Basal ganglia signalling mechanisms and aging

毫无疑问，衰老过程涉及到不同组织和器官的许多变化。到目前为止，人们已经认识到，主要参与运动控制的基底节回路是最容易受到年龄相关效应的影响，这些效应会导致粗大和精细的运动下降，如平衡和步态障碍、协调障碍和运动减慢。然而，目前尚不清楚这些变化在衰老过程中是如何调节的。需要更好地了解基底节回路在正常和病理行为(如帕金森氏病或亨廷顿病，主要被认为是运动障碍)中所起的具体作用，以便促进特定疗法的发展，这些疗法可以准确地靶向或调节被破坏的通路的活动，并最终重建受影响系统的平衡。我们最近发现纹状体前额叶ENK+神经元中TrkB信号的丢失导致年龄依赖性的自发多动，与纹状体前额叶激活减少相关，证明纹状体ENK+MSN中的BDNF-TrkB信号有助于间接通路对运动行为的抑制控制。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相关性运动缺陷的例子。在这里，我们建议识别与运动活动控制相关的基因和相关的分子通路。为了做到这一点，我们已经能够汇集一支独特的专业团队，涵盖行为、神经生物学、基因表达、细胞内信号传递和蛋白质化学。这将允许使用最先进的组合方法首先了解调节年龄依赖的运动活动的基本机制，同时探索新的途径，探索针对衰老期间生活质量下降的治疗干预措施。

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.