Do microbes play a role in Alzheimer's disease?

Alzheimer's disease is a complex and progressive condition that affects essential neurological functions such as memory and reasoning. In the brain, neuronal loss, synaptic dysfunction, proteinopathy, neurofibrillary tangles, and neuroinflammation are the hallmarks of Alzheimer's disease pathophysiology. In addition, recent evidence has highlighted that microbes, whether commensal or pathogenic, also have the ability to interact with their host and to regulate its immune system, therefore participating in the exchanges that lead to peripheral inflammation and neuropathology. Because of this intimate relationship, bacteria, viruses, fungi, and protozoa have been implicated in the development of Alzheimer's disease. Here, we bring together current and most recent evidence of the role of microbes in Alzheimer's disease, raising burning questions that need to be addressed to guide therapeutic approaches and potential prophylactic strategies.

Exercise mitigates a gut microbiota-mediated reduction in adult hippocampal neurogenesis and associated behaviours in rats.

Lifestyle factors, especially exercise, impact the manifestation and progression of psychiatric and neurodegenerative disorders such as depression and Alzheimer's disease, mediated by changes in hippocampal neuroplasticity. The beneficial effects of exercise may be due to its promotion of adult hippocampal neurogenesis (AHN). Gut microbiota has also been showed to be altered in a variety of brain disorders, and disturbances of the microbiota have resulted in alterations in brain and behaviour. However, whether exercise can counteract the negative effects of altered gut microbiota on brain function remains under explored. To this end, chronic disruption of the gut microbiota was achieved using an antibiotic cocktail in rats that were sedentary or allowed voluntary access to running wheels. Sedentary rats with disrupted microbiota displayed impaired performance in hippocampal neurogenesis-dependent tasks: the modified spontaneous location recognition task and the novelty suppressed feeding test. Performance in the elevated plus maze was also impaired due to antibiotics treatment. These behaviours, and an antibiotics-induced reduction in AHN were attenuated by voluntary exercise. The effects were independent of changes in the hippocampal metabolome but were paralleled by caecal metabolomic changes. Taken together these data highlight the importance of the gut microbiota in AHN-dependent behaviours and demonstrate the power of lifestyle factors such as voluntary exercise to attenuate these changes.

Microbiota from Alzheimer's patients induce deficits in cognition and hippocampal neurogenesis.

Alzheimer's disease is a complex neurodegenerative disorder leading to a decline in cognitive function and mental health. Recent research has positioned the gut microbiota as an important susceptibility factor in Alzheimer's disease by showing specific alterations in the gut microbiome composition of Alzheimer's patients and in rodent models. However, it is unknown whether gut microbiota alterations are causal in the manifestation of Alzheimer's symptoms. To understand the involvement of Alzheimer's patient gut microbiota in host physiology and behaviour, we transplanted faecal microbiota from Alzheimer's patients and age-matched healthy controls into microbiota-depleted young adult rats. We found impairments in behaviours reliant on adult hippocampal neurogenesis, an essential process for certain memory functions and mood, resulting from Alzheimer's patient transplants. Notably, the severity of impairments correlated with clinical cognitive scores in donor patients. Discrete changes in the rat caecal and hippocampal metabolome were also evident. As hippocampal neurogenesis cannot be measured in living humans but is modulated by the circulatory systemic environment, we assessed the impact of the Alzheimer's systemic environment on proxy neurogenesis readouts. Serum from Alzheimer's patients decreased neurogenesis in human cells in vitro and were associated with cognitive scores and key microbial genera. Our findings reveal for the first time, that Alzheimer's symptoms can be transferred to a healthy young organism via the gut microbiota, confirming a causal role of gut microbiota in Alzheimer's disease, and highlight hippocampal neurogenesis as a converging central cellular process regulating systemic circulatory and gut-mediated factors in Alzheimer's.

Benralizumab for eosinophilic granulomatosis with polyangiitis.

