Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
J Neurophysiol. 2021 Dec 1;126(6):2119-2129. doi: 10.1152/jn.00251.2021. Epub 2021 Nov 24.
Neuroimmune signaling is increasingly identified as a critical component of various illnesses, including chronic pain, substance use disorder, and depression. However, the underlying neural mechanisms remain unclear. Proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), may play a role by modulating synaptic function and long-term plasticity. The midbrain structure periaqueductal gray (PAG) plays a well-established role in pain processing, and although TNF-α inhibitors have emerged as a therapeutic strategy for pain-related disorders, the impact of TNF-α on PAG neuronal activity has not been thoroughly characterized. Recent studies have identified subpopulations of ventrolateral PAG (vlPAG) with opposing effects on nociception, with dopamine (DA) neurons driving pain relief in contrast to GABA neurons. Therefore, we used slice physiology to examine the impact of TNF-α on neuronal activity of both these subpopulations. We focused on female mice since the PAG is a sexually dimorphic region and most studies use male subjects, limiting our understanding of mechanistic variations in females. We selectively targeted GABA and DA neurons using transgenic reporter lines. Following exposure to TNF-α, there was an increase in excitability of GABA neurons along with a reduction in glutamatergic synaptic transmission. In DA neurons, TNF-α exposure resulted in a robust decrease in excitability along with a modest reduction in glutamatergic synaptic transmission. Interestingly, TNF-α had no effect on inhibitory transmission onto DA neurons. Collectively, these data suggest that TNF-α differentially affects the function of GABA and DA neurons in female mice and enhances our understanding of how TNF-α-mediated signaling modulates vlPAG function. This study describes the effects of TNF-α on two distinct subpopulations of neurons in the vlPAG. We show that TNF-α alters both neuronal excitability and glutamatergic synaptic transmission on GABA and dopamine neurons within the vlPAG of female mice. This provides critical new information on the role of TNF-α in the potential modulation of pain, since activation of vlPAG GABA neurons drives nociception, whereas activation of dopamine neurons drives analgesia.
神经免疫信号正逐渐被认为是各种疾病的关键组成部分，包括慢性疼痛、物质使用障碍和抑郁症。然而，潜在的神经机制尚不清楚。促炎细胞因子，如肿瘤坏死因子-α（TNF-α），可能通过调节突触功能和长期可塑性发挥作用。中脑结构导水管周围灰质（PAG）在疼痛处理中起着既定的作用，尽管 TNF-α 抑制剂已成为治疗与疼痛相关疾病的一种策略，但 TNF-α 对 PAG 神经元活性的影响尚未得到充分描述。最近的研究已经确定了腹外侧 PAG（vlPAG）中具有相反的镇痛作用的亚群，多巴胺（DA）神经元驱动疼痛缓解，而 GABA 神经元则相反。因此，我们使用切片生理学来检查 TNF-α对这两个亚群神经元活性的影响。我们专注于雌性小鼠，因为 PAG 是一个性别二态区域，并且大多数研究使用雄性动物作为研究对象，这限制了我们对雌性动物中机制变化的理解。我们使用转基因报告线有针对性地靶向 GABA 和 DA 神经元。暴露于 TNF-α后，GABA 神经元的兴奋性增加，谷氨酸能突触传递减少。在 DA 神经元中，TNF-α 暴露导致兴奋性显著降低，同时谷氨酸能突触传递适度减少。有趣的是，TNF-α对 DA 神经元的抑制性传递没有影响。总的来说，这些数据表明，TNF-α以不同的方式影响雌性小鼠中 GABA 和 DA 神经元的功能，并增强了我们对 TNF-α 介导的信号如何调节 vlPAG 功能的理解。这项研究描述了 TNF-α对雌性小鼠 vlPAG 中两个不同神经元亚群的影响。我们表明，TNF-α改变了 vlPAG 中 GABA 和多巴胺神经元的神经元兴奋性和谷氨酸能突触传递。这为 TNF-α在潜在调节疼痛中的作用提供了关键的新信息，因为激活 vlPAG GABA 神经元会引起疼痛，而激活多巴胺神经元会产生镇痛作用。
