Social stress contributes to the development of depressive and anxiety symptomatology and promotes pro-inflammatory signaling in the central nervous system. In this study, we explored the effects of a lipid messenger with anti-inflammatory properties - oleoylethanolamide (OEA) - on the behavioral deficits caused by social stress in both male and female mice.

Adult mice were assigned to an experimental group according to the stress condition (control or stress) and treatment (vehicle or OEA, 10 mg/kg, i.p.). Male mice in the stress condition underwent a protocol consisting of four social defeat (SD) encounters. In the case of female mice, we employed a procedure of vicarious SD. After the stress protocol resumed, anxiety, depressive-like behavior, social interaction, and prepulse inhibition (PPI) were assessed. In addition, we characterized the stress-induced inflammatory profile by measuring IL-6 and CX3CL1 levels in the striatum and hippocampus.

Our results showed that both SD and VSD induced behavioral alterations. We found that OEA treatment restored PPI deficits in socially defeated mice. Also, OEA affected differently stress-induced anxiety and depressive-like behavior in male and female mice. Biochemical analyses showed that both male and female stressed mice showed increased levels of IL-6 in the striatum compared to control mice. Similarly, VSD female mice exhibited increased striatal CX3CL1 levels. These neuroinflammation-associated signals were not affected by OEA treatment.

In summary, our results confirm that SD and VSD induced behavioral deficits together with inflammatory signaling in the striatum and hippocampus. We observed that OEA treatment reverses stress-induced PPI alterations in male and female mice. These data suggest that OEA can exert a buffering effect on stress-related sensorimotor gating behavioral processing.

Post-COVID syndrome has unveiled intricate connections between inflammation, depressive psychopathology, and cognitive impairment. This study investigates these relationships in 101 COVID-19 survivors, focusing on sex-specific variations. Utilizing path modelling techniques, we analyzed the interplay of a one-month 48-biomarker inflammatory panel, with three-months of depressive symptoms and cognitive performance. The findings indicate that cognitive impairment is influenced by both inflammation and depression in the overall cohort. However, prominent sex-specific differences emerged. In females, a lingering imbalance between pro- and anti-inflammatory responses-likely reflecting the long-lasting immune alterations triggered by COVID-19-significantly affects cognitive functioning and shows a marginal, though not statistically significant, association with depressive symptoms. This suggests that a mixed inflammatory profile may contribute to these outcomes. Conversely, in males, inflammation was inversely associated with depression severity, with protective effects from regulatory mediators (IL-2, IL-4, IL-6, IL-15, LIF, TNF-α, β-NGF) against depression. In males, cognitive impairment appeared to be driven mainly by depressive symptoms, with minimal influence from inflammatory markers. These results highlight distinct sex-specific pathways in immune and inflammatory responses post-COVID-19, potentially shaped by endocrine mechanisms. The findings suggest that persistent inflammation may foster long-term neuropsychiatric sequelae, possibly through its effects on the brain, and underscore the need for sex-tailored therapeutic strategies to address the lasting impact of COVID-19.

The influenza vaccine has reliably been associated with mild, within-person increases in inflammation. However, the field lacks rigorous experimental work comparing the effects of the influenza vaccine to a placebo control on changes in plasma inflammatory cytokines and self-reported sickness behavior. In a double-blind, randomized, placebo-controlled trial, 102 participants received either the influenza vaccine or saline placebo. Four cytokines were measured in plasma 24-hours following injection; participants also reported on psychosocial outcomes, specifically sickness behavior, positive/negative affect, sleep, and subjective social disconnection. All cytokines-IL-6, IL-10, TNF-α, IFN-γ-were significantly increased in the influenza vaccine condition compared to placebo. None of the psychosocial outcomes differed by condition. This study fills a gap in the literature by presenting critical causal evidence that the influenza vaccine leads to elevated levels of four inflammatory cytokines, compared to placebo control. However, a more robust increase in inflammation or a larger sample size may be necessary to observe differences in self-reported sickness behavior and other psychosocial outcomes.

Neuropsychiatric disorders that result from stress exposure are highly associated with central inflammation. Our previous work established that females selectively exhibit heightened proinflammatory cytokine production within the noradrenergic locus coeruleus (LC) along with a hypervigilant behavioral phenotype in response to witnessing social stress. Notably, ablation of microglia using pharmacological techniques prevents this behavioral response. These studies were designed to further investigate the impact of stress-induced neuroimmune signaling on the long-term behavioral and neuronal consequences of social stress exposure in females using chemogenetics. We first characterized the use of an AAV-CD68-Gi-DREADD virus targeted to microglia within the LC and confirmed viral transduction, selectivity, and efficacy. Clozapine-n-oxide (CNO) was used for the suppression of microglial reactivity during acute and chronic exposure to vicarious/witness social defeat in female rats. Chemogenetic-mediated inhibition of microglial reactivity during stress blunted the neuroimmune response to stress and prevented both acute and long-term hypervigilant behavioral responses. Further, a history of microglial suppression during stress prevented the heightened LC activity typically observed in response to stress cues. These studies are among the first to use a chemogenetic approach to inhibit central microglia in vivo and establish LC microglia as a key driver of the behavioral and neuronal responses to social stress in females.

Interpersonal connectedness is a central feature of human interaction that can be compromised during illness. Nonverbal signals play a crucial role in this context, and humans, like other animals, have evolved a behavioral immune system that enables individuals to detect subtle cues of sickness in others. Conversely, sick individuals often tend to avoid social interaction, a key component of sickness behavior. The coordination of body movements between two individuals (movement synchrony) is a measure of the quality of relationships that could provide insights into an interlocutor's sickness state. In the present study, we explored the effect of lipopolysaccharide (LPS) administration, a naturalistic stimulus for inflammation-induced sickness, on movement synchrony in healthy volunteers randomly assigned to a double-blind interview with a non-treated interviewer conducted 2.5 h after intravenous injection of either LPS (N = 26) or placebo (N = 25). Movement synchrony was assessed by automated video analysis of subject's and interviewer's head movements. Lagged cross-correlations were used to objectively quantify coordination in dyads and to assess patterns of temporal movement synchronization. Data analysis revealed that dyads with subjects under placebo displayed a pattern of movement coordination comparable to that seen in previous studies. However, dyads with subjects under LPS showed a loss of simultaneous movement (i.e. moving at the same time) with the interview partner, which is normally the temporal domain providing the highest level of synchrony. Together, the findings suggest that immediate social interaction is attenuated when one interlocutor is exposed to systemic inflammation, while the other is unaffected. This effect can be attributed to both sickness behavior on one hand and correlates of the behavioral immune system on the other hand.

