Uncertainty and stress: Why it causes diseases and how it is mastered by the brain

The term 'stress' - coined in 1936 - has many definitions, but until now has lacked a theoretical foundation. Here we present an information-theoretic approach - based on the 'free energy principle' - defining the essence of stress; namely, uncertainty. We address three questions: What is uncertainty? What does it do to us? What are our resources to master it? Mathematically speaking, uncertainty is entropy or 'expected surprise'. The 'free energy principle' rests upon the fact that self-organizing biological agents resist a tendency to disorder and must therefore minimize the entropy of their sensory states. Applied to our everyday life, this means that we feel uncertain, when we anticipate that outcomes will turn out to be something other than expected - and that we are unable to avoid surprise. As all cognitive systems strive to reduce their uncertainty about future outcomes, they face a critical constraint: Reducing uncertainty requires cerebral energy. The characteristic of the vertebrate brain to prioritize its own high energy is captured by the notion of the 'selfish brain'. Accordingly, in times of uncertainty, the selfish brain demands extra energy from the body. If, despite all this, the brain cannot reduce uncertainty, a persistent cerebral energy crisis may develop, burdening the individual by 'allostatic load' that contributes to systemic and brain malfunction (impaired memory, atherogenesis, diabetes and subsequent cardio- and cerebrovascular events). Based on the basic tenet that stress originates from uncertainty, we discuss the strategies our brain uses to avoid surprise and thereby resolve uncertainty

Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity

Excitatory amino acids play a key role in both adaptive and deleterious effects of stressors on the brain, and dysregulated glutamate homeostasis has been associated with psychiatric and neurological disorders. Here, we elucidate mechanisms of epigenetic plasticity in the hippocampus in the interactions between a history of chronic stress and familiar and novel acute stressors that alter expression of anxiety- and depressive-like behaviors. We demonstrate that acute restraint and acute forced swim stressors induce differential effects on these behaviors in naive mice and in mice with a history of chronic-restraint stress (CRS). They reveal a key role for epigenetic up- and down-regulation of the putative presynaptic type 2 metabotropic glutamate (mGlu2) receptors and the postsynaptic NR1/NMDA receptors in the hippocampus and particularly in the dentate gyrus (DG), a region of active neurogenesis and a target of antidepressant treatment. We show changes in DG long-term potentiation (LTP) that parallel behavioral responses, with habituation to the same acute restraint stressor and sensitization to a novel forced-swim stressor. In WT mice after CRS and in unstressed mice with a BDNF loss-of-function allele (BDNF Val66Met), we show that the epigenetic activator of histone acetylation, P300, plays a pivotal role in the dynamic up- and down-regulation of mGlu2 in hippocampus via histone-3-lysine-27-acetylation (H3K27Ac) when acute stressors are applied. These hippocampal responses reveal a window of epigenetic plasticity that may be useful for treatment of disorders in which glutamatergic transmission is dysregulated

Social stress increases the susceptibility to infection in the ant Harpegnathos saltator

Aggressive interactions between members of a social group represent an important source of social stress with all its negative follow-ups. We used the ponerine ant Harpegnathos saltator to study the effects of frequent aggressive interactions on the resistance to different stressors. In these ants, removal or death of reproducing animals results in a period of social instability within the colony that is characterized by frequent ritualized aggressive interactions leading to the establishment of a new dominance structure. Animals are more susceptible to infections during this period, whereas their resistance against other stressors remained unchanged. This is associated with a shift from glutathione-S-transferase activities towards glutathione peroxidase activities, which increases the antioxidative capacity at the expense of their immune competence

Generational status and duration of residence predict diabetes prevalence among Latinos: the California Men's Health Study

<p>Abstract</p> <p>Background</p> <p>Diabetes disproportionately affects Latinos. However, examining Latinos as one group obscures important intra-group differences. This study examined how generational status, duration of US residence, and language preference are associated with diabetes prevalence and to what extent these explain the higher prevalence among Latinos.</p> <p>Methods</p> <p>We determined nativity, duration of US residence, language preference, and diabetes prevalence among 11 817 Latino, 6109 black, and 52 184 white participants in the California Men's Health Study. We combined generational status and residence duration into a single migration status variable with levels: ≥ third generation; second generation; and immigrant living in the US for > 25, 16-25, 11-15, or ≤ 10 years. Language preference was defined as language in which the participant took the survey. Logistic regression models were specified to assess the associations of dependent variables with prevalent diabetes.</p> <p>Results</p> <p>Diabetes prevalence was 22%, 23%, and 11% among Latinos, blacks, and whites, respectively. In age-adjusted models, we observed a gradient of risk of diabetes by migration status among Latinos. Further adjustment for socioeconomic status, obesity and health behaviors only partially attenuated this gradient. Language preference was a weak predictor of prevalent diabetes in some models and not significant in others. In multivariate models, we found that odds of diabetes were higher among US-born Latinos than US-born blacks.</p> <p>Conclusion</p> <p>Generational status and residence duration were associated with diabetes prevalence among middle-aged Latino men in California. As the Latino population grows, the burden of diabetes-associated disease is likely to increase and demands public health attention.</p

