Differential expression of H19, BC1, MIAT1, and MALAT1 long non-coding RNAs within key brain reward regions after repeated morphine treatment.

Morphine-induced analgesic tolerance and dependence are significant limits of pain control; however, the exact molecular mechanisms underlying morphine tolerance and dependence have remained unclear. The role of long non-coding RNAs (lncRNAs) in morphine tolerance and dependence is yet to be determined. We aimed to explore the association of specific lncRNAs expression in key brain reward regions after repeated injection of morphine. Male Wistar rats received subcutaneous injections of twice-daily morphine (10 mg/kg) or saline (1 mL/kg) for eight days. On day 8 of the repeated injections, induction of morphine analgesic tolerance and dependence was confirmed through a hotplate test and a naloxone-precipitated withdrawal analysis, respectively. Expression of H19, BC1, MIAT1, and MALAT1 lncRNAs was determined from the midbrain, striatum, hypothalamus, prefrontal cortex (PFC), and hippocampus by real-time PCR on day 8 of the repeated injections. The H19 expression was significantly different between morphine-treated and control saline-treated rats in all investigated areas except for the hippocampus. The BC1 expression significantly altered in the midbrain, hypothalamus, and hippocampus, but not in the striatum and PFC after repeated morphine treatment. The MIAT1 and MALAT1 expression site-specifically altered in the midbrain, hypothalamus, and striatum; however, no significant changes were detected in their expression in the PFC and hippocampus after repeated morphine treatment. We conclude that alterations in the expression of these lncRNAs in the brain reward regions especially in the midbrain, striatum and hypothalamus may have critical roles in the development of morphine dependence and tolerance, which need to be considered in future researches.

Superior Frontal Gyrus TOMM40-APOE Locus DNA Methylation in Alzheimer's Disease.

BACKGROUND: The APOE ɛ4 allele is the strongest known genetic risk factor for sporadic Alzheimer's disease (AD). The neighboring TOMM40 gene has also been implicated in AD due to its close proximity to APOE. OBJECTIVE: Here we tested whether methylation of the TOMM40-APOE locus may influence ApoE protein levels and AD pathology. METHODS: DNA methylation levels across the TOMM40-APOE locus and ApoE levels were measured in superior frontal gyrus tissues of 62 human brains genotyped for APOE and scored for AD neuropathology. RESULTS: Methylation levels within the TOMM40 CpG island in the promoter or APOE CpG island in Exon 4 did not differ between APOE ɛ4 carriers versus non-carriers. However, APOE ɛ4 carriers had significantly higher methylation the APOE promoter compared with non-carriers. Although DNA methylation at TOMM40, APOE promoter region, or APOE did not differ between AD pathological groups, there was a negative association between TOMM40 methylation and CERAD scores. ApoE protein concentrations did not significantly different between APOE ɛ4 carriers and non-carriers, or between AD pathological groups. Finally, there was no correlation between ApoE protein concentrations and DNA methylation levels. CONCLUSION: APOE gene methylation may not be affected by genotype, relate to AD pathology or ApoE protein levels in the superior frontal gyrus, though, DNA methylation at the ApoE promoter differed between genotype. DNA methylation at TOMM40 associated with amyloid-ß plaques and longitudinal fluid intelligence. In sum, these results suggest a complicated regulation of the TOMM40-APOE locus in the brain in controlling ApoE protein levels and AD neuropathology.

Sex Comparison of Knee Extensor Size, Strength, and Fatigue Adaptation to Sprint Interval Training.

