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Neuroscience and Psychiatry |

Estrogen, Stress, and Depression A Neurocognitive Model

Paul Newhouse, MD1,2; Kimberly Albert, BS1,3
[+] Author Affiliations
1Center for Cognitive Medicine, Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee
2Geriatric Research, Education, and Clinical Center, Veterans Affairs Tennessee Valley Health System, Nashville
3Neuroscience Graduate Program, University of Vermont, Burlington
JAMA Psychiatry. 2015;72(7):727-729. doi:10.1001/jamapsychiatry.2015.0487.
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This Neuroscience and Psychiatry article proposes that changing levels of estradiol may directly modify the activity of dorsal and ventral emotional regulation nodes and circuits, modifying the cognitive and emotional consequences of life stress and leading to depression in women.

Increased vulnerability for depression in women begins with puberty and declines after menopause. Studies have shown that perimenopause produces increased vulnerability for depressive symptoms and new-onset depression even among women with no history of affective disorders. While the reason or reasons for vulnerability to such disorders in women remain to be fully understood, the strongest candidate is the influence of cycling levels of gonadal steroids, particularly estradiol (the predominant circulating estrogen), on neurotransmitter systems and mood regulatory systems, interacting with biological vulnerability and life stress. Alterations in how the brain conducts emotional processing and encodes and retrieves emotional information may be critical to sex and age differences in the incidence, prevalence, and treatment of emotional and cognitive disorders. The menopause transition is a neurobiological and endocrine event that has effects on a variety of tissue and organ systems; alterations in mood regulation during this stage may inform our understanding of sex hormone effects on emotional cognition.

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Figure.
Proposed Effect of Differing Estradiol Levels During the Menstrual Cycle or Perimenopause on Dorsal and Ventral Emotional Systems and Interaction With Negative or Stressful Life Events (eg, Trauma)

A, Low-estradiol early follicular phase. B, High-estradiol periovulatory phase. Relative size of shapes indicates increased or reduced effects or activity. High-estradiol level phases during the menstrual cycle enhance the activity of dorsal regulatory structures during or following stressful events and lead to reduced activity of structures associated with negative emotions and better reappraisal, less negative emotional memory, and reduced negative affective state. This relationship changes during low-estradiol phases. (Based on concepts from Phillips et al.2) ACC indicates anterior cingulate cortex; DLPFC, dorsolateral prefrontal cortex; DMPFC, dorsomedial prefrontal cortex; E2, 17β-estradiol; OFC, orbitofrontal cortex; V-ACC, ventral anterior cingulate cortex; and VLPFC, ventrolateral prefrontal cortex.

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