SNORA69 is up-regulated in the lateral habenula of individuals with major depressive disorder.

Major depressive disorder (MDD) is a complex and potentially debilitating illness whose etiology and pathology remains unclear. Non-coding RNAs have been implicated in MDD, where they display differential expression in the brain and the periphery. In this study, we quantified small nucleolar RNA (snoRNA) expression by small RNA sequencing in the lateral habenula (LHb) of individuals with MDD (n = 15) and psychiatrically-healthy controls (n = 15). We uncovered five snoRNAs that exhibited differential expression between MDD and controls (FDR < 0.01). Specifically, SNORA69 showed increased expression in MDD and was technically validated via RT-qPCR. We further investigated the expression of Snora69 in the LHb and peripheral blood of an unpredicted chronic mild stress (UCMS) mouse model of depression. Snora69 was specifically up-regulated in mice that underwent the UCMS paradigm. SNORA69 is known to guide pseudouridylation onto 5.8S and 18S rRNAs. We quantified the relative abundance of pseudouridines on 5.8S and 18S rRNA in human post-mortem LHb samples and found increased abundance of pseudouridines in the MDD group. Overall, our findings indicate the importance of brain snoRNAs in the pathology of MDD. Future studies characterizing SNORA69's role in MDD pathology is warranted.

The dangerous "West Coast Swing" by hyperglycaemia and chronic stress in the mouse hippocampus: Role of kynurenine catabolism.

Growing epidemiological studies highlight a bi-directional relationship between depressive symptoms and diabetes mellitus. However, the detrimental impact of their co-existence on mental health suggests the need to treat this comorbidity as a separate entity rather than the two different pathologies. Herein, we characterized the peculiar mechanisms activated in mouse hippocampus from the concurrent development of hyperglycaemia, characterizing the different diabetes subtypes, and chronic stress, recognized as a possible factor predisposing to major depression. Our work demonstrates that kynurenine overproduction, leading to apoptosis in the hippocampus, is triggered in a different way depending on hyperglycaemia or chronic stress. Indeed, in the former, kynurenine appears produced by infiltered macrophages whereas, in the latter, peripheral kynurenine preferentially promotes resident microglia activation. In this scenario, QA, derived from kynurenine catabolism, appears a key mediator causing glutamatergic synapse dysfunction and apoptosis, thus contributing to brain atrophy. We demonstrated that the coexistence of hyperglycaemia and chronic stress worsened hippocampal damage through alternative mechanisms, such as GLUT-4 and BDNF down-expression, denoting mitochondrial dysfunction and apoptosis on one hand and evoking the compromission of neurogenesis on the other. Overall, in the degeneration of neurovascular unit, hyperglycaemia and chronic stress interacted each other as the partners of a "West Coast Swing" in which the leading role can be assumed alternatively by each partner of the dance. The comprehension of these mechanisms can open novel perspectives in the management of diabetic/depressed patients, but also in the understanding the pathogenesis of other neurodegenerative disease characterized by the compromission of hippocampal function.

The Human Affectome.

Over the last decades, theoretical perspectives in the interdisciplinary field of the affective sciences have proliferated rather than converged due to differing assumptions about what human affective phenomena are and how they work. These metaphysical and mechanistic assumptions, shaped by academic context and values, have dictated affective constructs and operationalizations. However, an assumption about the purpose of affective phenomena can guide us to a common set of metaphysical and mechanistic assumptions. In this capstone paper, we home in on a nested teleological principle for human affective phenomena in order to synthesize metaphysical and mechanistic assumptions. Under this framework, human affective phenomena can collectively be considered algorithms that either adjust based on the human comfort zone (affective concerns) or monitor those adaptive processes (affective features). This teleologically-grounded framework offers a principled agenda and launchpad for both organizing existing perspectives and generating new ones. Ultimately, we hope the Human Affectome brings us a step closer to not only an integrated understanding of human affective phenomena, but an integrated field for affective research.

Cerebral Metabolic Signature of Chronic Benzodiazepine Use in Nondemented Older Adults: An FDG-PET Study in the MEMENTO Cohort.

