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Sex Differences in Molecular and Cellular Substrates of Stress
Open accessAbstract
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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“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.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [52]
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“…stress-induced levels of these hormones in women, while others find the opposite (i.e., men are higher) or no difference (Uhart et al. 2006; Kirschbaum et al. 1999, 1995, 1992; Seeman et al. 2001; Kudielka and Kirschbaum 2005; Gallucci et al. 1993; Heuser et al. 1994; Friedmann and…”
Research works printed but not linked: 1
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Metadata
- 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
- PMC
- PMC3378920
- 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
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- 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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