Q: What is “in vivo time-lapse multiphoton microscopy”? How is it being utilized in your research?
A: Brain and spinal cord injuries cause profound neurological deficits and long-term disability due to detrimental alterations in the structure and function of neuronal circuits. Although neuronal injury is associated with several neurobehavioral and neuropathological characteristics, how changes in intrinsic neuronal properties alter the interaction between neurons and non-neuronal cells remains a central mystery in neuroscience. Much of the progress to address this question has come from either studies that use in vitro surrogate models or in vivo endpoint studies. These experimental models, however, do not provide the spectrum of variables that influence the behavioral or systemic changes that occur in response to injury or disease. By using in vivo time-lapse multiphoton microscopy, it is possible to image the system (both neuronal and vascular networks) ‘at play’ from hours to weeks and months after damage to the brain or spinal cord.

Q: If you don’t mind, please tell us some of the therapies that you have designed to improve people’s neurological function.
A: During development, embryonic neurons experience a drastic decline in axon growth capacity as axons approach their target field, thereby allowing a motile growth cone to differentiate into a presynaptic terminal specialized for neurotransmitter release. During my postdoctoral training, I questioned whether the transition from the growing to the transmitting phase represents one of the first key steps in the gradual loss of axon growth and regeneration ability. By using whole transcriptomic sequencing and bioinformatic analysis, followed by gain- and loss-of function experiments, I recently discovered that Cacna2d2, the gene encoding the Alpha2delta2 subunit of voltage-gated calcium channels, functions as a developmental switch that limits axon growth and regeneration. Cacna2d2 gene deletion or silencing promoted axon growth in vitro. In vivo, Alpha2delta2 pharmacological blockade through systemic Gabapentinoids administration promoted robust regeneration of sensory axons after spinal cord injury in adult mice. Gabapentinoids (e.g., pregabalin and gabapentin) are given to spinal cord injury individuals as a first-tier treatment to manage chronic neuropathic pain conditions. More recently, we found that Alpha2delta2 negatively regulates axon growth and regeneration of corticospinal neurons, the cells that originate the corticospinal tract. Increased Alpha2delta2 expression in corticospinal neurons contributed to loss of corticospinal regrowth ability during postnatal development and after SCI (Spinal cord injury). In contrast, Alpha2delta2 pharmacological blockade through gabapentinoids administration promoted corticospinal structural plasticity and regeneration in adulthood. We demonstrated that regenerating corticospinal axons functionally integrate into spinal circuits. Mice administered gabapentinoids recovered upper extremity function after cervical spinal cord injury. Importantly, such recovery relies on reorganization of the corticospinal pathway, as chemogenetic silencing of injured corticospinal neurons transiently abrogated recovery. We now have evidence that the same treatment strategy effectively promotes structural plasticity of corticospinal neurons and neurological recovery after stroke in mice. Interestingly, a multi-center, cohort study has found that SCI individuals receiving gabapentinoids have enhanced motor recovery if they are administered within the first months after injury. Together, these exciting results set up an opportunity to re-purpose Gabapentinoids as a novel treatment strategy to repair the injured central nervous system.