OBJECTIVE: We sought to examine the association between chronic Benzodiazepine (BZD) use and brain metabolism obtained from 2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET) in the MEMENTO clinical cohort of nondemented older adults with an isolated memory complaint or mild cognitive impairment at baseline. METHODS: Our analysis focused on 3 levels: (1) the global mean brain standardized uptake value (SUVR), (2) the Alzheimer's disease (AD)-specific regions of interest (ROIs), and (3) the ratio of total SUVR on the brain and different anatomical ROIs. Cerebral metabolism was obtained from 2-deoxy-2-fluoro-D-glucose-FDG-PET and compared between chronic BZD users and nonusers using multiple linear regressions adjusted for age, sex, education, APOE ε 4 copy number, cognitive and neuropsychiatric assessments, history of major depressive episodes and antidepressant use. RESULTS: We found that the SUVR was significantly higher in chronic BZD users (n = 192) than in nonusers (n = 1,122) in the whole brain (beta = 0.03; p = 0.038) and in the right amygdala (beta = 0.32; p = 0.012). Trends were observed for the half-lives of BZDs (short- and long-acting BZDs) (p = 0.051) and Z-drug hypnotic treatments (p = 0.060) on the SUVR of the right amygdala. We found no significant association in the other ROIs. CONCLUSION: Our study is the first to find a greater global metabolism in chronic BZD users and a specific greater metabolism in the right amygdala. Because the acute administration of BZDs tends to reduce brain metabolism, these findings may correspond to a compensatory mechanism while the brain adapts with global metabolism upregulation, with a specific focus on the right amygdala.

Improvement of hedonic perception of odors as a marker of treatment response to escitalopram: olfactory changes through an open-label antidepressant trial

Objectives: To assess olfactory functions (threshold, identification, and hedonic valence) of depressed subjects before and after an 8-week trial of escitalopram and compare the results of responders and nonresponders. Methods: Fifty-two depressed subjects were recruited. Participants received escitalopram and were evaluated at two visits: baseline (V0) and week 8 (V8). They were categorized as responders (Montgomery-Åsberg Depression Rating Scale [MADRS] score reduction of > 50%) or nonresponders to treatment. Participants were evaluated with the Mini International Neuropsychiatric Interview (MINI) at V0 and, at V0 and V8, completed psychometric and olfactory assessments, including MADRS and the State-Trait Anxiety Inventory (STAI), as well as the Sniffin' Sticks® test (threshold and identification tasks). The hedonic valence of smell was assessed on a 10-cm linear scale after presenting two pleasant and two unpleasant odors. Forty-three participants completed the study (24 responders and 19 nonresponders). The Mann-Whitney, chi-square, and Fisher's exact tests were used to compare olfactory, clinical, and demographic variables between groups and within the same group at V0 and V8. The Spearman coefficient was used to calculate the correlation between clinical characteristics and olfactory variables. Results: The hedonic score of pleasant odors increased significantly between V0 and V8 only for responders (V = 61.5, p = 0.018), with no significant change in nonresponders (V = 90.5, p = 0.879). Comparison of olfactory performances between groups at V0 and V8 separately did not show a significant difference between responders and nonresponders to escitalopram. Olfactory threshold and identification scores were not different between V0 and V8 for responders or nonresponders. Conclusion: Depressed subjects have olfactory anhedonia, which appears to regress following a positive antidepressant response. Hedonic valence may be an indicator of cognitive changes associated with depression; improvement of this valence may indicate a clinical response to antidepressants.

Improvement of hedonic perception of odors as a marker of treatment response to escitalopram: olfactory changes through an open-label antidepressant trial.

OBJECTIVES: To assess olfactory functions (threshold, identification, and hedonic valence) of depressed subjects before and after an 8-week trial of escitalopram and compare the results of responders and nonresponders. METHODS: Fifty-two depressed subjects were recruited. Participants received escitalopram and were evaluated at two visits: baseline (V0) and week 8 (V8). They were categorized as responders (Montgomery-Åsberg Depression Rating Scale [MADRS] score reduction of > 50%) or nonresponders to treatment. Participants were evaluated with the Mini International Neuropsychiatric Interview (MINI) at V0 and, at V0 and V8, completed psychometric and olfactory assessments, including MADRS and the State-Trait Anxiety Inventory (STAI), as well as the Sniffin' Sticks® test (threshold and identification tasks). The hedonic valence of smell was assessed on a 10-cm linear scale after presenting two pleasant and two unpleasant odors. Forty-three participants completed the study (24 responders and 19 nonresponders). The Mann-Whitney, chi-square, and Fisher's exact tests were used to compare olfactory, clinical, and demographic variables between groups and within the same group at V0 and V8. The Spearman coefficient was used to calculate the correlation between clinical characteristics and olfactory variables. RESULTS: The hedonic score of pleasant odors increased significantly between V0 and V8 only for responders (V = 61.5, p = 0.018), with no significant change in nonresponders (V = 90.5, p = 0.879). Comparison of olfactory performances between groups at V0 and V8 separately did not show a significant difference between responders and nonresponders to escitalopram. Olfactory threshold and identification scores were not different between V0 and V8 for responders or nonresponders. CONCLUSION: Depressed subjects have olfactory anhedonia, which appears to regress following a positive antidepressant response. Hedonic valence may be an indicator of cognitive changes associated with depression; improvement of this valence may indicate a clinical response to antidepressants.

