Basal ganglia signalling mechanisms and aging

毫无疑问，衰老过程涉及不同组织和器官的许多变化。现在人们认识到，主要参与运动控制的基底神经节回路是最容易受到年龄相关影响的影响之一，导致粗运动和精细运动下降，如平衡和步态缺陷，协调缺陷和运动减慢。然而，这些变化在衰老过程中是如何调节的还不清楚，更好地理解基底神经节回路在正常和病理行为中的具体作用，即直接和间接途径，（例如帕金森氏症或亨廷顿氏症，主要考虑运动障碍）为了促进特异性治疗的发展，这种治疗可以精确地靶向或调节被破坏的通路的活性，并最终重建受影响的平衡，系统我们最近发现，纹状体ENK+神经元中TrkB信号的丢失导致年龄依赖性自发性运动过度，与纹状体ENK+激活减少相关，表明纹状体ENK+ MSNs中的BDNF-TrkB信号有助于抑制控制间接途径施加的运动行为。因此，我们建立了一个独特的小鼠模型，提供了一个罕见的年龄依赖性运动缺陷的例子。在这里，我们建议确定相关的基因和相关的分子通路的自发活动控制。为了做到这一点，我们已经能够汇集一个独特的专业团队，涵盖行为，神经生物学，基因表达，细胞内信号和蛋白质化学。这将允许使用组合的最先进的方法，首先了解调节年龄依赖性运动活动的基本机制，同时研究新的途径，以探索治疗干预措施，防止衰老期间生活质量的下降。

Without a doubt aging process involves many changes in the different tissues and organs. It is recognized by now that the basal ganglia circuits, which are primarily involved with movement control, are one of the most vulnerable to age-related effects causing gross and fine motor declines, such as balance and gait deficits, coordination deficits, and slowing of movement. It is unclear, however, how these changes are regulated during aging.A much better understanding of the specific roles played by the basal ganglia circuits, namely the direct and indirect pathways, both in normal and pathological behaviors (such us Parkinson's or Huntington's disease, considered mainly movement disorders) is needed in order to facilitate development of specific therapies that could precisely target or modulate the activity of the pathway disrupted and eventually reestablish balance to the affected system. We have recently shown that loss of TrkB signalling in striatopallidal ENK+ neurons lead to age-dependent spontaneous hyperlocomotion, associated with reduced striatopallidal activation, demonstrating that BDNF-TrkB signaling in striatal ENK+ MSNs contributes to the inhibitory control of locomotor behavior exerted by the indirect pathway.Hence, we have established a unique mouse model that provides a rare example of age-dependent locomotor defect. Here we propose to identify the genes and associated molecular pathways relevant to locomotor activity control. In order to do so we have been able to bring together a unique team of expertise covering behaviour, neurobiology, gene expression, intracellular signalling and protein chemistry. This will allow the use of combinatorial state of the art approaches to first of all understand basic mechanisms regulating age-dependent locomotor activity and at the same time to investigate novel avenues to explore therapeutic interventions against loss of quality of life during aging.