Uncovering microglial pathways driving sex-specific neurobiological effects in stress and depression
09 Aug 2021-Vol. 16, pp 100320-100320
TL;DR: In this article, a review examines the evidence for sex-specific microglia-neuron interactions in preclinical stress models and in patients with major depressive disorder (MDD).
Abstract: Women suffer from major depressive disorder (MDD) more often than men and report greater MDD symptom severity. Mounting evidence suggests that sex differences in MDD may be driven, in part, by sex-specific neurobiological mechanisms. Chronic stress is a significant risk factor in MDD, and preclinical rodent models show differential patterns of stress-induced neural remodeling and cognitive-behavioral dysfunction in males and females. For instance, chronic stress leads to synapse loss in the medial prefrontal cortex in male rodents yet has either no effect on- or increases-synapse number in females. Recent reports have implicated microglia, the immune cells of the brain, in MDD, and findings demonstrate sex-specific microglial signatures in both preclinical stress models and MDD patients. Given that microglia can remodel neural architecture, modulate synaptic transmission, and affect subsequent changes in behavior, it is plausible that microglial pathways contribute to differential stress effects on neuroplasticity and function in males and females. As such, this review examines the evidence for sex-specific microglia-neuron interactions in preclinical stress models and in patients with MDD. Discoveries highlighted herein demonstrate divergent microglial contributions in males and females and suggest that future studies investigating stress-linked disorders should be guided by sex-dependent neurobiological and behavioral findings. Examining these pathways represents a clear avenue toward both a richer understanding of brain, behavior, and immunity, and innovative psychoneuroimmunology-based applications in personalized medicine.
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TL;DR: In this article , the authors provide an overview of sex-specific immune, endocrine, vascular and transcriptional mediated changes that could affect neurovascular integrity and possibly contribute to the pathogenesis of mental disorders.
20 citations
TL;DR: It is proposed that sex differences in neuronal function and inflammatory signaling in circuits centered on the amygdala are involved in sex-dependent effects on stress-induced alcohol seeking and suggest that this is an important area for future studies.
10 citations
TL;DR: In this paper , a 50 µg/kg dose of dexamethasone (DEX) was administered to dams subcutaneously from gestational days 16 to 18 and a series of behavioral assessments were performed in the offspring.
Abstract: Fetal microglia that are particularly sensitive cells to the changes in utero environment might be involved in the sex-biased onset and vulnerability to psychiatric disorders. To address this issue, we administered a 50 µg/kg dexamethasone (DEX) to dams subcutaneously from gestational days 16 to 18 and a series of behavioral assessments were performed in the offspring. Prenatal exposure to dexamethasone (PN-DEX) induced schizophrenia (SCZ)-relevant behaviors in male mice and depressive-like behavior in female mice. SCZ-relevant behavioral patterns occurred in 10-week-old (10 W) male mice but not in 4-week-old (4 W) male mice. Microglia in the medial prefrontal cortex (mPFC) and the striatum (STR) of 10 W males prenatally treated with dexamethasone (10 W PN-DEX-M) showed hyper-ramified morphology and dramatically reduced spine density in mPFC. Immunofluorescence studies indicated that microglia in the mPFC of the 10 W PN-DEX-M group interacted with pre-synaptic Bassoon and post-synaptic density 95 (PSD95) puncta. PN-DEX-M also showed significantly changed dopamine system proteins. However, a testosterone surge during adolescence was not a trigger on SCZ-relevant behavior occurrence in 10 W PN-DEX-M. Furthermore, females prenatally treated with dexamethasone (PN-DEX-F) displayed depressive-like behavior, in addition to HPA-axis activation and inflammatory microglial phenotypes in their hippocampus (HPC). We propose that altered microglial function, such as increased synaptic pruning, may be involved in the occurrence of SCZ-relevant behavior in PN-DEX-M and sex-biased abnormal behavior in the PN-DEX model.
5 citations
TL;DR: In this article , the authors performed RNA-seq and ATAC-seq to study microglia-specific epigenomic changes in mice after 12 weeks of exposure to mild stress.
2 citations
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References
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TL;DR: Lifetime prevalence estimates are higher in recent cohorts than in earlier cohorts and have fairly stable intercohort differences across the life course that vary in substantively plausible ways among sociodemographic subgroups.