ABSTRACT: Bagley, L, Al-Shanti, N, Bradburn, S, Baig, O, Slevin, M, and McPhee, JS. Sex comparison of knee extensor size, strength, and fatigue adaptation to sprint interval training. J Strength Cond Res 35(1): 64-71, 2021-Regular sprint interval training (SIT) improves whole-body aerobic capacity and muscle oxidative potential, but very little is known about knee extensor anabolic or fatigue resistance adaptations, or whether effects are similar for men and women. The purpose of this study was to compare sex-related differences in knee extensor size, torque-velocity relationship, and fatigability adaptations to 12-week SIT. Sixteen men and 15 women (mean [SEM] age: 41 [±2.5] years) completed measurements of total body composition assessed by dual energy X-ray absorptiometry, quadriceps muscle cross-sectional area (CSAQ) assessed by magnetic resonance imaging, the knee extensor torque-velocity relationship (covering 0-240°·s-1) and fatigue resistance, which was measured as the decline in torque from the first to the last of 60 repeated concentric knee extensions performed at 180°·s-1. Sprint interval training consisted of 4 × 20-second sprints on a cycle ergometer set at an initial power output of 175% of power at V̇o2max, 3 times per week for 12 weeks. Quadriceps muscle cross-sectional area increased by 5% (p = 0.023) and fatigue resistance improved 4.8% (p = 0.048), with no sex differences in these adaptations (sex comparisons: p = 0.140 and p = 0.282, respectively). Knee extensor isometric and concentric torque was unaffected by SIT in both men and women (p > 0.05 for all velocities). Twelve-week SIT, totaling 4 minutes of very intense cycling per week, significantly increased fatigue resistance and CSAQ similarly in men and women, but did not significantly increase torque in men or women. These results suggest that SIT is a time-effective training modality for men and women to increase leg muscle size and fatigue resistance.

A history of opioid exposure in females increases the risk of metabolic disorders in their future male offspring.

Worldwide consumption of opioids remains at historic levels. Preclinical studies report intergenerational effects on the endogenous opioid system of future progeny following preconception morphine exposure. Given the role of endogenous opioids in energy homeostasis, such effects could impact metabolism in the next generation. Thus, we examined diet-induced modifications in F1 male progeny of morphine-exposed female rats (MORF1). When fed a high fat-sugar diet (FSD) for 6 weeks, MORF1 males display features of emerging metabolic syndrome; they consume more food, gain more weight, and develop fasting-induced hyperglycemia and hyperinsulinemia. In the hypothalamus, proteins involved in energy homeostasis are modified and RNA sequencing revealed down-regulation of genes associated with neuronal plasticity, coupled with up-regulation of genes associated with immune, inflammatory, and metabolic processes that are specific to FSD-maintained MORF1 males. Thus, limited preconception morphine exposure in female rats increases the risk of metabolic syndrome/type 2 diabetes in the next generation.

A meta-analysis of peripheral tocopherol levels in age-related cognitive decline and Alzheimer's disease.

Objectives: Findings from observational studies and clinical trials on the associations between vitamin E and dementia remain controversial. Here we conducted a meta-analysis to determine the difference in blood tocopherols levels between patients with Alzheimer's disease (AD) or age-related poor cognitive function and healthy controls.Methods: Standardised mean difference (SMD) and 95% confidence intervals (CIs) were calculated and entered into a random effects model. Study quality, heterogeneity and publication bias were also investigated.Results: Thirty-one articles were included in the meta-analysis, which included analyses for α-, ß-, γ- and δ-tocopherols. These results indicated that individuals with AD or age-related cognitive deficits and mild cognitive impairment (MCI) had lower circulatory concentrations of α-tocophenol compared with healthy controls (AD: SMD = -0.97, 95% confidence interval [CI] = -1.27 to -0.68, Z = 6.45, P < 0.00001; age-related cognitive deficits and MCI: SMD = -0.72, 95% CI = -1.12 to -0.32, Z = -3., P < 0.0005). Levels of ß-, γ- and δ-tocophenols did not significantly differ between groups of AD and age-related cognitive deficits compared to controls.Discussion: These results suggest that lower α-tocopherol levels have a strong association with AD and MCI supporting evidence for the role of diet and vitamin E in AD risk and age-related cognitive decline.

Epigenetic Regulation of BMAL1 with Sleep Disturbances and Alzheimer's Disease.

BACKGROUND: An early symptom of Alzheimer's disease (AD) is a disturbance of the circadian rhythm that is associated with disrupted sleep/wake cycles. OBJECTIVE: To investigate if BMAL1, a key gene that drives the circadian cycle, is epigenetically regulated in brains in relation to longitudinal changes in cognition, sleep quality, and AD neuropathology. METHODS: Frontal cortex tissues were acquired from the Manchester Brain Bank (N = 96). DNA methylation at six CpG sites at the promoter of BMAL1, determined using bisulfite pyrosequencing, was tested for associations with Braak stage, CERAD score and Thal phase, longitudinal changes in cognition, sleep measurements and cross-section measures of depressive symptoms (BDI score). RESULTS: Methylation across all the CpGs strongly correlated with each other. We found increased CpG2 methylation with higher Braak (t(92), p = 0.015) and CERAD (t(94), p = 0.044) stages. No significance was found between longitudinal fluid intelligence, processing speed and memory tests, but methylation at CpG1 (r = 0.20, p = 0.05) and CpG4 (r = 0.20, p = 0.05) positively correlated with vocabulary. CpG2 positively correlated with cross-sectional fluid intelligence (r = 0.20 p = 0.05) and vocabulary (r = 0.22 p = 0.03). Though longitudinal analysis revealed no significance between sleep duration, midsleep and efficiency for any of the CpG sites, CpG3 (B = 0.03, 95% CI, p = 0.03) and CpG5 (B = 0.04, 95% CI, p = 0.01) significantly correlated with night wake. CpG4 correlated with depressive symptoms (B = -0.27, 95% CI, p = 0.02). CONCLUSION: Methylation of BMAL1 associated with tau pathology, changes in cognitive measures, a measure of sleep and depressive symptoms, suggesting an involvement of the circadian cycle.

