Functional integration of new neurons into hippocampal networks and poststroke comorbidities following neonatal stroke in mice

Abstract

Stroke in the developing brain is an important cause of chronic neurological morbidities including neurobehavioral dysfunction and epilepsy. Here, we describe a mouse model of neonatal stroke resulting from unilateral carotid ligation that results in acute seizures, long-term hyperactivity, spontaneous lateralized circling behavior, impaired cognitive function and epilepsy. Explorationdependent induction of immediate early gene, Arc (activity-regulated cytoskeleton associated protein) in hippocampal neurons was examined in the general population of neurons versus neurons that were generated ~ 1week after the ischemic insult and labeled with BrdU. Although Arc was inducible in a network specific manner after severe neonatal stroke, it was impaired, not only in the ipsilateral injured but also in the contralateral uninjured hippocampi when examined at 6 months after the neonatal stroke. Severity of the stroke-injury and the acquired post-stroke epilepsy, both negatively correlated with Arc-induction and new neuron integration into functional circuits in the injured hippocampi.

Meteorin is a Chemokinetic Factor in Neuroblast Migration and Promotes Stroke-Induced Striatal Neurogenesis

“…It is possible that the enhancement of neurogenesis found here, leading to 70% higher number of new mature neurons in the striatum at 33 days after the insult, is still too low to be translated into a behavioral improvement. Another possibility is that the behavioral assessments at 33 days after stroke were performed too early, since functional development and integration of the new neurons are not completed until 6 to 8 weeks, even several months, post-ischemia (Hou et al, 2008;Lai et al, 2008;Kadam et al, 2010).…”

Systemic Injection of CD34+-Enriched Human Cord Blood Cells Modulates Poststroke Neural and Glial Response in a Sex-Dependent Manner in CD1 Mice

“…However, most of our functional outcome measures were insensitive to the brain injury and therefore unable to assess response to treatment. We previously demonstrated in this model that newborn cells in the SGZ after stroke injury become mature dentate granule neurons, and a cell subset integrate into visual-spatial memory circuits after stroke [40]. However, additional work is needed to determine whether the increased SGZ cell proliferation in males, 9 days after stroke and 7 days after CBSC treatment, results in an increase in SGZ neurons, which mature and appropriately integrate.…”

“…However, additional work is needed to determine whether the increased SGZ cell proliferation in males, 9 days after stroke and 7 days after CBSC treatment, results in an increase in SGZ neurons, which mature and appropriately integrate. Because it takes about 3-4 weeks for newborn SGZ neurons that survive to migrate to the granule cell layer and manifest a high rate of glutamatergic synaptogenesis, Arc expression, and connectivity [40,41], future studies will determine whether the sex-dependent effects of cord blood-derived stem cells result in long-term cognitive improvements,…”

Shp2 in Forebrain Neurons Regulates Synaptic Plasticity, Locomotion, and Memory Formation in Mice

“…Hyperactivity is frequently associated with reduced neural activity or neuronal loss after brain injury (37)(38)(39)(40). We therefore next measured the expression of IEGs, including those for c-Fos, Zif268, Npas4, Arc, Homer1a, and Bdnf, in the brains of Shp2 cKO mice as an index of neuronal activity (41,42).…”

“…Hyperactivity is often associated with a reduction in neuronal activity in both humans and animals (38)(39)(40). BDNF induces activation of Ras-MAPK signaling and a marked increase in synaptic transmission in mouse hippocampal slices (60), suggesting the importance of BDNF signaling in the regulation of neuronal activity.…”