Major depressive disorder, one of the most widespread mental illnesses, brings about enormous individual and socioeconomic consequences. Conventional monoaminergic antidepressants require weeks to months to produce a therapeutic response, and approximately one-third of the patients fail to respond to these drugs and are considered treatment-resistant. Although recent studies have demonstrated that ketamine, an N-methyl-D-aspartate receptor antagonist, produces rapid antidepressant effects in treatment-resistant patients, it also has undesirable side effects. Hence, rapid-acting antidepressants that have fewer adverse effects than ketamine are urgently required. D-series (RvD1-RvD6) and E-series (RvE1-RvE4) resolvins are endogenous lipid mediators derived from docosahexaenoic and eicosapentaenoic acids, respectively. These mediators reportedly play a pivotal role in the resolution of acute inflammation. In this review, we reveal that intracranial infusions of RvD1, RvD2, RvE1, RvE2, and RvE3 produce antidepressant-like effects in various rodent models of depression. Moreover, the behavioral effects of RvD1, RvD2, and RvE1 are mediated by the activation of the mechanistic target of rapamycin complex 1, which is essential for the antidepressant-like actions of ketamine. Finally, we briefly provide our perspective on the possible role of endogenous resolvins in stress resilience.

During pregnancy and the postpartum, there are dynamic fluctuations in steroid and peptide hormone levels as well as inflammatory signalling. These changes are required for a healthy pregnancy and can persist well beyond the postpartum. Many of the same hormone and inflammatory signalling changes observed during the perinatal period also play a role in symptoms related to autoimmune disorders, psychiatric disorders, and perhaps neurodegenerative disease later in life. In this review, we outline hormonal and immunological shifts linked to pregnancy and the postpartum and discuss the possible role of these shifts in increasing psychiatric, neurodegenerative disease risk and autoimmune symptoms during and following pregnancy. Furthermore, we discuss how key variables such as the number of births (parity) and sex of the fetus can influence inflammatory signalling, and possibly future disease risk, but are not often studied. We conclude by discussing the importance of studying female experiences such as pregnancy and parenting on physiology and disease.

Peripheral inflammatory markers, including serum interleukin 6 (IL-6), are associated with depression, but less is known about how these markers associate with depression at different stages of the life course.

We examined the associations between serum IL-6 levels at baseline and subsequent depression symptom trajectories in two longitudinal cohorts: ALSPAC (age 10-28 years; N = 4,835) and UK Biobank (39-86 years; N = 39,613) using multilevel growth curve modeling. Models were adjusted for sex, BMI, and socioeconomic factors. Depressive symptoms were measured using the Short Moods and Feelings Questionnaire in ALSPAC (max time points = 11) and the Patient Health Questionnaire-2 in UK Biobank (max time points = 8).

Higher baseline IL-6 was associated with worse depression symptom trajectories in both cohorts (largest effect size: 0.046 [ALSPAC, age 16 years]). These associations were stronger in the younger ALSPAC cohort, where additionally higher IL-6 levels at age 9 years was associated with worse depression symptoms trajectories in females compared to males. Weaker sex differences were observed in the older cohort, UK Biobank. However, statistically significant associations (pFDR <0.05) were of smaller effect sizes, typical of large cohort studies.

These findings suggest that systemic inflammation may influence the severity and course of depressive symptoms across the life course, which is apparent regardless of age and differences in measures and number of time points between these large, population-based cohorts.

Major Depressive Disorder (MDD) is a heterogeneous disorder that affects twice as many women than men. Precluding advances in more tailored and efficacious treatments for depression is the lack of reliable biomarkers. While depression is linked to elevations in inflammatory immune system functioning, this relationship is not evident among all individuals with depression and may vary based on symptom subtypes and/or sex. This systematic review and meta-analysis examined whether inflammatory immune peripheral markers of depression are sex-specific. PRISMA guidelines were followed for the systematic review, and a comprehensive search strategy that identified studies from PubMed and PsycInfo was applied. Studies were included if they reported C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor (TNF)-α and/or IL-1β for males and/or females among depressed and healthy adults. We identified 23 studies that satisfied these inclusion criteria. Random-effects meta-analysis models were fit, and measures of association were summarized between levels of circulating markers of inflammation in depressed and healthy males and females. Sex-based analyses revealed elevated levels of CRP among females with depression (Cohen's d = 0.19) relative to their healthy counterparts (p = 0.02), an effect not apparent among males (Cohen's d = -0.01). Similarly, levels of IL-6 were increased among females with depression compared to healthy controls (Cohen's d = 0.51; p = 0.04), but once again this was not found among males (Cohen's d = 0.16). While TNF-α levels were elevated among individuals with depression compared to controls (p = 0.01), no statistically significant sex differences were found. The meta-analysis for IL-1β resulted in only three articles, and thus, results are presented in the supplemental section. This meta-analysis advances our understanding of the unique involvement of inflammatory biomarkers in depression among men and women, which may help inform more tailored sex-specific treatment approaches in the future.

There is only sparse knowledge on the psychological burden of patients who have periprosthetic joint infections. The aim of our study was to assess the need for psychological support following total joint arthroplasty of the hip and knee. A special focus was set on patients who had aseptic and septic complications.

A total of 13,976 patients who underwent total hip (n = 6,926) or total knee arthroplasty (n = 7,050) between January 1, 2012 and December 31, 2019 at a single institution were retrospectively evaluated for the postoperative need for a psychological consultation. Data were collected on age, sex, type of surgery, and indications for revision procedures. The need for a psychological consultation was assessed during the daily postoperative visits, which were further coordinated by 2 institutional psychologists.

The average age was 68 years (range, 12 to 100), and there were 63.5% women. The overall rate of psychological consultations was 1.7%. Patients who had a septic indication for revision surgery had an 18.7-fold higher rate of postoperative psychological consultations compared to patients following primary surgery and a 5.4-fold higher rate compared to patients who had an aseptic indication. In detail, this rate was 1.0% in the primary subgroup, compared to 7.7% following revision arthroplasty (P < .001). In the revision subgroup, the rate was 17.9% for septic and 3.3% for aseptic revision arthroplasty cases (P < .001). Postoperative psychological consultations were twice as frequent in women (2.1%) compared to men (1.0%), P < .001.

The present study raises awareness of the markedly high psychological burden in revision arthroplasty cases, in the view of the high estimated number of unknown cases. There is a significant correlation between periprosthetic joint infectionsand the postoperative need for a psychological consultation, with women being at an even higher risk. Health care providers should aim at offering psychological support for patients who have a septic complication, with affected patients being at risk for psychological stress.

IV.

Sex differences in immune-based disorders are well-established, with female sex associated with a markedly heightened risk of autoimmune disease. Female sex is also overrepresented in other conditions associated with elevated inflammation, including depression, chronic pain, and chronic fatigue. The mechanisms underlying these disparities are unclear. This study used an experimental model of inflammatory challenge to interrogate molecular mechanisms that may contribute to female vulnerability to disorders with an inflammatory basis.

In this analysis of a secondary outcome from a randomized controlled trial, 111 participants (67 female) received either a bolus injection of endotoxin (n = 59) or placebo (n = 52). Participants provided blood samples before and 0.5 h post-injection for assessment of differential activation of key pro-inflammatory (i.e., activator protein (AP)-1; nuclear factor (NF)-κB) and immunoregulatory (i.e., glucocorticoid receptor (GR); cAMP response element binding protein (CREB)) signaling pathways via genome-wide expression profiling and promoter-based bioinformatics analyses.

