Astrocytic tumour necrosis factor underlies neuron function in cognition

Pro-inflammatory cytokines have been demonstrated to have a diverse range of actions on the functioning of the CNS, and in particular learning and memory behaviours. Details of the mechanisms of action of cytokines are still to be determined. Purpose: This study uses immunohistochemistry techniques (IHC) to investigate cellular changes present in the hippocampal formation as a result of up-regulation of astrocyte-produced tumour necrosis factor (TNF)α (GFAP-TNFα+/+), prior to onset of behavioural deficits. These findings are compared directly to the hippocampal formation of a TNFα knock-out model (TNFα-/-) in which marked alterations in learning and memory are observed at the same time-point (12 wks) and to age-match wild-type mice (WT). This time period is of critical importance for further elucidating the role of TNFα in hippocampal dependent learning and memory. Methods: Hippocampi from TNFα-/-, GFAP-TNFα+/+ and WT (n = 5) were subjected to indirect IHC for the analysis of TNFα levels and distribution in regions CA1, CA3 and the dentate gyrus (DG). Results: In GFAP-TNFα+/+ there was a demonstrated accumulation of TNFα in hippocampal neurons prior to the onset of hippocampal-dependent behavioural deficits. GFAP-TNFα+/+ mice also showed a significant increase in TNFα in regions CA3 and the DG (p = <0.05) when compared to WT and TNFα-/- mice. WT mice demonstrated immunoreactivity of TNFα in regions CA1 and the DG. Conclusion: These findings suggest that astrocyte-produced TNFα is essential for normal development and functioning of the CA1 region of the hippocampus in cognitive processes. However, an overproduction of astrocytic TNFα accumulates in the neurons of the CA3 and DG regions and likely produces functional deficits, as seen in 6 months plus mice, through these regions

A systematic review of the impact of social cognitive deficits on psychosocial functioning in major depressive disorder and opportunities for therapeutic intervention

Available online 18 February 2019Social cognition is the ability to identify, perceive and interpret socially relevant information from the external world. It is an important adaptive trait, but is frequently affected in major depressive disorder by a mood-congruent interpretive bias. The present review examined the existing body of literature to determine (i) the impact social cognitive deficits in depression have on psychosocial functioning; and (ii) the utility of psychotropic, psychological and procedural interventions employed to target these deficits. A total of 107 studies met inclusion criteria for review. Social cognitive performance was found to adversely impact depressed patients' psychosocial functioning across the key domains of general cognitive functioning and quality of life. Secondly, many current therapies were found to have a normalising effect on the social cognitive abilities of subjects with major depressive disorder, both at a neural and functional level. In particular, certain anti-depressant medications corrected facial affect recognition deficits, while several psychotherapeutic approaches improved impairments in theory of mind and negative interpretive bias.Michael James Weightman, Matthew James Knight, Bernhard Theodor Baun

Anti-inflammatory treatment of depression: study protocol for a randomised controlled trial of vortioxetine augmented with celecoxib or placebo

BACKGROUND:In patients with major depressive disorder (MDD), antidepressant response and remission rates are low, highlighting the need for new treatment approaches. Recently, the abundant literature linking inflammatory processes and depressive symptoms have led to the hypothesis that selecting treatment for MDD based on the patient's inflammatory status could be a promising strategy to improve outcomes in patients suffering from MDD. The aim of the randomised control trial we propose is to investigate the antidepressant efficacy of the combined treatment of MDD with antidepressant medication plus anti-inflammatory medication in individuals with raised inflammation levels. For the first time, this study will prospectively test the efficacy of an antidepressant plus anti-inflammatory augmentation based on baseline inflammatory maker levels in MDD using a randomised controlled trial design. METHODS:This study proposes to measure blood C-reactive protein (CRP) levels before the initiation of treatment in 200 participants with MDD. Study participants are then assigned into one of two study strata: either into the 'Depression with inflammation' stratum (CRP levels > 3 mg/L); or into the 'Depression without inflammation' stratum (CRP levels ≤ 3 mg/L). Within each of the two study strata, participants randomly receive either antidepressant medication alone (vortioxetine) plus anti-inflammatory medication (celecoxib) or vortioxetine plus placebo for six weeks. At the end of the treatment period, participants have the opportunity to continue vortioxetine alone for a six-month post-trial period. Clinical outcomes are measured at baseline, fortnightly during the treatment period and at the three-month and six-month post-trial visits. The primary outcome is change in MADRS score, with a primary endpoint of a score reduction by 50% from baseline to six weeks (end of augmentation treatment with celecoxib). Secondary clinical outcomes are changes in the cognitive dimensions of depression (cognitive function, emotion processing and social cognition). Biological outcome measures (levels of CRP and other inflammatory markers) are measured at baseline, after six weeks of treatment and at the six-month post-trial visit. DISCUSSION:The current study will generate novel evidence for biomarker-based personalised antidepressant treatment selection based on patient inflammatory status before treatment. TRIAL REGISTRATION:Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000527369p . Registered on 11 April 2017.Célia Fourrier, Emma Sampson, Natalie T. Mills and Bernhard T. Baun

