Emotion, Cognition & Behavior Research Group, Korea Brain Research Institute, Daegu 41062, South Korea.
Department of Physiology, College of Korean Medicine, Daegu Haany University, Daegu 42158, South Korea.
J Neurosci. 2022 Dec 7;42(49):9180-9192. doi: 10.1523/JNEUROSCI.0577-22.2022. Epub 2022 Oct 24.
Nociceptive signals interact with various regions of the brain, including those involved in physical sensation, reward, cognition, and emotion. Emerging evidence points to a role of nociception in the modulation of the mesolimbic reward system. The mechanism by which nociception affects dopamine (DA) signaling and reward is unclear. The lateral hypothalamus (LH) and the lateral habenula (LHb) receive somatosensory inputs and are structurally connected with the mesolimbic DA system. Here, we show that the LH-LHb pathway is necessary for nociceptive modulation of this system using male Sprague Dawley rats. Our extracellular single-unit recordings and head-mounted microendoscopic calcium imaging revealed that nociceptive stimulation by tail pinch excited LHb and LH neurons, which was inhibited by chemical lesion of the LH. Tail pinch increased activity of GABA neurons in ventral tegmental area, decreased the extracellular DA level in the nucleus accumbens ventrolateral shell in intact rats, and reduced cocaine-increased DA concentration, which was blocked by disruption of the LH. Furthermore, tail pinch attenuated cocaine-induced locomotor activity, 22 and 50 kHz ultrasonic vocalizations, and reinstatement of cocaine-seeking behavior, which was inhibited by chemogenetic silencing of the LH-LHb pathway. Our findings suggest that nociceptive stimulation recruits the LH-LHb pathway to inhibit mesolimbic DA system and drug reinstatement. The LHb and the LH have been implicated in processing nociceptive signals and modulating DA release in the mesolimbic DA system. Here, we show that the LH-LHb pathway is critical for nociception-induced modulation of mesolimbic DA release and cocaine reinstatement. Nociceptive stimulation alleviates extracellular DA release in the mesolimbic DA system, cocaine-induced psychomotor activities, and reinstatement of cocaine-seeking behaviors through the LH-LHb pathway. These findings provide novel evidence for sensory modulation of the mesolimbic DA system and drug addiction.
伤害性刺激与大脑的各个区域相互作用，包括参与躯体感觉、奖励、认知和情绪的区域。新出现的证据表明伤害性感受在调制中脑边缘奖赏系统中起作用。伤害性感受影响多巴胺（DA）信号和奖赏的机制尚不清楚。外侧下丘脑（LH）和外侧缰核（LHb）接收躯体感觉输入，并且与中脑边缘 DA 系统在结构上相连。在这里，我们使用雄性 Sprague Dawley 大鼠表明，LH-LHb 通路对于该系统的伤害性调节是必要的。我们的细胞外单细胞记录和头戴式微型内窥镜钙成像显示，尾部夹捏引起的伤害性刺激兴奋 LHb 和 LH 神经元，而 LH 的化学损伤抑制了这些神经元的兴奋。尾部夹捏增加了腹侧被盖区 GABA 神经元的活性，减少了完整大鼠伏隔核腹侧被盖区壳外侧的细胞外 DA 水平，并降低了可卡因增加的 DA 浓度，而 LH 的破坏则阻断了这一作用。此外，尾部夹捏减弱了可卡因诱导的运动活动、22 和 50 kHz 超声发声以及可卡因寻求行为的复燃，而 LH-LHb 通路的化学遗传沉默抑制了这些作用。我们的研究结果表明，伤害性刺激募集 LH-LHb 通路抑制中脑边缘 DA 系统和药物复燃。LHb 和 LH 被认为参与处理伤害性信号和调节中脑边缘 DA 系统中的 DA 释放。在这里，我们表明，LH-LHb 通路对于伤害性刺激诱导的中脑边缘 DA 释放和可卡因复燃的调节至关重要。伤害性刺激通过 LH-LHb 通路减轻中脑边缘 DA 系统中细胞外 DA 的释放、可卡因引起的精神运动活动以及可卡因寻求行为的复燃。这些发现为感觉调制中脑边缘 DA 系统和药物成瘾提供了新的证据。