Relative to males, females exhibited greater endotoxin-induced increases in bioinformatic measures of CREB transcription factor activity (p's < 0.01). However, contrary to hypotheses, female vs. male sex was not associated with greater increases in activation of NF-κB, AP-1, or GR in response to endotoxin vs. placebo administration.

This work suggests CREB signaling as a critical upstream biological pathway that should be further interrogated as a mechanism of female vulnerability to immune-related disorders. Future work should clarify whether increased CREB signaling indicates sex differences in activity of the sympathetic nervous system or other physiological pathways that signal through CREB, such as prostaglandin release.

Previous studies have reported the correlation of dysregulated blood cell indices and peripheral inflammatory markers with depression in adults but limited studies have examined this correlation in early adolescents.

This study used data from the Chinese Early Adolescents Cohort Study, which was conducted in Anhui, China. Students' depression symptoms were repeatedly measured using the Chinese version of the Center for Epidemiological Studies Depression Scale for Children. Students' blood samples were collected in September 2019 and September 2021. The peripheral blood cell counts and inflammatory marker levels were determined using routine blood tests. Multivariable regression models were used to explore the associations between blood cell indices and adolescent depressive symptoms in both the whole sample and the sex-stratified samples.

The white blood cell (WBC) count, neutrophil count (NC), platelet (PLT) count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, and systemic immune inflammation index (SII) were positively correlated with the severity of depressive symptoms during follow-up. The mean corpuscular volume (MCV), mean hemoglobin (HGB) volume (MCH), and mean corpuscular HGB concentration (MCHC) exhibited negative temporal correlations with depressive symptoms. Additionally, several sex-specific blood cell markers were correlated with depression. Male adolescents with increased red blood cell (RBC) and female adolescents with decreased HGB levels and upregulated WBC, NC, NLR, and SII levels exhibited severe depressive symptoms at follow-up.

These findings suggested the potential usefulness of peripheral blood cell indices in the assessment of depression in early adolescents.

Neuropsychiatric disorders that result from stress exposure are highly associated with central inflammation. Our previous work established that females selectively exhibit heightened proinflammatory cytokine production within the noradrenergic locus coeruleus (LC) along with a hypervigilant behavioral phenotype in response to witnessing social stress, and ablation of microglia using pharmacological techniques prevents this behavioral response. These studies were designed to further investigate the impact of stress-induced neuroimmune signaling on the long-term behavioral and neuronal consequences of social stress exposure in females using chemogenetics. We first characterized the use of an AAV-CD68-Gi-DREADD virus targeted to microglia within the LC and confirmed viral transduction, selectivity, and efficacy. Clozapine-n-oxide (CNO) was used for the suppression of microglial reactivity during acute and chronic exposure to vicarious/witness social defeat in female rats. Chemogenetic-mediated inhibition of microglial reactivity during stress blunted the neuroimmune response to stress and prevented both acute and long-term hypervigilant behavioral responses. Further, a history of microglial suppression during stress prevented the heightened LC activity typically observed in response to stress cues. These studies are among the first to use a chemogenetic approach to inhibit microglia within the female brain in vivo and establish LC inflammation as a key mechanism underlying the behavioral and neuronal responses to social stress in females.

Exposure to adversity early in life (ELA) has been associated with elevated risk for depression during adolescence, particularly for females; the mechanisms underlying this association, however, are poorly understood. One potential mechanism linking ELA and sex differences in depressive symptoms is sleep disturbances, which increase during adolescence and are more common in females. Here, we examined whether sleep disturbances mediate the association between ELA and increases in depressive symptoms during adolescence and whether this mediation differs by sex.

224 (N = 132 females) youth were recruited at age 9-13 years and assessed every 2 years across three timepoints. At the first timepoint, we conducted extensive interviews about stressful events participants experienced; participants provided subjective severity ratings of events and we objectively scored the severity of each event. Self-reported sleep disturbances and depressive symptoms were assessed at all timepoints. We conducted linear mixed models to estimate both initial levels and changes in sleep disturbances and depressive symptoms, and moderated mediation analyses to test whether initial levels and/or changes in sleep disturbances mediated the association of ELA (objective and subjective) with increases in depressive symptoms across adolescence and whether the mediations differed by sex.

While higher initial levels and increases in sleep problems were uniquely associated with increases in depressive symptoms for males and females, they were related to ELA differently by sex. For females, greater ELA (both objectively and subjectively rated) was associated with higher initial levels of sleep problems, which in turn were associated with increases in depressive symptoms from early to late adolescence. In contrast, for males, ELA exposure was not associated with either initial levels of, or increases in, sleep problems.

These findings highlight the role of sleep disturbances during the transition to adolescence in mediating sex differences in the effects of ELA on depressive symptoms.

The study aimed to investigate whether an exercise-induced pro-inflammatory response alters the perception as well as visual exploration of emotional body language in social interactions.

In a within-subject design, 19 male, healthy adults aged between 19 and 33 years performed a downhill run for 45 min at 70% of their VO2max on a treadmill to induce maximal myokine blood elevations, leading to a pro-inflammatory status. Two control conditions were selected: a control run with no decline and a rest condition without physical exercise. Blood samples were taken before (T0), directly after (T1), 3 h after (T3), and 24 h after (T24) each exercise for analyzing the inflammatory response. 3 h after exercise, participants observed point-light displays (PLDs) of human interactions portraying four emotions (happiness, affection, sadness, and anger). Participants categorized the emotional content, assessed the emotional intensity of the stimuli, and indicated their confidence in their ratings. Eye movements during the entire paradigm and self-reported current mood were also recorded.

The downhill exercise condition resulted in significant elevations of measured cytokines (IL6, CRP, MCP-1) and markers for muscle damage (Myoglobin) compared to the control running condition, indicating a pro-inflammatory state after the downhill run. Emotion recognition rates decreased significantly after the downhill run, whereas no such effect was observed after control running. Participants' sensitivity to emotion-specific cues also declined. However, the downhill run had no effect on the perceived emotional intensity or the subjective confidence in the given ratings. Visual scanning behavior was affected after the downhill run, with participants fixating more on sad stimuli, in contrast to the control conditions, where participants exhibited more fixations while observing happy stimuli.

Our study demonstrates that inflammation, induced through a downhill running model, impairs perception and emotional recognition abilities. Specifically, inflammation leads to decreased recognition rates of emotional content of social interactions, attributable to diminished discrimination capabilities across all emotional categories. Additionally, we observed alterations in visual exploration behavior. This confirms that inflammation significantly affects an individual's responsiveness to social and affective stimuli.

