Journal article
Sex-specific effects of alcohol on neurobehavioral performance and endoplasmic reticulum stress: an analysis using neuron-specific MANF deficient mice
Frontiers in pharmacology, Vol.15, 1407576
07/26/2024
DOI: 10.3389/fphar.2024.1407576
PMCID: PMC11310019
PMID: 39130640
Abstract
Excessive alcohol exposure can cause neurobehavioral deficits and structural alterations in the brain. Emerging research evidence suggests that endoplasmic reticulum (ER) stress plays an important role in alcohol-induced neurotoxicity. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress inducible protein and is responsible to maintain ER homeostasis. MANF is highly expressed in both the developing and mature brain. We have previously shown that MANF deficiency exacerbated alcohol induced neurodegeneration and ER stress in the developing brain. However, little is known regarding the role of MANF in alcohol induced neuronal damage in the adult brain. In this study, we used a neuron-specific MANF knockout (KO) mouse model to investigate the effect of MANF deficiency on acute binge alcohol exposure-induced neurobehavioral deficits and ER stress. Adult male and female MANF KO mice and littermate controls received daily alcohol gavage (5 g/kg) for 10 days and then subjected to a battery of neurobehavioral tests including rotarods, balance beam, DigiGait, open field, elevated plus maze, Barnes maze, and three-chamber sociability task. Female MANF KO animals were more susceptible to alcohol-induced body weight loss. Alcohol exposure did not affect motor function, however female but not male MANF KO mice exhibited an increased locomotor activity in open field test. Learning and memory was not significantly impaired, but it was altered by MANF deficiency in females while it was affected by alcohol treatment in males. Both alcohol-exposed male and female MANF KO mice displayed increased sociability. Alcohol induced the expression of ER chaperones GRP78 and GRP94 and altered the levels of several unfolded protein response (UPR) and neuroinflammation markers in MANF KO mice in a sex-specific manner. The expression of MANF interacting proteins neuroplastin, PDIA1, and PDIA6 was increased in MANF KO mice, and was further induced by alcohol. In conclusion, alcohol exposure and neuronal MANF deficiency interacted to alter neurobehavioral outcomes, ER homeostasis and neuroinflammation in a sex-specific manner.
Details
- Title: Subtitle
- Sex-specific effects of alcohol on neurobehavioral performance and endoplasmic reticulum stress: an analysis using neuron-specific MANF deficient mice
- Creators
- Wen Wen - University of IowaHui Li - University of IowaMarisol Lauffer - University of Iowa, Psychological and Brain SciencesDi Hu - University of IowaZuohui Zhang - University of IowaHong Lin - University of IowaYongchao Wang - Vanderbilt University Medical CenterMariah Leidinger - University of IowaJia Luo - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Frontiers in pharmacology, Vol.15, 1407576
- Publisher
- FRONTIERS MEDIA SA
- DOI
- 10.3389/fphar.2024.1407576
- PMID
- 39130640
- PMCID
- PMC11310019
- ISSN
- 1663-9812
- eISSN
- 1663-9812
- Grant note
- National Institute on Alcohol Abuse and Alcoholism: AA017226, AA015407
We are grateful for the technical support, products, and/or services provided to our research by the Mouse Biology Program (MBP) at the University of California Davis. We thank the support of University of Iowa Neural Circuits and Behavior Core, Comparative Pathology Laboratory Research Core, and Central Microscopy core.DAS:The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.r The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Institute on Alcohol Abuse and Alcoholism (AA017226 and AA015407).
- Language
- English
- Date published
- 07/26/2024
- Academic Unit
- The University of Iowa Institute for Vision Research; Psychological and Brain Sciences; Pathology
- Record Identifier
- 9984691554102771
Metrics
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