BACKGROUND: Benralizumab is effective in the treatment of eosinophilic asthma and is being investigated for the treatment of other eosinophil-associated diseases. Reports on the use of benralizumab for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA) are limited to case reports and small case series. METHODS: We conducted a multicentre, retrospective study including EGPA patients treated with off-label benralizumab. The primary endpoint was the rate of complete response defined as no disease activity (Birmingham Vasculitis Activity Score=0) and a prednisone dose ≤4 mg/day. Partial response was defined as no disease activity and a prednisone dose ≥4 mg/day. RESULTS: Sixty-eight patients were included, including 31 (46%) who had previously received mepolizumab. The use of benralizumab was warranted by uncontrolled asthma in 54 (81%), persistent ear, nose and throat (ENT) manifestations in 27 (40%) and persistent glucocorticoids (GCs) use in 48 (74%) patients. Median (IQR) follow-up after starting benralizumab was 23 (9-34) months. Thirty-three patients (49%) achieved a complete response, 24 (36%) achieved a partial response and 10 (15%) did not respond. Among the 57 patients who initially responded, 10 (18%) eventually required further line treatments. GCs were discontinued in 23 patients (38%). Prior mepolizumab use was associated with a higher rate of primary failure (26.7% vs 5.4%, p=0.034) and less frequent GCs discontinuation (14.8% vs 55.9%, p=0.001). Vasculitis flares occurred in 7 patients (11%) and were associated with histological evidence of vasculitis and/or antineutrophil cytoplasmic antibodies positivity at benralizumab initiation (p=0.004). CONCLUSIONS: Benralizumab appears to be an effective treatment for refractory asthma or ENT manifestations in EGPA and allows GC-sparing. However, its efficacy was lower after prior failure of mepolizumab.

Outrunning a bad diet: Interactions between exercise and a Western-style diet for adolescent mental health, metabolism and microbes.

Adolescence is a period of biological, psychological and social changes, and the peak time for the emergence of mental health problems. During this life stage, brain plasticity including hippocampal neurogenesis is increased, which is crucial for cognitive functions and regulation of emotional responses. The hippocampus is especially susceptible to environmental and lifestyle influences, mediated by changes in physiological systems, resulting in enhanced brain plasticity but also an elevated risk for developing mental health problems. Indeed, adolescence is accompanied by increased activation of the maturing hypothalamic-pituitary-adrenal axis, sensitivity to metabolic changes due to increased nutritional needs and hormonal changes, and gut microbiota maturation. Importantly, dietary habits and levels of physical activity significantly impact these systems. In this review, the interactions between exercise and Western-style diets, which are high in fat and sugar, on adolescent stress susceptibility, metabolism and the gut microbiota are explored. We provide an overview of current knowledge on implications of these interactions for hippocampal function and adolescent mental health, and speculate on potential mechanisms which require further investigation.

Environmental signals perceived by the brain abate pro-metastatic monocytes by dampening glucocorticoids receptor signaling.

While positive social-behavioral factors predict longer survival in cancer patients, the underlying mechanisms are unknown. Since tumor metastasis are the major cancer mortality factor, we investigated how an enriched environment (EE) conductive to enhanced sensory, cognitive and motor stimulation impact metastatic progression in lungs following intravasation in the circulation. We find that mice housed in EE exhibited reduced number of lung metastatic foci compared to control mice housed in a standard environment (SE). Compared to SE mice, EE mice increased lung inflammation as early as 4 days after circulating tumor cells extravasation. The impact of environmental signals on lung metastasis is independent of adrenergic receptors signaling. By contrast, we find that serum corticosterone levels are lower in EE mice and that glucocorticoid receptor (GR) antagonist reduces the number of lung metastasis in SE mice. In addition, the difference of the number of lung metastasis between SE and EE mice is abolished when inflammatory monocytes are rendered deficient in GR signaling. This decreased GR signaling in inflammatory monocytes of SE mice results in an exacerbated inflammatory profile in the lung. Our study shows that not only EE reduces late stages of metastatic progression in lungs but disclose a novel anti-tumor mechanism whereby GR-dependent reprogramming of inflammatory monocytes can inhibit metastatic progression in lungs. Moreover, while inflammatory monocytes have been shown to promote cancer progression, they also have an anti-tumor effect, suggesting that their role is more complex than currently thought.