Regulation of interleukin 6 by a polymorphic CpG within the frontal cortex in Alzheimer's disease.

The cytokine interleukin 6 (IL-6) has been linked to the pathogenesis of Alzheimer's disease (AD). This is the first study to investigate the genetic and epigenetic interactions in the control of IL-6 in human brain and its relation to AD neuropathology in prefrontal cortex tissues from AD and controls genotyped for the SNP -174 C/G rs1800795, a polymorphic CpG in which the G allele creates a CpG site. Within CC homozygotes there were significantly higher brain levels of IL-6 protein compared to G allele carriers. The C allele that resulted in an absence of methylation at a CpG was also associated with significant changes in methylation at neighboring CpGs. Furthermore, there were significant differences in methylation between CC and CG/GG at CpG sites in the AD and control groups. That DNA methylation was altered in the brains by the presence of rs1800795, which further correlated with protein levels suggests the presence of a polymorphic CpG and genetic-epigenetic interactions in the regulation of IL-6 in the prefrontal cortex within AD brains.

Molecular mechanisms underlying actions of certain long noncoding RNAs in Alzheimer's disease.

Long non-coding RNAs (lncRNAs) are a group of non-protein coding RNAs that have more than 200 nucleotides. LncRNAs play an important role in the regulation of protein-coding genes at the transcriptional and post-transcriptional levels. They are found in most organs, with a high prevalence in the central nervous system. Accumulating data suggests that lncRNAs are involved in various neurodegenerative disorders, including the onset and progression of Alzheimer's disease (AD). Recent insights suggest lncRNAs, such as BACE1-AS, 51A, 17A, NDM29 and AS-UCHL1, are dysregulated in AD tissues. Furthermore, there are ongoing efforts to explore the clinical usability of lncRNAs as biomarkers in the disease. In this review, we explore the mechanisms by which aberrant expressions of the most studied lncRNAs contribute to the neuropathologies associated with AD, including amyloid ß plaques and neurofibrillary tangles. Understanding the molecular mechanisms of lncRNAs in patients with AD will reveal novel diagnosis strategies and more effective therapeutic targets.

Dysregulation of BDNF in Prefrontal Cortex in Alzheimer's Disease.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is essential for neurogenesis and has been implicated in Alzheimer's disease (AD). However, few studies have investigated together the epigenetic, transcriptional, and translational regulation of this peptide in the brain in relation to AD. OBJECTIVE: To investigate mechanisms underlying how BDNF is possibly dysregulated in the brain in relation to aging and AD neuropathology. METHODS: Prefrontal cortex tissues were acquired from the Manchester Brain Bank (N = 67). BDNF exon I, and exon IV-containing transcripts and total long 3' transcript gene expression were determined by quantitative PCR and bisulfite pyrosequencing was used to quantify DNA methylation within promoters I and IV. Protein concentrations were quantified via ELISA. RESULTS: BDNF exon IV and total long 3' isoform gene expression levels negatively associated with donor's age at death (IV: r = -0.291, p = 0.020; total: r = -0.354, p = 0.004). Expression of BDNF exon I- containing isoform was significantly higher in Met-carriers of the rs6265 variant, compared to Val-homozygotes, when accounting for donor ages (F = 6.455, p = 0.014). BDNF total long 3' transcript expression was significantly lower in those with early AD neuropathology, compared to those without any neuropathology (p = 0.021). There were no associations between BDNF promoter I and IV methylation or protein levels with ages, rs6265 genotype or AD neuropathology status. CONCLUSION: Prefrontal cortex BDNF gene expression is associated with aging, rs6265 carrier status, and AD neuropathology in a variant-specific manner that seems to be independent of DNA methylation influences.