Changes in cerebral connectivity and brain tissue pulsations with the antidepressant response to an equimolar mixture of oxygen and nitrous oxide: an MRI and ultrasound study.

Nitrous oxide (N2O) has recently emerged as a potential fast-acting antidepressant but the cerebral mechanisms involved in this effect remain speculative. We hypothesized that the antidepressant response to an Equimolar Mixture of Oxygen and Nitrous Oxide (EMONO) would be associated with changes in cerebral connectivity and brain tissue pulsations (BTP). Thirty participants (20 with a major depressive episode resistant to at least one antidepressant and 10 healthy controls-HC, aged 25-50, only females) were exposed to a 1-h single session of EMONO and followed for 1 week. We defined response as a reduction of at least 50% in the MADRS score 1 week after exposure. Cerebral connectivity of the Anterior Cingulate Cortex (ACC), using ROI-based resting state fMRI, and BTP, using ultrasound Tissue Pulsatility Imaging, were compared before and rapidly after exposure (as well as during exposure for BTP) among HC, non-responders and responders. We conducted analyses to compare group × time, group, and time effects. Nine (45%) depressed participants were considered responders and eleven (55%) non-responders. In responders, we observed a significant reduction in the connectivity of the subgenual ACC with the precuneus. Connectivity of the supracallosal ACC with the mid-cingulate also significantly decreased after exposure in HC and in non-responders. BTP significantly increased in the three groups between baseline and gas exposure, but the increase in BTP within the first 10 min was only significant in responders. We found that a single session of EMONO can rapidly modify the functional connectivity in the subgenual ACC-precuneus, nodes within the default mode network, in depressed participants responders to EMONO. In addition, larger increases in BTP, associated with a significant rise in cerebral blood flow, appear to promote the antidepressant response, possibly by facilitating optimal drug delivery to the brain. Our study identified potential cerebral mechanisms related to the antidepressant response of N2O, as well as potential markers for treatment response with this fast-acting antidepressant.

SNORD90 induces glutamatergic signaling following treatment with monoaminergic antidepressants.

Pharmacotherapies for the treatment of major depressive disorder were serendipitously discovered almost seven decades ago. From this discovery, scientists pinpointed the monoaminergic system as the primary target associated with symptom alleviation. As a result, most antidepressants have been engineered to act on the monoaminergic system more selectively, primarily on serotonin, in an effort to increase treatment response and reduce unfavorable side effects. However, slow and inconsistent clinical responses continue to be observed with these available treatments. Recent findings point to the glutamatergic system as a target for rapid acting antidepressants. Investigating different cohorts of depressed individuals treated with serotonergic and other monoaminergic antidepressants, we found that the expression of a small nucleolar RNA, SNORD90, was elevated following treatment response. When we increased Snord90 levels in the mouse anterior cingulate cortex (ACC), a brain region regulating mood responses, we observed antidepressive-like behaviors. We identified neuregulin 3 (NRG3) as one of the targets of SNORD90, which we show is regulated through the accumulation of N6-methyladenosine modifications leading to YTHDF2-mediated RNA decay. We further demonstrate that a decrease in NRG3 expression resulted in increased glutamatergic release in the mouse ACC. These findings support a molecular link between monoaminergic antidepressant treatment and glutamatergic neurotransmission.

Neurostimulation as a treatment for mood disorders in patients: recent findings.