Cognition and related neural findings on methamphetamine use disorder: insights and treatment implications from schizophrenia research

Despite the prevalence of methamphetamine (meth) use disorder, research on meth is disproportionately scarce compared to research on other illicit drugs. Existing evidence highlights cognitive deficits as an impediment against daily function and treatment of chronic meth use. Similar deficits are also observed in schizophrenia, and this review therefore draws on schizophrenia research by examining similarities and differences between the two disorders on cognition and related neural findings. While meth use disorder and schizophrenia are two distinct disorders, they are highly co-morbid and share impairments in similar cognitive domains and altered brain structure/function. This narrative review specifically identifies overlapping features such as deficits in learning and memory, social cognition, working memory and inhibitory/impulse control. We report that while working memory deficits are a core feature of schizophrenia, such deficits are inconsistently observed following chronic meth use. Similar structural and functional abnormalities are also observed in cortical and limbic regions between the two disorders, except for cingulate activity where differences are observed. There is growing evidence that targeting cognitive symptoms may improve functional outcome in schizophrenia, with evidence of normalized abnormal brain activity in regions associated with cognition. Considering the overlap between meth use disorder and schizophrenia, targeting cognitive symptoms in people with meth use disorder may also improve treatment outcome and daily function.Alexandre A. Guerin, Yvonne Bonomo, Andrew John Lawrence, Bernhard Theodor Baune, Eric J. Nestler, Susan L. Rossell and Jee Hyun Ki

Duration of environmental enrichment determines astrocyte number and cervical lymph node T lymphocyte proportions but not the microglial number in middle-aged C57BL/6 mice

Published: 18 March 2020Environmental enrichment (EE) has been shown to modulate behavior and immunity. We recently reported that both short and long-term EE enhance baseline locomotion and alleviate depressive-like behavior, but only long-term EE affects locomotion adversely in a threatening environment and enhances anxiety-like behavior in middle-age mice. We have now investigated whether the observed changes in behavior after short- and long-term EE were associated with underlying immune changes. Hence, at the end of behavioral testing, mice were sacrificed, and brains and cervical lymph nodes were collected to investigate the differential effects of the duration of EE (short- and long-term) on the number of immunopositive glial cells in the dentate gyrus, CA1, CA2, and CA3 regions of the hippocampus and proportions of T cell subsets in the cervical lymph nodes using immunohistochemistry and flow cytometry, respectively. EE, regardless of duration, caused an increase in microglia number within the dentate gyrus, CA1 and CA3 hippocampal regions, but only long-term EE increased astrocytes number within the dentate gyrus and CA3 hippocampal regions. A significantly higher proportion of CD8+ naive T cells was observed after long-term EE vs. short-term EE. No significant differences were observed in the proportion of central memory and effector memory T cells or early activated CD25+ cells between any of the test groups. Our results suggest that EE, irrespective of duration, enhances the numbers of microglia, but long-term EE is required to modify astrocyte number and peripheral T cell proportions in middle-aged mice. Our findings provide new insights into the therapeutic effects of EE on various brain disorders, which may be at least partly mediated by glial and neuroimmune modulation.Gaurav Singhal, Julie Morgan1, Magdalene C. Jawahar, Frances Corrigan, Emily J. Jaehne, Catherine Toben ... et al

Effects of aging on the motor, cognitive and affective behaviors, neuroimmune responses and hippocampal gene expression

The known effects of aging on the brain and behavior include impaired cognition, increases in anxiety and depressive-like behaviors, and reduced locomotor activity. Environmental exposures and interventions also influence brain functions during aging. We investigated the effects of normal aging under controlled environmental conditions and in the absence of external interventions on locomotor activity, cognition, anxiety and depressive-like behaviors, immune function and hippocampal gene expression in C57BL/6 mice. Healthy mice at 4, 9, and 14 months of age underwent behavioral testing using an established behavioral battery, followed by cellular and molecular analysis using flow cytometry, immunohistochemistry, and quantitative PCR. We found that 14-month-old mice showed significantly reduced baseline locomotion, increased anxiety, and impaired spatial memory compared to younger counterparts. However, no significant differences were observed for depressive-like behavior in the forced-swim test. Microglia numbers in the dentate gyrus, as well as CD8+ memory T cells increased towards late middle age. Aging processes exerted a significant effect on the expression of 43 genes of interest in the hippocampus. We conclude that aging is associated with specific changes in locomotor activity, cognition, anxiety-like behaviors, neuroimmune responses and hippocampal gene expression.Gaurav Singhal, Julie Morgan, Magdalene C.Jawahar, Frances Corrigan, Emily J.Jaehn