Maternal social environment affects offspring cognition through behavioural and immune pathways in rats.

The social environment of lactation is a key etiological factor for the occurrence of postpartum disorders affecting women and their children. Postpartum depression and anxiety disorders are highly prevalent in new mothers and negatively affect offspring's cognitive development through mechanisms which are still unclear. Here, using a rat model, we manipulated the maternal social environment during lactation and explored the pathways through which social isolation (vs. the opportunity for limited social interaction with another lactating female, from 1 day before parturition to postpartum day 16) and chronic social conflict (daily exposure to a male intruder from postpartum day 2 to day 16) affect offspring learning and memory, measured at 40 to 60 days of age. We specifically explored the consequences of these social treatments on two main hypothesized mediators likely to affect offspring neurophysiological development: the quality of maternal care and maternal inflammation factors (brain-derived neurotrophic factor, granulocyte-macrophage colony-stimulating factor, intercellular adhesion molecule 1, tissue inhibitor of metalloproteinases 1 and vascular endothelial growth factor) likely to influence offspring development through lactation. Maternal rats which had the opportunity to interact with another lactating female spent more time with their pups which, in turn, displayed improved working and reference memory. Social stress affected maternal plasma levels of cytokines that were associated with cognitive deficits in their offspring. However, females subjected to social stress were protected from these stress-induced immune changes and associated offspring cognitive impairment by increased social affiliation. These results underscore the effects of social interaction for new mothers and their offspring and can be used to inform the development of clinical preventative measures and interventions.

Neuroinflammation in mild cognitive impairment and Alzheimer's disease: A meta-analysis.

BACKGROUND: Increasingly, evidence from brain imaging supports the role of neuroinflammation in dementia progression. Yet, it is not clear if there are patterns of spatial and temporal susceptibility to neuroinflammatory processes in the brain that may correspond to dementia staging or symptom expression. METHODS: We searched literature databases for case-control studies examining levels of translocator protein (TSPO) levels using positron emission tomography, representing neuroinflammation, in regional analyses between healthy controls and mild cognitive impairment (MCI) or Alzheimer's disease (AD) subjects. Standardised mean differences (SMDs) were calculated and results meta-analysed using random-effects models. Quality assessments, sensitivity analysis, subgroup analysis and meta-regressions were also performed. RESULTS: Twenty-eight studies comprising 755 (HC = 318, MCI = 168, AD = 269) participants and 37 brain regions were included. Compared to HCs, AD participants had increased TSPO levels throughout the brain (SMD range: 0.43-1.76), especially within fronto-temporal regions. MCI subjects also had increased TSPO levels, mainly within the neocortex, with more modest effects (SMD range: 0.46 - 0.90). Meta-regression analysis identified an inverse association between TSPO levels in the parietal region and Mini-Mental State Examination scores, a proxy for disease severity, in AD subjects (estimate: -0.11, 95% confidence interval: -0.21 to -0.02; P = 0.024). CONCLUSIONS: Our findings support the association of increased neuroinflammation during the progression of MCI and AD, relative to HCs.

An anti-inflammatory diet as a potential intervention for depressive disorders: A systematic review and meta-analysis.

BACKGROUND & AIMS: There is a large body of evidence which supports the role of inflammation in the pathophysiology of mental health disorders, including depression. Dietary patterns have been shown to modulate the inflammatory state, thus highlighting their potential as a therapeutic tool in disorders with an inflammatory basis. Here we conduct a systematic review and meta-analysis of current literature addressing whether there is a link between the inflammatory potential of a diet and risk of depression or depressive symptoms. METHODS: A systematic literature search was performed to identify studies that reported an association between the inflammatory potential of the diet and risk of depressive symptoms or diagnosis of depression. Random effect models were used to meta-analyse effect sizes. Quality assessment, publication bias, sensitivity and subgroup analyses were also performed. RESULTS: Eleven studies, with a total of 101,950 participants at baseline (age range: 16-72 years old), were eligible for review. A significant association between a pro-inflammatory diet and increased risk of depression diagnosis or symptoms was evident, relative to those on an anti-inflammatory diet (OR: 1.40, 95% confidence intervals: 1.21-1.62, P < 0.001). No publication bias was detected; however, some study heterogeneity was evident (I2 = 63%, P < 0.001). Subgroup analyses suggested the main source of study heterogeneity was the study design (cross-sectional or longitudinal) and the effect measure used (odds ratio, hazard ratio or relative risk). CONCLUSION: These results provide an association between pro-inflammatory diet and risk of depression. Thus, adopting an anti-inflammatory diet may be an effective intervention or preventative means of reducing depression risk and symptoms.