PURPOSE OF REVIEW: The use of neurostimulation to treat mood disorders dates back to the 1930s. Recent studies have explored various neurostimulation methods aimed at both restoring a healthy brain and reducing adverse effects in patients. The purpose of this review is to explore the most recent hypotheses and clinical studies investigating the effects of stimulating the brain on mood disorders. RECENT FINDINGS: Recent work on brain stimulation and mood disorders has focused mainly on three aspects: enhancing efficacy and safety by developing new approaches and protocols, reducing treatment duration and chances of relapse, and investigating the physiological and pathological mechanisms behind treatment outcomes and possible adverse effects.This review includes some of the latest studies on both noninvasive techniques, such as transcranial magnetic stimulation, magnetic seizure therapy, transcranial direct current stimulation, transcranial alternating current stimulation, electroconvulsive treatment, and invasive techniques, such as deep brain stimulation and vagus nerve stimulation. SUMMARY: Brain stimulation is widely used in clinical settings; however, there is a lack of understanding about its neurobiological mechanism. Further studies are needed to understand the neurobiology of brain stimulation and how it can be used to treat mood disorders in their diversity, including comorbidities with other illnesses.

Glutamatergic synapse in autism: a complex story for a complex disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder whose pathophysiological mechanisms are still unclear. Hypotheses suggest a role for glutamate dysfunctions in ASD development, but clinical studies investigating brain and peripheral glutamate levels showed heterogenous results leading to hypo- and hyper-glutamatergic hypotheses of ASD. Recently, studies proposed the implication of elevated mGluR5 densities in brain areas in the pathophysiology of ASD. Thus, our objective was to characterize glutamate dysfunctions in adult subjects with ASD by quantifying (1) glutamate levels in the cingulate cortex and periphery using proton magnetic resonance spectroscopy and metabolomics, and (2) mGluR5 brain density in this population and in a validated animal model of ASD (prenatal exposure to valproate) at developmental stages corresponding to childhood and adolescence in humans using positron emission tomography. No modifications in cingulate Glu levels were observed between individuals with ASD and controls further supporting the difficulty to evaluate modifications in excitatory transmission using spectroscopy in this population, and the complexity of its glutamate-related changes. Our imaging results showed an overall increased density in mGluR5 in adults with ASD, that was only observed mostly subcortically in adolescent male rats prenatally exposed to valproic acid, and not detected in the stage corresponding to childhood in the same animals. This suggest that clinical changes in mGluR5 density could reflect the adaptation of the glutamatergic dysfunctions occurring earlier rather than being key to the pathophysiology of ASD.

An ecological animal model of subthreshold depression in adolescence: behavioral and resting state 18F-FDG PET imaging characterization.

The different depressive disorders that exist can take root at adolescence. For instance, some functional and structural changes in several brain regions have been observed from adolescence in subjects that display either high vulnerability to depressive symptoms or subthreshold depression. For instance, adolescents with depressive disorder have been shown to exhibit hyperactivity in hippocampus, amygdala and prefrontal cortex as well as volume reductions in hippocampus and amygdala (prefrontal cortex showing more variable results). However, no animal model of adolescent subthreshold depression has been developed so far. Our objective was to design an animal model of adolescent subthreshold depression and to characterize the neural changes associated to this phenotype. For this purpose, we used adolescent Swiss mice that were evaluated on 4 tests assessing cognitive abilities (Morris water maze), anhedonia (sucrose preference), anxiety (open-field) and stress-coping strategies (forced swim test) at postnatal day (PND) 28-35. In order to identify neural alterations associated to behavioral profiles, we assessed brain resting state metabolic activity in vivo using 18F-FDG PET imaging at PND 37. We selected three profiles of mice distinguished in a composite Z-score computed from performances in the behavioral tests: High, Intermediate and Low Depressive Risk (HDR, IDR and LDR). Compared to both IDR and LDR, HDR mice were characterized by passive stress-coping behaviors, low cognition and high anhedonia and anxiety and were associated with significant changes of 18F-FDG uptakes in several cortical and subcortical areas including prelimbic cortex, infralimbic cortex, nucleus accumbens, amygdala, periaqueductal gray and superior colliculus, all displaying higher metabolic activity, while only the thalamus was associated with lower metabolic activity (compared to IDR). LDR displayed an opposing behavioral phenotype and were associated with significant changes of 18F-FDG uptakes in the dorsal striatum and thalamus that both exhibited markedly lower metabolic activity in LDR. In conclusion, our study revealed changes in metabolic activities that can represent neural signatures for behavioral profiles predicting subthreshold depression at adolescence in a mouse model.

Decrease in ultrasound Brain Tissue Pulsations as a potential surrogate marker of response to antidepressant.

