Inflaming sex differences in mood disorders

Rainville, Jennifer R.; Hodes, Georgia E.

doi:10.1038/s41386-018-0124-7

Cited by 80 publications

(53 citation statements)

References 289 publications

(310 reference statements)

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“…Related to this point, chronic intoxication activated inflammatory signaling and cell death pathways in female but not male mice, and confirmation studies showed that ethanol dependent females exhibited significant neuronal degeneration in cortical regions, whereas cell death in males was significantly reduced ( Hashimoto and Wiren, 2008 ; Wilhelm et al, 2015 ). Finally, a broader implication of the current findings is pertinent to sex differences in the immune system and the relationship to mood disorders (reviewed in Rainville and Hodes, 2018 ). Taken in conjunction with sex differences in mood and anxiety disorders (e.g., Altemus et al, 2014 ), future studies examining potential immune or stress-related mechanisms that may contribute to stress and ethanol susceptibility and associated mood disorders will be important.…”

Section: Discussionmentioning

confidence: 93%

Binge Ethanol Drinking Produces Sexually Divergent and Distinct Changes in Nucleus Accumbens Signaling Cascades and Pathways in Adult C57BL/6J Mice

Finn¹,

Hashimoto²,

Cozzoli³

et al. 2018

Front. Genet.

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We previously determined that repeated binge ethanol drinking produced sex differences in the regulation of signaling downstream of Group 1 metabotropic glutamate receptors in the nucleus accumbens (NAc) of adult C57BL/6J mice. The purpose of the present study was to characterize RNA expression differences in the NAc of adult male and female C57BL/6J mice following 7 binge ethanol drinking sessions, when compared with controls consuming water. This binge drinking procedure produced high intakes (average >2.2 g/kg/30 min) and blood ethanol concentrations (average >1.3 mg/ml). Mice were euthanized at 24 h after the 7th binge session, and focused qPCR array analysis was employed on NAc tissue to quantify expression levels of 384 genes in a customized Mouse Mood Disorder array, with a focus on glutamatergic signaling (3 arrays/group). We identified significant regulation of 50 genes in male mice and 70 genes in female mice after 7 ethanol binges. Notably, 14 genes were regulated in both males and females, representing common targets to binge ethanol drinking. However, expression of 10 of these 14 genes was strongly dimorphic (e.g., opposite regulation for genes such as Crhr2, Fos, Nos1, and Star), and only 4 of the 14 genes were regulated in the same direction (Drd5, Grm4, Ranbp9, and Reln). Interestingly, the top 30 regulated genes by binge ethanol drinking for each sex differed markedly in the male and female mice, and this divergent neuroadaptive response in the NAc could result in dysregulation of distinct biological pathways between the sexes. Characterization of the expression differences with Ingenuity Pathway Analysis was used to identify Canonical Pathways, Upstream Regulators, and significant Biological Functions. Expression differences suggested that hormone signaling and immune function were altered by binge drinking in female mice, whereas neurotransmitter metabolism was a central target of binge ethanol drinking in male mice. Thus, these results indicate that the transcriptional response to repeated binge ethanol drinking was strongly influenced by sex, and they emphasize the importance of considering sex in the development of potential pharmacotherapeutic targets for the treatment of alcohol use disorder.

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Section: Discussionmentioning

confidence: 93%

Binge Ethanol Drinking Produces Sexually Divergent and Distinct Changes in Nucleus Accumbens Signaling Cascades and Pathways in Adult C57BL/6J Mice

Finn¹,

Hashimoto²,

Cozzoli³

et al. 2018

Front. Genet.

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“…Compared to males, female patients reported greater decrease in HRQL despite having a similar self-reported severity of the disease [15]. Although not yet fully understood, sex differences regarding mood disorders might be related not only to hormonal differences but also to diversities in the immune system [16]. Women show higher numbers of innate and adaptive immune cells and have a higher incidence of disorders associated with an increased immune response such as autoimmune diseases and allergies [17,18].…”

Section: Discussionmentioning

confidence: 99%

Sex Differences in Adults with Insect Venom Allergy regarding Psychological Distress, Attitudes toward the Emergency Medication, and Factual Knowledge about the Disease

Schoeben

Bubak

Schaarschmidt

et al. 2020

Int Arch Allergy Immunol

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Background: Hymenoptera venom allergy (HVA) has a prevalence of 3% in adults. Although patients have no ongoing symptoms, they often suffer from an impairment of their psychological well-being and quality of life. Objective: The aim of this study was to analyze sex-specific differences regarding the psychological burden caused by this allergy and handling of the emergency medication. Method: Study participants filled out a questionnaire including sociodemographic and disease-specific characteristics, the Hospital Anxiety and Depression Score (HADS), and theoretical knowledge about the emergency medication set (EMS). Additionally, an objective structured clinical examination was used to assess practical knowledge and handling of the EMS. Results: Fifty-six patients were included (55.4% females). Female patients showed higher subjective anxiety levels due to HVA compared to men (mean 7.2 vs. 4.6, p = 0.0003). Furthermore, the HADS revealed that women had a significant higher anxiety level, especially after Mueller grade I–II anaphylactic reactions (mean 6.3 vs. 2.8, p = 0.0134). This was associated with a higher theoretical but not practical knowledge about their disease. On the other hand, males were less inclined to carry the emergency medication “always” or “almost always” (56 vs. 87.1%, p = 0.0015) but showed higher self-assurance in using it (mean 7.3 vs. 6.1, p = 0.0446). Conclusions: This clinical study provides evidence for sex differences in coping with HVA. The results suggest that females should be monitored more closely for allergy-associated anxiety symptoms, while men need more encouragement to carry the emergency medication.