Dysregulation of C-X-C motif ligand 10 during aging and association with cognitive performance.

Chronic low-grade inflammation during aging (inflammaging) is associated with cognitive decline and neurodegeneration; however, the mechanisms underlying inflammaging are unclear. We studied a population (n = 361) of healthy young and old adults from the MyoAge cohort. Peripheral levels of C-X-C motif chemokine ligand 10 (CXCL10) was found to be higher in older adults, compared with young, and negatively associated with working memory performance. This coincided with an age-related reduction in blood DNA methylation at specific CpGs within the CXCL10 gene promoter. In vitro analysis supported the role of DNA methylation in regulating CXCL10 transcription. A polymorphism (rs56061981) that altered methylation at one of these CpG sites further associated with working memory performance in 2 independent aging cohorts. Studying prefrontal cortex samples, we found higher CXCL10 protein levels in those with Alzheimer's disease, compared with aged controls. These findings support the association of peripheral inflammation, as demonstrated by CXCL10, in aging and cognitive decline. We reveal age-related epigenetic and genetic factors which contribute to the dysregulation of CXCL10.

In vivo cholinergic basal forebrain atrophy predicts cognitive decline in de novo Parkinson's disease.

See Gratwicke and Foltynie (doi:10.1093/brain/awx333) for a scientific commentary on this article.Cognitive impairments are a prevalent and disabling non-motor complication of Parkinson's disease, but with variable expression and progression. The onset of serious cognitive decline occurs alongside substantial cholinergic denervation, but imprecision of previously available techniques for in vivo measurement of cholinergic degeneration limit their use as predictive cognitive biomarkers. However, recent developments in stereotactic mapping of the cholinergic basal forebrain have been found useful for predicting cognitive decline in prodromal stages of Alzheimer's disease. These methods have not yet been applied to longitudinal Parkinson's disease data. In a large sample of people with de novo Parkinson's disease (n = 168), retrieved from the Parkinson's Progressive Markers Initiative database, we measured cholinergic basal forebrain volumes, using morphometric analysis of T1-weighted images in combination with a detailed stereotactic atlas of the cholinergic basal forebrain nuclei. Using a binary classification procedure, we defined patients with reduced basal forebrain volumes (relative to age) at baseline, based on volumes measured in a normative sample (n = 76). Additionally, relationships between the basal forebrain volumes at baseline, risk of later cognitive decline, and scores on up to 5 years of annual cognitive assessments were assessed with regression, survival analysis and linear mixed modelling. In patients, smaller volumes in a region corresponding to the nucleus basalis of Meynert were associated with greater change in global cognitive, but not motor scores after 2 years. Using the binary classification procedure, patients classified as having smaller than expected volumes of the nucleus basalis of Meynert had ∼3.5-fold greater risk of being categorized as mildly cognitively impaired over a period of up to 5 years of follow-up (hazard ratio = 3.51). Finally, linear mixed modelling analysis of domain-specific cognitive scores revealed that patients classified as having smaller than expected nucleus basalis volumes showed more severe and rapid decline over up to 5 years on tests of memory and semantic fluency, but not on tests of executive function. Thus, we provide the first evidence that volumetric measurement of the nucleus basalis of Meynert can predict early cognitive decline. Our methods therefore provide the opportunity for multiple-modality biomarker models to include a cholinergic biomarker, which is currently lacking for the prediction of cognitive deterioration in Parkinson's disease. Additionally, finding dissociated relationships between nucleus basalis status and domain-specific cognitive decline has implications for understanding the neural basis of heterogeneity of Parkinson's disease-related cognitive decline.

Association of Peripheral Interleukin-6 with Global Cognitive Decline in Non-demented Adults: A Meta-Analysis of Prospective Studies.