Previous cross-sectional studies found excessive Brain Tissue Pulsations (BTP) in mid-life depression, which could constitute a mechanism of brain damage in depression. However, it remains unclear whether successful antidepressant therapy restores BTP amplitudes. In this prospective study, we investigated longitudinal changes in BTP in patients with a major depressive episode (MDE), among responders and non-responders to escitalopram. Fifty-two individuals with a MDE, free of antidepressants at baseline, were included in an 8-week open-labeled escitalopram trial. Ultrasound Tissue Pulsatility Imaging (TPI) was applied to measure resting BTP and BTP reactivity in an orthostatic challenge, at baseline and at week 8. TPI data were available for 48 participants divided into responders (n = 28, 58.3%) and non-responders (n = 20, 41.7%) according to change in the MADRS score. MaxBTP significantly decreased between baseline and week 8, only in responders. In addition, changes in MaxBTP during the orthostatic challenge were no longer significant at week 8 but only in responders. Because excessive BTP constitutes a potential mechanism for brain damage, our results suggest that a successful pharmacotherapy could benefit patients to lower the risk of brain damage in individuals with depression, a population exposed to stroke, small arteries disease and brain atrophy. TPI could provide a surrogate biomarker to monitor antidepressant response and brain health in depression in clinical routine.

Child abuse associates with increased recruitment of perineuronal nets in the ventromedial prefrontal cortex: a possible implication of oligodendrocyte progenitor cells.

Child abuse (CA) is a strong predictor of psychopathologies and suicide, altering normal trajectories of brain development in areas closely linked to emotional responses such as the prefrontal cortex (PFC). Yet, the cellular underpinnings of these enduring effects are unclear. Childhood and adolescence are marked by the protracted formation of perineuronal nets (PNNs), which orchestrate the closure of developmental windows of cortical plasticity by regulating the functional integration of parvalbumin interneurons into neuronal circuits. Using well-characterized post-mortem brain samples, we show that a history of CA is specifically associated with increased densities and morphological complexity of WFL-labeled PNNs in the ventromedial PFC (BA11/12), possibly suggesting increased recruitment and maturation of PNNs. Through single-nucleus sequencing and fluorescent in situ hybridization, we found that the expression of canonical components of PNNs is enriched in oligodendrocyte progenitor cells (OPCs), and that they are upregulated in CA victims. These correlational findings suggest that early-life adversity may lead to persistent patterns of maladaptive behaviors by reducing the neuroplasticity of cortical circuits through the enhancement of developmental OPC-mediated PNN formation.

Benzodiazepine use and neuroimaging markers of Alzheimer's disease in nondemented older individuals: an MRI and 18F Florbetapir PET study in the MEMENTO cohort.

Recent evidence suggests an association between benzodiazepines (BZDs) use and lower brain amyloid load, a hallmark of AD pathophysiology. Other AD-related markers include hippocampal atrophy, but the effect of BZDs on hippocampal volume remains unclear. We aimed at 1) replicating findings on BZDs use and brain amyloid load and 2) investigating associations between BZDs use and hippocampal volume, in the MEMENTO clinical cohort of nondemented older adults with isolated memory complaint or light cognitive impairment at baseline. Total Standardized Uptake Value Ratio (SUVR) of brain amyloid load and hippocampal volume (HV) were obtained, respectively, from 18F Florbetapir positron emission tomography (PET) and magnetic resonance imaging (MRI), and compared between BZD chronic users and nonusers using multiple linear regressions adjusted for age, sex, educational level, ApoE ε4 genotype, cognitive and neuropsychiatric assessments, history of major depressive episodes and antidepressant intake. BZD users were more likely to manifest symptoms of depression, anxiety and apathy. In the MRI subgroup, BZD users were also more frequently females with low education and greater clinical impairments as assessed with the clinical dementia rating scale. Short- versus long-acting BZDs, Z-drugs versus non-Z-drugs BZDs, as well as dose and duration of BZD use, were also considered in the analyses. Total SUVR and HV were significantly lower and larger, respectively, in BZD users (n = 38 in the PET subgroup and n = 331 in the MRI subgroup) than in nonusers (n = 251 in the PET subgroup and n = 1840 in the MRI subgroup), with a medium (Cohen's d = -0.43) and low (Cohen's d = 0.10) effect size, respectively. Short-acting BZDs and Z-drugs were more significantly associated with larger HV. We found no effect of dose and duration of BZD use. Our results support the involvement of the GABAergic system as a potential target for blocking AD-related pathophysiology, possibly via reduction in neuronal activity and neuroinflammation. Future longitudinal studies may confirm the causal effect of BZDs to block amyloid accumulation and hippocampal atrophy.

