Abstract
Traumatic brain injury (TBI) is frequently characterized by neuronal, axonal and myelin loss, reactive gliosis and neuroinflammation, often associated with functional deficits. Endogenous repair mechanisms include production of new neurons from precursor cells, but usually the new neurons fail to integrate and survive more than a few weeks. This is in part mediated by the toxic and inflammatory environment present in the injured brain which activates precursor cells to proliferate and differentiate but limits survival of the newborn progeny. Therefore, an understanding of mechanisms that regulate production and survival of newborn neurons and the neuroinflammatory response after brain injury may lead to therapeutic options to improve outcomes. Suppressor of Cytokine Signaling 2 (SOCS2) promotes hippocampal neurogenesis and survival of newborn neurons in the adult brain and regulates anti-inflammatory responses in the periphery, suggesting it may be a useful candidate to improve outcomes of TBI. In this study the functional and cellular responses of SOCS2 over-expressing transgenic (SOCS2Tg) mice were compared to wildtype littermates following mild or moderately severe TBI. Unlike wildtype controls, SOCS2Tg mice showed functional improvement on a ladder test, with a smaller lesion volume at 7d post injury and increased numbers of proliferative CD11b+ microglia/macrophages at 35d post-injury in the mild injury paradigm. At 7d post-moderately severe injury there was an increase in the area covered by cells expressing an anti-inflammatory M2 phenotype marker (CD206+) but no difference in cells with a pro-inflammatory M1 phenotype marker (CD16/32+). No effect of SOCS2 overexpression was observed in production or survival of newborn neurons, even in the presence of the neuroprotective agent erythropoietin (EPO). Therefore, SOCS2 may improve outcome of TBI in mice by regulating aspects of the neuroinflammatory response, promoting a more anti-inflammatory environment, although this was not sufficient to enhance survival of newborn cortical neurons.
Highlights
Traumatic brain injury (TBI) affects millions of people worldwide
Only a handful of studies have identified limited numbers of newborn neurons in the perilesional cortex after TBI [12,13,14]. These findings suggest that endogenous adult neurogenesis has the potential to be reparative after TBI but needs to be aided with appropriate factors that can stimulate sufficient neural precursor cell (NPC) proliferation, provide an ideal microenvironment for successful NPC differentiation and importantly enhance newborn neuron survival
SOCS2 over-expressing transgenic (SOCS2Tg) and WT mice were subjected to TBI, administered a daily dose of EdU for 7d and immunohistological and behavioral analyses were performed to assess effects of Suppressor of Cytokine Signaling 2 (SOCS2) overexpression on outcome
Summary
Traumatic brain injury (TBI) affects millions of people worldwide. In the United Sates alone up to 1.7 million people report to have sustained a TBI annually [1]. Despite its high prevalence and socioeconomic impact, strategies for treatment of TBI are lacking. Primary trauma and secondary neuroinflammatory events lead to neuronal loss and this is accompanied by a range of behavioral and cognitive deficits whose exact nature and extent varies depending on the location, mode and severity of injury [2, 3]. Replacement of lost neurons to recover function/s after TBI remains an important bottleneck in the development of effective therapeutic treatments. Strategies under investigation to overcome this bottleneck include exogenous neural precursor cell (NPC) transplantation and stimulation of endogenous adult neurogenesis
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