Cited by 160Stress Responses and CortisolNeuropeptides and Animal PhysiologyNeurotransmitter Receptor Influence on Behavior

Sex Differences in Molecular and Cellular Substrates of Stress

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Bangasser, Debra A., Valentino, Rita J.·2012·Cellular and Molecular Neurobiology

Abstract

Women are twice as likely as men to suffer from stress-related psychiatric disorders, like unipolar depression and post-traumatic stress disorder. Although the underlying neural mechanisms are not well characterized, the pivotal role of stress in the onset and severity of these diseases has led to the idea that sex differences in stress responses account for this sex bias. Corticotropin-releasing factor (CRF) orchestrates stress responses by acting both as a neurohormone to initiate the hypothalamic-pituitary-adrenal (HPA) axis and as a neuromodulator in the brain. One target of CRF modulation is the locus coeruleus (LC)-norepinephrine system, which coordinates arousal components of the stress response. Hypersecretion of CRF and dysregulation of targets downstream from CRF, such as the HPA axis and LC-norepinephrine system, are characteristic features of many stress-related psychiatric diseases, suggesting a causal role for CRF and its targets in the development of these disorders. This review will describe sex differences in CRF and the LC-norepinephrine system that can increase stress sensitivity in females, making them vulnerable to stress-related disorders. Evidence for gonadal hormone regulation of hypothalamic CRF is discussed as an effect that can lead to increased HPA axis activity in females. Sex differences in the structure of LC neurons that create the potential for hyperarousal in response to emotional stimuli are described. Finally, sex differences at the molecular level of the CRF(1) receptor that make the LC-norepinephrine system more reactive in females are reviewed. The implications of these sex differences for the treatment of stress-related psychiatric disorders also will be discussed.

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  • CRF activation of the locus coeruleus is accentuated in females and dopamine in the PFC is increased by estrogen.

    “For example, CRF activation of the locus coeruleus is accentuated in females52 and dopamine in the PFC is increased by estrogen53, suggesting mechanisms that may underlie the increased vulnerability of females to stress exposure.”

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Research works printed but not linked: 4

  1. Page ME Abercrombie ED 1999 Discrete local application of corticotropin-releasing factor increases locus coeruleus discharge and extracellular norepinephrine in rat hippocampus Synapse 33 304 313 10421711
  2. Shipley MT Fu L Ennis M Liu W Aston-Jones G 1996 Dendrites of locus coeruleus neurons extend preferentially into two pericoerulear zones J Comp Neurol 365 56 68 8821441
  3. Valentino RJ Chen S Zhu Y Aston-Jones G 1996 Evidence for divergent projections of corticotropin-releasing hormone neurons of Barrington’s nucleus to the locus coeruleus and spinal cord Brain Res 732 1 15 8891263
  4. Valentino RJ Van Bockstaele E Steckler TKN 2005 Functional interactions between stress neuromediator and the locus coeruleur-noradrenaline system Handbook of Stress and the Brain Elsevier The Netherlands 465 486

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Authors
Bangasser, D. A., & Valentino, R. J.
Affiliations
Children's Hospital of Philadelphia (US)
Corresponding author
Valentino, Rita J.
Venue
Cellular and Molecular Neurobiology
Published
2012-04-10
Volume
32
Issue
5
Pages
709-723
ISSN
  • 0272-4340 (ISSN-L)
  • 1573-6830
OpenAlex
W2067632849
Cited by
160
References
181
Citations by year
2026: 10 · 2025: 5 · 2024: 6 · 2023: 15 · 2022: 13 · 2021: 7 · 2020: 12 · 2019: 9 · 2018: 11 · 2017: 12 · 2016: 14 · 2015: 15 · 2014: 16 · 2013: 14 · 2012: 1
FWCI
5.86
Type
journal article
Language
en
Open access
Locations
  • Cellular and Molecular Neurobiology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
Funders
National Institute of Mental Health (MH 092438, K99MH092438, MH 40008, R00MH092438, R01MH040008)
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
sex differences, stress response, corticotropin-releasing factor, locus coeruleus, norepinephrine, hypothalamic-pituitary-adrenal axis, CRF1 receptor, gonadal hormones, major depressive disorder, post-traumatic stress disorder, hyperarousal, stress-related psychiatric disorders
MeSH terms
Corticotropin-Releasing Hormone, Female, Humans, Locus Coeruleus, Male, Sex Characteristics, Stress, Psychological, Signal Transduction, Receptors, Corticotropin-Releasing Hormone

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