Histaminergic Innervation of the Ventral Anterior Thalamic Nucleus Alleviates Motor Deficits in a 6-OHDA-Induced Rat Model of Parkinson’s Disease
Han‑Ting Xu1 · Xiao‑Ya Xi1 · Shuang Zhou1 · Yun‑Yong Xie1 · Zhi‑San Cui1 · Bei‑Bei Zhang1 · Shu‑Tao Xie1 · Hong‑Zhao Li1 · Qi‑Peng Zhang1,2 · Yang Pan4 · Xiao‑Yang Zhang1,2 · Jing‑Ning Zhu1,2,31 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
2 Institute for Brain Sciences, Nanjing University, Nanjing 210023, China
3 Chemistry and Biomedicine Innovation Center (ChemBIC), ChemBioMed Interdisciplinary Research Center, Nanjing University, Nanjing 210023, China
4 Department of Geriatric Neurology, Afliated Brain Hospital of Nanjing Medical University, Nanjing 210029, China
Abstract
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 Ca2+-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.
Keywords
Histamine; H1 receptor; H2 receptor; Ventral anterior nucleus of the thalamus; Parkinson’s disease
