Chronic Stress Exposure Alters the Gut Barrier: Sex-Specific Effects on Microbiota and Jejunum Tight Junctions.

Background: Major depressive disorder (MDD) is the leading cause of disability worldwide. Of individuals with MDD, 30% to 50% are unresponsive to common antidepressants, highlighting untapped causal biological mechanisms. Dysfunction in the microbiota-gut-brain axis has been implicated in MDD pathogenesis. Exposure to chronic stress disrupts blood-brain barrier integrity; still, little is known about intestinal barrier function in these conditions, particularly for the small intestine, where absorption of most foods and drugs takes place. Methods: We investigated how chronic social or variable stress, two mouse models of depression, impact the jejunum intestinal barrier in males and females. Mice were subjected to stress paradigms followed by analysis of gene expression profiles of intestinal barrier-related targets, fecal microbial composition, and blood-based markers. Results: Altered microbial populations and changes in gene expression of jejunum tight junctions were observed depending on the type and duration of stress, with sex-specific effects. We used machine learning to characterize in detail morphological tight junction properties, identifying a cluster of ruffled junctions in stressed animals. Junctional ruffling is associated with inflammation, so we evaluated whether lipopolysaccharide injection recapitulates stress-induced changes in the jejunum and observed profound sex differences. Finally, lipopolysaccharide-binding protein, a marker of gut barrier leakiness, was associated with stress vulnerability in mice, and translational value was confirmed on blood samples from women with MDD. Conclusions: Our results provide evidence that chronic stress disrupts intestinal barrier homeostasis in conjunction with the manifestation of depressive-like behaviors in a sex-specific manner in mice and, possibly, in human depression.

Sex-specific effects of voluntary wheel running on behavior and the gut microbiota-immune-brain axis in mice.

Physical exercise has been positioned as a promising strategy to prevent and/or alleviate anxiety and depression, but the biological processes associated with its effects on mental health have yet to be entirely determined. Although the prevalence of depression and anxiety in women is about twice that of men, very few studies have examined whether physical exercise could affect mental health differently according to sex. This study examined, in singly-housed mice, the sex-specific effects of voluntary exercise on depressive- and anxiety-like behaviors as well as on different markers along the gut microbiota-immune-brain axis. Male and female C57BL/6N mice had voluntary access to running wheels in their home-cages for 24 days or were left undisturbed in identical home-cages without running wheels. Behaviors were then examined in the open field, splash, elevated plus maze, and tail suspension tests. Gene expression of pro-inflammatory cytokines, microglia activation-related genes, and tight junction proteins was determined in the jejunum and the hippocampus, while microbiota composition and predicted function were verified in cecum contents. Voluntary exercise reduced anxiety-like behaviors and altered grooming patterns in males exclusively. Although the exercise intervention resulted in changes to brain inflammatory activity and to cecal microbiota composition and inferred function in both sexes, reductions in the jejunal expression of pro-inflammatory markers were observed in females only. These findings support the view that voluntary exercise, even when performed during a short period, is beneficial for mental and intestinal health and that its sex-specific effects on behavior could be, at least in part, related to some components of the gut microbiota-immune-brain axis.

Understanding the impact of radical changes in diet and the gut microbiota on brain function and structure: rationale and design of the EMBRACE study.

BACKGROUND: Bariatric surgery leads to profound changes in gut microbiota and dietary patterns, both of which may interact to impact gut-brain communication. Though cognitive function improves postsurgery, there is a large variability in outcomes. How bariatric surgery-induced modifications in the gut microbiota and dietary patterns influence the variability in cognitive function is still unclear. OBJECTIVES: To elucidate the associations between bariatric surgery-induced changes in dietary and gut microbiota patterns with cognition and brain structure. SETTING: University hospital. METHODS: A total of 120 adult patients (≥30 years) scheduled to undergo a primary bariatric surgery along with 60 age-, sex-, and body mass index-matched patients on the surgery waitlist will undergo assessments 3-months presurgery and 6- and 12-month postsurgery (or an equivalent time for the waitlist group). Additionally, 60 age-and sex-matched nonbariatric surgery eligible individuals will complete the presurgical assessments only. Evaluations will include sociodemographic and health behavior questionnaires, physiological assessments (anthropometrics, blood-, urine-, and fecal-based measures), neuropsychological cognitive tests, and structural magnetic resonance imaging. Cluster analyses of the dietary and gut microbiota changes will define the various dietary patterns and microbiota profiles, then using repeated measures mixed models, their associations with global cognitive and structural brain alterations will be explored. RESULTS: The coordinating study site (Centre intégré universitaire de santé et de services sociaux du Nord-de-l'Île-de-Montréal, QC, Canada), provided the primary ethical approval (Research Ethics Board#: MP-32-2022-2412). CONCLUSIONS: The insights generated from this study can be used to develop individually-targeted neurodegenerative disease prevention strategies, as well as providing critical mechanistic information.

