Timing is everything: differential effects of chronic stress on fear extinction
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Stress disorders cause abnormal regulation of fear-related behaviors. In most rodent models of these effects, stress was administered before fear conditioning, thereby assessing its impact on both the formation and extinction of fear memories, not the latter alone. Here, we dissociated the two processes by also administering stress after fear conditioning, and then compared how pre-conditioning versus post-conditioning exposure to chronic stress affects subsequent acquisition and recall of fear extinction.
Male Wistar rats were subjected to chronic immobilization stress (2 h/day, 10 days); the morphological effects of which were analyzed using modified Golgi-Cox staining across brain areas mediating the formation and extinction of fear memories. Separate groups of rats underwent fear conditioning followed by acquisition and recall of extinction, wherein stress was administered either before or after fear conditioning.
When fear memories were formed after chronic stress, both acquisition and retrieval of extinction was impaired. Strikingly, these deficits were absent when fear memories were formed before the same stress. Chronic stress also reduced dendritic spine density in the infralimbic prefrontal cortex, but enhanced it in the basolateral amygdala.
Chronic stress, administered either before or after fear learning, had distinct effects on the acquisition and recall of fear extinction memories. Stress also strengthened the structural basis of synaptic connectivity in the amygdala, but weakened it in the prefrontal cortex. Thus, despite eliciting a specific pattern of brain region-specific morphological changes, the timing of the same stress gave rise to strikingly different behavioral effects on the extinction of fear.
KeywordsPlasticity Amygdala Hippocampus Prefrontal cortex Dendritic spines Learning and memory Chronic stress
The authors would like to acknowledge Dr. Siddhartha Datta for his help with analysis of the contextual freezing data.
PC and SC contributed to the experimental design. PC performed the experiments and analyzed the data. PC and SC interpreted the results. PC and SC wrote the manuscript.
This work was supported by funds from the Department of Atomic Energy and Department of Biotechnology, Government of India, and the Madan and Usha Sethi Fellowship.
Compliance with ethical standards
All maintenance and experimental procedures were approved by the Institutional Ethics Committee, National Centre for Biological Sciences, India.
Conflict of interest
The authors declare that they have no conflict of interest.
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