Females uniquely vulnerable to alcohol-induced neurotoxicity show altered glucocorticoid signaling

Clare Wilhelm, Joel G. Hashimoto, Melissa L. Roberts, Shelley H. Bloom, Douglas K. Beard, Kristine Wiren

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Abstract Women are more sensitive to the harmful effects of alcohol (EtOH) abuse than men, yet the underlying mechanisms remain poorly understood. Previous gene expression analysis of the medial prefrontal cortex (mPFC) following a chronic intoxication paradigm using continuous 72 h vapor inhalation found that females, but not males, exhibit an inflammatory response at peak withdrawal that is associated with cell damage. Given that glucocorticoids can function as anti-inflammatories, are known to increase with EtOH exposure, and influence neurotoxicity, we hypothesized that males and females may exhibit an altered corticosterone (CORT) response following chronic intoxication. Analysis of serum CORT levels revealed the expected increase during withdrawal with no difference between males and females, while control males but not females exhibited higher CORT concentrations than naive animals. Glucocorticoid signaling characterized using focused qPCR arrays identified a sexually dimorphic response in the mPFC during withdrawal, particularly among astrocyte-enriched genes. These genes include aquaporin-1 (Aqp1), sphingosine kinase 1 (Sphk1) and connective tissue growth factor (Ctgf); genes associated with inflammatory signaling, and tissue damage and repair. Bioinformatic analysis also revealed activation of inflammatory signaling and cell death pathways in females. Confirmation studies showed that female mice exhibited significant neuronal degeneration within the anterior cingulate cortex (ACC). By contrast, EtOH exposure lead to a significant reduction in cell death in males. Thus, distinct glucocorticoid signaling pathways are associated with sexually dimorphic neurotoxicity, suggesting one mechanism by which EtOH-exposed females are particularly vulnerable to the damaging effects of alcohol in the CNS.

Original languageEnglish (US)
Article number44024
Pages (from-to)102-116
Number of pages15
JournalBrain Research
Volume1601
DOIs
StatePublished - Mar 19 2015

Fingerprint

Glucocorticoids
Alcohols
Corticosterone
Prefrontal Cortex
Cell Death
Aquaporin 1
Genes
Connective Tissue Growth Factor
Gyrus Cinguli
Computational Biology
Astrocytes
Inhalation
Alcoholism
Anti-Inflammatory Agents
Gene Expression
Serum

Keywords

  • Alcohol
  • Astrocyte
  • Glucocorticoid signaling
  • Neurodegeneration
  • Neurotoxicity

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Developmental Biology
  • Molecular Biology

Cite this

Females uniquely vulnerable to alcohol-induced neurotoxicity show altered glucocorticoid signaling. / Wilhelm, Clare; Hashimoto, Joel G.; Roberts, Melissa L.; Bloom, Shelley H.; Beard, Douglas K.; Wiren, Kristine.

In: Brain Research, Vol. 1601, 44024, 19.03.2015, p. 102-116.

Research output: Contribution to journalArticle

Wilhelm, Clare ; Hashimoto, Joel G. ; Roberts, Melissa L. ; Bloom, Shelley H. ; Beard, Douglas K. ; Wiren, Kristine. / Females uniquely vulnerable to alcohol-induced neurotoxicity show altered glucocorticoid signaling. In: Brain Research. 2015 ; Vol. 1601. pp. 102-116.
@article{f6751891cf3540fd861a29e3e4057e6d,
title = "Females uniquely vulnerable to alcohol-induced neurotoxicity show altered glucocorticoid signaling",
abstract = "Abstract Women are more sensitive to the harmful effects of alcohol (EtOH) abuse than men, yet the underlying mechanisms remain poorly understood. Previous gene expression analysis of the medial prefrontal cortex (mPFC) following a chronic intoxication paradigm using continuous 72 h vapor inhalation found that females, but not males, exhibit an inflammatory response at peak withdrawal that is associated with cell damage. Given that glucocorticoids can function as anti-inflammatories, are known to increase with EtOH exposure, and influence neurotoxicity, we hypothesized that males and females may exhibit an altered corticosterone (CORT) response following chronic intoxication. Analysis of serum CORT levels revealed the expected increase during withdrawal with no difference between males and females, while control males but not females exhibited higher CORT concentrations than naive animals. Glucocorticoid signaling characterized using focused qPCR arrays identified a sexually dimorphic response in the mPFC during withdrawal, particularly among astrocyte-enriched genes. These genes include aquaporin-1 (Aqp1), sphingosine kinase 1 (Sphk1) and connective tissue growth factor (Ctgf); genes associated with inflammatory signaling, and tissue damage and repair. Bioinformatic analysis also revealed activation of inflammatory signaling and cell death pathways in females. Confirmation studies showed that female mice exhibited significant neuronal degeneration within the anterior cingulate cortex (ACC). By contrast, EtOH exposure lead to a significant reduction in cell death in males. Thus, distinct glucocorticoid signaling pathways are associated with sexually dimorphic neurotoxicity, suggesting one mechanism by which EtOH-exposed females are particularly vulnerable to the damaging effects of alcohol in the CNS.",
keywords = "Alcohol, Astrocyte, Glucocorticoid signaling, Neurodegeneration, Neurotoxicity",
author = "Clare Wilhelm and Hashimoto, {Joel G.} and Roberts, {Melissa L.} and Bloom, {Shelley H.} and Beard, {Douglas K.} and Kristine Wiren",
year = "2015",
month = "3",
day = "19",
doi = "10.1016/j.brainres.2015.01.002",
language = "English (US)",
volume = "1601",
pages = "102--116",
journal = "Brain Research",
issn = "0006-8993",
publisher = "Elsevier",