Enduring effects of an unhealthy diet during adolescence on systemic but not neurobehavioural measures in adult rats.

Introduction: Adolescence is an important stage of maturation for various brain structures. It is during this time therefore that the brain may be more vulnerable to environmental factors such as diet that may influence mood and memory. Diets high in fat and sugar (termed a cafeteria diet) during adolescence have been shown to negatively impact upon cognitive performance, which may be reversed by switching to a standard diet during adulthood. Consumption of a cafeteria diet increases both peripheral and central levels of interleukin-1ß (IL-1ß), a pro-inflammatory cytokine which is also implicated in cognitive impairment during the ageing process. It is unknown whether adolescent exposure to a cafeteria diet potentiates the negative effects of IL-1ß on cognitive function during adulthood.Methods: Male Sprague-Dawley rats consumed a cafeteria diet during adolescence after which time they received a lentivirus injection in the hippocampus to induce chronic low-grade overexpression of IL-1ß. After viral integration, metabolic parameters, circulating and central pro-inflammatory cytokine levels, and cognitive behaviours were assessed.Results: Our data demonstrate that rats fed the cafeteria diet exhibit metabolic dysregulations in adulthood, which were concomitant with low-grade peripheral and central inflammation. Overexpression of hippocampal IL-1ß in adulthood impaired spatial working memory. However, adolescent exposure to a cafeteria diet, combined with or without hippocampal IL-1ß in adulthood did not induce any lasting cognitive deficits when the diet was replaced with a standard diet in adulthood. Discussion: These data demonstrate that cafeteria diet consumption during adolescence induces metabolic and inflammatory changes, but not behavioural changes in adulthood.

Prior maternal separation stress alters the dendritic complexity of new hippocampal neurons and neuroinflammation in response to an inflammatory stressor in juvenile female rats.

Stress during critical periods of neurodevelopment is associated with an increased risk of developing stress-related psychiatric disorders, which are more common in women than men. Hippocampal neurogenesis (the birth of new neurons) is vulnerable to maternal separation (MS) and inflammatory stressors, and emerging evidence suggests that hippocampal neurogenesis is more sensitive to stress in the ventral hippocampus (vHi) than in the dorsal hippocampus (dHi). Although research into the effects of MS stress on hippocampal neurogenesis is well documented in male rodents, the effect in females remains underexplored. Similarly, reports on the impact of inflammatory stressors on hippocampal neurogenesis in females are limited, especially when female bias in the prevalence of stress-related psychiatric disorders begins to emerge. Thus, in this study we investigated the effects of MS followed by an inflammatory stressor (lipopolysaccharide, LPS) in early adolescence on peripheral and hippocampal inflammatory responses and hippocampal neurogenesis in juvenile female rats. We show that MS enhanced an LPS-induced increase in the pro-inflammatory cytokine IL-1ß in the vHi but not in the dHi. However, microglial activation was similar following LPS alone or MS alone in both hippocampal regions, while MS prior to LPS reduced microglial activation in both dHi and vHi. The production of new neurons was unaffected by MS and LPS. MS and LPS independently reduced the dendritic complexity of new neurons, and MS exacerbated LPS-induced reductions in the complexity of distal dendrites of new neurons in the vHi but not dHi. These data highlight that MS differentially primes the physiological response to LPS in the juvenile female rat hippocampus.

