Mechanisms of estradiol in fear circuitry: implications for sex differences in psychopathology

Abstract

Over the past two decades, substantial knowledge has been attained about the mechanisms underlying the acquisition and subsequent extinction of conditioned fear. Knowledge gained on the biological basis of Pavlovian conditioning has led to the general acceptance that fear extinction may be a useful model in understanding the underlying mechanisms in the pathophysiology of anxiety disorders and may also be a good model for current therapies treating these disorders. Lacking in the current knowledge is how men and women may or may not differ in the biology of fear and its extinction. It is also unclear how the neural correlates of fear extinction may mediate sex differences in the etiology, maintenance, and prevalence of psychiatric disorders. In this review, we begin by highlighting the epidemiological differences in incidence rate. We then discuss how estradiol (E2), a primary gonadal hormone, may modulate the mechanisms of fear extinction and mediate some of the sex differences observed in psychiatric disorders.

Sex differences in conditioned stimulus discrimination during context-dependent fear learning and its retrieval in humans: the role of biological sex, contraceptives and menstrual cycle phases

“…48 Previous studies in humans have suggested activational effects of estrogens on fear conditioning and, in particular, extinction (recall) processes, as shown by differences between free-cycling women and those using hormonal contraceptives as well as differences during menstrual cycle phases. 8 It was thus suggested that current sex hormone status may have a stronger impact than biological sex on fear and extinction processes. Our data stand in contrast to this and support the notion that sex differences may be more dependent on organizational effects 49 as we find strong sex differences on both fear acquisition and retrieval/expression but little evidence for a modulatory role of current sex hormone status.…”

“…Similarly, the role of sex differences in humans has often been neglected and studies often included only male participants. 7,8 When including female participants, studies should control for menstrual cycle phase and the use of hormonal contraceptives because both factors have been shown to have an impact on these brain areas. 9 Obviously, this puts a heavy burden on time management and substantially increases the required number of participants.…”

“…Biologically determined sex differences in anxiety-related behaviour may arise through different mechanisms. 8 They can become hard-wired during early brain development (organizational effects) or arise through phasic variation in sex hormone levels during later phases in life (activational effects). While these mechanisms are not mutually exclusive, support for the latter comes from the observation that sex differences in the prevalence of anxiety do not emerge until puberty 10 and that low levels of ovarian hormone levels (e.g., postpartum, premenstrual and perimenopausal) coincide with increased incidences of anxiety symptoms and disorder onset.…”

“…11,12 Series of rodent studies and studies in naturally cycling females have shown that high levels of estrogens -both occurring naturally during the menstrual cycle and induced pharmacologically -are favourable for extinction memory consolidation, as indicated by enhanced extinction recall. At the same time, low levels have been shown to be disadvantageous for these processes 7,8,[13][14][15][16] and associated with impaired fear inhibition. 17 These studies suggest that the consolidation of extinction memory is critically modulated by fluctuating estrogen levels through the menstrual cycle and may be medi ated through facilitation of (hippocampal) neuronal plasticity.…”

“…17 These studies suggest that the consolidation of extinction memory is critically modulated by fluctuating estrogen levels through the menstrual cycle and may be medi ated through facilitation of (hippocampal) neuronal plasticity. 8 If estrogen in fact modulates the success of experimental fear extinction, this might be of high clinical relevance. Fear extinction is used as a model for exposure-based cognitive behavioural therapy (CBT 18 ), and consequently fluctuations in estrogen levels might affect the outcome of CBT during different menstrual cycle phases.…”