Survival and Interplay of γ-Aminobutyric Acid-Producing Psychobiotic Candidates with the Gut Microbiota in a Continuous Model of the Human Colon.

Over decades, probiotic research has focused on their benefits to gut health. Recently, the gut microbiota has been proven to share bidirectional connections with the brain through the gut-brain axis. Therefore, the manipulation of this axis via probiotics has garnered interest. We have recently isolated and characterized in vitro probiotic candidates producing γ-aminobutyric acid (GABA), a major neuromodulator of the enteric nervous system. This study investigates the growth and competitiveness of selected GABA-producing probiotic candidates (Bifidobacterium animalis, Streptococcus thermophilus, and Lactobacillus delbrueckii subsp. bulgaricus) in the presence of human gut microbiota ex vivo in a model mimicking physiological and microbiological conditions of the human proximal colon. Supplementation with GABA-producing probiotic candidates did not affect the overall gut microbiota diversity over 48 h of treatment. However, these candidates modulated the microbiota composition, especially by increasing the Bacteroidetes population, a key gut microbe associated with anti-inflammatory activities. The level of microbiota-generated SCFAs within 12 h of treatment was also increased, compared to the control group. Results from this study demonstrate the probiotic potential of the tested GABA-producing bacteria and their impact on gut microbiota structure and metabolism, suggesting their suitability for gut health-promoting applications.

Screening, characterization and growth of γ-aminobutyric acid-producing probiotic candidates from food origin under simulated colonic conditions.

AIMS: This study aims to isolate probiotic bacteria candidates from various starter cultures and fermented foods and characterize their ability to produce γ-aminobutyric acid (GABA). GABA is a major inhibitory neuromediator of the central and enteric nervous systems with a role in several health disorders. METHODS AND RESULTS: Fourteen strains of lactic acid bacteria were isolated from food environment and screened for the presence of the glutamate decarboxylase (gadB) gene using PCR and GAD enzymatic assay. The identified potent GABA-producers included Strep. thermophilus, Lactiplantibacillus plantarum and Lact. delbrueckii subsp. bulgaricus. GC-FID analyses confirmed the high GABA production capacity of Strep. thermophilus ST16 (1641.5 ± 154.15 µmol l-1 ), Strep. thermophilus ST8 (1724.5 ± 48.08 µmol/L). To a lesser extent, Bif. animalis ST20, Lact. acidophilus LP16-2 and Ent. faecium ST3 produced 947.5 ± 70.71, 918.0 ± 121.42, and 907.83 ± 55.15 µmol/L of GABA, respectively. These potent strains were able to grow and produce GABA in MRS broth and pre-fermented Macfarlane broth, the latter medium mimicking the nutrient and metabolome composition encountered in the colon. The identified bioactive strains exhibited strong biological safety and probiotic potential profiles as indicated by sensitivity to antibiotics, absence of virulence factors and survival in gastrointestinal conditions. CONCLUSIONS: Several GABA producing probiotic candidates, including Bif. animals ST20, Strep. thermophilus ST8, Lact. acidophilus LP16-2, L. plantarum LP6 & LP9, and Ent. faecium ST3, have shown potential to grow under simulated colonic conditions. SIGNIFICANCE AND IMPACT OF STUDY: Findings from this study provide evidence of the suitability of the isolated GABA-producing probiotic candidates for the development of health-oriented functional food products.

Fracture Risk Following an Atypical Femoral Fracture.