Background: Elevated biomarkers of systemic inflammation have been reported in individuals with cognitive decline, however, most of the literature concerns cross-sectional analyses that have produced mixed results. This study investigates the etiology of this association by performing meta-analyses on prospective studies investigating the relationship between baseline interleukin-6 (IL-6), an established marker of peripheral inflammation, with cognitive decline risk in non-demented adults at follow-up. Methods: We reviewed studies reporting peripheral IL-6 with future cognitive decline, up to February 2017 by searching the PubMed, Science Direct, Scopus and Google Scholar databases. Studies which contained odds ratios (ORs) for the association between circulating baseline IL-6 and longitudinal cognitive performance in non-demented community dwelling older adults were pooled in random-effects models. Results: The literature search retrieved 5,642 potential articles, of which 7 articles containing 8 independent aging cohorts were eligible for review. Collectively, these studies included 15,828 participants at baseline. Those with high circulating IL-6 were 1.42 times more likely to experience global cognitive decline at follow-up, over a 2-7-year period, compared to those with low IL-6 (OR 1.42, 95% CI 1.18-1.70; p < 0.001). Subgroup and sensitivity analyses suggests that this association is independent of the study sample size, duration of follow-up and cognitive assessments used. Conclusions: These results add further evidence for the association between high peripheral inflammation, as measured by blood IL-6, and global cognitive decline. Measuring circulating IL-6 may be a useful indication for future cognitive health.

Sex differences in the effects of 12†weeks sprint interval training on body fat mass and the rates of fatty acid oxidation and VO2max during exercise.

BACKGROUND: The purpose of this study was to examine whether very short duration, very high intensity sprint interval training (SIT) leads to loss of body fat mass in association with improvements to VO2max and fatty acid oxidation, and to assess the extent of sex dimorphism in these physiological responses. METHODS: A total of 24 men and 17 women (mean (SEM) age: 39 (±2) years; body mass index 24.6 (0.6)) completed measurements of the maximal rate of oxygen uptake (VO2max) and fatty acid oxidation (FATmax). Body fat and lean mass were measured by dual emission x-ray absorptiometry, and fasting blood lipid, glucose and insulin profiles were assessed before and after training. SIT consisted of 4×20 s sprints on a cycle ergometer at approximately 175% VO2max, three times per week for 12 weeks. RESULTS: Fat mass decreased by 1.0 kg, although men lost statistically significantly more fat than women both when expressed in Kg and as % body fat. VO2max increased by around 9%, but women improved VO2max significantly more than men. FATmax improved by around 13%, but fasting plasma glucose, insulin, total triglyceride, total cholesterol and high-density lipoprotein (HDL) did not change after training, while low-density lipoprotein decreased by 8% (p=0.028) and the HDL:Total Cholesterol ratio improved by 6%. There were no sex differences in these metabolic responses to training. CONCLUSIONS: These results show lower body fat %, and higher rates of fatty acid oxidation and VO2max after 12 weeks of training for just 4 min per week. Notably, women improved VO2max more than men, while men lost more fat than women.

Association between osteocalcin and cognitive performance in healthy older adults.

INTRODUCTION: cognitive deterioration and reductions of bone health coincide with increasing age. We examine the relationship between bone composition and plasma markers of bone remodelling with measures of cognitive performance in healthy adults. METHODS: this cross-sectional study included 225 old (52% women, mean age: 74.4 ± 3.3 years) and 134 young (52% women, mean age: 23.4 ± 2.7 years) adult participants from the MyoAge project. Whole body bone mineral density was measured by dual-energy X-ray absorptiometry. Blood analyses included a panel of bone-related peptides (dickkopf-1, osteoprotegerin, osteocalcin (OC), osteopontin, sclerostin, parathyroid hormone and fibroblast growth factor 23), as well as serum calcium and 25-hydroxy vitamin D assays. A selection of cognitive domains (working memory capacity, episodic memory, executive functioning and global cognition) was assessed with a standardised neuropsychological test battery. RESULTS: adjusting for covariates and multiple testing revealed that plasma OC levels were positively associated with measures of executive functioning (ß = 0.444, P < 0.001) and global cognition (ß = 0.381, P = 0.001) in the older women. DISCUSSION: these correlative results demonstrate a positive association between OC, a factor known to regulate bone remodelling, with cognitive performance in older non-demented women. Further work should address possible mechanistic interpretations in humans.

Effects of exercise on adolescent and adult hypothalamic and hippocampal neuroinflammation.