Administration of low-dose lipopolysaccharide (LPS) to healthy humans is a translational approach to analyze the effects of acute systemic inflammation and sickness behavior. Although studies documented that LPS-induced inflammation can alter social behavior, its impact on empathy remains poorly understood. In this double-blind, placebo-controlled study, 52 healthy female volunteers received an intravenous injection of either LPS (0.4 ng/kg body weight) or placebo and completed the Social Interaction Empathy Task (SIET) two hours after injection. Physiological responses (blood pressure, heart rate, body temperature, cytokines, cortisol) were analyzed along with sickness symptoms and mood before and after LPS or placebo administration. LPS application led to significant increases in plasma cytokines and sickness symptoms as well as low mood. Moreover, volunteers receiving LPS showed significantly less empathy for other's psychological pain than those who received placebo. Furthermore, LPS-injected volunteers with more severe sickness symptoms displayed higher pain ratings in the first-person perspective. Thus, low-grade inflammation reduces empathy for other's psychological pain which might reflect an adaptive strategy to save energy by not responding empathetically when sick oneself.

Recent evidence has documented associations between higher levels of inflammation and social approach behaviors toward close others in laboratory-based tasks. Yet it is unknown if this translates to interactions with close others in daily life. Given that momentary experiences of social connection have both relational and health consequences, this is a critical gap in our knowledge. To address the association between inflammation and momentary social connection experiences in close relationships, 55 participants provided blood samples on two consecutive days, which were assayed for circulating levels of the inflammatory marker interleukin-6 (IL-6). After providing the first blood sample, participants received the annual influenza vaccine as a mild inflammatory challenge. Participants also reported on cognitive, affective, and behavioral indicators of social connection with a specific close other multiple times across the two study days. Results indicated that levels of IL-6 were positively associated with temporally-proximal indicators of momentary social connection with a close other. Specifically, higher levels of IL-6 were associated with greater feelings of comfort from the close other, greater desire to be near them, and higher reported relationship quality. Greater IL-6 reactivity to the vaccine was only associated with increased reported relationship quality. These data add to the existing literature suggesting that higher levels of IL-6 may motivate social approach toward a close other, extending evidence to now include momentary social connection experiences in daily life.

Studies have revealed the effects of childhood adversity, anxiety, and negative coping on sleep quality in older adults, but few studies have focused on the association between childhood adversity and sleep quality in rural older adults and the potential mechanisms of this influence. In this study, we aim to evaluate sleep quality in rural older adults, analyze the impact of adverse early experiences on their sleep quality, and explore whether anxiety and negative coping mediate this relationship.

Data were derived from a large cross-sectional study conducted in Deyang City, China, which recruited 6,318 people aged 65 years and older. After excluding non-agricultural household registration and lack of key information, a total of 3,873 rural older adults were included in the analysis. Structural equation modelling (SEM) was used to analyze the relationship between childhood adversity and sleep quality, and the mediating role of anxiety and negative coping.

Approximately 48.15% of rural older adults had poor sleep quality, and older adults who were women, less educated, widowed, or living alone or had chronic illnesses had poorer sleep quality. Through structural equation model fitting, the total effect value of childhood adversity on sleep quality was 0.208 (95% CI: 0.146, 0.270), with a direct effect value of 0.066 (95% CI: 0.006, 0.130), accounting for 31.73% of the total effect; the total indirect effect value was 0.142 (95% CI: 0.119, 0.170), accounting for 68.27% of the total effect. The mediating effects of childhood adversity on sleep quality through anxiety and negative coping were significant, with effect values of 0.096 (95% CI: 0.078, 0.119) and 0.024 (95% CI: 0.014, 0.037), respectively. The chain mediating effect of anxiety and negative coping between childhood adversity and sleep quality was also significant, with an effect value of 0.022 (95% CI: 0.017, 0.028).

Anxiety and negative coping were important mediating factors for rural older adult's childhood adversity and sleep quality. This suggests that managing anxiety and negative coping in older adults may mitigate the negative effects of childhood adversity on sleep quality.

Although females are at relatively greater risk for a variety of disorders, including depression, the biological mechanisms underlying this striking health disparity remain unclear. To address this issue, we highlight sex differences in stress susceptibility as a key mechanism potentially driving this effect and describe the interacting inflammatory, hormonal, epigenomic, and social-environmental mechanisms involved.

Using the Social Signal Transduction Theory of Depression as a theoretical framework, women's elevated risk for depression may stem from a tight link between life stress, inflammation, and depression in women. Further, research finds hormonal contraceptive use alters cortisol and inflammatory reactivity to acute stress in ways that may increase depression risk in females. Finally, beyond established epigenetic mechanisms, mothers may transfer risk for depression to their female offspring through stressful family environments, which influence stress generation and stress-related gene expression. Together, these findings provide initial, biologically plausible clues that may help explain the relatively greater risk for depression in females vs. males. Looking forward, much more research is needed to address the longstanding underrepresentation of females in biomedical research on the biology of stress and depression.

Chronic rhinosinusitis (CRS) is a persistent inflammation of the sinuses. As a result of long-term discomfort, patients may experience symptoms of common mental disorders such as anxiety and depression. This may affect the quality of life and disease progression. However, there is still uncertainty about the extent of the problem.

This meta-analysis aimed to determine the prevalence of depression and anxiety symptoms in patients with CRS.

We searched PubMed, Embase, Web of Science, Cochrane Library, and CBM databases for relevant studies published before 15 July 2022 in patients with CRS with concomitant depression and anxiety symptoms.

Two authors independently performed screening and quality assessment using validated tools. Extraction of data using predefined standardised data collection spreadsheets. Heterogeneity and inconsistency were checked using the I² statistic.

The meta-analysis included 32 articles involving 56 933 patients. The prevalence of depression and anxiety symptoms was estimated at 24.7% (95% CI, 21.3% to 28. 1%) and 29.7% (95% CI, 19.3% to 40.2%). Subgroup analysis revealed the following: (1) CRS without nasal polyps (CRSsNP): 26.2% (95% CI, 21.9% to 30.5%), CRS with nasal polyps(CRSwNP): 20% (95% CI, 15.9% to 24%); (2) Female patients: 36. 1% (95% CI, 25.3% to 46.9%), male patients: 24.3% (95% CI, 12. 1% to 36.6%); and (3) The average age≤50 years patients: 29.8% (95% CI, 21.3% to 38.2%), the average age>50 years patients: 22. 1% (95% CI, 17.1% to 27%).

A significant proportion of people with CRS have symptoms of depression and anxiety, and early screening for depression and anxiety in people with CRS is critical. And, more attention needs to be given to females and patients with CRSsNP during screening.

CRD42022345959).