Quality of life of children treated for unilateral hearing loss: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the treatments' consequences for unilateral hearing loss in children. DESIGN: Systematic review and meta-analysis (CRD42018109417). The MEDLINE, CENTRAL, ISRCTN and ClinicalTrials databases were searched between September 2018 and May 2019. Articles were screened and data were collected independently by two authors following the Cochrane and Preferred Reporting Items for Systematic review and Meta-Analysis guidelines. The risk of bias was evaluated using the Cochrane tool, the Newcastle-Ottawa Scale, the National Institute of Health, USA tool and considering the risk of confounding. In the studies with the lowest risk of bias, a meta-analysis was conducted. INTERVENTIONS: Validated hearing rehabilitation devices. PATIENTS: 6-15 years old children with moderate to profound unilateral hearing loss. MAIN OUTCOME MEASURES: The primary study outcome was children's quality of life. Academic performances were studied as an additional outcome. RESULTS: 731 unique articles were identified from the primary search. Of these, 18 articles met the Population, Intervention, Control, Outcomes and Study design selection criteria. In the eight studies with the lowest risk of bias, two meta-analysis were conducted. There was not enough data on academic results to conduct a meta-analysis. In 73 children included in a fixed effect meta-analysis (two studies), no effect of treatment could be shown (g=-0.20, p=0.39). In 61 children included in a random-effect meta-analysis (six studies), a strong positive effect of hearing treatment on quality of life was demonstrated (g=1.32, p<0.05). CONCLUSIONS: The treatment of unilateral hearing loss seems to improve children's quality of life. Further research is needed to identify the most effective treatment and its corresponding indications.

The adiponectin receptor agonist AdipoRon normalizes glucose metabolism and prevents obesity but not growth retardation induced by glucocorticoids in young mice.

OBJECTIVE: Glucocorticoids (GCs) are highly effective anti-inflammatory and immunosuppressive drugs. However, prolonged GC therapy may cause numerous adverse effects leading to diabetes and obesity, as well as bone disorders such as osteoporosis in adults and growth retardation in children and adolescents. Prevention and care of the GC-induced adverse effects remain challenging. We have previously demonstrated the efficacy of a treatment with a non-peptidic agonist of adiponectin receptors, AdipoRon, to reverse behaviour disorders and fat mass gain induced by long-term GC treatment. In this work, we have established a relevant model of GC-induced growth and metabolic disorders and determined that AdipoRon is a potential therapeutic tool to reverse these metabolic disturbances. METHODS: 5-Week-old mice were treated continuously with or without corticosterone (35 mg/L) in drinking water for seven consecutive weeks. Taking advantage of this mouse model displaying various growth and metabolic disorders, we assayed whether AdipoRon (daily intraperitoneal injection of 1 mg/kg/day for the last 20 days) might prevent the GC-induced adverse effects. The control group was treated with vehicle only. Nutritional behaviors and metabolic parameters were followed-up throughout the treatment. Serum insulin and leptin levels were measured by ELISA. Computed tomography and histological analysis of adipose tissue were assessed at the end of the experimental procedure. RESULTS: We found that GC treatment in young mice resulted in continuously increased body weight gain associated with a food intake increase. Compared to vehicle-, GC-treated mice displayed early major hyperleptinemia (up to 6-fold more) and hyperinsulinemia (up to 20-fold more) maintained throughout the treatment. At the end of the experimental procedure, GC-treated mice displayed bone growth retardation (e.g. femur length 15.1 versus 14.0 mm, P < 0.01), higher abdominal adipose tissue volume (4.1 versus 2.3, P < 0.01) and altered glucose metabolism compared to control mice. Interestingly, AdipoRon prevented GC-induced effects on energy metabolism such as abdominal adiposity, insulinemia and leptinemia. However, AdipoRon failed to counteract bone growth retardation. CONCLUSION: We characterized the very early pathological steps induced by long-term GC in young mice in a relevant model, including growth retardation, fat mass gain and glucose homeostasis dysregulation. The adiponectin system stimulation enabled normalization of the adipose tissue and metabolic features of GC-treated mice. Adiponectin receptor agonists such as AdipoRon might constitute a novel way to counteract some GC-induced adverse effects.

