The neurobiological basis of sex differences in learned fear and its inhibition

Abstract

Learning that certain cues or environments predict threat enhances survival by promoting appropriate fear and the resulting defensive responses. Adapting to changing stimulus contingencies by learning that such cues no longer predict threat, or distinguishing between these threat-related and other innocuous stimuli, also enhances survival by limiting fear responding in an appropriate manner to conserve resources. Importantly, a failure to inhibit fear in response to harmless stimuli is a feature of certain anxiety and trauma-related disorders, which are also associated with dysfunction of the neural circuitry underlying learned fear and its inhibition. Interestingly, these disorders are up to twice as common in women, compared to men. Despite this striking sex difference in disease prevalence, the neurobiological factors involved remain poorly understood. This is due in part to the majority of relevant preclinical studies having neglected to include female subjects alongside males, which has greatly hindered progress in this field. However, more recent studies have begun to redress this imbalance and emerging evidence indicates that there are significant sex differences in the inhibition of learned fear and associated neural circuit function. This paper provides a narrative review on sex differences in learned fear and its inhibition through extinction and discrimination, along with the key gonadal hormone and brain mechanisms involved. Understanding the endocrine and neural basis of sex differences in learned fear inhibition may lead to novel insights on the neurobiological mechanisms underlying the enhanced vulnerability to develop anxiety-related disorders that are observed in women.

Keywords: discrimination; extinction; fear conditioning; female; generalization; male.

Figure 1

Brain areas involved in learned fear and its inhibition in (a) rats (adapted from Paxinos & Watson, 2007) and (b) humans (adapted from Allen Human Brain Atlas; Ball, Gilbert, & Overly, 2012). AMYG: amygdala; DH; dorsal hippocampus; HIPP: hippocampus; PFC: prefrontal cortex

Figure 2

Schematic representation of fluctuations in the levels of estrogen and progesterone over the course of the (a) estrous cycle in female rats and (b) menstrual cycle in women. Vertical dotted lines represent the approximate time of ovulation (adapted from Maeng & Milad, 2015)