Immune dysregulation has been widely observed in patients with psychiatric disorders. This study aims to examine the association between HLA alleles and depression and anxiety. Using data from the UK Biobank, we performed regression analyses to assess the association of 359 HLA alleles with depression and anxiety, as determined by Patient Health Questionnaire (PHQ) score (n = 120,033), self-reported depression (n = 121,685), general anxiety disorder (GAD-7) score (n = 120,590), and self-reported anxiety (n = 108,310). Subsequently, we conducted gene environmental interaction study (GEIS) to evaluate the potential effects of interactions between HLA alleles and environmental factors on the risk of depression and anxiety. Sex stratification was implemented in all analysis. Our study identified two significant HLA alleles associated with self-reported depression, including HLA-C*07:01 (β = -0.015, p = 5.54 × 10-5 ) and HLA-B*08:01 (β = -0.015, p = 7.78 × 10-5 ). Additionally, we identified four significant HLA alleles associated with anxiety score, such as HLA-DRB1*07:01 (β = 0.084, p = 9.28 × 10-5 ) and HLA-B*57:01 (β = 0.139, p = 1.22 × 10-4 ). GEIS revealed that certain HLA alleles interacted with environmental factors to influence mental health outcomes. For instance, HLA-A*02:07 × cigarette smoking was associated with depression score (β = 0.976, p = 1.88 × 10-6 ). Moreover, sex stratification analysis revealed significant sex-based differences in the interaction effects of certain HLA alleles with environmental factors. Our findings indicate the considerable impact of HLA alleles on the risks of depression and anxiety, providing valuable insights into the functional relevance of immune dysfunction in these conditions.

Dementia caregiving has been linked to multiple health risks, including infectious illness, depression, anxiety, immune dysregulation, weakened vaccine responses, slow wound healing, hypertension, cardiovascular disease, metabolic syndrome, diabetes, frailty, cognitive decline, and reduced structural and functional integrity of the brain. The sustained overproduction of proinflammatory cytokines is a key pathway behind many of these risks. However, contrasting findings suggest that some forms of caregiving may have beneficial effects, such as maintaining caregivers' health and providing a sense of meaning and purpose which, in turn, may contribute to lower rates of functional decline and mortality. The current review synthesizes these disparate literatures, identifies methodological sources of discrepancy, and integrates caregiver research with work on aging biomarkers to propose a research agenda that traces the mechanistic pathways of caregivers' health trajectories with a focus on the unique stressors facing spousal caregivers as compared to other informal caregivers. Combined with a focus on psychosocial moderators and mechanisms, studies using state-of-the-art molecular aging biomarkers such as telomere length, p16INK4a, and epigenetic age could help to reconcile mixed literature on caregiving's sequelae by determining whether and under what conditions caregiving-related experiences contribute to faster aging, in part through inflammatory biology. The biomarkers predict morbidity and mortality, and each contributes non-redundant information about age-related molecular changes -together painting a more complete picture of biological aging. Indeed, assessing changes in these biopsychosocial mechanisms over time would help to clarify the dynamic relationships between caregiving experiences, psychological states, immune function, and aging.

Patients characterized by stress-related disorders such as depression display elevated circulating concentrations of pro-inflammatory cytokines and a hyperactive HPA axis. Psychedelics are demonstrating promising results in treatment of such disorders, however the mechanisms of their therapeutic effects are still unknown. To date the evidence of acute and persisting effects of psychedelics on immune functioning, HPA axis activity in response to stress, and associated psychological outcomes is preliminary. To address this, we conducted a placebo-controlled, parallel group design comprising of 60 healthy participants who received either placebo (n = 30) or 0.17 mg/kg psilocybin (n = 30). Blood samples were taken to assess acute and persisting (7 day) changes in immune status. Seven days' post-administration, participants in each treatment group were further subdivided: 15 underwent a stress induction protocol, and 15 underwent a control protocol. Ultra-high field (7-Tesla) magnetic resonance spectroscopy was used to assess whether acute changes in glutamate or glial activity were associated with changes in immune functioning. Finally, questionnaires assessed persisting self-report changes in mood and social behavior. Psilocybin immediately reduced concentrations of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α), while other inflammatory markers (interleukin (IL)- 1β, IL-6, and C-reactive protein (CRP)) remained unchanged. Seven days later, TNF-α concentrations returned to baseline, while IL-6 and CRP concentrations were persistently reduced in the psilocybin group. Changes in the immune profile were related to acute neurometabolic activity as acute reductions in TNF-α were linked to lower concentrations of glutamate in the hippocampus. Additionally, the more of a reduction in IL-6 and CRP seven days after psilocybin, the more persisting positive mood and social effects participants reported. Regarding the stress response, after a psychosocial stressor, psilocybin did not significantly alter the stress response. Results are discussed in regards to the psychological and therapeutic effects of psilocybin demonstrated in ongoing patient trials.

Psychoneuroimmunology and immunopsychiatry are quickly approaching a critical point where the clinical translatability of their evidence base will be tested. To maximize chances for translational success, we believe researchers must adopt causal inference techniques that augment the causal relevance of estimates given theorized causal structures. To illustrate the utility of incorporating causal inference perspectives into psychoneuroimmunology, we applied directed acyclic graphs and a combination of empirical and simulated data to demonstrate the consequences of controlling for adiposity when testing the association between inflammation and depression under the plausible causal structure of increases in adipose tissue leading to greater inflammation that in turn promotes depression. Effect size estimates were pulled from a dataset combining the Midlife in the United States 2 (MIDUS-2) and MIDUS Refresher datasets. Data were extracted and used to simulate data reflecting an adiposity → inflammation → depression causal structure. Next, a Monte Carlo simulation study with 1,000 iterations and three sample size scenarios (Ns = 100, 250, and 500) was conducted testing whether controlling for adiposity when estimating the relation between inflammation and depression influenced the precision of this estimate. Across all simulation scenarios, controlling for adiposity reduced precision of the inflammation → depression estimate, suggesting that researchers primarily interested in quantifying inflammation → depression associations should not control for adiposity. This work thus underscores the importance of incorporating causal inference approaches into psychoneuroimmunological research.

Anhedonia, as evidenced by impaired pleasurable response to reward, reduced reward motivation, and/or deficits in reward-related learning, is a common feature of depression. Such deficits in reward processing are also an important clinical target as a risk factor for depression onset. Unfortunately, reward-related deficits remain difficult to treat. To address this gap and inform the development of effective prevention and treatment strategies, it is critical to understand the mechanisms that drive impairments in reward function. Stress-induced inflammation is a plausible mechanism of reward deficits. The purpose of this paper is to review evidence for two components of this psychobiological pathway: 1) the effects of stress on reward function; and 2) the effects of inflammation on reward function. Within these two areas, we draw upon preclinical and clinical models, distinguish between acute and chronic effects of stress and inflammation, and address specific domains of reward dysregulation. By addressing these contextual factors, the review reveals a nuanced literature which might be targeted for additional scientific inquiry to inform the development of precise interventions.

Forced displacement and war trauma cause high rates of post-traumatic stress, anxiety disorders and depression in refugee populations. We investigated the impact of forced displacement on mental health status, gender, presentation of type 2 diabetes (T2D) and associated inflammatory markers among Syrian refugees in Lebanon.

Mental health status was assessed using the Harvard Trauma Questionnaire (HTQ) and the Hopkins Symptom Checklist-25 (HSCL-25). Additional metabolic and inflammatory markers were analyzed.

