The Francis Crick Institute, London, NW1 1AT, UK.
J Physiol. 2020 Oct;598(19):4371-4383. doi: 10.1113/JP280158. Epub 2020 Jul 29.
Photoinhibition of endogenous activity of lateral hypothalamic orexin neurons causes place preference and reduces innate avoidance Endogenous activity of orexin neurons correlates with place preference Mediobasal hypothalamic Agrp neurons inhibit orexin neurons via GABA, and chemogenetic suppression of Agrp neurons increases avoidance in an orexin receptor-dependent manner.
Hypothalamic orexin/hypocretin neurons integrate multiple sensory cues and project brain-wide to orchestrate diverse innate behaviours. Their loss impairs many context-appropriate actions, but the motivational characteristics of orexin cell activity remain unclear. We and others previously approached this question by artificial orexin stimulation, which could induce either rewarding (positive valence) or aversive (negative valence) brain activity. It is unknown to what extent such approaches replicate natural/endogenous orexin signals, which rapidly fluctuate during wakefulness. Here we took an alternative approach, focusing on observing and silencing natural orexin cell signals associated with a fundamental innate behaviour, self-paced spatial exploration. We found that mice are more likely to stay in places paired with orexin cell optosilencing. The orexin cell optosilencing also reduced avoidance of places that mice find innately aversive. Correspondingly, calcium recordings revealed that orexin cell activity rapidly reduced upon exiting the innately aversive places. Furthermore, we provide optogenetic evidence for an inhibitory GABAergic Agrp→orexin hypothalamic neurocircuit, and find that Agrp cell suppression increases innate avoidance behaviour, consistent with orexin disinhibition. These results imply that exploration may be motivated and oriented by a need to reduce aversive orexin cell activity, and suggest a hypothalamic circuit for fine-tuning orexin signals to changing ethological priorities.
光抑制外侧下丘脑食欲素神经元的内源性活动会引起位置偏好并减少先天回避 食欲素神经元的内源性活动与位置偏好相关 中脑基底部 Agrp 神经元通过 GABA 抑制食欲素神经元，并且 Agrp 神经元的化学遗传抑制以依赖于食欲素受体的方式增加回避。
下丘脑食欲素/下丘脑分泌素神经元整合多种感觉线索，并向大脑广泛投射，以协调多种先天行为。它们的缺失会损害许多适当的行为，但食欲素细胞活动的动机特征仍不清楚。我们和其他人之前通过人工食欲素刺激来解决这个问题，这种刺激可以诱导奖赏（正效价）或厌恶（负效价）的大脑活动。目前尚不清楚这种方法在多大程度上复制了自然/内源性食欲素信号，这些信号在清醒时会迅速波动。在这里，我们采取了一种替代方法，专注于观察和沉默与基本先天行为——自我调节空间探索相关的自然食欲素细胞信号。我们发现，与光遗传学沉默相关的位置会使小鼠更有可能停留在与食欲素细胞光遗传学沉默相关的位置。食欲素细胞光遗传学沉默也减少了小鼠天生厌恶的地方的回避。相应地，钙记录显示，食欲素细胞活性在进入天生厌恶的地方时迅速降低。此外，我们提供了光遗传学证据，证明了抑制性 GABAergic Agrp→orexin 下丘脑神经回路的存在，并且发现 Agrp 细胞抑制增加了先天回避行为，这与食欲素去抑制一致。这些结果表明，探索可能是由减少厌恶的食欲素细胞活动的需求驱动和定向的，并表明存在一个下丘脑回路，可以根据不断变化的行为优先级来微调食欲素信号。
