Increased expression of growth-related proteins and hippocampal neurogenesis in brains of adult rats following experimental traumatic brain injury

The potential of mature central nervous system (CNS) neurons to regenerate following injury represents a fundamental issue in neurobiology. The regional expression of proteins associated with axonal elongation, such as microtubule-associated-protein 1B (MAP1B), its phosphorylated isoform (MAP1B-P), growth-associated protein-43 (GAP-43), and polysialylated-neural-cell-adhesion-molecule (PSA-NCAM), was examined using immunohistochemistry from 24 hours to 2 months following lateral fluid percussion traumatic brain injury (TBI) of moderate severity (2.4–2.6 atm) in anesthetized rats. Uninjured (control) rats were subjected to anesthesia and surgery without injury, or anesthesia alone. Within the site of maximal injury, only increases in MAP1B and MAP1B-P were observed. Increased immunoreactivity was observed bilaterally for all growth-related proteins evaluated. By 24 hours post-injury, MAP1B and MAP1B-P increased within cortex (p \u3c 0.01) and hippocampus (p \u3c 0.001), while MAP1B-P was also elevated in thalamus (p \u3c 0.05). Within the dentate gyrus, increased immunoreactivity was observed for all proteins examined. By 48 hours post-injury, GAP-43 was elevated within the inner molecular layers of the dentate gyrus (p \u3c 0.005) and within stratum lacunosum moleculare (p \u3c 0.01), stratum radiatum (p \u3c 0.005) and stratum oriens (p \u3c 0.05) of the hippocampus. Increased numbers of PSA-NCAM-labeled neurons were observed in the granule layers of the dentate gyrus from 48 hours through 2 weeks post-injury ( p \u3c 0.0005). To determine whether post-injury increases in growth-related proteins within the dentate gyrus occur in conjunction with hippocampal neurogenesis, 5′-bromo-2′-deoxyuridine (BrdU)-labeled cells were evaluated. To determine whether these increases occur in response to TBI-induced axotomy of mossy fibers, anterograde and retrograde tract-tracing studies of mossy fibers were employed. Mossy fibers were capable of transporting anterograde and retrograde tracers, suggesting that these tracts are not axotomized. The number of mitotically active (BrdU+) cells observed in the dentate gyrus at 72 hours and at 2 weeks post-injury was significantly increased ( p \u3c 0.0001) compared to uninjured controls. By 2 weeks post-injury, newly-generated granule cells extended axons to the CA3 region. Taken together, these findings of compensatory hippocampal neurogenesis and increased expression of growth-related proteins following TBI suggest the existence of a temporary post-traumatic state in which the CNS may have increased regenerative potential. Enhancement of such a response may be one therapeutic strategy in treating CNS injury