Abstract: Context Little is known about lifetime prevalence or age of onset of DSM-IV disorders. Objective To estimate lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the recently completed National Comorbidity Survey Replication. Design and Setting Nationally representative face-to-face household survey conducted between February 2001 and April 2003 using the fully structured World Health Organization World Mental Health Survey version of the Composite International Diagnostic Interview. Participants Nine thousand two hundred eighty-two English-speaking respondents aged 18 years and older. Main Outcome Measures Lifetime DSM-IV anxiety, mood, impulse-control, and substance use disorders. Results Lifetime prevalence estimates are as follows: anxiety disorders, 28.8%; mood disorders, 20.8%; impulse-control disorders, 24.8%; substance use disorders, 14.6%; any disorder, 46.4%. Median age of onset is much earlier for anxiety (11 years) and impulse-control (11 years) disorders than for substance use (20 years) and mood (30 years) disorders. Half of all lifetime cases start by age 14 years and three fourths by age 24 years. Later onsets are mostly of comorbid conditions, with estimated lifetime risk of any disorder at age 75 years (50.8%) only slightly higher than observed lifetime prevalence (46.4%). Lifetime prevalence estimates are higher in recent cohorts than in earlier cohorts and have fairly stable intercohort differences across the life course that vary in substantively plausible ways among sociodemographic subgroups. Conclusions About half of Americans will meet the criteria for a DSM-IV disorder sometime in their life, with first onset usually in childhood or adolescence. Interventions aimed at prevention or early treatment need to focus on youth.
17,213 citations
TL;DR: It is shown that microglia actively engulf synaptic material and play a major role in synaptic pruning during postnatal development in mice and this work suggests that deficits in microglian function may contribute to synaptic abnormalities seen in some neurodevelopmental disorders.
Abstract: Microglia are highly motile phagocytic cells that infiltrate and take up residence in the developing brain, where they are thought to provide a surveillance and scavenging function. However, although microglia have been shown to engulf and clear damaged cellular debris after brain insult, it remains less clear what role microglia play in the uninjured brain. Here, we show that microglia actively engulf synaptic material and play a major role in synaptic pruning during postnatal development in mice. These findings link microglia surveillance to synaptic maturation and suggest that deficits in microglia function may contribute to synaptic abnormalities seen in some neurodevelopmental disorders.
3,011 citations
TL;DR: It is shown that microglia engulf presynaptic inputs during peak retinogeniculate pruning and that engulfment is dependent upon neural activity and themicroglia-specific phagocytic signaling pathway, complement receptor 3(CR3)/C3.
2,864 citations
TL;DR: There are striking similarities across countries in patterns of major depression and of bipolar disorder and the differences in rates for major depression across countries suggest that cultural differences or different risk factors affect the expression of the disorder.
Abstract: Objective. —To estimate the rates and patterns of major depression and bipolar disorder based on cross-national epidemiologic surveys. Design and Setting. —Population-based epidemiologic studies using similar methods from 10 countries: the United States, Canada, Puerto Rico, France, West Germany, Italy, Lebanon, Taiwan, Korea, and New Zealand. Participants. —Approximately 38 000 community subjects. Outcome Measures. —Rates, demographics, and age at onset of major depression and bipolar disorder. Symptom profiles, comorbidity, and marital status with major depression. Results. —The lifetime rates for major depression vary widely across countries, ranging from 1.5 cases per 100 adults in the sample in Taiwan to 19.0 cases per 100 adults in Beirut. The annual rates ranged from 0.8 cases per 100 adults in Taiwan to 5.8 cases per 100 adults in New Zealand. The mean age at onset shows less variation (range, 24.8-34.8 years). In every country, the rates of major depression were higher for women than men. By contrast, the lifetime rates of bipolar disorder are more consistent across countries (0.3/100 in Taiwan to 1.5/100 in New Zealand); the sex ratios are nearly equal; and the age at first onset is earlier (average, 6 years) than the onset of major depression. Insomnia and loss of energy occurred in most persons with major depression at each site. Persons with major depression were also at increased risk for comorbidity with substance abuse and anxiety disorders at all sites. Persons who were separated or divorced had significantly higher rates of major depression than married persons in most of the countries, and the risk was somewhat greater for divorced or separated men than women in most countries. Conclusions. —There are striking similarities across countries in patterns of major depression and of bipolar disorder. The differences in rates for major depression across countries suggest that cultural differences or different risk factors may affect the expression of the disorder.
2,245 citations
TL;DR: It is found that microglia could be specifically depleted from the brain upon diphtheria toxin administration and removal of brain-derived neurotrophic factor (BDNF) frommicroglia largely recapitulated the effects of microglian depletion.
1,890 citations