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


• Spontaneous fear resurgence occurs months after mild brain injury
• TBI, without neurological deficits, leads to risk-taking and slow learning
• PTSD-like deficits occur in conjunction with myelin changes, but not cell density
• Fronto-cortical Bdnf mRNA exons I and IV decrease 3 weeks after mild brain injury



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.


5. Conclusion

We found here that mild TBI, and to a lesser extent craniotomy, produce long-term fear extinction deficits. TBI also induced risk taking behaviors, and reduced processing speed and cognitive flexibility. Three months after TBI, there were morphological changes and myelin loss in the CC, the cortex adjacent to the primary lesion site, and in several areas involved in conditioned fear. Bdnf transcription in the mPFC was reduced by TBI, but also craniotomy. Further studies with this murine model are necessary to determine whether re-equilibrating BDNF signalling few weeks after brain injury can restore the behavioral and neurobiological deficits.

Indeed, alterations of cortico-thalamo-amygdalar myelinated pathways may be linked with the decrease in Bdnf mRNA in cortical areas critical for fear extinction consolidation. Diffusion tensor imaging studies revealed similar alterations in PTSD patients (Sanjuan et al., 2013) while TBI patients display decreased BDNF levels late after injury (Schober et al., 2012). As BDNF induces white matterneuroprotection by promoting myelination via a direct action on oligodendrocytes (Husson et al., 2005; Xiao et al., 2010), the late onset of PTSD symptoms and reduction of processing speed after brain injury (Johnson and Lovell, 2011) might be prevented by treatments that increase cortical trophic factors. Systemic BDNF TrkBagonist (Andero et al., 2011) or neural stem cell cortical transplantation promoting TBI functional recovery via BDNF (Johnson and Lovell, 2011), may provide treatment for symptom relapses in the TBI/PTSD comorbidity.



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