Ernest Gallo Clinic and Research Center, Emeryville, California 94608, USA.
J Neurosci. 2013 May 1;33(18):7618-26. doi: 10.1523/JNEUROSCI.2588-12.2013.
The lateral hypothalamus (LH) sends a dense glutamatergic and peptidergic projection to dopamine neurons in the ventral tegmental area (VTA), a cell group known to promote reinforcement and aspects of reward. The role of the LH to VTA projection in reward-seeking behavior can be informed by using optogenetic techniques to dissociate the actions of LH neurons from those of other descending forebrain inputs to the VTA. In the present study, we identify the effect of neurotensin (NT), one of the most abundant peptides in the LH to VTA projection, on excitatory synaptic transmission in the VTA and reward-seeking behavior. Mice displayed robust intracranial self-stimulation of LH to VTA fibers, an operant behavior mediated by NT 1 receptors (Nts1) and NMDA receptors. Whole-cell patch-clamp recordings of VTA dopamine neurons demonstrated that NT (10 nm) potentiated NMDA-mediated EPSCs via Nts1. Results suggest that NT release from the LH into the VTA activates Nts1, thereby potentiating NMDA-mediated EPSCs and promoting reward. The striking behavioral and electrophysiological effects of NT and glutamate highlight the LH to VTA pathway as an important component of reward.
外侧下丘脑 (LH) 向腹侧被盖区 (VTA) 的多巴胺神经元发出密集的谷氨酸能和肽能投射，VTA 是已知促进强化和奖励方面的细胞群。使用光遗传学技术将 LH 神经元的作用与 VTA 中的其他下行前脑输入的作用区分开来，可以了解 LH 到 VTA 投射在寻求奖励行为中的作用。在本研究中，我们确定了神经降压素 (NT) 的作用，NT 是 LH 到 VTA 投射中最丰富的肽之一，对 VTA 中的兴奋性突触传递和寻求奖励行为的影响。小鼠表现出强烈的 LH 到 VTA 纤维的颅内自我刺激，这是一种由 NT1 受体 (Nts1) 和 NMDA 受体介导的操作性行为。VTA 多巴胺神经元的全细胞膜片钳记录表明，NT(10nm) 通过 Nts1 增强 NMDA 介导的 EPSC。结果表明，LH 向 VTA 释放的 NT 激活 Nts1，从而增强 NMDA 介导的 EPSC 并促进奖励。NT 和谷氨酸的显著行为和电生理效应突出了 LH 到 VTA 通路作为奖励的重要组成部分。