Long-term Vertigo Control and Vestibular Function After Low-dose On-demand Transtympanic Gentamicin for Refractory Menière's Disease.

OBJECTIVE: To describe the long-term clinical vertigo control along with measured lateral canal vestibular function in patients with unilateral refractory Menière's disease (MD) treated with gentamicin transtympanic injections (TTI). STUDY DESIGN: Retrospective analytic study. SETTING: Tertiary referral center. PATIENTS: Thirty-eight patients treated by TTI for medically refractory unilateral MD, defined by the 1995 AAO-HNS criteria, between May 2006 and December 2012. INTERVENTION(S): One-year course of treatment with gentamicin TTI following a low dose on-demand protocol. TTI were repeated in new courses of treatment when MD recurrence occurred. MAIN OUTCOME MEASURE(S): AAO-HNS class of control, caloric tests (CalT), recurrence rate. RESULTS: After an average clinical follow-up of 71 months, all patients entered a class of control A (78%) or B (22%), with an average of 2.3 TTI received. The mean maximal obtained deficit was 88.5%, and the mean long-term deficit was 85.5%. Ten (26%) patients had disease recurrence requiring a new course of treatment. A value of the first CalT in the 3 months following the first TTI strictly higher than 78% was significantly associated with disease control and the absence of symptom recurrence (p≤0.01). In the "recurrence" group, four patients had a significantly lower mean value of all CalT performed after the first TTI when compared with other patients (p≤0.001), indicating gentamicin resistance CONCLUSION:: Achieving a sustainable vestibular deficit on caloric testing is key for MD symptom control after gentamicin TTI. Gentamicin resistance must be diagnosed early to adapt therapeutic strategies.

Adiporon, an adiponectin receptor agonist acts as an antidepressant and metabolic regulator in a mouse model of depression.

Major depression is a psychiatric disorder with complex etiology. About 30% of depressive patients are resistant to antidepressants that are currently available, likely because they only target the monoaminergic systems. Thus, identification of novel antidepressants with a larger action spectrum is urgently required. Epidemiological data indicate high comorbidity between metabolic and psychiatric disorders, particularly obesity and depression. We used a well-characterized anxiety/depressive-like mouse model consisting of continuous input of corticosterone for seven consecutive weeks. A panel of reliable behavioral tests were conducted to assessing numerous facets of the depression-like state, including anxiety, resignation, reduced motivation, loss of pleasure, and social withdrawal. Furthermore, metabolic features including weight, adiposity, and plasma biological parameters (lipids, adipokines, and cytokines) were investigated in corticosterone-treated mice. Our data show that chronic administration of corticosterone induced the parallel onset of metabolic and behavioral dysfunctions in mice. AdipoRon, a potent adiponectin receptor agonist, prevented the corticosterone-induced early onset of moderate obesity and metabolic syndromes. Moreover, in all the behavioral tests, daily treatment with AdipoRon successfully reversed the corticosterone-induced depression-like state in mice. AdipoRon exerted its pleiotropic actions on various systems including hippocampal neurogenesis, serotonergic neurotransmission, neuroinflammation, and the tryptophan metabolic pathway, which can explain its antidepressant properties. Our study highlights the pivotal role of the adiponergic system in the development of both metabolic and psychiatric disorders. AdipoRon may constitute a promising novel antidepressant.

[Adiponectin: an endogenous molecule with anti-inflammatory and antidepressant properties?] / L'adiponectine - Un anti-inflammatoire et anti-dépresseur endogène ?

Adiponectin (ApN) is a hormone produced by adipose tissue, yet the plasma level of ApN is decreased in overweight and obese people, as well as in people with diabetes. In the periphery, this decrease in circulating levels of ApN induces the establishment of a chronic low-grade inflammatory state and is involved in the development of insulin resistance and atheromas. Conversely, "favorable" living conditions, weight loss and regular physical exercise increase ApN blood concentration. Some forms of ApN can reach the brain parenchyma through the cerebrospinal fluid. In the brain, the increase in ApN exerts powerful antidepressant and anxiolytic effects, in particular by fighting against neuroinflammation.

