Organic Cation Transporter 3: A Cellular Mechanism Underlying Rapid, Non-Genomic Glucocorticoid Regulation of Monoaminergic Neurotransmission, Physiology, and Behavior

Corticosteroid hormones act at intracellular glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) to alter gene expression, leading to diverse physiological and behavioral responses. In addition to these classical genomic effects, corticosteroid hormones also exert rapid actions on physiology and behavior through a variety of non-genomic mechanisms, some of which involve GR or MR, and others of which are independent of these receptors. One such GR-independent mechanism involves corticosteroid-induced inhibition of monoamine transport mediated by “uptake2” transporters, including organic cation transporter 3 (OCT3), a low-affinity, high-capacity transporter for norepinephrine, epinephrine, dopamine, serotonin and histamine. Corticosterone directly and acutely inhibits OCT3-mediated transport. This review describes the studies that initially characterized uptake2 processes in peripheral tissues, and outlines studies that demonstrated OCT3 expression and corticosterone-sensitive monoamine transport in the brain. Evidence is presented supporting the hypothesis that corticosterone can exert rapid, GR-independent actions on neuronal physiology and behavior by inhibiting OCT3-mediated monoamine clearance. Implications of this mechanism for glucocorticoid-monoamine interactions in the context-dependent regulation of behavior are discussed

The Canmore Declaration: Statement of Principles for Planetary Health

The term planetary health—denoting the interdependence between human health and place at all scales—emerged from the environmental and preventive health movements of the 1970–80s; in 1980, Friends of the Earth expanded the World Health Organization definition of health, stating: “health is a state of complete physical, mental, social and ecological well-being and not merely the absence of disease—personal health involvesplanetary health”. Planetary health is not a new discipline; it is an extension of a concept understood by our ancestors, and remains the vocation of multiple disciplines. Planetary health, inseparably bonded to human health, is formally defined by the inVIVO Planetary Health network as the interdependent vitality of all natural and anthropogenic ecosystems (social, political and otherwise). Here, we provide the historical background and philosophies that have guided the network, and summarize the major themes that emerged at the 7th inVIVO meeting in Canmore, Alberta, Canada. We also provide the Canmore Declaration, a Statement of Principles for Planetary Health. This consensus statement, framed by representative participants, expands upon the 1986 Ottawa Charter for Health Promotion and affirms the urgent need to consider the health of people, places and the planet as indistinguishable

Mycobacterium vaccae NCTC 11659, a Soil-Derived Bacterium with Stress Resilience Properties, Modulates the Proinflammatory Effects of LPS in Macrophages

Inflammatory conditions, including allergic asthma and conditions in which chronic low-grade inflammation is a risk factor, such as stress-related psychiatric disorders, are prevalent and are a significant cause of disability worldwide. Novel approaches for the prevention and treatment of these disorders are needed. One approach is the use of immunoregulatory microorganisms, such as&nbsp;Mycobacterium vaccae&nbsp;NCTC 11659, which have anti-inflammatory, immunoregulatory, and stress-resilience properties. However, little is known about how&nbsp;M. vaccae&nbsp;NCTC 11659 affects specific immune cell targets, including monocytes, which can traffic to peripheral organs and the central nervous system and differentiate into monocyte-derived macrophages that, in turn, can drive inflammation and neuroinflammation. In this study, we investigated the effects of&nbsp;M. vaccae&nbsp;NCTC 11659 and subsequent lipopolysaccharide (LPS) challenge on gene expression in human monocyte-derived macrophages. THP-1 monocytes were differentiated into macrophages, exposed to&nbsp;M. vaccae&nbsp;NCTC 11659 (0, 10, 30, 100, 300 &micro;g/mL), then, 24 h later, challenged with LPS (0, 0.5, 2.5, 250 ng/mL), and assessed for gene expression 24 h following challenge with LPS. Exposure to&nbsp;M. vaccae&nbsp;NCTC 11659 prior to challenge with higher concentrations of LPS (250 ng/mL) polarized human monocyte-derived macrophages with decreased&nbsp;IL12A,&nbsp;IL12B, and&nbsp;IL23A&nbsp;expression relative to&nbsp;IL10&nbsp;and&nbsp;TGFB1&nbsp;mRNA expression. These data identify human monocyte-derived macrophages as a direct target of&nbsp;M. vaccae&nbsp;NCTC 11659 and support the development of&nbsp;M. vaccae&nbsp;NCTC 11659 as a potential intervention to prevent stress-induced inflammation and neuroinflammation implicated in the etiology and pathophysiology of inflammatory conditions and stress-related psychiatric disorders. &nbsp; </div

Toxoplasma gondii Serointensity and Seropositivity: Heritability and Household-Related Associations in the Old Order Amish

Toxoplasma gondii (T. gondii) is an intracellular parasite infecting one third of the world&rsquo;s population. Latent T. gondii infection has been associated with mental illness, including schizophrenia and suicidal behavior. T. gondii IgG antibody titers were measured via ELISA. The heritability of T. gondii IgG was estimated using a mixed model that included fixed effects for age and sex and random kinship effect. Of 2017 Old Order Amish participants, 1098 had positive titers (54.4%). The heritability for T. gondii serointensity was estimated to be 0.22 (p = 1.7 &times; 10&minus;8 and for seropositivity, it was estimated to be 0.28 (p = 1.9 &times; 10&minus;5). Shared household environmental effects (i.e., household effects) were also determined. Household effects, modeled as a random variable, were assessed as the phenotypic covariance between any two individuals who had the same current address (i.e., contemporaneous household), and nuclear household (i.e., the phenotypic covariance between parents and children only, not other siblings or spouses). Household effects did not account for a significant proportion of variance in either T. gondii serointensity or T. gondii seropositivity. Our results suggest a significant familial aggregation of T. gondii serointensity and seropositivity with significant heritability. The shared household does not contribute significantly to family aggregation with T. gondii, suggesting that there are possible unmeasured non-household shared and non-shared environmental factors that may play a significant role. Furthermore, the small but significant heritability effects justify the exploration of genetic vulnerability to T. gondii exposure, infection, virulence, and neurotropism</div

