Guillaumin Mathilde C C, Burdakov Denis
Department of Health Sciences and Technology, ETH Zürich, Zurich, Switzerland.
Front Neurosci. 2021 Mar 11;15:644313. doi: 10.3389/fnins.2021.644313. eCollection 2021.
Across sleep and wakefulness, brain function requires inter-neuronal interactions lasting beyond seconds. Yet, most studies of neural circuit connectivity focus on millisecond-scale interactions mediated by the classic fast transmitters, GABA and glutamate. In contrast, neural circuit roles of the largest transmitter family in the brain-the slow-acting peptide transmitters-remain relatively overlooked, or described as "modulatory." Neuropeptides may efficiently implement sustained neural circuit connectivity, since they are not rapidly removed from the extracellular space, and their prolonged action does not require continuous presynaptic firing. From this perspective, we review actions of evolutionarily-conserved neuropeptides made by brain-wide-projecting hypothalamic neurons, focusing on lateral hypothalamus (LH) neuropeptides essential for stable consciousness: the orexins/hypocretins. Action potential-dependent orexin release inside and outside the hypothalamus evokes slow postsynaptic excitation. This excitation does not arise from modulation of classic neurotransmission, but involves direct action of orexins on their specific G-protein coupled receptors (GPCRs) coupled to ion channels. While millisecond-scale, GABA/glutamate connectivity within the LH may not be strong, re-assessing LH microcircuits from the peptidergic viewpoint is consistent with slow local microcircuits. The sustained actions of neuropeptides on neuronal membrane potential may enable core brain functions, such as temporal integration and the creation of lasting permissive signals that act as "eligibility traces" for context-dependent information routing and plasticity. The slowness of neuropeptides has unique advantages for efficient neuronal processing and feedback control of consciousness.
在睡眠和清醒状态下，大脑功能需要神经元之间持续数秒以上的相互作用。然而，大多数关于神经回路连接性的研究都集中在由经典快速递质γ-氨基丁酸（GABA）和谷氨酸介导的毫秒级相互作用上。相比之下，大脑中最大的递质家族——慢作用肽递质——在神经回路中的作用仍然相对被忽视，或者被描述为“调节性的”。神经肽可能有效地实现持续的神经回路连接，因为它们不会迅速从细胞外空间清除，并且它们的延长作用不需要突触前持续放电。从这个角度出发，我们综述了由投射至全脑的下丘脑神经元产生的进化保守神经肽的作用，重点关注对稳定意识至关重要的外侧下丘脑（LH）神经肽：食欲素/下丘脑泌素。下丘脑内外依赖动作电位的食欲素释放会引发缓慢的突触后兴奋。这种兴奋并非源于对经典神经传递的调节，而是涉及食欲素对与其偶联至离子通道的特定G蛋白偶联受体（GPCR）的直接作用。虽然LH内毫秒级的GABA/谷氨酸连接可能不强，但从肽能角度重新评估LH微回路与缓慢的局部微回路是一致的。神经肽对神经元膜电位的持续作用可能实现核心脑功能，如时间整合以及产生持久的许可信号，这些信号作为上下文依赖的信息路由和可塑性的“合格痕迹”。神经肽的缓慢特性在高效的神经元处理和意识的反馈控制方面具有独特优势。