Effect of High-Intensity Power Training on Cognitive Function in Older Adults With Type 2 Diabetes: Secondary Outcomes of the GREAT2DO Study

We sought to determine the effects of 12 months of power training on cognition, and whether improvements in body composition, muscle strength, and/or aerobic capacity (VO2peak) were associated with improvements in cognition in older adults with type 2 diabetes (T2D). Participants with T2D were randomized to power training or low-intensity sham exercise control condition, 3 days per week for 12 months. Cognitive outcomes included memory, attention/speed, executive function, and global cognition. Other relevant outcomes included VO2peak, strength, and whole body and regional body composition. One hundred and three adults with T2D (mean age 67.9 years; standard deviation [SD] 5.9; 50.5% women) were enrolled and analyzed. Unexpectedly, there was a nearly significant improvement in global cognition (p = .05) in the sham group relative to power training, although both groups improved over time (p .05). Although power training did not significantly improve cognition compared to low-intensity exercise control, improvements in cognitive function in older adults were associated with hypothesized improvements in body composition and strength after power training.Ren Ru Zhao, Yorgi Mavros, Jacinda Meiklejohn, Kylie A. Anderberg, Nalin Singh, Shelley Kay, Michael K. Baker, Yi Wang, Mike Climstein, Anthony O, Sullivan, Nathan De Vos, Bernhard T. Baune, Steven N. Blair, David Simar, and Maria A. Fiatarone Sing

Interrogating Associations Between Polygenic Liabilities and Electroconvulsive Therapy Effectiveness

BACKGROUND: Electroconvulsive therapy (ECT) is the most effective treatment for severe major depressive episodes (MDEs). Nonetheless, firmly established associations between ECT outcomes and biological variables are currently lacking. Polygenic risk scores (PRSs) carry clinical potential, but associations with treatment response in psychiatry are seldom reported. Here, we examined whether PRSs for major depressive disorder, schizophrenia (SCZ), cross-disorder, and pharmacological antidepressant response are associated with ECT effectiveness. METHODS: A total of 288 patients with MDE from 3 countries were included. The main outcome was a change in the 17-item Hamilton Depression Rating Scale scores from before to after ECT treatment. Secondary outcomes were response and remission. Regression analyses with PRSs as independent variables and several covariates were performed. Explained variance (R2) at the optimal p-value threshold is reported. RESULTS: In the 266 subjects passing quality control, the PRS-SCZ was positively associated with a larger Hamilton Depression Rating Scale decrease in linear regression (optimal p-value threshold = .05, R2 = 6.94%, p < .0001), which was consistent across countries: Ireland (R2 = 8.18%, p = .0013), Belgium (R2 = 6.83%, p = .016), and the Netherlands (R2 = 7.92%, p = .0077). The PRS-SCZ was also positively associated with remission (R2 = 4.63%, p = .0018). Sensitivity and subgroup analyses, including in MDE without psychotic features (R2 = 4.42%, p = .0024) and unipolar MDE only (R2 = 9.08%, p < .0001), confirmed the results. The other PRSs were not associated with a change in the Hamilton Depression Rating Scale score at the predefined Bonferroni-corrected significance threshold. CONCLUSIONS: A linear association between PRS-SCZ and ECT outcome was uncovered. Although it is too early to adopt PRSs in ECT clinical decision making, these findings strengthen the positioning of PRS-SCZ as relevant to treatment response in psychiatry

Quantifying Between-Cohort and Between-Sex Genetic Heterogeneity in Major Depressive Disorder

Major depressive disorder (MDD) is clinically heterogeneous with prevalence rates twice as high in women as in men. There are many possible sources of heterogeneity in MDD most of which are not measured in a sufficiently comparable way across study samples. Here, we assess genetic heterogeneity based on two fundamental measures, between-cohort and between-sex heterogeneity. First, we used genome-wide association study (GWAS) summary statistics to investigate between-cohort genetic heterogeneity using the 29 research cohorts of the Psychiatric Genomics Consortium (PGC; N cases = 16,823, N controls = 25,632) and found that some of the cohort heterogeneity can be attributed to ascertainment differences (such as recruitment of cases from hospital vs community sources). Second, we evaluated between-sex genetic heterogeneity using GWAS summary statistics from the PGC, Kaiser Permanente GERA, UK Biobank and the Danish iPSYCH studies but did not find convincing evidence for genetic differences between the sexes. We conclude that there is no evidence that the heterogeneity between MDD data sets and between sexes reflects genetic heterogeneity. Larger sample sizes with detailed phenotypic records and genomic data remain the key to overcome heterogeneity inherent in assessment of MDD