Absence of the Neurogenic Response to a Repeated Concussive-Like Injury and Associated Deficits in Strategy Flexibility

Traumatic brain injury (TBI) causes transient but robust increases in hippocampal neurogenesis, referred to here as the neurogenic response, which is distinct from baseline or constitutive levels of neurogenesis. The neurogenic response may reflect a restorative process for cognitive recovery from TBI. It is unknown whether the hippocampus remains capable of eliciting another neurogenic response to a subsequent TBI, and whether a potential loss in this endogenous repair mechanism affects cognitive recovery from a repeated TBI. To address this, 2-month-old male and female mice received a sham or mild TBI (mTBI) using the closed-head concussive injury model. Mice received another sham or mTBI procedure 3 weeks later. Mitotic and immature neuronal markers were used to assess the proliferative and neurogenic responses. Neurogenesis-sensitive strategy flexibility was assessed as the functional outcome using the reversal water maze task 1 month after the second procedure. The experimenters collecting the data were blind to the group assignment of each mouse. Proliferation and neurogenesis were higher after a single mTBI but not after a second mTBI. Noteworthy, deficits in the neurogenic response were observed despite normal levels of constitutive neurogenesis. There were no deficits in the radial glia-like stem cell pool, but their proliferative rates to the second mTBI did not increase. The lack of a proliferative response was unlikely due to the injury interval as the dampened responses, which included blunted increases in glial fibrillary acidic protein (GFAP) immunoreactivity, were as pronounced when a longer injury interval (2 month) was used. In contrast to the aberrant neurogenesis observed in more severe TBI models, neurons born after a single or second mTBI had normal dendritic branches, suggesting a beneficial role in hippocampal restoration. In line with this finding, mice with a second mTBI had impairments in neurogenesis-sensitive strategy flexibility, whereas mice with a single mTBI did not. These impairments were specific to strategy flexibility: Mice with two mTBIs had intact reference memory in the water maze. In conclusion, our findings demonstrate that a loss in the neurogenic response to a subsequent mTBI occurs weeks after a single mTBI and that this deficit is not transient. A loss in this endogenous repair mechanism could in part contribute to worse cognitive recovery after a repeated mTBI. Although our data may indicate that the absence of the neurogenic response could include impairments in the proliferative capacity of the radial glia-like stem cells, an alternative explanation could involve adaptative responses that alter the injury severity of the second mTBI. These possible explanations need to be validated in order to move forward with therapeutic strategies to reengage the neurogenic response.