Adolescence is a period of significant brain plasticity that can be affected by environmental factors, including the degree of physical activity. Here we hypothesized that adolescent rats would be more sensitive to the beneficial metabolic and anti-inflammatory effects of voluntary exercise than adult rats, whose more mature brains have less capacity for plasticity. We tested this by giving adolescent and adult Wistar rats four weeks' voluntary access to running wheels. At the end of this period we assessed metabolic effects, including weight and circulating leptin and ghrelin, as well as performance in a novel object recognition test of memory and central changes in neuronal proliferation, survival, synaptic density, and inflammatory markers in hippocampus. We found exercise reduced fat mass and circulating leptin levels in both adults and adolescents but suppressed total weight gain and lean mass in adults only. Exercise stimulated neuronal proliferation in the suprapyramidal blade of the dentate gyrus in both adults and adolescents without altering the number of mature neurons during this time frame. Exercise also increased dentate microglial numbers in adolescents alone and microglial numbers in this region were inversely correlated with performance in the novel object recognition test. Together these data suggest that adolescent hippocampal microglia are more sensitive to the effects of exercise than those of adults, but this leads to no apparent improvement in recognition memory. © 2016 Wiley Periodicals, Inc.

Transgenerational Social Stress, Immune Factors, Hormones, and Social Behavior.

A social signal transduction theory of depression has been proposed that states that exposure to social adversity alters the immune response and these changes mediate symptoms of depression such as anhedonia and impairments in social behavior The exposure of maternal rats to the chronic social stress (CSS) of a male intruder depresses maternal care and impairs social behavior in the F1 and F2 offspring of these dams. The objective of the present study was to characterize basal peripheral levels of several immune factors and related hormone levels in the adult F2 offspring of CSS exposed dams and assess whether changes in these factors are associated with previously reported deficits in allogrooming behavior. CSS decreased acid glycoprotein (α1AGP) and intercellular adhesion molecule-1 (ICAM-1) in F2 females, and increased granulocyte macrophage-colony stimulating factor (GM-CSF) in F2 males. There were also sex dependent changes in IL-18, tissue inhibitors of metalloproteinases 1 (TIMP-1), and vascular endothelial growth factor (VEGF). Progesterone was decreased and alpha melanocyte stimulating hormone (α-MSH) was increased in F2 males, and brain-derived neurotrophic factor (BDNF) was decreased in F2 females. Changes in α1AGP, GM-CSF, progesterone, and α-MSH were correlated with decreased allogrooming in the F2 offspring of stressed dams. These results support the hypothesis that transgenerational social stress affects both the immune system and social behavior, and also support previous studies on the adverse effects of early life stress on immune functioning and stress associated immunological disorders, including the increasing prevalence of asthma. The immune system may represent an important transgenerational etiological factor in disorders which involve social and/or early life stress associated changes in social behavior, such as depression, anxiety, and autism, as well as comorbid immune disorders. Future studies involving immune and/or endocrine assessments and manipulations will address specific questions of function and causation, and may identify novel preventative measures and treatments for the growing number of immune mediated disorders.

Social stress during lactation, depressed maternal care, and neuropeptidergic gene expression.

Depression and anxiety can be severely detrimental to the health of both the affected woman and her offspring. In a rodent model of postpartum depression and anxiety, chronic social stress exposure during lactation induces deficits in maternal care and increases anxiety. Here, we extend previous findings by expanding the behavioral analyses, assessing lactation, and examining several neural systems within amygdalar and hypothalamic regions involved in the control of the stress response and expression of maternal care that may be mediating the behavioral changes in stressed dams. Compared with control dams, those exposed to chronic social stress beginning on day 2 of lactation show impaired maternal care and lactation and increased maternal anxiety on day 9 of lactation. Saccharin-based anhedonia and maternal aggression were increased and lactation was also impaired on day 16 of lactation. These behavioral changes were correlated with a decrease in oxytocin mRNA expression in the medial amygdala, and increases in the expressions of corticotrophin-releasing hormone mRNA in the central nucleus of the amygdala, glucocorticoid receptor mRNA in the paraventricular nucleus, and orexin 2 receptor mRNA in the supraoptic nucleus of stressed compared with control dams. The increase in glucocorticoid receptor mRNA in the paraventricular nucleus was negatively correlated with methylation of a CpG site in the promoter region. In conclusion, the data support the hypothesis that social stress during lactation can have profound effects on maternal care, lactation, and anxiety, and that these behavioral effects are mediated by central changes in stress and maternally relevant neuropeptide systems.