Oral Presentation The International Congress of Neuroendocrinology 2014

Circuit and sex-specific markers of failed fear suppression (#66)

Rebecca Shansky

Only a small fraction of people who experience a severe trauma will develop PTSD as a result, but susceptibility is twice as high in women as in men. The neurobiological basis of this discrepancy is not known, but identification of biological markers that distinguish resilience and vulnerability in each sex could lead to better prevention strategies and more nuanced treatments. In animal models, individual differences in behavior during fear conditioning and extinction may be a useful tool for probing the mechanisms that underlie variability in aversive learning processes. However, despite the robust sex differences observed in patient populations, fear conditioning and extinction research in animals has been conducted almost exclusively in males. Here we took advantage of naturally occurring behavioral variability in large cohorts of male and female rats that underwent classic fear conditioning and extinction regimens, identifying subpopulations of animals that exhibited high (HF) or low (LF) levels of freezing on an extinction retrieval test. Retrospective analysis of behavior during fear conditioning and extinction revealed that, remarkably, HF/LF distinctions were not observed until extinction in males, but emerged during fear conditioning in females. To identify neuroanatomical markers of these behavioral phenotypes, we performed 3D reconstructions of neurons in the infralimbic-basolateral amygdala pathway, and found that HF males, but not females, exhibited distinct morphological features in these neurons. Together, our findings suggest that the mechanisms and circuitry underlying successful or failed extinction maintenance are discrete in males and females, holding implications for understanding sex differences in PTSD etiology.