The brain is the central organ involved in perceiving and adapting to social and physical stressors via multiple interacting mediators, from the cell surface to the cytoskeleton to epigenetic regulation and nongenomic mechanisms. A key result of stress is structural remodeling of neural architecture, which may be a sign of successful adaptation, whereas persistence of these changes when stress ends indicates failed resilience. Excitatory amino acids and glucocorticoids have key roles in these processes, along with a growing list of extra- and intracellular mediators that includes endocannabinoids and brain-derived neurotrophic factor (BDNF). The result is a continually changing pattern of gene expression mediated by epigenetic mechanisms involving histone modifications and CpG methylation and hydroxymethylation as well as by the activity of retrotransposons that may alter genomic stability. Elucidation of the underlying mechanisms of plasticity and vulnerability of the brain provides a basis for understanding the efficacy of interventions for anxiety and depressive disorders as well as age-related cognitive decline.

/pdf/mechanisms-of-stress-in-the-brain-53o8rpi06t.pdf

Mechanisms of stress in the brain

Stress is a state of the mind, involving both brain and body as well as their interactions; it differs among individuals and reflects not only major life events but also the conflicts and pressures of daily life that alter physiological systems to produce a chronic stress burden that, in turn, is a factor in the expression of disease. This burden reflects the impact of not only life experiences but also genetic variations and individual health behaviors such as diet, physical activity, sleep, and substance abuse; it also reflects stable epigenetic modifications in development that set lifelong patterns of physiological reactivity and behavior through biological embedding of early environments interacting with cumulative change from experiences over the lifespan. Hormones associated with the chronic stress burden protect the body in the short run and promote adaptation (allostasis), but in the long run, the burden of chronic stress causes changes in the brain and body that can lead to disease (allostatic load and overload). Brain circuits are plastic and remodeled by stress to change the balance between anxiety, mood control, memory, and decision making. Such changes may have adaptive value in particular contexts, but their persistence and lack of reversibility can be maladaptive. However, the capacity of brain plasticity to effects of stressful experiences in adult life has only begun to be explored along with the efficacy of top-down strategies for helping the brain change itself, sometimes aided by pharmaceutical agents and other treatments.

/pdf/brain-on-stress-how-the-social-environment-gets-under-the-5ckg41ymxp.pdf

Brain on stress: How the social environment gets under the skin

Stress Effects on Neuronal Structure: Hippocampus, Amygdala, and Prefrontal Cortex

Alzheimer disease (AD) is the most common form of neurodegenerative disease, estimated to contribute 60–70% of all cases of dementia worldwide. According to the prevailing amyloid cascade hypothesis, amyloid-β (Aβ) deposition in the brain is the initiating event in AD, although evidence is accumulating that this hypothesis is insufficient to explain many aspects of AD pathogenesis. The discovery of increased levels of inflammatory markers in patients with AD and the identification of AD risk genes associated with innate immune functions suggest that neuroinflammation has a prominent role in the pathogenesis of AD. In this Review, we discuss the interrelationships between neuroinflammation and amyloid and tau pathologies as well as the effect of neuroinflammation on the disease trajectory in AD. We specifically focus on microglia as major players in neuroinflammation and discuss the spatial and temporal variations in microglial phenotypes that are observed under different conditions. We also consider how these cells could be modulated as a therapeutic strategy for AD. Accumulating evidence indicates important roles for microglial activation and neuroinflammation in Alzheimer disease (AD). Here, Leng and Edison describe the interplay between microglial activation and AD-related pathologies and discuss how microglial priming and activation might influence the trajectory of AD.

Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?

Epidemiological studies link short sleep duration and circadian disruption with higher risk of metabolic syndrome and diabetes. We tested the hypotheses that prolonged sleep restriction with concurrent circadian disruption, as can occur in people performing shift work, impairs glucose regulation and metabolism. Healthy adults spent >5 weeks under controlled laboratory conditions in which they experienced an initial baseline segment of optimal sleep, 3 weeks of sleep restriction (5.6 hours of sleep per 24 hours) combined with circadian disruption (recurring 28-hour "days"), followed by 9 days of recovery sleep with circadian re-entrainment. Exposure to prolonged sleep restriction with concurrent circadian disruption, with measurements taken at the same circadian phase, decreased the participants' resting metabolic rate and increased plasma glucose concentrations after a meal, an effect resulting from inadequate pancreatic insulin secretion. These parameters normalized during the 9 days of recovery sleep and stable circadian re-entrainment. Thus, in humans, prolonged sleep restriction with concurrent circadian disruption alters metabolism and could increase the risk of obesity and diabetes.

