BACKGROUND Previous studies indicated the involvement of cholinergic neurons in seizure; however, the specific role of the medial septum (MS)-hippocampus cholinergic circuit in temporal lobe epilepsy (TLE) has not yet been completely elucidated. METHODS In the current study, we used magnetic resonance imaging and diffusion tensor imaging to characterize the pathological change of the MS-hippocampus circuit in 42 patients with TLE compared with 22 healthy volunteers. Using optogenetics and chemogenetics, combined with in vivo or in vitro electrophysiology and retrograde rabies virus tracing, we revealed a direct MS-hippocampus cholinergic circuit that potently attenuates seizure through driving somatostatin inhibition in animal TLE models. RESULTS We found that patients with TLE with hippocampal sclerosis showed a decrease of neuronal fiber connectivity of the MS-hippocampus compared with healthy people. In the mouse TLE model, MS cholinergic neurons ceased firing during hippocampal seizures. Optogenetic and chemogenetic activation of MS cholinergic neurons (but not glutamatergic or GABAergic [gamma-aminobutyric acidergic] neurons) significantly attenuated hippocampal seizures, while specific inhibition promoted hippocampal seizures. Electrophysiology combined with modified rabies virus tracing studies showed that direct (but not indirect) MS-hippocampal cholinergic projections mediated the antiseizure effect by preferentially targeting hippocampal GABAergic neurons. Furthermore, chemogenetic inhibition of hippocampal somatostatin-positive (rather than parvalbumin-positive) subtype of GABAergic neurons reversed the antiseizure effect of the MS-hippocampus cholinergic circuit, which was mimicked by activating somatostatin-positive neurons. CONCLUSIONS These findings underscore the notable antiseizure role of the direct cholinergic MS-hippocampus circuit in TLE through driving the downstream somatostatin effector. This may provide a better understanding of the changes of the seizure circuit and the precise spatiotemporal control of epilepsy.

中文翻译：

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直接中隔-海马胆碱能回路通过驱动生长抑素抑制来减轻癫痫发作

背景 先前的研究表明胆碱能神经元参与癫痫发作。然而，内侧中隔（MS）-海马胆碱能回路在颞叶癫痫（TLE）中的具体作用尚未完全阐明。方法在目前的研究中，我们使用磁共振成像和弥散张量成像来表征 42 名 TLE 患者与 22 名健康志愿者的 MS-海马回路的病理变化。使用光遗传学和化学遗传学，结合体内或体外电生理学和逆行狂犬病病毒追踪，我们揭示了一个直接的 MS-海马胆碱能回路，它通过在动物 TLE 模型中驱动生长抑素抑制来有效减弱癫痫发作。结果我们发现，与健康人相比，患有海马硬化症的 TLE 患者的 MS 海马神经元纤维连接性降低。在小鼠 TLE 模型中，MS 胆碱能神经元在海马癫痫发作期间停止放电。MS 胆碱能神经元（但不是谷氨酸能或 GABA 能 [γ-氨基丁酸能] 神经元）的光遗传学和化学遗传学激活显着减弱了海马癫痫发作，而特定抑制促进了海马癫痫发作。电生理学结合改良的狂犬病病毒追踪研究表明，直接（但不是间接）MS-海马胆碱能投射通过优先靶向海马 GABA 能神经元来介导抗癫痫作用。此外，GABA 能神经元的海马生长抑素阳性（而不是小清蛋白阳性）亚型的化学遗传学抑制逆转了 MS-海马胆碱能回路的抗癫痫作用，这通过激活生长抑素阳性神经元来模拟。结论这些发现强调了直接胆碱能 MS-海马回路通过驱动下游生长抑素效应物在 TLE 中的显着抗癫痫作用。这可以更好地了解癫痫发作回路的变化和癫痫的精确时空控制。结论这些发现强调了直接胆碱能 MS-海马回路通过驱动下游生长抑素效应物在 TLE 中的显着抗癫痫作用。这可以更好地了解癫痫发作回路的变化和癫痫的精确时空控制。结论这些发现强调了直接胆碱能 MS-海马回路通过驱动下游生长抑素效应物在 TLE 中的显着抗癫痫作用。这可以更好地了解癫痫发作回路的变化和癫痫的精确时空控制。