Impact of Tryptophan Depletion on Executive System Function during Menopause is Moderated by Childhood Adversity.
Many healthy women with no history of cognitive dysfunction experience subjective executive difficulties during menopause. Preclinical literature suggests latent effects of early life adversity on serotonin function may play a role in this phenomenon. However, evidence in human participants regarding the mechanisms by which loss of estradiol contributes to this vulnerability is lacking. Here we examined the impact of tryptophan depletion (TD) and adverse childhood experiences (ACE) on brain activation during a working memory task in menopausal women. We hypothesized that an interactive effect between ACE and TD would be observed when women were hypogonadal, and that treatment with estradiol would attenuate this effect. Thirty-three women underwent functional imaging at four time points (123 total scans) in this double-blind, placebo controlled, cross-over study. The effects of TD, ACE, and TD × ACE were evaluated using a voxel-wise, mixed-effects, 2 × 2 ANOVA. In the absence of exogenous estradiol, a TD by ACE interaction was observed on BOLD signal in the right DLPFC such that TD increased activation in high ACE subjects but decreased activation in low ACE subjects. While a similar interaction was observed with placebo treatment, treatment with estradiol attenuated the effects of ACE and TD such that no between or within group differences were observed. Together, these results suggest that early life adversity may have a lasting impact on serotonergic circuits underlying executive function that are unmasked by loss of estradiol during menopause.
Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.|Penn PROMOTES Research on Sex and Gender in Health, University of Pennsylvania, Philadelphia, PA, USA.
Sheila
S
Shanmugan
Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
James
J
Loughead
Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Wen
W
Cao
Penn PROMOTES Research on Sex and Gender in Health, University of Pennsylvania, Philadelphia, PA, USA.|Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.|Department of Obstetrics and Gynecology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Mary D
MD
Sammel
Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Theodore D
TD
Satterthwaite
Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Kosha
K
Ruparel
Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Ruben C
RC
Gur
Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.|Penn PROMOTES Research on Sex and Gender in Health, University of Pennsylvania, Philadelphia, PA, USA.|Department of Obstetrics and Gynecology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
C Neill
CN
Epperson
D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002648:Child; D002649:Child Abuse / Q000523:psychology* / Q000639:trends; D018592:Cross-Over Studies; D004311:Double-Blind Method; D056344:Executive Function / Q000502:physiology*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000639:trends; D008593:Menopause / Q000378:metabolism* / Q000523:psychology*; D008875:Middle Aged; D009483:Neuropsychological Tests; D014364:Tryptophan / Q000172:deficiency*
D014364:Tryptophan