Although symptomatic stress scores were observed in both men and women, women consistently displayed higher symptomatic anxiety/depression scores with the HSCL-25 (2.13 ± 0.58 versus 1.95 ± 0.63). With the HTQ, however, only women aged 35-55 years displayed symptomatic post-traumatic stress disorder (PTSD) scores (2.18 ± 0.43). Furthermore, a significantly higher prevalence of obesity, prediabetes and undiagnosed T2D were observed in women participants (23.43, 14.91 and 15.18%, respectively). Significantly high levels of the inflammatory marker serum amyloid A were observed in women (11.90 ± 11.27 versus 9.28 ± 6.93, P = 0.036).

Symptomatic PTSD, anxiety/depression coupled with higher levels of inflammatory marker and T2D were found in refugee women aged between 35 and 55 years favoring the strong need for psychosocial therapeutic interventions in moderating stress-related immune dysfunction and development of diabetes in this subset of female Syrian refugees.

Studies in human and experimental animal models support a role of inflammation in the aetiology of depression, yet the precise role played by sleep disturbance (i.e., difficulties falling or maintaining sleep) is poorly understood. Consistent evidence from prospective epidemiological studies suggests sleep disturbance as a predictor of major depression episodes and depression recurrence. In parallel, up to 20% of individuals with sleep disturbance have low-grade peripheral inflammation (i.e., CRP>3 mg/l), and preliminary longitudinal evidence showed that sleep disturbance may even predict the levels of inflammation. Therefore, it is possible that sleep disturbance may increase inflammation, which in turn may contribute (i.e., mediate) to the onset - or worsening - of depression. Alternatively, sleep disturbance may serve as a vulnerability factor and increase the risk of developing depressive symptoms when facing an immune challenge. The aim of this review was to summarise the state of the science on the role of sleep disturbance in contributing to depression-related inflammation. A research agenda is also proposed to advance the study of sleep disturbance in the psychoneuroimmunology of depression.

Major depressive disorder represents a serious public health challenge worldwide; however, the underlying cellular and molecular mechanisms are mostly unknown. Here, we profile the dorsolateral prefrontal cortex of female cynomolgus macaques with social stress-associated depressive-like behaviors using single-nucleus RNA-sequencing and spatial transcriptomics. We find gene expression changes associated with depressive-like behaviors mostly in microglia, and we report a pro-inflammatory microglia subpopulation enriched in the depressive-like condition. Single-nucleus RNA-sequencing data result in the identification of six enriched gene modules associated with depressive-like behaviors, and these modules are further resolved by spatial transcriptomics. Gene modules associated with huddle and sit alone behaviors are expressed in neurons and oligodendrocytes of the superficial cortical layer, while gene modules associated with locomotion and amicable behaviors are enriched in microglia and astrocytes in mid-to-deep cortical layers. The depressive-like behavior associated microglia subpopulation is enriched in deep cortical layers. In summary, our findings show cell-type and cortical layer-specific gene expression changes and identify one microglia subpopulation associated with depressive-like behaviors in female non-human primates.

Glutamate and increased inflammation have been separately implicated in the pathophysiology of schizophrenia and the extent of clinical response to antipsychotic treatment. Despite the mechanistic links between pro-inflammatory and glutamatergic pathways, the relationships between peripheral inflammatory markers and brain glutamate in schizophrenia have not yet been investigated. In this study, we tested the hypothesis that peripheral levels of pro-inflammatory cytokines would be positively associated with brain glutamate levels in schizophrenia. Secondary analyses determined whether this relationship differed according to antipsychotic treatment response. The sample consisted of 79 patients with schizophrenia, of whom 40 were rated as antipsychotic responders and 39 as antipsychotic non-responders. Brain glutamate levels were assessed in the anterior cingulate cortex (ACC) and caudate using proton magnetic resonance spectroscopy (1H-MRS) and blood samples were collected for cytokine assay on the same study visit (IL-6, IL-8, IL-10, TNF- α and IFN-γ). Across the whole patient sample, there was a positive relationship between interferon-gamma (IFN-γ) and caudate glutamate levels (r = 0.31, p = 0.02). In the antipsychotic non-responsive group only, there was a positive relationship between interleukin-8 (IL-8) and caudate glutamate (r = 0.46, p = 0.01). These findings provide evidence to link specific peripheral inflammatory markers and caudate glutamate in schizophrenia and may suggest that this relationship is most marked in patients who show a poor response to antipsychotic treatment.

Drawing on recent evidence that inflammation may promote social affiliative motivation, the present research proposes a novel perspective that inflammation may be associated with more social media use. In a cross-sectional analysis of a nationally representative sample, Study 1 (N = 863) found a positive association between C-reactive protein (CRP), a biomarker of systemic inflammation, and the amount of social media use by middle-aged adults. Study 2 (N = 228) showed that among college students CRP was prospectively associated with more social media use 6 weeks later. Providing stronger evidence of the directionality of this effect, Study 3 (N = 171) showed that in college students CRP predicted increased social media use in the subsequent week even after controlling for current week's use. Additionally, in exploratory analyses of CRP and different types of social media use in the same week, CRP was only associated with using social media for social interaction and not for other purposes (e.g., entertainment). The present research sheds light on the social effects of inflammation and highlights potential benefits of using social media as a context for studying the impact of inflammation on social motivation and behavior.

Efforts to improve treatment for adults with major depression (MD) and childhood maltreatment (CM) have identified inflammation as a potential target to improve health. Network models have emerged as a new way to understand the relationship between depressive symptoms and inflammation. However, none have accounted for the role of childhood maltreatment in the link between depressive symptoms and inflammation, or sex differences commonly found in these constructs.

Data from two waves of the Midlife Development in the United States study were used in this study (N = 1917). The Center for Epidemiological Studies Depression (CES-D) scale and Childhood Trauma Questionnaire, and six inflammation markers served as nodes in an undirected psychometric network analysis. Edges between nodes were calculated using partial Spearman's correlation. Separate networks were modeled for males and females.

The total network revealed several associations between nodes of CM, MD, and inflammation, with emotional abuse having a strong association with somatic complaints. Network comparison testing revealed male-female network invariance, with several edge differences between male and female networks. Males and females showed differences in associations across inflammatory markers and depressive symptom clusters, particularly among somatic complaints and interpersonal difficulties.

Specific associations between dimensions of inflammation, CM, and MD may represent important targets for treatment. Network models disaggregated by sex showed that males and females may have fundamentally different associations between these constructs, suggesting that future studies should consider sex-specific interventions.

Women are at increased risk for psychosocial stress-related anxiety disorders, yet mechanisms regulating this risk are unknown. Psychosocial stressors activate microglia, and the resulting neuroimmune responses that females exhibit heightened sensitivity to may serve as an etiological factor in their elevated risk. However, studies examining the role of microglia during stress in females are lacking.