CD8+ T cells are essential for the effects of enriched environment on hippocampus-dependent behavior, hippocampal neurogenesis and synaptic plasticity.

Enriched environment (EE) induces plasticity changes in the brain. Recently, CD4+ T cells have been shown to be involved in brain plasticity processes. Here, we show that CD8+ T cells are required for EE-induced brain plasticity in mice, as revealed by measurements of hippocampal volume, neurogenesis in the DG of the hippocampus, spinogenesis and glutamatergic synaptic function in the CA of the hippocampus. As a consequence, EE-induced behavioral benefits depend, at least in part, on CD8+ T cells. In addition, we show that spleen CD8+ T cells from mice housed in standard environment (SE) and EE have different properties in terms of 1) TNFα release after in vitro CD3/CD28 or PMA/Iono stimulation 2) in vitro proliferation properties 3) CD8+ CD44+ CD62Llow and CD62Lhi T cells repartition 4) transcriptomic signature as revealed by RNA sequencing. CD8+ T cells purified from the choroid plexus of SE and EE mice also exhibit different transcriptomic profiles as highlighted by single-cell mRNA sequencing. We show that CD8+ T cells are essential mediators of beneficial EE effects on brain plasticity and cognition. Additionally, we propose that EE differentially primes CD8+ T cells leading to behavioral improvement.

Globular Adiponectin Limits Microglia Pro-Inflammatory Phenotype through an AdipoR1/NF-κB Signaling Pathway.

We recently reported that increased levels of Adiponectin (ApN) in the brain led to microglia phenotype and activation state regulation, thus reducing both global brain inflammation and depressive-like behaviors in mice. Apart from this, little is known on ApN molecular effects on microglia, although these cells are crucial in both physiological and pathological processes. Here we fill this gap by studying the effects and targets of ApN toward neuroinflammation. Our findings suggest that ApN deficiency in mice leads to a higher sensitivity of mice to neuroinflammation that is due to enhanced microglia responsiveness to a pro-inflammatory challenge. Moreover, we show that globular ApN (gApN) exerts direct in vivo anti-inflammatory actions on microglia by reducing IL-1ß, IL-6, and TNFα synthesis. In vitro, gApN anti-inflammatory properties are confirmed in brain-sorted microglia, primary cultured and microglia cell line (BV2), but are not observed on astrocytes. Our results also show that gApN blocks LPS-induced nitrosative and oxidative stress in microglia. Finally, we demonstrate for the first time that these anti-inflammatory and anti-oxidant actions of gApN on microglia are mediated through an AdipoR1/NF-κB signaling pathway.

Fatty acids from fat cell lipolysis do not activate an inflammatory response but are stored as triacylglycerols in adipose tissue macrophages.

AIMS/HYPOTHESIS: Activation of macrophages by fatty acids (FAs) is a potential mechanism linking obesity to adipose tissue (AT) inflammation and insulin resistance. Here, we investigated the effects of FAs released during adipocyte lipolysis on AT macrophages (ATMs). METHODS: Human THP-1 macrophages were treated with media from human multipotent adipose-derived stem (hMADS) adipocytes stimulated with lipolytic drugs. Macrophages were also treated with mixtures of FAs and an inhibitor of Toll-like receptor 4, since this receptor is activated by saturated FAs. Levels of mRNA and the secretion of inflammation-related molecules were measured in macrophages. FA composition was determined in adipocytes, conditioned media and macrophages. The effect of chronic inhibition or acute activation of fat cell lipolysis on ATM response was investigated in vivo in mice. RESULTS: Whereas palmitic acid alone activates THP-1, conditioned media from hMADS adipocyte lipolysis had no effect on IL, chemokine and cytokine gene expression, and secretion by macrophages. Mixtures of FAs representing de novo lipogenesis or habitual dietary conditions also had no effect. FAs derived from adipocyte lipolysis were taken up by macrophages and stored as triacylglycerol droplets. In vivo, chronic treatment with an antilipolytic drug did not modify gene expression and number of ATMs in mice with intact or defective Tlr4. Stimulation of adipocyte lipolysis increased storage of neutral lipids by macrophages without change in number and phenotype. CONCLUSIONS/INTERPRETATION: Our data suggest that adipocyte lipolysis does not activate inflammatory pathways in ATMs, which instead may act as scavengers of FAs.