Atypical femoral fractures (AFFs) occurring during the course of osteoporosis treatment usually lead to discontinuation of anti-resorptive (AR) drugs. However, the risk of fracture after an AFF is unknown. We conducted a follow-up study of patients with AFF matched 1:3 for age and gender with patients with a peripheral major osteoporotic fracture (pMOF), in the setting of a fracture liaison service, to investigate the incidence of subsequent low-trauma fractures. Fifty-five patients with AFF (95% women, age [mean ± standard deviation] 75 ± 10 years, 89% exposed to AR drugs), followed for 6.2 ± 3.7 years, were compared to 165 matched controls with a pMOF (hip 85%) followed for 4.3 ± 2.6 years. During the follow-up, 38% of patients in the AFF group and 16% in the pMOF group received AR therapies. Continuation of AR drugs after an AFF was associated with contralateral AFF in 27% of subjects. The risks of new low-trauma, major osteoporotic and imminent (within 2 years) fractures, were similar between the two groups: incidence rate ratio (95% confidence interval [CI]) of subsequent fracture following AFF relative to pMOF, 1.30 (95% CI, 0.82-2.04), 1.28 (95% CI, 0.74-2.15), and 1.11 (95% CI, 0.54-2.15), respectively. Moreover, the risk of sustaining multiple fractures per participant was significantly increased among patients with AFF compared to pMOF (hazard ratio 1.48 [95% CI, 1.00-2.19]; p = 0.049). When taking mortality into account, the risk of subsequent fractures tended to be higher in the AFF group (sub-hazard ratio 1.42 [95% CI, 0.95-2.12]). In conclusion, patients who sustained an AFF are at high risk of subsequent fragility fractures, at least equal or even greater to the risk observed after a pMOF. However, continuation of AR drugs increases the risk of contralateral AFF. Therefore, optimal modalities for secondary fracture prevention after AFF require further evaluation. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Beyond the neuro-immune interplay in depression: Could gut microbes be the missing link?

Accumulating evidence have positioned inflammatory signaling pathways as crucial routes by which microbes inhabiting the gastrointestinal tract (the gut microbiota) communicate with the host brain to influence behavior, with impacts on mental illnesses. In this short review, an overview of inflammatory and gut microbiota status in human depression and in rodent models of the illness are provided. Next, potential inflammatory pathways mediating the communications between the gut and the brain under stressful conditions are described. Finally, dietary interventions targeting the gut microbiota-immune-brain axis in the context of depression are briefly discussed.

Stress-induced disturbances along the gut microbiota-immune-brain axis and implications for mental health: Does sex matter?

Women are roughly twice as likely as men to suffer from stress-related disorders, especially major depression and generalized anxiety. Accumulating evidence suggest that microbes inhabiting the gastrointestinal tract (the gut microbiota) interact with the host brain and may play a key role in the pathogenesis of mental illnesses. Here, the possibility that sexually dimorphic alterations along the gut microbiota-immune-brain axis could play a role in promoting this female bias of mood and anxiety disorders will be discussed. This review will also analyze the idea that gut microbes and sex hormones influence each other, and that this reciprocal crosstalk may come to modulate inflammatory players along the gut microbiota-immune-brain axis and influence behavior in a sex-dependent way.

Mindfulness and psychoeducation to manage stress in amnestic mild cognitive impairment: A pilot study.

Objectives: Amnestic mild cognitive impairment (aMCI) often corresponds to the prodromal stage of Alzheimer disease (AD). The aMCI stage represents a crucial time window to apply preventive interventions in an attempt to delay cognitive decline. Stress, one of AD's modifiable risk factors frequently co-occurring with aMCI, stands out as a key intervention target. The goal of this study was to assess the impacts of two non-pharmacological interventions, mindfulness and psychoeducation, on stress at the psychological and physiological levels among aMCI older adults. Methods: Forty-eight aMCI participants were randomized between a mindfulness-based intervention (MBI) and a psychoeducation-based intervention (PBI) for eight weekly sessions. Anxiety symptoms, perceived stress levels, cortisol awakening response (CAR), and coping strategies were assessed pre- and post-intervention. Mindfulness attitudes and time dedicated to at-home meditative practices were evaluated in the MBI group. Results: The main results revealed a slight reduction of the CAR among MBI participants who practiced meditation at home the most and a decrease in perceived stress levels in the PBI group. Both interventions enhanced problem-focused coping strategies. Conclusion: In sum, this pilot study supports the potential of MBI and PBI to reduce stress at the physiological and psychological level, respectively, and increase coping strategies in older adults at risk for AD.

