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Impact of exogenous estradiol on task-based and resting-state neural signature during and after fear extinction in healthy women


Fluctuations of endogenous estrogen modulates fear extinction, but the influence of exogenous estradiol is less studied. Moreover, little focus has been placed on the impact of estradiol on broad network connectivity beyond the fear extinction circuit. Here, we examined the effect of acute exogenous estradiol administration on fear extinction-induced brain activation, whole-brain functional connectivity (FC) during the fear extinction task and post-extinction resting-state. Ninety healthy women (57 using oral contraceptives [OC], 33 naturally cycling [NC]) were fear conditioned on day 1. They ingested an estradiol or placebo pill prior to extinction learning on day 2 (double-blind design). Extinction memory was assessed on day 3. Task-based functional MRI data were ascertained on days 2 and 3 and resting-state data were collected post-extinction on day 2 and pre-recall on day 3. Estradiol administration significantly modulated the neural signature associated with fear extinction learning and memory, consistent with prior studies. Importantly, estradiol administration induced significant changes in FC within multiple networks, including the default mode and somatomotor networks during extinction learning, post-extinction, and during extinction memory recall. Exploratory analyses revealed that estradiol impacted ventromedial prefrontal cortex (vmPFC) activation and FC differently in the NC and OC women. The data implicate a more diffused and significant effect of acute estradiol administration on multiple networks. Such an effect might be beneficial to modulating attention and conscious processes in addition to engaging neural processes associated with emotional learning and memory consolidation.

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Fig. 1: Estradiol levels and skin conductance responses (SCRs) across experimental phases.
Fig. 2: Correlations between estradiol level and brain activation during extinction learning and extinction retention test.
Fig. 3: Correlations between estradiol level and task-based functional connectivity.
Fig. 4: Correlations between estradiol level and post-extinction resting-state functional connectivity.
Fig. 5: Mediation analyses.


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This work was funded by National Institute of Mental Health grants R61-MH126090-01 (MRM), R01-MH097880-01 (MRM).

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Conceptualization: EBF, MRM; Funding acquisition: EBF, MRM; Methodology: MRM; Validation: JCS, RCG, MRM; Project administration: MZH, JCS, LB, MFM, AA, EBF, MRM; Supervision: LB, MFM, AA, RCG, EBF; Investigation: MZH, JCS, JJ, MFM; Data curation: ZW, MZH, JJ; Statistical analyses: ZW; Software: ZW; Visualization: ZW; Writing-original draft: ZW, MRM; Writing-review and editing: all authors.

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Correspondence to Mohammed R. Milad.

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Wen, Z., Hammoud, M.Z., Scott, J.C. et al. Impact of exogenous estradiol on task-based and resting-state neural signature during and after fear extinction in healthy women. Neuropsychopharmacol. (2021).

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