Hu Xiao-Qian, Wu Kenneth Lap-Kei, Rong Kang-Lin, Ya Ke, Yung Wing-Ho, Shum Daisy Kwok-Yan, Chan Ying-Shing
Department of Rehabilitation Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
Nat Aging. 2025 May 28. doi: 10.1038/s43587-025-00884-4.
Navigational decline is a metric distinct from aging-related cognitive degradation, yet the affected circuits and synaptic changes remain elusive. This study identified a long-range excitatory projection from parvalbumin (PV) neurons in the brainstem medial vestibular nucleus (MVN) of mice that monosynaptically innervates the midbrain dorsal tegmental nucleus (DTN). This PV projection exhibits high neuronal excitability and synaptic plasticity as electrophysiological traits. In vivo chemogenetic inhibition of the PV projection impaired the navigational performance of adult mice. Navigational deficits in aged mice linked to both diminished innervation and synaptic drive of the PV pathway were pinpointed as hallmarks of the aging process. Strikingly, targeted activation of this pathway mitigated navigational impairments in older mice. In sum, our results revealed an excitatory PV pathway that impacts navigation. Rescue from aging-related navigational decline by activation of a spared projection pathway further highlights the potential for targeted therapies.
导航能力下降是一种与衰老相关的认知衰退不同的指标，然而受影响的神经回路和突触变化仍然难以捉摸。本研究确定了小鼠脑干内侧前庭核（MVN）中帕瓦丁（PV）神经元发出的一种长距离兴奋性投射，该投射单突触支配中脑背侧被盖核（DTN）。这种PV投射表现出高神经元兴奋性和作为电生理特征的突触可塑性。对PV投射进行体内化学遗传抑制会损害成年小鼠的导航能力。与PV通路的神经支配减少和突触驱动减弱相关的老年小鼠的导航缺陷被确定为衰老过程的标志。令人惊讶的是，该通路的靶向激活减轻了老年小鼠的导航障碍。总之，我们的结果揭示了一条影响导航的兴奋性PV通路。通过激活一条备用投射通路来挽救与衰老相关的导航能力下降，进一步凸显了靶向治疗的潜力。
