Mechanisms of Juvenile Neurogenesis and Post-Stroke Recovery: Determining the Role of Age-Associated Neuroimmune Interactions

PROJECT SUMMARY Endogenous tissue regeneration following ischemia (via enhanced neurogenesis or stem cell therapy) has been highly sought, but the low survival rate of newly generated/newborn neurons limited the therapeutic potential of adult neurogenesis. However, the young injured brain has a greater degree of plasticity and capacity for repair compared to the adult. In a juvenile model of middle cerebral artery occlusion, we observe a remarkable increase in neurogenesis in the juvenile striatum at 30d post-ischemia that is coupled with improved behavioral and electrophysiological outcomes, which we did not observe in adults. The gap in knowledge addressed in the current proposal involves investigating the age-associated differences in cellular signaling responsible for enhanced neurogenesis and improved functional recovery following ischemic stroke in juveniles that is not found in adults. The mechanisms of juvenile neurogenesis are not yet understood, but we have identified protective early immune responses in the acute phase of juvenile stroke as a potential mechanism of endogenous neuronal regeneration and subsequent functional recovery. This finding is contrary to reports of proinflammatory signaling in adults during the acute phase after stroke, which is generally seen as deleterious to neuronal survival. Determining the mechanisms of juvenile neurogenesis and functional recovery, and identifying novel targets for post-stroke treatment is the focus of this grant. We propose to apply these results in adults to stimulate neurogenesis and promote recovery, with the long-term goal of augmenting neurogenesis in combination with stem cell therapy to dramatically improve neuronal survival, replacement, and post-ischemic functional outcomes in both juveniles and adults. We plan to test the central hypothesis that the juvenile brain differs from the adult brain, and newborn neurons survive and mature in the damaged post- ischemic juvenile brain, enhancing neural network function and behavioral recovery through support from stroke-induced anti-inflammatory signaling. We will test this hypothesis by pursuing the following aims: 1) neurogenesis is both required and necessary for improved neuronal repair and enhanced post-ischemic behavioral/electrophysiological outcomes, 2) post-ischemic anti-inflammatory signaling is essential for neurogenesis and functional recovery, and 3) endogenous neurogenesis can be enhanced in juveniles and adults through stimulation of anti-inflammatory signaling during the acute phase of stroke. We will use transgenic mice, viral labeling, chemogenetics, molecular assays, neurobehavioral tests, and in vivo electrophysiology to investigate mechanisms of neurogenesis in the juvenile brain and subsequent functional recovery after stroke. The proposed research will greatly improve our understanding of the mechanisms underlying juvenile neurogenesis and the instrumental immunomodulatory pathways supporting newborn neuron survival and functional recovery, identifying new and innovative approaches to stroke treatment in both adults and children.