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，必须阐明年龄依赖性运动缺陷的细胞和分子机制，因为这些信息对于开发在老年时保留和恢复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，对所有自主运动都是必不可少的。由脊髓中的突触创建的复杂回路整合了运动命令和感觉反馈，从而对正确执行复杂运动做出了重要贡献，例如保持平衡，协调和精细运动控制。不幸的是，随着人类年龄的增长，执行这些运动功能的能力逐渐减弱，这表明潜在的系统发生了有害的变化。在这方面，候选人最近发现，在老年小鼠中，α运动神经元胞体上的多巴胺能、胆碱能和GABA能突触输入的数量显著减少。与此同时，甘氨酸能输入似乎没有变化，α运动神经元胞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运动神经元和脊髓驻留胶质细胞是否在衰老过程中发生了减轻或加剧这些变化的内在变化。这些知识上的空白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会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会发生内在的年龄相关变化？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？候选人将回答每个这些问题，使用各种细胞，分子，生物化学和成像分析在这两个博士前和博士后阶段的奖学金。此外，候选人将参加许多专业发展活动，包括参加会议，参加内部和外部培训计划，以及在实验室和课堂上指导初级学员。布朗大学是这个奖学金的博士前阶段的理想场所。在赞助商的帮助下，候选人将在同等地位的机构中确定博士后导师。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个老龄化研究人员，同时大大有助于我们的知识老化运动系统。

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.