Sex differences in fear extinction

Abstract

Despite the exponential increase in fear research during the last years, few studies have included female subjects in their design. The need to include females arises from the knowledge gap of mechanistic processes underlying the behavioral and neural differences observed in fear extinction. Moreover, the exact contribution of sex and hormones in relation to learning and behavior is still largely unknown. Insights from this field could be beneficial as fear-related disorders are twice as prevalent in women compared to men. Here, we review an up-to-date summary of animal and human studies in adulthood that report sex differences in fear extinction from a structural and functional approach. Furthermore, we describe how these factors could contribute to the observed sex differences in fear extinction during normal and pathological conditions.

Keywords: Extinction; Fear; Female; Human; Male; Rodent; Sex.

Figure 1.

Scaled representation of estradiol and progesterone levels during the distinct phases of the estrous (rodent) and menstrual cycle (human). The result of subjecting females to Fear Extinction (FE) training during each phase is shown at the top as fear extinction recall (FE_R). The FE_R of females undergoing FE training under high or low estrogen states appears on the right. * denotes additional within-session effects of the cycle during FE training. D: diestrus, E: estrus, E2: estradiol, EF: early follicular phase, LF: late follicular phase, LL: late luteal phase, M: metestrus, ML: mid luteal phase, P: proestrus. Information obtained from: 1. Milad et al., 2009, 2. Gruene et al., 2015, 3. Rey et al., 2014, 4. Milad et al., 2010, 5. Zeidan et al., 2011, 6 Pineles et al., 2016, 7. Graham & Milad 2013

Figure 2.

Schematic representation of the brain structures where sex differences in fear extinction are reported. The main findings of animal and human research appear enlisted under each structure. BA: basal amygdala, dACC: dorsal anterior cingulate cortex, E2: estradiol, EMD: estrus, metestrus, diestrus phases of estrous cycle, ER-β: estrogen receptor beta, F: females, FC: fear conditioning, FE: fear extinction: FE_R: fear extinction recall, FE_TR: fear extinction training, HC: hormonal contraceptives, IL: infralimbic cortex, LA: lateral amygdala, M: male, M/ F: male and female, PrL: prelimbic cortex, PTSD: posttraumatic stress disorder, vmPFC: ventromedial prefrontal cortex.