Inhibition of injury-induced cell proliferation in the dentate gyrus of the hippocampus impairs spontaneous cognitive recovery after traumatic brain injury

J Neurotrauma. 2015 Apr 1;32(7):495-505. doi: 10.1089/neu.2014.3545. Epub 2015 Jan 22.

Abstract

Neurogenesis persists throughout life in the neurogenic regions of the mature mammalian brain, and this response is enhanced after traumatic brain injury (TBI). In the hippocampus, adult neurogenesis plays an important role in hippocampal-dependent learning and memory functions and is thought to contribute to the spontaneous cognitive recovery observed after TBI. Utilizing an antimitotic agent, arabinofuranosyl cytidine (Ara-C), the current study investigated the direct association of injury-induced hippocampal neurogenesis with cognitive recovery. In this study, adult rats received a moderate lateral fluid percussion injury followed by a 7-day intraventricular infusion of 2% Ara-C or vehicle. To examine the effect of Ara-C on cell proliferation, animals received intraperitoneal injections of 5-bromo-2-deoxyuridine (BrdU), to label dividing cells, and were sacrificed at 7 days after injury. Brain sections were immunostained for BrdU or doublecortin (DCX), and the total number of BrdU(+) or DCX(+) cells in the hippocampus was quantified. To examine the outcome of inhibiting the injury-induced cell proliferative response on cognitive recovery, animals were assessed on Morris water maze (MWM) tasks at 21-25 or 56-60 days postinjury. We found that a 7-day infusion of Ara-C significantly reduced the total number of BrdU(+) and DCX(+) cells in the dentate gyrus (DG) in both hemispheres. Moreover, inhibition of the injury-induced cell proliferative response in the DG completely abolished the innate cognitive recovery on MWM performance at 56-60 days postinjury. These results support the causal relationship of injury-induced hippocampal neurogenesis on cognitive functional recovery and suggest the importance of this endogenous repair mechanism on restoration of hippocampal function.

Keywords: Ara-C; Morris water maze; cognition; hippocampus; neurogenesis; traumatic brain injury.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain Injuries / physiopathology*
  • Brain Injuries / psychology
  • Cell Proliferation / drug effects
  • Cell Proliferation / physiology*
  • Cognition / drug effects
  • Cognition / physiology*
  • Cytarabine / pharmacology
  • Dentate Gyrus / drug effects
  • Dentate Gyrus / physiopathology*
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Neurogenesis / drug effects
  • Neurogenesis / physiology*
  • Neurons / drug effects
  • Neurons / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Recovery of Function / drug effects
  • Recovery of Function / physiology*

Substances

  • Cytarabine