Towards a Standard Approach for Wear Testing of Wheel and Rail Materials

Examination of the literature for wear testing methodologies for wheel and rail material reveals that while only a few different techniques have been used there is a wide variety in exactly how the tests have been conducted and the resulting data reported. This makes comparison of the data very difficult. This work, carried out as part of the International Collaborative Research Initiative (ICRI) which is aiming to bring together wheel/rail interface researchers from across the world to collate data and knowledge to try to solve some of the common problems that are faced, has examined the different approaches used and attempted to pull together all the good practice used into a test specification for future twin disc testing for wheel and rail materials. Adoption of the method will allow data to be compared reliably and eventually enable data to be compiled into wear maps to use as input, for example, to multi-body dynamics simulation wear prediction tools

Genetic variation in human NPY expression affects stress response and emotion

Understanding inter- individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y ( NPY) is anxiolytic(1,2) and its release is induced by stress(3). NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories(4-6). Here we show that haplotype- driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in postmortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype- driven NPY expression predicted higher emotion- induced activation of the amygdala, as well as diminished resiliency as assessed by pain/ stress- induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism ( SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter- individual variation in resiliency to stress, a risk factor for many diseases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62768/1/nature06858.pd

White matter changes in microstructure associated with a maladaptive response to stress in rats

In today's society, every individual is subjected to stressful stimuli with different intensities and duration. This exposure can be a key trigger in several mental illnesses greatly affecting one's quality of life. Yet not all subjects respond equally to the same stimulus and some are able to better adapt to them delaying the onset of its negative consequences. The neural specificities of this adaptation can be essential to understand the true dynamics of stress as well as to design new approaches to reduce its consequences. In the current work, we employed ex vivo high field diffusion magnetic resonance imaging (MRI) to uncover the differences in white matter properties in the entire brain between Fisher 344 (F344) and Sprague-Dawley (SD) rats, known to present different responses to stress, and to examine the effects of a 2-week repeated inescapable stress paradigm. We applied a tract-based spatial statistics (TBSS) analysis approach to a total of 25 animals. After exposure to stress, SD rats were found to have lower values of corticosterone when compared with F344 rats. Overall, stress was found to lead to an overall increase in fractional anisotropy (FA), on top of a reduction in mean and radial diffusivity (MD and RD) in several white matter bundles of the brain. No effect of strain on the white matter diffusion properties was observed. The strain-by-stress interaction revealed an effect on SD rats in MD, RD and axial diffusivity (AD), with lower diffusion metric levels on stressed animals. These effects were localized on the left side of the brain on the external capsule, corpus callosum, deep cerebral white matter, anterior commissure, endopiriform nucleus, dorsal hippocampus and amygdala fibers. The results possibly reveal an adaptation of the SD strain to the stressful stimuli through synaptic and structural plasticity processes, possibly reflecting learning processes.We thank Neurospin (high field MRI center CEA Saclay) for providing its support for MRI acquisition. JB was supported by grants from Fondation pour la Recherche Médicale (FRM) and Groupe Pasteur Mutualité (GPM). This work was supported by a grant from ANR (SIGMA). This work was performed on a platform of France Life Imaging (FLI) network partly funded by the grant ANR-11-INBS-0006. This work and RM were supported by a fellowship of the project FCT-ANR/NEU-OSD/0258/2012 founded by FCT/MEC (www.fct.pt) and by Fundo Europeu de Desenvolvimento Regional (FEDER). AC was supported by a grant from the Fondation NRJ.info:eu-repo/semantics/publishedVersio

Post-Training Reward Partially Restores Chronic Stress Induced Effects in Mice

Reduced responsiveness to positive stimuli is a core symptom of depression, known as anhedonia. In the present study, we assessed the expression of anhedonia in our chronic stress mouse model using a subset of read-out parameters. In line with this, we investigated in how far chronic stress would affect the facilitating effect of post-training self-administration of sugar, as we previously observed in naïve mice. Male C57BL/6J mice were repeatedly and at unpredictable times exposed to rats (no physical contact) over the course of two weeks. Following novelty exploration, (non-) spatial learning and memory processes with and without post-training sugar acting as reinforcer, emotionality, reward sensitivity and corticosterone levels were determined. We found that (1) the effects of chronic stress persisted beyond the period of the actual rat exposure. (2) Post-training self-administration of sugar as reinforcer improved spatial performance in naïve mice, whereas (3) in stressed mice sugar partially “normalized” the impaired performance to the level of controls without sugar. Chronic stress (4) increased behavioral inhibition in response to novelty; (5) induced dynamic changes in the pattern of circadian corticosterone secretion during the first week after rat stress and (6) increased the intake of sucrose and water. (7) Chronic stress and sugar consumed during spatial training facilitated the memory for the location of the sucrose bottle weeks later. Concluding, our chronic stress paradigm induces the expression of anhedonia in mice, at different levels of behavior. The behavioral inhibition appears to be long lasting in stressed mice. Interestingly, sugar consumed in close context with spatial learning partially rescued the stress-induced emotional and cognitive impairments. This suggests that reward can ameliorate part of the negative consequences of chronic stress on memory