Palatable Food Dampens the Long-Term Behavioral and Endocrine Effects of Juvenile Stressor Exposure but May Also Provoke Metabolic Syndrome in Rats.

The juvenile period is marked by a reorganization and growth of important brain regions including structures associating with reward seeking behaviors such as the nucleus accumbens (NA) and prefrontal cortex (PFC). These changes are impacted by stressors during the juvenile period and may lead to a predisposition to stress induced psychopathology and abnormal development of brain reward systems. Like in humans, adult rodents engage certain coping mechanisms such as increases in the consumption of calorie-rich palatable foods to reduce stress, but this behavior can lead to obesity and metabolic disorders. In this study, we examined whether stressors during the juvenile period led to increased caloric intake when a palatable diet was accessible, and whether this diet attenuated adult stress responses. In addition, we examined if the stress buffering effects produced by the palatable diet were also accompanied by an offset propensity towards obesity, and by alterations in mRNA expression of dopamine (DA) receptors in the NA and PFC in adulthood. To this end, juvenile male Wistar rats underwent episodic stressor exposure (forced swim, elevated platform stress and restraint) on postnatal days (PD) 27-29 and received access to regular chow or daily limited access to a palatable diet until adulthood. At the age of 2 months, rats were tested on a social interaction test that screens for anxiety-like behaviors and their endocrine responses to an acute stressor. Animals were sacrificed, and their brains processed to detect differences in DA receptor subtype expression in the PFC and NA using qPCR. Results showed that rats that were stressed during the juvenile period displayed higher social anxiety and a sensitized corticosterone response as adults and these effects were attenuated by access to the palatable diet. Nevertheless, rats that experienced juvenile stress and consumed a palatable diet showed greater adiposity in adulthood. Interestingly, the same group displayed greater mRNA expression of DA receptors at the NA. This suggests that access to a palatable diet mitigates the behavioral and endocrine effects of juvenile stressor exposure in adulthood, but at the cost of metabolic imbalances and a sensitized dopaminergic system.

Post-weaning Environmental Enrichment in Male CD-1 Mice: Impact on Social Behaviors, Corticosterone Levels and Prefrontal Cytokine Expression in Adulthood.

Environmental enrichment is typically associated with enhanced well-being, improved cognitive function and stress resilience. However, in some instances grouping adult male mice in enriched conditions promoted a stressful environment, which resulted in elevated endocrine, monoamine and inflammatory outcomes in response to subsequent stressor exposure. The current investigation examined whether raising male mice in an enriched environment (EE) would modulate social and anxiety-like behaviors in early adulthood and influence brain expression of pro-inflammatory cytokines and brain-derived neurotrophic factor (BDNF). Immediately after weaning (postnatal day [PD] 21), CD-1 male mice were housed with their siblings (3/cage) for 6 weeks in an EE or a standard (SE) environment. Body weights and aggressive interactions were monitored weekly. Social avoidance behaviors in the social interaction test and anxiety-like behaviors in the elevated-plus maze were examined in early adulthood. Ninety minutes following the behavioral tests, mice were sacrificed and a blood sample and the prefrontal cortex (PFC) were collected for the determination of plasma corticosterone levels as well as cytokine and BDNF mRNA expression. Mice raised in an EE exhibited more wounds and gained less weight than mice housed in a SE. Enriched mice also spent a greater amount of time in proximity of a social target in the social interaction test and made fewer transitions into the closed arms of the elevated-plus maze. Interestingly, the elevated plasma corticosterone and upregulated prefrontal interleukin (IL)-1ß expression observed after the social interaction test among the SE mice were not apparent among those housed in an EE. Enrichment also increased prefrontal BDNF expression, especially among mice that experienced the social interaction test. These results suggest that although raising male mice in an EE may elicit aggressive interactions between sibling cage-mates (as indicated by a high number of wounds), this environment also enhances social behaviors and limits the corticosterone and cytokine impacts of mild social stressors encountered in early adulthood.