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“…These findings demonstrate striking sex differences in the persistent changes in basal gene expression after a subchronic immune challenge. (Importantly, this suggests that differential vulnerability to cognitive decline, memory impairments, and affective disorders (Himanen et al, 2006;Hogue et al, 2003;Lavoie et al, 2017;Léveillé et al, 2017;Liossi et al, 2009;Niemeier et al, 2007;Rainville and Hodes, 2018;Suarez et al, 2015) after illness or injury may be mediated by sex differences in the changes in gene expression and transcriptional regulation that persist long after immune challenge.…”

Section: Discussionmentioning

confidence: 99%

“…These sex-specific patterns of enduring changes in gene expression after subchronic immune challenge are consistent with strikingly different patterns of gene expression in the brain of males and females after stress or drugs of abuse (Hodes et al, 2015;Mychasiuk et al, 2016;Finn et al, 2018;Randesi et al, 2018), and further demonstrate that environmental insults have sex-specific implications for enduring changes in gene expression, neural function, and vulnerability to subsequent stressors. Such sex differences in transcriptional regulation may also provide new insights into differential vulnerability to cognitive decline, memory impairments, and affective disorders (Hogue et al, 2003;Liossi and Wood, 2014;Rainville and Hodes, 2019).…”

Section: Discussionmentioning

confidence: 99%

Enduring and sex-specific changes in hippocampal gene expression after a subchronic immune challenge

Tchessalova

Tronson

2019

Preprint

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Acknowledgements:We would like to acknowledge the University of Michigan Bioinformatics core for their expertise and data analysis of differentially expressed genes and the University of Michigan DNA sequencing core for their processing of samples. We would like to sincerely thank Dr. Shigeki Iwase and Christina Vallianatos for their advice, support, and assistance with prepping of the RNA samples. We would also very much like to thank them for allowing us to use their laboratory equipment for RNA extraction.We thank Ms. Brynne Raines, Ms. Melanie Gil, and Ms. Caitlin Posillico for their extensive feedback on this manuscript. ABSTRACTMajor illnesses, including major surgery, heart attack, and sepsis, can cause long-lasting cognitive impairments, depression, and progressive memory decline that persist well after recovery from the original illness. Similarly, in animal models, immune challenge results in impairments of learning and memory as well as increased depression-like behaviors. Although neuroimmune signaling is now well established as playing a crucial role in the modulation of neural functions, how transient immune signaling mediates enduring changes in cognition, memory, and emotion remains unknown. We have recently demonstrated that a series of intermittent injections of lipopolysaccharides over a two-week period resulted in sex-specific patterns of memory deficits that persist at least several months after the end of the immune challenge. Here, we examined the persistent changes in hippocampal gene expression three months after this subchronic systemic immune challenge in males and in females. We used RNA-sequencing as a large-scale, unbiased approach to identify both persistent changes in gene expression long after an immune challenge, and changes in transcriptional response to a subsequent immune challenge. Males and females differed in number and patterns of gene expression in the hippocampus. In males, we observed enduring dysregulation of gene expression three months after the end of a subchronic immune challenge, in the absence of an additional insult. In contrast, females showed few persistent changes under basal conditions, but striking dysregulation of gene expression in response to an additional acute LPS injection. Striking sex differences in the specific genes, pathways, and biological processes affected were observed both after subchronic immune challenge and after a subsequent insult. Thus, subchronic systemic immune activation has enduring and sex-specific consequences for gene expression and response to subsequent stimuli. Such persistent changes in neural functions further suggest that in both males and females, neuroimmune signaling during illness contributes to subsequent vulnerability or resilience to cognitive decline, memory impairments, and affective disorders.

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Inflaming sex differences in mood disorders

Cited by 80 publications

References 289 publications

Binge Ethanol Drinking Produces Sexually Divergent and Distinct Changes in Nucleus Accumbens Signaling Cascades and Pathways in Adult C57BL/6J Mice

Binge Ethanol Drinking Produces Sexually Divergent and Distinct Changes in Nucleus Accumbens Signaling Cascades and Pathways in Adult C57BL/6J Mice

Sex Differences in Adults with Insect Venom Allergy regarding Psychological Distress, Attitudes toward the Emergency Medication, and Factual Knowledge about the Disease

Enduring and sex-specific changes in hippocampal gene expression after a subchronic immune challenge

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