UC San Diego

Damage to the central nervous system (CNS) such as from brain or spinal cord injury leads to permanent functional impairment, resulting in substantial social and economic burden. Sustained functional deficits are due in large part to the limitation of axon growth after injury. Damaged axons do not regenerate after CNS injury, whereas uninjured axons show some degree of spontaneous sprouting after CNS injury. Sprouting is believed to contribute to partial (albeit often insufficient) recovery in individuals with less severe injury or stroke, and can be promoted by manipulating axon growth regulators in model organisms, suggesting a potential approach to enhance recovery in humans. Nonetheless, our understanding of the molecular regulation of sprouting is incomplete. My dissertation work investigates the degree to which factors expressed by neurons and other CNS cell-types regulate axon sprouting and whether promotion of sprouting improves functional recovery from injury. I investigated the cell- type specific roles of a classically described myelin-associated inhibitor of axon growth, Nogo, and a novel neuron-intrinsic regulator of axon growth, DLK, in sprouting of the corticospinal tract (CST) after experimental unilateral pyramidotomy in mice. In order to evaluate whether promotion of CST sprouting correlates with improved functional recovery from injury, I evaluated and optimized behavioral tests to monitor functional recovery from pyramidotomy. I found that oligodendrocytic-specific deletion of Nogo enhances CST sprouting, showing for the first time that Nogo specifically expressed by oligodendrocytes restricts sprouting and spinal axon growth after CNS injury, supporting a longstanding but heretofore untested hypothesis. I was not able to detect a functional benefit associated with this enhanced sprouting, highlighting the challenge in harnessing structural plasticity to promote functional recovery. Additionally, I provide the first evidence for a role of DLK in sprouting and spinal axon growth after CNS injury that, to our surprise, supports a growth-reducing role for DLK in CST sprouting. These results illustrate that sprouting is an accessible form of axonal growth following CNS injury that can be modulated by manipulating neuron-intrinsic or extrinsic factors, but that building on enhanced sprouting to promote functional recovery remains a challenge.