Steven Bradburn

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.

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.

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.

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 (β = 0.444, P < 0.001) and global cognition (β = 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.

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 in Parkinson’s disease show variable onset, severity and progression. Ray et al. demonstrate that the future cognitive status of newly diagnosed patients can be predicted from the volume of the nucleus basalis of Meynert, with implications for the development of interventions for cognitive decline in Parkinson’s disease dementia.

Intergenerational accumulation of impairments in maternal behavior following postnatal social stress

Early adversity such as depressed maternal care can have long-term physiological and behavioral effects on offspring and future generations. Exposure to chronic social stress (CSS), an ethologically model of postpartum depression and anxiety, during lactation impairs maternal care and exerts similar effects on the F1 dam offspring of the stressed F0 dams. These changes associate with increased corticosterone and neuroendocrine alterations. CSS F2 offspring further display decreased social behavior as juveniles and adults and decreased basal levels of corticosterone. This current study investigates the intergenerational inheritance of alterations in maternal behavior in F2 CSS dams together with neuroendocrine and immune markers to explore whether aspects of maternal behavior are intergenerationally inherited through immune and neuroendocrine mechanisms. We find that defects in maternal care behavior persist into the F2 generation with F2 dams exhibiting a pervasively depressed maternal care and increased restlessness throughout lactation. This occurs together with reduced basal cortisol (in contrast to an increase in F1 dams), a lack of changes in neuroendocrine gene expression, and reduced serum ICAM-1 (intercellular adhesion molecule-1) levels - a marker for inflammation and blood–brain barrier integrity. The data support the hypothesis that the effects of chronic social stress can accumulate across multiple generations to depress maternal care, increase restlessness and alter basal functioning of the immune system and hypothalamic pituitary adrenal axis.

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.

Mechanisms Linking Depression, Immune System and Epigenetics During Aging

Abstract The process of aging is accompanied by the development of chronic, low-level inflammation referred to as inflammaging. This is associated with diseases, such as cardiovascular disease and dementia, and susceptibility to depression. The molecular mechanisms orchestrating depression- and age-associated inflammation are of current interest considering their potential as a therapeutic target. Given that genetics explains the minority of inflammatory variability, it is believed that environmental and gene-environmental interactions are more influential in regulating the immune system. Therefore, attention is now turning to epigenetic mechanisms, that is, those that impact gene regulation but do not alter the underlying genetic code, to bridge the understanding between inflammatory exacerbations throughout aging and depression. This chapter will introduce the inflammaging process and explore the exciting advances in epigenetic research, including DNA methylation, histone acetylation, and microRNAs, in the control of inflammatory genes during aging and depression.

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 Alzheimers 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.

Translational Animal Models for the Study of Epigenetics and the Environment

Epigenetics provides a means of understanding how environmental factors might alter heritable changes in gene expression without changing DNA sequence, and hence the origin, of some diseases that are not explained by conventional genetic mechanisms. To date, the study of gene–environment interactions in the human population has been dominated by epidemiology. However, recent research, driven by animal models in which early environmental factors can be manipulated in a controlled manner, is now advancing clinical studies by addressing specifically the mechanisms by which gene–environment interactions can predispose individuals towards disease.