Enriched environment decreases microglia and brain macrophages inflammatory phenotypes through adiponectin-dependent mechanisms: Relevance to depressive-like behavior.

Regulation of neuroinflammation by glial cells plays a major role in the pathophysiology of major depression. While astrocyte involvement has been well described, the role of microglia is still elusive. Recently, we have shown that Adiponectin (ApN) plays a crucial role in the anxiolytic/antidepressant neurogenesis-independent effects of enriched environment (EE) in mice; however its mechanisms of action within the brain remain unknown. Here, we show that in a murine model of depression induced by chronic corticosterone administration, the hippocampus and the hypothalamus display increased levels of inflammatory cytokines mRNA, which is reversed by EE housing. By combining flow cytometry, cell sorting and q-PCR, we show that microglia from depressive-like mice adopt a pro-inflammatory phenotype characterized by higher expression levels of IL-1ß, IL-6, TNF-α and IκB-α mRNAs. EE housing blocks pro-inflammatory cytokine gene induction and promotes arginase 1 mRNA expression in brain-sorted microglia, indicating that EE favors an anti-inflammatory activation state. We show that microglia and brain-macrophages from corticosterone-treated mice adopt differential expression profiles for CCR2, MHC class II and IL-4recα surface markers depending on whether the mice are kept in standard environment or EE. Interestingly, the effects of EE were abolished when cells are isolated from ApN knock-out mouse brains. When injected intra-cerebroventricularly, ApN, whose level is specifically increased in cerebrospinal fluid of depressive mice raised in EE, rescues microglia phenotype, reduces pro-inflammatory cytokine production by microglia and blocks depressive-like behavior in corticosterone-treated mice. Our data suggest that EE-induced ApN increase within the brain regulates microglia and brain macrophages phenotype and activation state, thus reducing neuroinflammation and depressive-like behaviors in mice.

Neurogenesis-independent antidepressant-like effects of enriched environment is dependent on adiponectin.

Environmental enrichment (EE) that combines voluntary physical exercise, sensory and social stimuli, causes profound changes in rodent brain at molecular, anatomical and behavioral levels. Here, we show that EE efficiently reduces anxiety and depression-like behaviors in a mouse model of depression induced by long-term administration of corticosterone. Mechanisms underlying EE-related beneficial effects remain largely unexplored; however, our results point toward adiponectin, an adipocyte-secreted protein, as a main contributor. Indeed, adiponectin-deficient (adipo(-/-)) mice did not benefit from all the EE-induced anxiolytic and antidepressant-like effects as evidenced by their differential responses in a series of behavioral tests. Conversely, a single intravenous injection of exogenous adiponectin restored the sensitivity of adipo(-/-) mice to EE-induced behavioral benefits. Interestingly, adiponectin depletion did not prevent the hippocampal neurogenesis induced by EE. Therefore, antidepressant properties of adiponectin are likely to be related to changes in signaling in the hypothalamus rather than through hippocampal-neurogenesis mechanisms. Additionally, EE did not modify the plasma levels of adiponectin but may favor the passage of adiponectin from the blood to the cerebrospinal fluid. Our findings provide advances in the understanding of the anxiolytic and antidepressant-like effects of EE and highlight adiponectin as a pivotal mediator.