Corticospinal neuron plasticity in response to developmental spinal cord axotomy. - PROJECT ABSTRACT Spinal cord injury (SCI) is a devastating condition with limited treatment options due to the restricted regenerative capacity of the mature central nervous system. Due to the heterogeneity of SCI along the neuraxis, it impairs various corticospinal circuitry that affects motor control. The corticospinal tract (CST), essential for voluntary movement, consists of diverse corticospinal neuron (CSN) subtypes, yet the establishment of these distinct spinal-projecting neurons remains unclear. Recent findings from the Sahni lab have identified early molecular differences in CSN subpopulations projecting to the cervical or thoracolumbar spinal cord from cortical regions outside the classical motor cortex; however, this molecular map is incomplete. Additionally, the lab has developed a novel microlesion technique to axotomize the developing CST, enabling the study of CSN plasticity and circuit formation during development. Understanding how CSN projection types and their postsynaptic spinal connectivity are established is crucial for developing strategies for functional recovery after SCI. This proposal aims to investigate the molecular mechanisms underlying CSN development and their long-range corticospinal circuits. My central hypothesis is that intrinsic regulators govern segmentally distinct CSN identities and spinal synaptic circuitry. Specific Aim 1 will identify molecular regulators of CSN diversity and determine whether segmental spinal targeting is governed by intrinsic mechanisms or target- derived retrograde signaling. Specific Aim 2 will explore how route of axon extension influences synaptic specificity and their implications for the evolution of cortical-motoneural connections and dexterity. To achieve these aims, we will utilize mouse models and employ techniques such as viral tracing and microlesion approaches. The findings will enhance our understanding of neurodevelopmental processes and may lead to new therapeutic strategies for SCI recovery. With the support of this F32 fellowship, I will strengthen my expertise in viral tracing, molecular profiling, and bioinformatics, preparing me to lead an independent research program focused on leveraging developmental mechanisms to repair the injured nervous system.