Microglia were manipulated in the stress-sensitive locus coeruleus (LC) of female rats in the context of social stress in two ways. First, intra-LC lipopolysaccharide (LPS; 0 or 3 μg/side, n = 5-6/group), a potent TLR4 agonist and microglial activator, was administered. One hour later, rats were exposed to control or an aggressive social defeat encounter between two males (WS, 15-min). In a separate study, females were treated with intra-LC or intra-central amygdala mannosylated liposomes containing clodronate (m-CLD; 0 or 25 μg/side, n = 13-14/group), a compound toxic to microglia. WS-evoked burying, cardiovascular responses, and sucrose preference were measured. Brain and plasma cytokines were quantified, and cardiovascular telemetry assessed autonomic balance.

Intra-LC LPS augmented the WS-induced burying response and increased plasma corticosterone and interleukin-1β (IL-1β). Further, the efficacy and selectivity of microinjected m-CLD was fully characterized. In the context of WS, intra-LC m-CLD attenuated the hypervigilant burying response during WS as well as the accumulation of intra-LC IL-1β. Intra-central amygdala m-CLD had no effect on WS-evoked behavior.

These studies highlight an innovative method for depleting microglia in a brain region specific manner and indicate that microglia in the LC differentially regulate hypervigilant WS-evoked behavioral and autonomic responses.

Depression, one of the most common diseases in older adults, carries significant risk for morbidity and mortality. Because of the burgeoning population of older adults, the enormous burden of late-life depression, and the limited efficacy of current antidepressants in older adults, biologically plausible models that translate into selective depression prevention strategies are needed. Insomnia predicts depression recurrence and is a modifiable target to prevent incident and recurrent depression in older adults. Yet, it is not known how insomnia gets converted into biological- and affective risk for depression, which is critical for identification of molecular targets for pharmacologic interventions, and for refinement of insomnia treatments that target affective responding to improve efficacy. Sleep disturbance activates inflammatory signaling and primes immune responses to subsequent inflammatory challenge. In turn, inflammatory challenge induces depressive symptoms, which correlate with activation of brain regions implicated in depression. This study hypothesizes that insomnia serves as a vulnerability factor for inflammation-related depression; older adults with insomnia will show heightened inflammatory- and affective responding to inflammatory challenge as compared to those without insomnia. To test this hypothesis, this protocol paper describes a placebo-controlled, randomized, double-blind study of low dose endotoxin in older adults (n = 160; 60-80 y) with insomnia vs. comparison controls without insomnia. The aims of this study are to examine differences in depressive symptoms, measures of negative affective responding, and measures of positive affective responding as a function of insomnia and inflammatory challenge. If the hypotheses are confirmed, older adults with two "hits", insomnia and inflammatory activation, would represent a high risk group to be prioritized for monitoring and for depression prevention efforts using treatments that target insomnia or inflammation. Moreover, this study will inform the development of mechanism-based treatments that target affect responses in addition to sleep behaviors, and which might also be coupled with efforts to reduce inflammation to optimize efficacy of depression prevention.

Depression is a heterogenous disorder with symptoms that present differently across individuals. In a subset of people depression is associated with alterations of the immune system that may contribute to disorder onset and symptomology. Women are twice as likely to develop depression and on average have a more sensitive adaptive and innate immune system when compared to men. Sex differences in pattern recognition receptors (PRRs), release of damage-associated molecular patterns (DAMPs), cell populations, and circulating cytokines play a critical role in inflammation onset. Sex differences in innate and adaptive immunity change the response of and repair to damage caused by dangerous pathogens or molecules in the body. This article reviews the evidence for sex specific immune responses that contribute to the sex differences in symptoms of depression that may account for the higher rate of depression in women.

The aim of this work was to summarize relationships between two subtypes of major depressive disorder (melancholic and atypical) and four core features of depression that reflect the domains identified consistently in previous studies of major depressive disorder endophenotypes (exaggerated reactivity to negative information, altered reward processing, cognitive control deficits, and somatic symptoms) on the one hand and selected peripheral inflammatory markers (C-reactive protein [CRP], cytokines, and adipokines) on the other.

A systematized review was conducted. The database used for searching articles was PubMed (MEDLINE).

According to our search, most peripheral immunological markers associated with major depressive disorder are not specific to a single depressive symptom group. The most evident examples are CRP, IL-6, and TNF-α. The strongest evidence supports the connection of peripheral inflammatory markers with somatic symptoms; weaker evidence indicates a role of immune changes in altered reward processing. The least amount of evidence was found for the role of peripheral inflammatory markers in exaggerated reactivity to negative information and cognitive control deficits. Regarding the depression subtypes, a tendency for higher CRP and adipokines was observed in atypical depression; increased IL-6 was found in melancholic depression.

Somatic symptoms of depression could be a manifestation of a specific immunological endophenotype of depressive disorder. Melancholic and atypical depression may be characterized by different profiles of immunological markers.

The impact of childhood maltreatment on multiple inflammatory cytokines among middle school students remains to be elucidated. This study aimed to examine the associations of different types of childhood maltreatment with peripheral serum inflammatory cytokines (interleukin-10, interleukin-1β, interleukin-6, interleukin-8, and tumor necrosis factor-α) in middle school students, and to explore the differences in these associations between boys and girls and between late (≥15 and<20 years) and early (≥11 and <15 years) adolescence.

A total of 1122 students were recruited from a boarding middle school. Each participant was asked to respond to a detailed questionnaire on childhood maltreatment, from whom one blood sample was drawn via venous blood.

In the overall sample there was no association between childhood maltreatment and peripheral serum inflammatory cytokines; (2) emotional abuse was significantly correlated with IL-1β only in girls (B = -0.16; 95% CI, -0.28~-0.03; p = 0.06); (3) in late adolescence, emotional abuse, emotional neglect, and childhood maltreatment had marked link with IL-8 (B = 0.39; 95%CI, 0.16~0.63; p = 0.01; B =0.20; 95% CI, 0.04~0.37; p = 0.08; B = 0.50; 95% CI, 0.18~0.82; p = 0.01, respectively).

These findings also strengthened an inference regarding the effects of childhood maltreatment on inflammation of students in late adolescence.

Perinatal mood and anxiety disorders encompass a range of mental health disorders that occur during pregnancy and up to 1 year postpartum, affecting approximately 20% of women. Traditional risk factors, such as a history of depression and pregnancy complications including preeclampsia, are known. Their predictive utility, however, is not specific or sensitive enough to inform clinical decision-making or prevention strategies for perinatal mood and anxiety disorders. Better diagnostic and prognostic models are needed for early identification and referral to treatment.

This study aimed to determine if a panel of novel third-trimester plasma protein biomarkers in pregnant women can be used to identify those who have a high predisposed risk for perinatal mood and anxiety disorders within 3 months postpartum.

