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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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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.
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fig4: 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.

Mentions: Another molecular pathway that has been shown to be critical for fear extinction learning is the phosphoinositide 3-kinase (PI3K) cascade. Successful fear extinction is associated with Akt phosphorylation in the CA180 and dephosphorylation in the amygdala.81 Infusing a PI3K inhibitor in the IL following extinction training resulted in impaired extinction consolidation in male rats.82 The MAPK/ERK and PI3K signaling pathways converge in the activation of cAMP response element-binding protein (CREB), resulting in transcription of brain-derived neurotrophic factor (BDNF), and may be a critical component of this model (Figure 4). BDNF is a neurotrophin that critically supports long-term potentiation (LTP), spinogenesis and dendritic plasticity, mechanisms that underlie learning and memory. Binding to receptor TrkB activates MAPK/ERK and PI3K pathways.83 BDNF and TrkB are expressed abundantly in the brain, including the PFC, hippocampus and amygdala. As these regions are involved in fear circuitry, it is unsurprising that BDNF modulates fear extinction.84,85 BDNF lowers the threshold for LTP induction, facilitates extinction consolidation in the amygdala and supports cue-dependent extinction in the hippocampus.86


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

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

fig4: 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.
Mentions: Another molecular pathway that has been shown to be critical for fear extinction learning is the phosphoinositide 3-kinase (PI3K) cascade. Successful fear extinction is associated with Akt phosphorylation in the CA180 and dephosphorylation in the amygdala.81 Infusing a PI3K inhibitor in the IL following extinction training resulted in impaired extinction consolidation in male rats.82 The MAPK/ERK and PI3K signaling pathways converge in the activation of cAMP response element-binding protein (CREB), resulting in transcription of brain-derived neurotrophic factor (BDNF), and may be a critical component of this model (Figure 4). BDNF is a neurotrophin that critically supports long-term potentiation (LTP), spinogenesis and dendritic plasticity, mechanisms that underlie learning and memory. Binding to receptor TrkB activates MAPK/ERK and PI3K pathways.83 BDNF and TrkB are expressed abundantly in the brain, including the PFC, hippocampus and amygdala. As these regions are involved in fear circuitry, it is unsurprising that BDNF modulates fear extinction.84,85 BDNF lowers the threshold for LTP induction, facilitates extinction consolidation in the amygdala and supports cue-dependent extinction in the hippocampus.86

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