/pdf/adverse-metabolic-consequences-in-humans-of-prolonged-sleep-3yq624hzie.pdf

Adverse Metabolic Consequences in Humans of Prolonged Sleep Restriction Combined with Circadian Disruption

Circadian (daily) rhythms are present in almost all plants and animals. In mammals, a brain clock located in the hypothalamic suprachiasmatic nucleus maintains synchrony between environmental light/dark cycles and physiology and behavior. Over the past 100 y, especially with the advent of electric lighting, modern society has resulted in a round-the-clock lifestyle, in which natural connections between rest/activity cycles and environmental light/dark cycles have been degraded or even broken. Instances in which rapid changes to sleep patterns are necessary, such as transmeridian air travel, demonstrate negative effects of acute circadian disruption on physiology and behavior. However, the ramifications of chronic disruption of the circadian clock for mental and physical health are not yet fully understood. By housing mice in 20-h light/dark cycles, incongruous with their endogenous ∼24-h circadian period, we were able to model the effects of chronic circadian disruption noninvasively. Housing in these conditions results in accelerated weight gain and obesity, as well as changes in metabolic hormones. In the brain, circadian-disrupted mice exhibit a loss of dendritic length and decreased complexity of neurons in the prelimbic prefrontal cortex, a brain region important in executive function and emotional control. Disrupted animals show decreases in cognitive flexibility and changes in emotionality consistent with the changes seen in neural architecture. How our findings translate to humans living and working in chronic circadian disruption is unknown, but we believe that this model can provide a foundation to understand how environmental disruption of circadian rhythms impacts the brain, behavior, and physiology.

https://www.pnas.org/content/pnas/108/4/1657.full.pdf

Disruption of circadian clocks has ramifications for metabolism, brain, and behavior

Numerous clinical and experimental studies have linked stress to changes in risk factors associated with the development of physiological syndromes, including metabolic disorders. How different mediators of the stress response, such as corticosterone (CORT), influence these changes in risk remains unclear. Although CORT has beneficial short-term effects, long-term CORT exposure can result in damage to the physiological systems it protects acutely. Disruption of this important physiologic signal is observed in numerous disparate disorders, ranging from depression to Cushing's syndrome. Thus, understanding the effects of chronic high CORT on metabolism and physiology is of key importance. We explored the effects of 4-wk exposure to CORT dissolved in the drinking water on the physiology and behavior of male mice. We used this approach as a noninvasive way of altering plasma CORT levels while retaining some integrity in the diurnal rhythm present in normal animals. This approach has advantages over methods involving constant CORT pellets, CORT injections, or adrenalectomy. We found that high doses of CORT (100 microg/ml) result in rapid and dramatic increases in weight gain, increased adiposity, elevated plasma leptin, insulin and triglyceride levels, hyperphagia, and decreased home-cage locomotion. A lower dose of CORT (25 microg/ml) resulted in an intermediate phenotype in some of these measures but had no effect on others. We propose that the physiological changes observed in the high-CORT animals approximate changes observed in individuals suffering from the metabolic syndrome, and that they potentially serve as a model for hypercortisolemia and stress-related obesity.

Endocrine and physiological changes in response to chronic corticosterone: a potential model of the metabolic syndrome in mouse.

https://www.cell.com/neuron/pdf/S0896-6273(14)00437-1.pdf

Anatomical Plasticity of Adult Brain Is Titrated by Nogo Receptor 1

Chronic, noninvasive glucocorticoid administration suppresses limbic endocannabinoid signaling in mice.

Progranulin (PGRN) is implicated in Alzheimer's disease (AD) as well as frontotemporal lobar degeneration. Genetic studies demonstrate an association of the common GRN rs5848 variant that results in reduced PGRN levels with increased risk for AD. However, the mechanisms by which PGRN reduction from the GRN AD risk variant or mutation exacerbates AD pathophysiology remain ill defined. Here, we show that the GRN AD risk variant has no significant effects on florbetapir positron emission tomographic amyloid imaging and cerebrospinal fluid (CSF) Aβ levels, whereas it is associated with increased CSF tau levels in human subjects of the Alzheimer's disease neuroimaging initiative studies. Consistent with the human data, subsequent analyses using the APPswe/PS1ΔE9 (APP/PS1) mouse model of cerebral amyloidosis show that PGRN deficiency has no exacerbating effects on Aβ pathology. In contrast and unexpectedly, PGRN deficiency significantly reduces diffuse Aβ plaque growth in these APP/PS1 mice. This protective effect is due, at least in part, to enhanced microglial Aβ phagocytosis caused by PGRN deficiency-induced expression of TYROBP network genes (TNG) including an AD risk factor Trem2. PGRN-deficient APP/PS1 mice also exhibit less severe axonal dystrophy and partially improved behavior phenotypes. While PGRN deficiency reduces these amyloidosis-related phenotypes, other neuronal injury mechanisms are increased by loss of PGRN, revealing a multidimensional interaction of GRN with AD. For example, C1q complement deposition at synapses is enhanced in APP/PS1 mice lacking PGRN. Moreover, PGRN deficiency increases tau AT8 and AT180 pathologies in human P301L tau-expressing mice. These human and rodent data suggest that global PGRN reduction induces microglial TNG expression and increases AD risk by exacerbating neuronal injury and tau pathology, rather than by accelerating Aβ pathology.

/pdf/opposing-effects-of-progranulin-deficiency-on-amyloid-and-3ru1tugemn.pdf

Sarah M. Bhagat

Papers

Disruption of circadian clocks has ramifications for metabolism, brain, and behavior

Endocrine and physiological changes in response to chronic corticosterone: a potential model of the metabolic syndrome in mouse.

Anatomical Plasticity of Adult Brain Is Titrated by Nogo Receptor 1

Chronic, noninvasive glucocorticoid administration suppresses limbic endocannabinoid signaling in mice.

Opposing Effects of Progranulin Deficiency on Amyloid and Tau Pathologies via Microglial TYROBP Network