}

TY - JOUR

T1 - Females uniquely vulnerable to alcohol-induced neurotoxicity show altered glucocorticoid signaling

AU - Wilhelm, Clare

AU - Hashimoto, Joel G.

AU - Roberts, Melissa L.

AU - Bloom, Shelley H.

AU - Beard, Douglas K.

AU - Wiren, Kristine

PY - 2015/3/19

Y1 - 2015/3/19

N2 - Abstract Women are more sensitive to the harmful effects of alcohol (EtOH) abuse than men, yet the underlying mechanisms remain poorly understood. Previous gene expression analysis of the medial prefrontal cortex (mPFC) following a chronic intoxication paradigm using continuous 72 h vapor inhalation found that females, but not males, exhibit an inflammatory response at peak withdrawal that is associated with cell damage. Given that glucocorticoids can function as anti-inflammatories, are known to increase with EtOH exposure, and influence neurotoxicity, we hypothesized that males and females may exhibit an altered corticosterone (CORT) response following chronic intoxication. Analysis of serum CORT levels revealed the expected increase during withdrawal with no difference between males and females, while control males but not females exhibited higher CORT concentrations than naive animals. Glucocorticoid signaling characterized using focused qPCR arrays identified a sexually dimorphic response in the mPFC during withdrawal, particularly among astrocyte-enriched genes. These genes include aquaporin-1 (Aqp1), sphingosine kinase 1 (Sphk1) and connective tissue growth factor (Ctgf); genes associated with inflammatory signaling, and tissue damage and repair. Bioinformatic analysis also revealed activation of inflammatory signaling and cell death pathways in females. Confirmation studies showed that female mice exhibited significant neuronal degeneration within the anterior cingulate cortex (ACC). By contrast, EtOH exposure lead to a significant reduction in cell death in males. Thus, distinct glucocorticoid signaling pathways are associated with sexually dimorphic neurotoxicity, suggesting one mechanism by which EtOH-exposed females are particularly vulnerable to the damaging effects of alcohol in the CNS.

AB - Abstract Women are more sensitive to the harmful effects of alcohol (EtOH) abuse than men, yet the underlying mechanisms remain poorly understood. Previous gene expression analysis of the medial prefrontal cortex (mPFC) following a chronic intoxication paradigm using continuous 72 h vapor inhalation found that females, but not males, exhibit an inflammatory response at peak withdrawal that is associated with cell damage. Given that glucocorticoids can function as anti-inflammatories, are known to increase with EtOH exposure, and influence neurotoxicity, we hypothesized that males and females may exhibit an altered corticosterone (CORT) response following chronic intoxication. Analysis of serum CORT levels revealed the expected increase during withdrawal with no difference between males and females, while control males but not females exhibited higher CORT concentrations than naive animals. Glucocorticoid signaling characterized using focused qPCR arrays identified a sexually dimorphic response in the mPFC during withdrawal, particularly among astrocyte-enriched genes. These genes include aquaporin-1 (Aqp1), sphingosine kinase 1 (Sphk1) and connective tissue growth factor (Ctgf); genes associated with inflammatory signaling, and tissue damage and repair. Bioinformatic analysis also revealed activation of inflammatory signaling and cell death pathways in females. Confirmation studies showed that female mice exhibited significant neuronal degeneration within the anterior cingulate cortex (ACC). By contrast, EtOH exposure lead to a significant reduction in cell death in males. Thus, distinct glucocorticoid signaling pathways are associated with sexually dimorphic neurotoxicity, suggesting one mechanism by which EtOH-exposed females are particularly vulnerable to the damaging effects of alcohol in the CNS.

KW - Alcohol

KW - Astrocyte

KW - Glucocorticoid signaling

KW - Neurodegeneration

KW - Neurotoxicity

UR - http://www.scopus.com/inward/record.url?scp=84924453121&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924453121&partnerID=8YFLogxK

U2 - 10.1016/j.brainres.2015.01.002

DO - 10.1016/j.brainres.2015.01.002

M3 - Article

C2 - 25601008

AN - SCOPUS:84924453121

VL - 1601

SP - 102

EP - 116

JO - Brain Research

JF - Brain Research

SN - 0006-8993

M1 - 44024

ER -