Functional Performances on Admission Predict In-Hospital Falls, Injurious Falls, and Fractures in Older Patients: A Prospective Study.

Falls are common among older inpatients and remain a great challenge for hospitals. Despite the relevance of physical impairments to falls, the prognostic value of performance-based functional measures for in-hospital falls and injurious falls remains unknown. This study aimed to determine the predictive ability and accuracy of various functional tests administered at or close to admission in a geriatric hospital to identify in-hospital fallers and injurious fallers. In this prospective study, conducted in a geriatric hospital in Geneva, Switzerland, 807 inpatients (mean age 85.0 years) were subjected to a battery of functional tests administered by physiotherapists within 3 days (interquartile range 1 to 6) of admission, including Short Physical Performance Battery (SPPB), simplified Tinetti, and Timed Up and Go tests. Patients were prospectively followed up for falls and injurious falls until discharge using mandatory standardized incident report forms and electronic patients' records. During a median length of hospital stay of 23 days (interquartile range 14 to 36), 329 falls occurred in 189 (23.4%) patients, including 161 injurious falls of which 24 were serious. In-hospital fallers displayed significantly poorer functional performances at admission on all tests compared with non-fallers (p < 0.001 for all). In multivariate analysis controlling for age, sex, previous falls, and fall as cause of admission, poorer functional performances on all functional tests predicted in-hospital falls and injurious falls (p < 0.001 for all). The SPPB only significantly predicted serious injurious falls (adjusted odds ratio [OR] = 0.76; 95% confidence interval [CI] 0.60-0.96) and fractures (adjusted OR = 0.76; 95% CI 0.59-0.98). In conclusion, poor functional performances, as assessed by SPPB, are independent predictors of in-hospital falls, injurious falls, and fractures in patients admitted to a geriatric hospital. These findings should help to design preventive strategies for in-hospital falls and support the adoption of objective performance-based functional measures into routine hospital practice. © 2018 American Society for Bone and Mineral Research.

Implications of the gut microbiota in vulnerability to the social avoidance effects of chronic social defeat in male mice.

Appreciable evidence suggests that perturbations within the gut microbiome and the immune system may play a key role in the pathogenesis of depression stemming from earlier stressful experiences. In the present investigation we examined whether microbial changes in cecum contents were associated with social avoidance behaviors, a feature of depression, and pro-inflammatory variations among socially stressed mice. Male C57BL/6 mice experienced social defeat or a control condition once a day for 10 consecutive days. Social avoidance behaviors were examined three weeks after the last defeat or control episode and blood, brain, and cecum contents were collected 24h afterward for the determination of corticosterone, pro-inflammatory cytokines, and microbial populations. Mice that were most susceptible to the behavioral effects of chronic social defeat (reflected by severe social avoidance behaviors) displayed the greatest changes within particular sets of bacteria at the phylum and genus taxonomic ranks. Although plasma and brain cytokines were not significantly altered in socially defeated mice, changes in the mRNA expression of interleukin (IL)-1ß and IL-6 within the prefrontal cortex were associated with elevated abundance of Flavobacterium spp. and reduced abundance of Turicibacter spp., which were also strongly correlated to social avoidance severity. Although at this time a causal connection cannot be inferred, these results point to the possibility that specific clusters of bacterial communities in cecum contents may be linked to vulnerability to social deficits stemming from prolonged social stressor experiences.

Fracture Prospectively Recorded From Prepuberty to Young Adulthood: Are They Markers of Peak Bone Mass and Strength in Males?

