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

Cover KK, Maeng LY, Lebrón-Milad K, Milad MR - Transl Psychiatry (2014)

Bottom Line: Over the past two decades, substantial knowledge has been attained about the mechanisms underlying the acquisition and subsequent extinction of conditioned fear.Lacking in the current knowledge is how men and women may or may not differ in the biology of fear and its extinction.In this review, we begin by highlighting the epidemiological differences in incidence rate.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Massachusetts General Hospital, Charlestown, MA, USA.

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.

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Related in: MedlinePlus

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.
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fig5: 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.

Mentions: ERs located in the cytoplasm and nucleus serve as ligand-activated transcription factors. The binding of E2 to its cytoplasmic receptor forms a steroid receptor complex that dimerizes, enters the nucleus and binds to the estrogen-response elements of target gene promoters to regulate transcription (Figure 5.1). It has been suggested that this genomic pathway mediates the long-term effects of E2 exposure, with gene products detected within 12–24 h.90 Activated nuclear ERs may also regulate gene expression indirectly by binding to transcription factors such as AP-1 and Sp1.91 These independent mechanisms enable selective estrogen receptor modulators such as tamoxifen to act as both an antagonist (via the estrogen-response element-dependent mechanism) and agonist (through AP-1 binding),92 data highlighting the complexity of the role that ERs and their ligands may have on synaptic plasticity.


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

Cover KK, Maeng LY, Lebrón-Milad K, Milad MR - Transl Psychiatry (2014)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150242&req=5

fig5: 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.
Mentions: ERs located in the cytoplasm and nucleus serve as ligand-activated transcription factors. The binding of E2 to its cytoplasmic receptor forms a steroid receptor complex that dimerizes, enters the nucleus and binds to the estrogen-response elements of target gene promoters to regulate transcription (Figure 5.1). It has been suggested that this genomic pathway mediates the long-term effects of E2 exposure, with gene products detected within 12–24 h.90 Activated nuclear ERs may also regulate gene expression indirectly by binding to transcription factors such as AP-1 and Sp1.91 These independent mechanisms enable selective estrogen receptor modulators such as tamoxifen to act as both an antagonist (via the estrogen-response element-dependent mechanism) and agonist (through AP-1 binding),92 data highlighting the complexity of the role that ERs and their ligands may have on synaptic plasticity.

Bottom Line: Over the past two decades, substantial knowledge has been attained about the mechanisms underlying the acquisition and subsequent extinction of conditioned fear.Lacking in the current knowledge is how men and women may or may not differ in the biology of fear and its extinction.In this review, we begin by highlighting the epidemiological differences in incidence rate.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Massachusetts General Hospital, Charlestown, MA, USA.

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.

Show MeSH
Related in: MedlinePlus