Spontaneous resurgence of conditioned fear weeks after successful extinction in brain injured mice

Prog Neuropsychopharmacol Biol Psychiatry. 2019 Jan 10;88:276-286. doi: 10.1016/j.pnpbp.2018.07.023. Epub 2018 Aug 7.


Mild traumatic brain injury (TBI) is a major risk factor for post-traumatic stress disorder (PTSD), and both disorders share common symptoms and neurobiological defects. Relapse after successful treatment, known as long-term fear resurgence, is common in PTSD patients and a major therapeutic hurdle. We induced a mild focal TBI by controlled cortical impact (CCI) in male C57BL/6 J mice and used fear conditioning to assess PTSD-like behaviors and concomitant alterations in the fear circuitry. We found for the first time that mild TBI, and to a lesser extent sham (craniotomy), mice displayed a spontaneous resurgence of conditioned fear when tested for fear extinction memory recall, despite having effectively acquired and extinguished conditioned fear 6 weeks earlier in the same context. Other characteristic symptoms of PTSD are risk-taking behaviors and cognitive deficits. CCI mice displayed risk-taking behaviors, behavioral inflexibility and reductions in processing speed compared to naïve mice. In conjunction with these changes there were alterations in amygdala morphology 3 months post-trauma, and decreased myelin basic protein density at the primary lesion site and in distant secondary sites such as the hippocampus, thalamus, and amygdala, compared to sham mice. Furthermore, activity-dependent brain-derived neurotrophic factor (BDNF) transcripts were decreased in the prefrontal cortex, a key region for fear extinction consolidation, following fear extinction training in both TBI and, to a lesser extent, sham mice. This study shows for the first time that a mild brain injury can generate a spontaneous resurgence of conditioned fear associated with defective BDNF signalling in the prefrontal cortex, PTSD-like behaviors, and have enduring effects on the brain.

Keywords: Barnes maze; Brain derived neurotrophic factor; Fear conditioning; Myelin basic protein; Post-traumatic stress disorder; Risk-taking behaviors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Brain Injuries / pathology
  • Brain Injuries / physiopathology*
  • Brain Injuries / psychology*
  • Conditioning, Classical / physiology*
  • Disease Models, Animal
  • Extinction, Psychological / physiology*
  • Fear / physiology*
  • Male
  • Maze Learning
  • Mental Recall
  • Mice
  • Mice, Inbred C57BL
  • Myelin Basic Protein / genetics
  • Myelin Basic Protein / metabolism
  • Psychomotor Disorders / etiology
  • RNA, Messenger / metabolism
  • Risk-Taking
  • Statistics, Nonparametric
  • Time Factors


  • Myelin Basic Protein
  • RNA, Messenger