Sex-Specific Neuroanatomical Correlates of Fear Expression in Prefrontal-Amygdala Circuits

Abstract

Background The neural projections from the infralimbic region of the prefrontal cortex (IL) to the amygdala are important for the maintenance of conditioned fear extinction. Neurons in this pathway exhibit a unique pattern of structural plasticity that is sex-dependent, but the relationship between the morphological characteristics of these neurons and successful extinction in males and females is unknown. Methods Using classic cued fear conditioning and extinction paradigm in large cohorts of male and female rats, we identified subpopulations of both sexes that exhibited high (HF) or low (LF) levels of freezing on an extinction retrieval test, representing failed or successful extinction maintenance, respectively. We then combined retrograde tracing with fluorescent intracellular microinjections to perform 3D reconstructions of IL neurons that project to the basolateral amygdala (BLA) in these groups. Results HF/LF males exhibited neuroanatomical distinctions that were not observed in HF vs. LF females. A retrospective analysis of behavior during fear conditioning and extinction revealed that despite no overall sex differences in freezing behavior, HF/LF phenotypes emerged in males during extinction, but in females during fear conditioning, which does not involve IL-BLA neurons. Conclusion Our results suggest that the neural processes underlying successful or failed extinction maintenance may be sex-specific. These findings are not only relevant to future basic research on sex differences in fear conditioning and extinction, but also to exposure-based clinical therapies, which are similar in premise to fear extinction, and which are primarily used to treat disorders that are more common in women than in men.

Activation of D1/5 Dopamine Receptors: A Common Mechanism for Enhancing Extinction of Fear and Reward-Seeking Behaviors

“…The trend for decreased preference in SKF 81297-treated mice during the Post-Extinction test led us to examine whether initial preference influenced the effect of SKF 81297 on extinction (Weber et al, 2007;Bernardi and Lattal, 2012;Gruene et al, 2015). To assess high or low cocaine preference, a median preference value was calculated from all subjects (48 animals) during the Pre-Ext Test, which occurred prior to delivery of SKF 81297.…”

Stress Effects on Neuronal Structure: Hippocampus, Amygdala, and Prefrontal Cortex

“…Recent behavioral work on male and female rats undergoing fear conditioning and extinction involving, respectively, the prelimbic and infralimbic PFC (Santini et al, 2008) has revealed sex differences based upon individual differences in efficacy of extinction (poor extinction, HF; good extinction, LF) that were evident in both males and females (Gruene et al, 2014). Despite no overall sex differences in freezing behavior, the HF/LF phenotypes emerged in males during extinction, but in females it emerged during fear conditioning, which does not involve infralimbic-BLA neurons.…”

Response-specific sex difference in the retention of fear extinction

“…A handful of studies have directly compared animals of both sexes on tests of cued and contextual fear conditioning. Some of these reports have shown that while males and females exhibit equivalent levels of fear conditioning to discrete cues (Maren et al 1994;Baran et al 2009;Milad et al 2009a;Barker and Galea 2010;Gruene et al 2015a;Fenton et al 2016), males often show evidence of better contextual conditioning (Maren et al 1994;Chang et al 2009;Barker and Galea 2010). Other studies have tested for sex differences in fear extinction learning, a form of learning through which animals learn to inhibit responding to cues that once signaled an aversive event.…”

“…Over the last several years, the study of fear extinction has received considerable attention (Milad and Quirk 2012) due in part to the fact that humans with PTSD display impaired extinction (Milad et al 2009b;Norrholm et al 2011). Recent findings in rodents are mixed with regard to sex differences in fear extinction with several studies reporting no difference between males and females (Milad et al 2009a;Rey et al 2014;Gruene et al 2015a), while others have found that females show weaker fear extinction (Baran et al 2009(Baran et al , 2010Matsuda et al 2015;Fenton et al 2016). Moreover, other studies have found that the retention of extinction learning in female rats varies depending on estrus stage such that rats exposed to extinction training while in proestrus show better retention of extinction (Milad et al 2009a;Rey et al 2014).…”