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