparent increase in wakefulness during activation, whereas inhibition decreased wakefulness mildly. It substantiated that the VMH CaMKIIa neurons contribute to wakefulness. Then in millisecond-scale control of neuronal activity, short-term and long-term optogenetic activation induced the initiation and maintenance of wakefulness, respectively. We also observed that mice reduced exploratory behaviors in classic anxiety tests while activating the VMH CaMKIIa neurons and were anxiolytic while inhibiting. Additionally, photostimulation of the VMH CaMKIIa axons in the paraventricular hypothalamus (PVH) mediated wakefulness and triggered anxiety-like behaviors as well. In conclusion, our results demonstrate that the VMH participates in the control of wakefulness and anxiety, and offer a neurological explanation for insomnia and anxiety, which may be valuable for therapeutic interventions such as medication and transcranial magnetic stimulation.
失眠和焦虑是两种常见且密切相关的临床问题，它们威胁着个体的身心健康。大脑中的一些核团和神经回路可能同时与失眠和焦虑有关。在本研究中，我们结合化学遗传学、光遗传学、多导睡眠记录和经典焦虑样行为测试，验证了腹内侧下丘脑（VMH）中的钙调蛋白依赖性蛋白激酶 II ɑ（CaMKIIɑ）神经元参与调节觉醒和焦虑。VMH CaMKIIɑ神经元的化学遗传学操作在激活时明显增加觉醒，而抑制则轻度降低觉醒。这证实了 VMH CaMKIIɑ神经元有助于觉醒。然后在毫秒级的神经元活动控制中，短期和长期光遗传学激活分别诱导了觉醒的起始和维持。我们还观察到，在激活 VMH CaMKIIɑ神经元时，小鼠在经典焦虑测试中减少了探索行为，而抑制时则表现出抗焦虑作用。此外，PVH 中的 VMH CaMKIIɑ轴突的光刺激也介导了觉醒，并引发了焦虑样行为。总之，我们的结果表明，VMH 参与了觉醒和焦虑的控制，为失眠和焦虑提供了神经学解释，这可能对药物治疗和经颅磁刺激等治疗干预具有重要意义。
