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.