Fractures are common in otherwise healthy children and adolescents. They result from trauma of varying severity. Some reflect a greater skeletal fragility. A long-term implication of these fractures is their potentiality to predict adult bone fragility and increased risk of osteoporosis in later life. Using dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT), and micro-finite element analysis (µFEA) measurements, we previously found in 124 healthy females, followed from the age of 7.9 to 20.4 years, substantial deficits in both structural and strength components of the radius in the 42 girls who sustained a fracture during skeletal development. The objective of the current study was to assess in healthy males the relationship between fracture during development and expression of bone fragility in adulthood. A cohort of 152 boys was followed from age 7.4 ± 04 (mean ± SD) to 22.6 ± 0.7 years, ie, when peak bone mass is attained. Ninety participants (59.2%) sustained at least one fracture during growth, with highest incidence within the 10- to 13-year age range. Forearm was the most frequent site of fractures. At 7.4 years, several bone DXA-measured variables (areal bone mineral density [aBMD], bone mineral content [BMC]) were lower in the group with a positive fracture history during skeletal development compared with the non-fractured group. In contrast, at 22.6 years, no DXA-measured sites, including forearm, indicated a deficit in the fractured group compared with the non-fractured group. Likewise, at 22.6 years, neither HR-pQCT nor µFEA measurements, including distal radius, showed a structural or strength deficit in the fractured group. These results markedly contrast with a similar prospective study using the same technical and clinical design in 124 healthy girls. In conclusion, our prospective studies suggest a sex difference in the predictability of bone fragility in young adults who sustained fractures during childhood and adolescence. This difference might be related to the degree of trauma severity, usually lower in girls than in boys. © 2017 American Society for Bone and Mineral Research.

Prepubertal Impact of Protein Intake and Physical Activity on Weight-Bearing Peak Bone Mass and Strength in Males.

Context: Peak bone mass (PBM) and strength are important determinants of fracture risk in later life. During growth, bone is responsive to changes in nutrition and physical activity (PA), particularly before pubertal maturation. Objective: In prepubertal healthy boys, protein intake (Prot-Int) enhances the impact of PA on weight-bearing bone. We hypothesized that the synergism between Prot-Int and PA on proximal femur as recorded at 7.4 years would track until PBM. Methods: A total of 124 boys were followed from 7.4 to 15.2 and 22.6 years. At 7.4 years, they were dichotomized according to the median of both PA and Prot-Int. Results: In boys with PA greater than the median (310 vs 169 kcal ⋅ d-1), higher vs low Prot-Int (57.7 vs 38.0 g ⋅ d-1) was associated with +9.8% greater femoral neck (FN) bone mineral content (BMC) (P = 0.027) at 7.4 years. At 15.2 and 22.6 years, this difference was maintained: FN BMC: +12.7% (P = 0.012) and +11.3% (P = 0.016), respectively. With PA greater than the median, in Prot-Int greater than vs less than the median, differences in FN BMC z scores were +0.60, +0.70, and +0.68 at 7.4, 15.2, and 22.6 years, respectively. Microfinite element analysis of distal tibia at 15.2 and 22.6 years indicated that in the 2 groups with PA greater than the median, cross-sectional area, stiffness, and failure load were greater in Prot-Int greater than vs less than the median. Conclusions: This study demonstrates the crucial influence of Prot-Int on the response to enhanced PA and the importance of prepubertal years for modifying the bone growth trajectory and, thereby, for achieving higher PBM and greater strength in healthy male participants.

Environmental factors associated with familial or non-familial forms of Paget's disease of bone.

OBJECTIVES: The most frequent mutation linked to Paget's disease of bone (PDB), p.Pro392Leu within SQSTM1 gene, leads to phenotypic characteristics of PDB, but this mutation is seemingly insufficient to result in complete pagetic osteoclast phenotype, suggesting that possible environmental factors play a role in PDB pathogenesis. We performed an exploratory study to identify environmental factors potentially associated with familial or non-familial form of PDB in the French-Canadian population. METHODS: We investigated environmental factors through a questionnaire in 176 pagetic patients, including 86 patients with a familial form, and 147 healthy controls. All participants lived in the same geographic area, within a 120km radius of Quebec City. Associations between environmental factors and familial and non-familial forms of PDB were searched. RESULTS: In the multivariate model adjusted for intra-familial correlation, PDB was associated with wood fired heating in childhood and/or adolescence (OR=2.10; 95% CI 1.13-3.90, P=0.02). In the multivariate model without considering correlation for family relatedness, familial form of PDB was associated with residency near a mine (OR=11.70; 95% CI 2.92-46.80, P<0.01) and hunting (OR=2.92; 95% CI 1.14-7.47, P=0.03). Wood fired heating during childhood and/or adolescence (P=0.02) was associated with both familial and non-familial forms. CONCLUSIONS: In conclusion, PDB was significantly associated with wood fired heating in childhood and/or adolescence, regardless of the form of PDB, familial or not.

