Cellular and molecular changes in the spinal cord that cause motor deficits in old age

随着年龄的增长，执行躯体运动功能的能力逐渐减弱，对个人的整体健康产生重大影响。因此，阐明年龄依赖性运动缺陷的细胞和分子机制是必要的，因为这些信息对于开发保护和恢复老年运动功能的治疗是必要的。α-运动神经元是运动系统的效应细胞，是所有随意运动的基础。由它们在脊髓中的突触形成的复杂回路整合了运动指令和感觉反馈，因此对复杂运动的正确执行做出了重要贡献，例如保持平衡、协调和精细的运动控制。不幸的是，随着年龄的增长，人类执行这些运动功能的能力会减弱，这表明潜在的系统会发生有害的变化。在这方面，候选人最近发现，老龄小鼠α-运动神经元体上的谷氨酸能、胆碱能和gaba能突触输入数量显著减少。同时，甘氨酸能输入似乎没有变化，α-运动神经元体的数量和大小也没有变化。这些发现表明运动神经回路的功能能力发生了重大变化，需要阐明这些突触改变的全部程度。此外，还必须确定α-运动神经元和脊髓内胶质细胞在衰老过程中是否发生了内在的变化，从而减轻或加剧了这些变化。这些知识上的差距导致了以下研究问题：1)α-运动神经元的树突和它们产生的突触是否随着年龄的增长而退化？2) α-运动神经元的生物物理特性是否发生了与年龄相关的内在变化？3)神经胶质细胞（如小胶质细胞和星形胶质细胞）在脊髓运动突触的丧失中起什么作用？在该奖学金的博士前和博士后阶段，候选人将使用各种细胞、分子、生化和成像分析来回答这些问题。此外，候选人将参加许多专业发展活动，包括出席会议，参加内部和外部培训计划，并在实验室和课堂上指导初级学员。布朗大学是攻读博士学位前阶段的理想场所。在赞助人的帮助下，候选人将在同等地位的机构确定博士后导师。总之，候选人在此概述了一个详细的计划，以进一步他的教育和培训，作为一名老龄化研究人员，同时为我们对衰老运动系统的了解做出重大贡献。

The capacity to carry out somatic motor functions progressively diminishes with advancing age, having a significant effect on the overall health of individuals. Therefore, it is imperative to elucidate the cellular and molecular mechanisms underlying age-dependent motor deficits, as this information is necessary to develop treatments that preserve and restore motor function in old age. α-motor neurons are the effector cells of the motor system and are essential to all voluntary movement. The complex circuits created by their synapses in the spinal cord integrate motor commands and sensory feedback, and thereby make vital contributions to the proper execution of complex movements such as maintaining balance, coordination, and fine motor control. Unfortunately, the ability to perform these motor functions diminishes with advancing age in humans, suggesting that the underlying system undergoes deleterious changes. In this regard, the candidate recently discovered that the number of glutamatergic, cholinergic, and GABAergic synaptic inputs onto the somata of α-motor neurons is significantly decreased in aged mice. Meanwhile, glycinergic inputs appear to be unchanged, as do the number and size of α-motor neuron somata. These findings suggest significant changes to the functional capacity of the motor neurocircuitry and require that the full extent of these synaptic alterations be elucidated. Further, it must be determined whether α-motor neurons and spinal cord-resident glia undergo intrinsic changes that mitigate or exacerbate these alterations during aging. These gaps in knowledge have led to the following research questions: 1) Do the dendritic arbors of α-motor neurons and the synapses they create degenerate with advancing age? 2) Do α-motor neurons undergo intrinsic age-related changes to their biophysical properties? 3) What role do glial cells, such as microglia and astrocytes, play in the loss of motor synapses in the spinal cord? The candidate will answer each of these questions using various cellular, molecular, biochemical, and imaging assays during both the predoctoral and postdoctoral phases of this fellowship. Further, the candidate will take part in numerous professional development activities, including attendance at conferences, participation in internal and external training programs, and mentorship of junior trainees in the lab and in the classroom. Brown University is an ideal setting for the predoctoral phase of this fellowship. With the help of the sponsor, the candidate will identify a postdoctoral mentor at an institution of equal standing. In sum, the candidate has herein outlined a detailed plan to further his education and training as an aging researcher, while contributing significantly to our knowledge of the aging motor system.