CRF-R1 Antagonist Treatment Exacerbates Circadian Corticosterone Secretion under Chronic Stress, but Preserves HPA Feedback Sensitivity.

Despite promising initial reports, corticotropin-releasing factor receptor type-1 (CRF-R1) antagonists have mostly failed to display efficacy in clinical trials for anxiety or depression. Rather than broad-spectrum antidepressant/anxiolytic-like drugs, they may represent an 'antistress' solution for single stressful situations or for patients with chronic stress conditions. However, the impact of prolonged CRF-R1 antagonist treatments on the hypothalamic-pituitary-adrenal (HPA) axis under chronic stress conditions remained to be characterized. Hence, our study investigated whether a chronic CRF-R1 antagonist (crinecerfont, formerly known as SSR125543, 20 mg·kg-1·day-1 ip, 5 weeks) would alter HPA axis basal circadian activity and negative feedback sensitivity in mice exposed to either control or chronic stress conditions (unpredictable chronic mild stress, UCMS, 7 weeks), through measures of fecal corticosterone metabolites, plasma corticosterone, and dexamethasone suppression test. Despite preserving HPA axis parameters in control non-stressed mice, the 5-week crinercerfont treatment improved the negative feedback sensitivity in chronically stressed mice, but paradoxically exacerbated their basal corticosterone secretion nearly all along the circadian cycle. The capacity of chronic CRF-R1 antagonists to improve the HPA negative feedback in UCMS argues in favor of a potential therapeutic benefit against stress-related conditions. However, the treatment-related overactivation of HPA circadian activity in UCMS raise questions about possible physiological outcomes with long-standing treatments under ongoing chronic stress.

Increasing Adult Hippocampal Neurogenesis Promotes Resilience in a Mouse Model of Depression.

Many studies evaluated the functional role of adult hippocampal neurogenesis (AHN) and its key role in cognitive functions and mood regulation. The effects of promoting AHN on the recovery of stress-induced symptoms have been well studied, but its involvement in stress resilience remains elusive. We used a mouse model enabling us to foster AHN before the exposure to unpredictable chronic mild stress (UCMS) to evaluate the potential protective effects of AHN on stress, assessing the depressive-like phenotype and executive functions. For this purpose, an inducible transgenic mouse model was used to delete the pro-apoptotic gene Bax from neural progenitors four weeks before UCMS, whereby increasing the survival of adult-generated neurons. Our results showed that UCMS elicited a depressive-like phenotype, highlighted by a deteriorated coat state, a higher immobility duration in the tail suspension test (TST), and a delayed reversal learning in a water maze procedure. Promoting AHN before UCMS was sufficient to prevent the development of stressed-induced behavioral changes in the TST and the water maze, reflecting an effect of AHN on stress resilience. Taken together, our data suggest that increasing AHN promotes stress resilience on some depressive-like symptoms but also in cognitive symptoms, which are often observed in MD.

Brain immune cells characterization in UCMS exposed P2X7 knock-out mouse.

