Synaptic mechanisms underlying reward seeking and compulsive drug use

项目A：疼痛诱导腹侧被盖区多巴胺神经元的适应，以驱动类似快感的行为。 疼痛是一种复杂的现象，由感觉和情感两部分组成。随着疼痛的持续，负面情绪状态的存在可能会导致负面情绪状态的发展，如快感缺失、焦虑和抑郁。虽然目前的药物治疗在减轻感觉障碍方面提供了很高的效力，但伴随疼痛的负面情绪状态仍然没有得到充分的治疗。来自人类和临床前研究的新证据表明，在疼痛状态下，情绪决策、奖励评估和奖励寻求或动机方面存在缺陷。这些缺陷可能会导致快感缺失和抑郁的发展。揭示介导这些疼痛诱导的负面情感状态的神经回路可能为开发更安全的疼痛治疗方法提供机会，并限制共病障碍的发展。 利用体内纤维光度法和体外膜片钳电生理学方法，我们报道了在大鼠中，疼痛引起的动机降低与VTA DA神经元的兴奋性降低和活动降低有关。VTA DA神经元兴奋性的降低与GABA能RMTg传入的抑制性驱动增加有关。此外，我们报道了VTA内投射NAC的DA神经元的化学激活足以克服疼痛引起的动机行为的减少。最后，通过抑制RMTg GABA能向VTA的输入来逆转与疼痛相关的蔗糖消耗的减少，通过增加蔗糖奖励的浓度来克服，并通过化学刺激RMTg GABA神经元在幼稚动物中模拟。综上所述，这些结果表明，疼痛体验降低了VTA DA神经元的活性和兴奋性，这部分是由RMTg增加的抑制性驱动驱动的。这种钝化的VTA DA活动随后会导致疼痛诱导的负面情绪状态。我们的发现代表了理解疼痛情绪成分背后的神经机制的关键一步，并可能为疼痛诱导的负面情绪的治疗提供新的靶点。 项目B：腹侧被盖区GABA能抑制伏隔核腹侧壳内胆碱能中间神经元促进奖赏增强。 从腹侧被盖区(VTA)到伏核(NAC)的长距离GABA能输入的研究相对较少，因此它在奖赏加工中的作用尚不清楚。在本研究中，我们发现，在雄性和雌性小鼠中，从VTA到NAc腹侧壳的长程GABA能投射，而不是到NAC背侧壳或NAC核心的GABA能投射，参与了奖励和强化行为。我们发现这种GABA能投射独占地突触到NAc腹侧壳内的胆碱能中间神经元(CINs)，从而通过抑制NAc腹侧CINs在调节强化/奖赏行为中发挥特殊功能。这些发现突出了VTA GABA能投射在结构和功能上的多样性，以及它们在NAc壳背腹侧梯度上的神经调制相互作用。它们还加深了我们对神经元回路的理解，这些回路直接与抑郁症和物质使用障碍等神经精神疾病有关。

Project A: Pain induces adaptations in ventral tegmental area dopamine neurons to drive anhedonia-like behavior. Pain is a complex phenomenon composed of sensory and emotional affective components. As pain persists, the presence of negative affective states can lead to the development of negative emotional states such as anhedonia, anxiety and depression. While current pharmacological therapies provide high potency in alleviating sensory disturbances, the negative affective states accompanying pain remain undertreated. Emerging evidence from human and preclinical studies show that there are deficits in emotional decision-making, reward evaluation and reward seeking, or motivation in pain states. These deficits can lead to the development of anhedonia and depression. Uncovering the neuronal circuitry mediating these pain-induced negative affective states may provide opportunities to develop safer therapies for pain treatment and limit the development of co-morbid disorders. Using in vivo fiber photometry and ex vivo patch-clamp electrophysiology, we report that in rats, the reduced motivation induced by pain is associated with decreased excitability and reduced activity of VTA DA neurons. This decreased excitability of VTA DA neurons is associated with increased inhibitory drive from GABAergic RMTg afferents. Furthermore, we report that chemogenetic activation of NAc-projecting DA neurons in the VTA is sufficient to overcome the pain-induced reduction in motivated behavior. Finally, a pain-associated decrease in sucrose consumption was reversed by inhibiting RMTg GABAergic input onto the VTA, overcome by increasing the concentration of the sucrose reward, and mimicked in naive animals by chemogenetic stimulation of RMTg GABA neurons. Together, these results indicate that the experience of pain decreases the activity and excitability of VTA DA neurons, which are partially driven by an increased inhibitory drive from the RMTg. This blunted VTA DA activity then contributes to pain-induced negative affective states. Our findings represent a crucial step in understanding the neural mechanisms underlying the emotional component of pain and may provide novel targets for the treatment of pain-induced negative affect. Project B: Ventral tegmental area GABAergic inhibition of cholinergic interneurons in the ventral nucleus accumbens shell promotes reward reinforcement. The long-range GABAergic input from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) is relatively understudied, and therefore its role in reward processing has remained unknown. In the present study, we show, in both male and female mice, that long-range GABAergic projections from the VTA to the ventral NAc shell, but not to the dorsal NAc shell or NAc core, are engaged in reward and reinforcement behavior. We show that this GABAergic projection exclusively synapses on to cholinergic interneurons (CINs) in the ventral NAc shell, thereby serving a specialized function in modulating reinforced/rewarded behavior through the inhibition of ventral NAc shell CINs. These findings highlight the diversity in the structural and functional topography of VTA GABAergic projections, and their neuromodulatory interactions across the dorsoventral gradient of the NAc shell. They also further our understanding of neuronal circuits that are directly implicated in neuropsychiatric conditions such as depression and substance use disorders.