Inflammation and the microbiome: implications for depressive disorders.

Inflammatory processes have been linked to depressive illness, possibly being driven by stressful experiences. As well changes in the balance between microbial species compromising the microbiome could be important in precipitating cytokines and other inflammatory factors that, in turn, influence several pathways leading to depression. In particular, hormonal (e.g. glucocorticoids), trophic (e.g. reductions of growth factors) and oxidative stress signaling in the brain can be altered by the inflammatory milieu, including excessive cytokine release, which contribute to the symptoms that characterize a depressed state (e.g. anhedonia, lethargy, disturbed feeding). Identifying the 'signature' of inflammatory changes evident in the microbiome of specific depressed patients could yield important biomarkers to guide the development of personalized approaches to treatment.

Cytokine variations and mood disorders: influence of social stressors and social support.

Stressful events have been implicated in the evolution of mood disorders. In addition to brain neurotransmitters and growth factors, the view has been offered that these disorders might be provoked by the activation of the inflammatory immune system as well as by de novo changes of inflammatory cytokines within the brain. The present review describes the impact of social stressors in animals and in humans on behavioral changes reminiscent of depressive states as well as on cytokine functioning. Social stressors increase pro-inflammatory cytokines in circulation as well as in brain regions that have been associated with depression, varying with the animal's social status and/or behavioral methods used to contend with social challenges. Likewise, in humans, social stressors that favor the development of depression are accompanied by elevated circulating cytokine levels and conversely, conditions that limit the cytokine elevations correlated with symptom attenuation or reversal. The implications of these findings are discussed in relation to the potentially powerful effects of social support, social identity, and connectedness in maintaining well-being and in diminishing symptoms of depression.

Interplay between pro-inflammatory cytokines and growth factors in depressive illnesses.

The development of depressive disorders had long been attributed to monoamine variations, and pharmacological treatment strategies likewise focused on methods of altering monoamine availability. However, the limited success achieved by treatments that altered these processes spurred the search for alternative mechanisms and treatments. Here we provide a brief overview concerning a possible role for pro-inflammatory cytokines and growth factors in major depression, as well as the possibility of targeting these factors in treating this disorder. The data suggest that focusing on one or another cytokine or growth factor might be counterproductive, especially as these factors may act sequentially or in parallel in affecting depressive disorders. It is also suggested that cytokines and growth factors might be useful biomarkers for individualized treatments of depressive illnesses.

Social agonistic distress in male and female mice: changes of behavior and brain monoamine functioning in relation to acute and chronic challenges.

Stressful events promote several neuroendocrine and neurotransmitter changes that might contribute to the provocation of psychological and physical pathologies. Perhaps, because of its apparent ecological validity and its simple application, there has been increasing use of social defeat (resident-intruder) paradigms as a stressor. The frequency of stress-related psychopathology is much greater in females than in males, but the typical resident-intruder paradigm is less useful in assessing stressor effects in females. An alternative, but infrequently used procedure in females involves exposing a mouse to a lactating dam, resulting in threatening gestures being expressed by the resident. In the present investigation we demonstrated the utility of this paradigm, showing that the standard resident-intruder paradigm in males and the modified version in females promoted elevated anxiety in a plus-maze test. The behavioral effects that reflected anxiety were more pronounced 2 weeks after the stressor treatment than they were 2 hr afterward, possibly reflecting the abatement of the stress-related of hyper-arousal. These treatments, like a stressor comprising physical restraint, increased plasma corticosterone and elicited variations of norepinephrine and serotonin levels and turnover within the prefrontal cortex, hippocampus and central amygdala. Moreover, the stressor effects were exaggerated among mice that had been exposed to a chronic or subchronic-intermittent regimen of unpredictable stressors. Indeed, some of the monoamine changes were more pronounced in females than in males, although it is less certain whether this represented compensatory changes to deal with chronic stressors that could result in excessive strain on biological systems (allostatic overload).