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.

Figure 1

Studies published within the past decade that focus on fear extinction research. To highlight the disparity in research focused on women and female animals, we used keywords ‘fear extinction' and ‘male' or ‘female'.

Figure 2

Sex differences in the lifetime incidence of psychiatric disorders vary from higher incidence in women, to no differences, to higher in men. Women/men lifetime incidence ratio was obtained directly from the publications referenced within the table or were calculated from the percentages of lifetime incidence published in the referenced studies. Superscripted letters next to each ratio reflects the citation from which we obtained such data: a, ref. ; b, ref. ; c, ref. ; d, ref. ; e, ; f, ref. ; g, ref. ; h, ref. ; i, ref. . *Of note, a sex bias for OCD is under debate and may depend on age; one study reports greater incidence among boys than girls. ADHD, attention deficit hyperactivity disorder; OCD, obsessive compulsive disorder; PTSD, posttraumatic stress disorder.

Figure 3

Relative estrogen receptor distribution within the rat fear extinction network. Estrogen receptor alpha (ERα left) is expressed moderately in the ventromedial prefrontal cortex (vmPFC) and hippocampus and strongly in the amygdala. Estrogen receptor beta (ERβ right) is weakly expressed in the vmPFC and amygdala and strongly in the hippocampus. These relative distributions are compiled from studies employing immunoreactivity and in situ hybridization methodologies.^{,,,, ,} Atlas images are adapted from Paxinos and Watson.

Figure 4

Schematic illustration of two molecular pathways implicated in fear extinction that are induced by estradiol (E2) or brain-derived neurotrophic factor (BDNF). In this diagram, PI3K (left) and MAPK/ERK (right) protein cascades may be activated by E2 or BDNF-bound membrane receptors. Both pathways phosphorylate CREB resulting in protein transcription, neuronal plasticity and memory formation and consolidation. Several examples of intra-pathway crosstalk are illustrated with facilitative activation represented with solid arrows and inhibitory actions by dashed lines. CREB, cAMP response element-binding protein; Gab1, GRB2-associated-binding protein 1; MAPK/ERK, mitogen-activated protein kinase/extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase kinase; MTOR, mammalian target of rapamycin; PDK1, pyruvate dehydrogenase lipoamide kinase isozyme 1; PI3K, phosphoinositide 3-kinase; RSK, ribosomal s6 kinase.

Figure 5

Schematic illustration of the different estrogen signaling pathways. Genomic ER pathway (1): estradiol mediates gene transcription by activating E2 receptors (ERs) located in the cytoplasm and nucleus, which bind to the estrogen-response element of gene promoters and induce gene transcription (hours to days). Membrane-bound ER pathway (2): membrane ERs activate intracellular cascades and neighboring GPCRs (such as metabotropic glutamate receptors), promoting CREB-modulated protein transcription. GPER pathway (3): localized in either the cell membrane or cytoplasm, E2-activated GPER initiates intracellular protein signaling resulting in CREB activation and gene transcription. Both membrane-bound ER and GPER pathways exert effects within seconds or minutes of activation. CREB, cAMP response element-binding protein; GPCR, G protein-coupled receptor; GPER, G protein-coupled estrogen receptor.

Figure 6

Future directions for exploring the role of estradiol in fear extinction and psychopathology. An apparent correlation between fluctuating estradiol states and vulnerability for fear and anxiety disorders necessitates further research into where, how and when estradiol modulates the fear extinction network. Investigating these questions may provide new options for targeted, and thus more effective, treatment and therapy in the clinic. BDNF, brain-derived neurotrophic factor; MAPK, mitogen-activated protein kinase; mPFC, medial prefrontal cortex; PI3K, phosphoinositide 3-kinase.