BACKGROUND: Several lines of evidence suggest that neuroinflammation might be a key neurobiological mechanism of depression. In particular, the P2X7 receptor (P2X7R), an ATP-gated ion channel involved in activation of the pro-inflammatory interleukin IL-1ß, has been shown to be a potential new pharmacological target in depression. The aim of this study was to explore the impact of unpredictable chronic mild stress (UCMS) on behavioural changes, hippocampal neurogenesis, and cellular characterisation of brain immune cells, in P2X7R Knock-Out (KO) mice. METHODS: P2X7R KO and wild-type (WT) mice were subjected to a 6-week UCMS protocol and received a conventional oral antidepressant (15 mg.kg-1 fluoxetine) or water per os. The mice then underwent behavioural tests consisting of the tail suspension test (TST), the elevated plus maze (EPM) test, the open field test, the splash test and the nest building test (week 7). Doublecortin immunostaining (DCX) of brain slices was used to assess neurogenesis in the dentate gyrus. Iba1 and TMEM119 immunostaining was used to characterise brain immune cells, Iba1 as a macrophage marker (including microglial cells) and TMEM119 as a potential specific resident microglial cells marker. RESULTS: After a 6-week UCMS exposure, P2X7R KO mice exhibited less deterioration of their coat state, spent a significantly smaller amount of time immobile in the TST and spent a larger amount of time in the open arms of the EPM. As expected, adult ventral hippocampal neurogenesis was significantly decreased by UCMS in WT mice, while P2X7R KO mice maintained ventral hippocampal neurogenesis at similar levels in both control and UCMS conditions. In stress-related brain regions, P2X7R KO mice also exhibited less recruitment of Iba1+/TMEM119+ and Iba1+/TMEM119- cells in the brain. The ratio between these two staining patterns revealed that brain immune cells were mostly composed of Iba1+/TMEM119+ cells (87 to 99%), and this ratio was affected neither by P2X7R genetic depletion nor by antidepressant treatment. DISCUSSION: Behavioural patterns, neurogenesis levels and density of brain immune cells in P2X7R KO mice after exposure to UCMS significantly differed from control conditions. Brain immune cells were mostly increased in brain regions known to be sensitive to UCMS exposure in WT but not in P2X7R KO mice. Considering Iba1+/TMEM119- staining might characterize peripheral immune cells, the ratio between Iba1+/TMEM119+ cells and IBA1+/TMEM119- cells, suggests that the rate of peripheral immune cells recruitment may not be modified neither by P2X7R gene expression nor by antidepressant treatment.

Validation of the French Version of the Positivity Scale (P Scale).

BACKGROUND: The purpose of this study is to assess the psychometric properties of the French version of the Positivity scale (P scale), a self-report measure of positivity, which is the tendency to view and address life and experience with a positive outlook. Positivity is seen as a latent factor underlying multiple cognitive concepts such as self-esteem, life satisfaction, and optimism. METHODS: We recruited 666 volunteers (540 women and 126 men). They completed the P scale online, as well as self-report measures of psychological well-being, self-esteem, satisfaction with life, general health, and personality dimensions. The study sample was randomly split into two sub-groups, one used for exploratory factor analysis and the other for confirmatory factor analysis. RESULTS: We found conflictual results related to the uni-dimensionality of the French version of the P scale. We found good internal consistency and high concurrent validity. CONCLUSION: The French version of the P scale demonstrated good psychometric qualities and is a reliable tool that can now be used by French researchers and clinicians to assess positivity.

Neuroinflammation and depression: A review.

Some recent clinical and preclinical evidence suggests that neuroinflammation is a key factor that interacts with the three neurobiological correlates of major depressive disorder: depletion of brain serotonin, dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis and alteration of the continuous production of adult-generated neurons in the dentate gyrus of the hippocampus. This review discusses the main players in brain immunity as well as how inflammation interacts with the above three mechanisms. It is reported that kynurenine (KYN) pathway alteration in favour of its excitotoxic component and HPA axis dysregulation have the common effect of increasing extracellular glutamate levels and glutamate neurotransmission, which can impact hippocampal neurogenesis. This pathophysiological cascade appears to be triggered or sustained and reinforced by any chronic inflammatory condition involving increased circulating markers of inflammation that are able to cross the blood-brain barrier and activate microglia; it can also be the consequence of primary brain neuroinflammation, such as in neurodegenerative disorders with early manifestations that are frequently depressive symptoms. Further recent data indicate that primary microglial activation may also result from a direct impact of chronic stress on vascular function. The intricated dynamic crosstalk between neuroinflammation and other relevant neurobiological correlates of depression add to evidence that neuroinflammation may be a key therapeutic target for future therapeutic strategies in major depressive disorder.

Cholesterol homeostasis: Researching a dialogue between the brain and peripheral tissues.

Cholesterol homeostasis is a highly regulated process in human body because of its several functions underlying the biology of cell membranes, the synthesis of all steroid hormones and bile acids and the need of trafficking lipids destined to cell metabolism. In particular, it has been recognized that peripheral and central nervous system cholesterol metabolism are separated by the blood brain barrier and are regulated independently; indeed, peripherally, it depends on the balance between dietary intake and hepatic synthesis on one hand and its degradation on the other, whereas in central nervous system it is synthetized de novo to ensure brain physiology. In view of this complex metabolism and its relevant functions in mammalian, impaired levels of cholesterol can induce severe cellular dysfunction leading to metabolic, cardiovascular and neurodegenerative diseases. The aim of this review is to clarify the role of cholesterol homeostasis in health and disease highlighting new intriguing aspects of the cross talk between its central and peripheral metabolism.