Attenuation of Microglial Activation with Minocycline Is Not Associated with Changes in Neurogenesis after Focal Traumatic Brain Injury in Adult Mice

Abstract

Neurogenesis is stimulated following injury to the adult brain and could potentially contribute to tissue repair. However, evidence suggests that microglia activated in response to injury are detrimental to the survival of new neurons, thus limiting the neurogenic response. The aim of this study was to determine the effect of the anti-inflammatory drug minocycline on neurogenesis and functional recovery after a closed head injury model of focal traumatic brain injury (TBI). Beginning 30 min after trauma, minocycline was administered for up to 2 weeks and bromodeoxyuridine was given on days 1–4 to label proliferating cells. Neurological outcome and motor function were evaluated over 6 weeks using the Neurological Severity Score (NSS) and ledged beam task. Microglial activation was assessed in the pericontusional cortex and hippocampus at 1 week post-trauma, using immunohistochemistry to detect F4/80. Following immunolabeling of bromodeoxyuridine, double-cortin, and NeuN, cells undergoing distinct stages of neurogenesis, including proliferation, neuronal differentiation, neuroblast migration, and long-term survival, were quantified at 1 and 6 weeks in the hippocampal dentate gyrus, as well as in the subventricular zone of the lateral ventricles and the pericontusional cortex. Our results show that minocycline successfully reduced microglial activation and promoted early neurological recovery that was sustained over 6 weeks. We also show for the first time in the closed head injury model, that early stages of neurogenesis were stimulated in the hippocampus and subventricular zone; however, no increase in new mature neurons occurred. Contrary to our hypothesis, despite the attenuation of activated microglia, minocycline did not support neurogenesis in the hippocampus, lateral ventricles, or pericontusional cortex, with none of the neurogenic stages being affected by treatment. These data provide evidence that a general suppression of microglial activation is insufficient to enhance neuronal production, suggesting that further work is required to elucidate the relationship between microglia and neurogenesis after TBI.