Xu Han-Ting, Xi Xiao-Ya, Zhou Shuang, Xie Yun-Yong, Cui Zhi-San, Zhang Bei-Bei, Xie Shu-Tao, Li Hong-Zhao, Zhang Qi-Peng, Pan Yang, Zhang Xiao-Yang, Zhu Jing-Ning
State Key Laboratory of Pharmaceutical Biotechnology, National Resource Center for Mutant Mice, Department of Anesthesiology, Nanjing Drum Tower Hospital, and Department of Physiology, School of Life Sciences, Nanjing University, Nanjing, 210023, China.
Institute for Brain Sciences, Nanjing University, Nanjing, 210023, China.
Neurosci Bull. 2025 Apr;41(4):551-568. doi: 10.1007/s12264-024-01320-0. Epub 2024 Dec 2.
The ventral anterior (VA) nucleus of the thalamus is a major target of the basal ganglia and is closely associated with the pathogenesis of Parkinson's disease (PD). Notably, the VA receives direct innervation from the hypothalamic histaminergic system. However, its role in PD remains unknown. Here, we assessed the contribution of histamine to VA neuronal activity and PD motor deficits. Functional magnetic resonance imaging showed reduced VA activity in PD patients. Optogenetic activation of VA neurons or histaminergic afferents significantly alleviated motor deficits in 6-OHDA-induced PD rats. Furthermore, histamine excited VA neurons via H1 and H2 receptors and their coupled hyperpolarization-activated cyclic nucleotide-gated channels, inward-rectifier K channels, or Ca-activated K channels. These results demonstrate that histaminergic afferents actively compensate for Parkinsonian motor deficits by biasing VA activity. These findings suggest that targeting VA histamine receptors and downstream ion channels may be a potential therapeutic strategy for PD motor dysfunction.
丘脑腹前核（VA）是基底神经节的主要靶点，与帕金森病（PD）的发病机制密切相关。值得注意的是，VA接受下丘脑组胺能系统的直接支配。然而，其在PD中的作用尚不清楚。在此，我们评估了组胺对VA神经元活动和PD运动缺陷的影响。功能磁共振成像显示PD患者的VA活动降低。对VA神经元或组胺能传入神经进行光遗传学激活可显著减轻6-羟基多巴胺诱导的PD大鼠的运动缺陷。此外，组胺通过H1和H2受体及其偶联的超极化激活环核苷酸门控通道、内向整流钾通道或钙激活钾通道兴奋VA神经元。这些结果表明，组胺能传入神经通过偏向VA活动来积极补偿帕金森病的运动缺陷。这些发现表明，靶向VA组胺受体和下游离子通道可能是治疗PD运动功能障碍的潜在策略。
