Temporally Specified Genetic Ablation of Neurogenesis Impairs Cognitive Recovery after Traumatic Brain Injury

Abstract

Significant spontaneous recovery occurs following essentially all forms of serious brain injury, though the mechanisms underlying this recovery are unknown. Given that many forms of brain injury such as traumatic brain injury (TBI) induce hippocampal neurogenesis, we investigated whether these newly generated neurons might play a role in recovery. By modeling TBI in transgenic mice, we determined that injury-induced newly generated neurons persisted over time and elaborated extensive dendritic trees that stably incorporated themselves throughout all neuronal layers of the dentate gyrus. When we selectively ablated dividing stem/progenitors at the time of injury with ganciclovir in a nestin-HSV-TK transgenic model, we eliminated injury-induced neurogenesis and subsequently diminished the progenitor pool. Moreover, using hippocampal-specific behavioral tests, we demonstrated that only injured animals with neurogenesis ablated at the time of injury lost the ability to learn spatial memory tasks. These data demonstrate a functional role for adult neurogenesis following brain injury and offer compelling and testable therapeutic options that might enhance recovery.

A small molecule p75NTR ligand protects neurogenesis after traumatic brain injury

“…This is consistent with the findings of some studies [61,62], although in others, an increase in progenitors and neurogenesis has been reported [29,39,63,64]. Interestingly, similar to our PSA-NCAM1 population results, a study by Yu et al [65] reported a loss of intermediate (Dcx1) progenitors early after injury in mice, which recovered over several days; however, the percentage of new intermediates (Dcx1/BrdU1) at 7 days was increased, dissimilar to our observations.…”

“…Interestingly, similar to our PSA-NCAM1 population results, a study by Yu et al [65] reported a loss of intermediate (Dcx1) progenitors early after injury in mice, which recovered over several days; however, the percentage of new intermediates (Dcx1/BrdU1) at 7 days was increased, dissimilar to our observations. There and in subsequent studies [29,64], the same laboratory observed an injury-induced increase in proliferation of early (nestin1) progenitors which resulted in long-term increases in new neurons. Partially consistent with this, we observed increased nuclear signal for the early progenitor protein Sox2 following injury; however, the overall long-term outcome was instead a diminution of surviving neurons generated in the postinjury period.…”

“…Damage to these structures likely underlies a significant portion of the behavioral and memory dysfunction that may result from even a relatively mild closed head injury [26,27]. Although there has been a lack of consensus on the role of adult neurogenesis in shaping hippocampus-dependent behaviors [18,28], recent work connects neurogenesis to normal hippocampal function and recovery following traumatic injury [29][30][31]. Notably, Blaiss et al [29] found that recovery of hippocampus-dependent, but not independent, behaviors were substantially impaired when neurogenesis was interrupted.…”

“…Although there has been a lack of consensus on the role of adult neurogenesis in shaping hippocampus-dependent behaviors [18,28], recent work connects neurogenesis to normal hippocampal function and recovery following traumatic injury [29][30][31]. Notably, Blaiss et al [29] found that recovery of hippocampus-dependent, but not independent, behaviors were substantially impaired when neurogenesis was interrupted. Thus, in particular, under conditions of traumatic injury, the maintenance of neurogenesis may influence functional outcomes.…”

Genetic Manipulation of Cell Death and Neuroplasticity Pathways in Traumatic Brain Injury

“…To better understand the role of neurogenesis in spontaneous recovery following trauma, Kernie and colleagues again used the nestin-HSV-TK GFP transgenic model [87]. Continuous administration of ganciclovir for 4 weeks following CCI ablated 90% of injury-induced hippocampal neurogenesis by 2 months after TBI without affecting astrogliosis.…”