We studied 52 women (n=34 with a risk for perinatal mood and anxiety disorders and n=18 controls) among whom mental health screening was conducted at 2 time points, namely in the third trimester and again at 3 months postdelivery. An elevated perinatal mood and anxiety disorder risk was identified by screening individuals with above-validated cutoffs for depression (Edinburgh Postnatal Depression Scale ≥12), anxiety (Overall Anxiety Severity and Impairment Scale ≥7), and/or posttraumatic stress disorder (Impact of Events Scale >26) at both time points. Plasma samples collected in the third trimester were screened using the aptamer-based SomaLogic SomaScan proteomic assay technology to evaluate perinatal mood and anxiety disorder-associated changes in the expression of 1305 protein analytes. Ingenuity Pathway Analysis was conducted to highlight pathophysiological relationships between perinatal mood and anxiety disorder-specific proteins found to be significantly up- or down-regulated in all subjects with perinatal mood and anxiety disorder and in those with perinatal mood and anxiety disorders and no preeclampsia.

From a panel of 53 significant perinatal mood and anxiety disorder-associated proteins, a unique 20-protein signature differentiated perinatal mood and anxiety disorder cases from controls in a principal component analysis (P<.05). This protein signature included NCAM1, NRCAM, and NTRK3 that converge around neuronal signaling pathways regulating axonal guidance, astrocyte differentiation, and maintenance of GABAergic neurons. Interestingly, when we restricted the analysis to subjects without preeclampsia, a 30-protein signature differentiated perinatal mood and anxiety disorder cases from all controls without overlap on the principal component analysis (P<.001). In the nonpreeclamptic perinatal mood and anxiety disorder group, we observed increased expression of proteins, such as CXCL11, CXCL6, MIC-B, and B2MG, which regulate leucocyte migration, inflammation, and immune function.

Participants with perinatal mood and anxiety disorders had a unique and distinct plasma protein signature that regulated a variety of neuronal signaling and proinflammatory pathways. Additional validation studies with larger sample sizes are needed to determine whether some of these molecules can be used in conjunction with traditional risk factors for the early detection of perinatal mood and anxiety disorders.

Ozone (O₃) is an air pollutant that primarily damages the lungs, but growing evidence supports the idea that O₃ also harms the brain; acute exposure to O₃ has been linked to central nervous system (CNS) symptoms such as depressed mood and sickness behaviors. However, the mechanisms by which O₃ inhalation causes neurobehavioral changes are limited. One hypothesis is that factors in the circulation bridge communication between the lungs and brain following O₃ exposure. In this study, our goals were to characterize neurobehavioral endpoints of O₃ exposure as they relate to markers of systemic and pulmonary inflammation, with a particular focus on serum amyloid A (SAA) and kynurenine as candidate mediators of O₃ behavioral effects. We evaluated O₃-induced dose-, time- and sex-dependent changes in pulmonary inflammation, circulating SAA and kynurenine and its metabolic enzymes, and sickness and depressive-like behaviors in Balb/c and CD-1 mice. We found that 3 parts per million (ppm) O₃, but not 2 or 1 ppm O₃, increased circulating SAA and lung inflammation, which were resolved by 48 h and was worse in females. We also found that indoleamine 2,3-dioxygenase (Ido1) mRNA expression was increased in the brain and spleen 24 h after 3 ppm O₃ and that kynurenine was increased in blood. Sickness and depressive-like behaviors were observed at all O₃ doses (1-3 ppm), suggesting that behavioral responses to O₃ can occur independently of increased SAA or neutrophils in the lungs. Using SAA knockout mice, we found that SAA did not contribute to O₃-induced pulmonary damage or inflammation, systemic increases in kynurenine post-O₃, or depressive-like behavior but did contribute to weight loss. Together, these findings indicate that acute O₃ exposure induces transient symptoms of sickness and depressive-like behaviors that may occur in the presence or absence of overt pulmonary neutrophilia and systemic increases of SAA. SAA does not appear to contribute to pulmonary inflammation induced by O₃, although it may contribute to other aspects of sickness behavior, as reflected by a modest effect on weight loss.

Depression and anxiety disorders carry a tremendous worldwide burden and emerge as a significant cause of disability among western societies. Both disorders are known to disproportionally affect women, as they are twice more likely to be diagnosed and moreover, they are also prone to suffer from female-specific mood disorders. Importantly, the prevalence of these affective disorders has notably risen after the COVID pandemic, especially in women. In this chapter, we describe factors that are possibly contributing to the expression of such sex differences in depression and anxiety. For this, we overview the effect of transcriptomic and genetic factors, the immune system, neuroendocrine aspects, and cognition. Furthermore, we also provide evidence of sex differences in antidepressant response and their causes. Finally, we emphasize the importance to consider sex as a biological variable in preclinical and clinical research, which may facilitate the discovery and development of new and more efficacious antidepressant and anxiolytic pharmacotherapies for both women and men.

Inflammation can have social consequences, which may be relevant to inflammation's link with depression. The current study tests whether a typhoid vaccine increases feelings of social disconnection and avoidance behavior.

In two full-day visits at least three weeks apart, 172 postmenopausal breast cancer survivors (Stage I-IIIA) each received a typhoid capsular polysaccharide vaccination and a saline placebo injection in a random sequence. Blood was drawn prior to the injection, as well as every 90 min thereafter for 8 h to assess the inflammatory response (interleukin-6, IL-6; interleukin-1 receptor antagonist, IL-1Ra). At both visits, women completed the Social Connection Scale at 0 and 8.5 h post-vaccination as well as implicit and explicit social avoidance tasks at 7 h post-vaccination.

The typhoid vaccine triggered rises in both inflammatory markers (ps < 0.01), but it did not impact feelings of social connection (p = .32), or performance on the implicit (p = .34) or explicit tasks (p = .37). Inflammatory rises did not predict feelings of social connection (ps > 0.64) or performance on explicit (ps > 0.73) or implicit (ps > 0.88) social avoidance tasks.

Milder inflammatory stimuli may not affect social processes. Higher levels of inflammation or, relatedly, more sickness symptoms may be necessary to recapitulate prior findings of social avoidance.

Stress is an important risk factor for modern chronic diseases, with distinct influences in males and females. The sex specificity of the mammalian stress response contributes to the sex-dependent development and impacts of coronary artery disease (CAD). Compared to men, women appear to have greater susceptibility to chronic forms of psychosocial stress, extending beyond an increased incidence of mood disorders to include a 2- to 4-fold higher risk of stress-dependent myocardial infarction in women, and up to 10-fold higher risk of Takotsubo syndrome-a stress-dependent coronary-myocardial disorder most prevalent in post-menopausal women. Sex differences arise at all levels of the stress response: from initial perception of stress to behavioural, cognitive, and affective responses and longer-term disease outcomes. These fundamental differences involve interactions between chromosomal and gonadal determinants, (mal)adaptive epigenetic modulation across the lifespan (particularly in early life), and the extrinsic influences of socio-cultural, economic, and environmental factors. Pre-clinical investigations of biological mechanisms support distinct early life programming and a heightened corticolimbic-noradrenaline-neuroinflammatory reactivity in females vs. males, among implicated determinants of the chronic stress response. Unravelling the intrinsic molecular, cellular and systems biological basis of these differences, and their interactions with external lifestyle/socio-cultural determinants, can guide preventative and therapeutic strategies to better target coronary heart disease in a tailored sex-specific manner.