Eighth Annual Conference of inVIVO Planetary Health: From Challenges to Opportunities

inVIVO Planetary Health (inVIVO) is a progressive scientific movement providing evidence, advocacy, and inspiration to align the interests and vitality of people, place, and planet. Our goal is to transform personal and planetary health through awareness, attitudes, and actions, and a deeper understanding of how all systems are interconnected and interdependent. Here, we present the abstracts and proceedings of our 8th annual conference, held in Detroit, Michigan in May 2019, themed "From Challenges, to Opportunities". Our far-ranging discussions addressed the complex interdependent ecological challenges of advancing global urbanization, including the biopsychosocial interactions in our living environment on physical, mental, and spiritual wellbeing, together with the wider community and societal factors that govern these. We had a strong solutions focus, with diverse strategies spanning from urban-greening and renewal, nature-relatedness, nutritional ecology, planetary diets, and microbiome rewilding, through to initiatives for promoting resilience, positive emotional assets, traditional cultural narratives, creativity, art projects for personal and community health, and exploring ways of positively shifting mindsets and value systems. Our cross-sectoral agenda underscored the importance and global impact of local initiatives everywhere by contributing to new normative values as part of a global interconnected grass-roots movement for planetary health.</p

Quantifying Variation across 16S rRNA Gene Sequencing Runs in Human Microbiome Studies

Recent microbiome research has incorporated a higher number of samples through more participants in a study, longitudinal studies, and metanalysis between studies. Physical limitations in a sequencing machine can result in samples spread across sequencing runs. Here we present the results of sequencing nearly 1000 16S rRNA gene sequences in fecal (stabilized and swab) and oral (swab) samples from multiple human microbiome studies and positive controls that were conducted with identical standard operating procedures. Sequencing was performed in the same center across 18 different runs. The simplified mock community showed limitations in accuracy, while precision (e.g., technical variation) was robust for the mock community and actual human positive control samples. Technical variation was the lowest for stabilized fecal samples, followed by fecal swab samples, and then oral swab samples. The order of technical variation stability was inverse of DNA concentrations (e.g., highest in stabilized fecal samples), highlighting the importance of DNA concentration in reproducibility and urging caution when analyzing low biomass samples. Coefficients of variation at the genus level also followed the same trend for lower variation with higher DNA concentrations. Technical variation across both sample types and the two human sampling locations was significantly less than the observed biological variation. Overall, this research providing comparisons between technical and biological variation, highlights the importance of using positive controls, and provides semi-quantified data to better understand variation introduced by sequencing runs

Circadian and wakefulness-sleep modulation of cognition in humans

Cognitive and affective processes vary over the course of the 24 h day. Time of day dependent changes in human cognition are modulated by an internal circadian timekeeping system with a near-24 h period. The human circadian timekeeping system interacts with sleep-wakefulness regulatory processes to modulate brain arousal, neurocognitive and affective function. Brain arousal is regulated by ascending brain stem, basal forebrain (BF) and hypothalamic arousal systems and inhibition or disruption of these systems reduces brain arousal, impairs cognition, and promotes sleep. The internal circadian timekeeping system modulates cognition and affective function by projections from the master circadian clock, located in the hypothalamic suprachiasmatic nuclei (SCN), to arousal and sleep systems and via clock gene oscillations in brain tissues. Understanding the basic principles of circadian and wakefulness-sleep physiology can help to recognize how the circadian system modulates human cognition and influences learning, memory and emotion. Developmental changes in sleep and circadian processes and circadian misalignment in circadian rhythm sleep disorders have important implications for learning, memory and emotion. Overall, when wakefulness occurs at appropriate internal biological times, circadian clockwork benefits human cognitive and emotion function throughout the lifespan. Yet, when wakefulness occurs at inappropriate biological times because of environmental pressures (e.g., early school start times, long work hours that include work at night, shift work, jet lag) or because of circadian rhythm sleep disorders, the resulting misalignment between circadian and wakefulness-sleep physiology leads to impaired cognitive performance, learning, emotion, and safety

Hygiene and other early childhood influences on the subsequent function of the immune system

AbstractThe immune system influences brain development and function. Hygiene and other early childhood influences impact the subsequent function of the immune system during adulthood, with consequences for vulnerability to neurodevelopmental and psychiatric disorders. Inflammatory events during pregnancy can act directly to cause developmental problems in the central nervous system (CNS) that have been implicated in schizophrenia and autism. The immune system also acts indirectly by “farming” the intestinal microbiota, which then influences brain development and function via the multiple pathways that constitute the gut–brain axis. The gut microbiota also regulates the immune system. Regulation of the immune system is crucial because inflammatory states in pregnancy need to be limited, and throughout life inflammation needs to be terminated completely when not required; for example, persistently raised levels of background inflammation during adulthood (in the presence or absence of a clinically apparent inflammatory stimulus) correlate with an increased risk of depression. A number of factors in the perinatal period, notably immigration from rural low-income to rich developed settings, caesarean delivery, breastfeeding and antibiotic abuse have profound effects on the microbiota and on immunoregulation during early life that persist into adulthood. Many aspects of the modern western environment deprive the infant of the immunoregulatory organisms with which humans co-evolved, while encouraging exposure to non-immunoregulatory organisms, associated with more recently evolved “crowd” infections. Finally, there are complex interactions between perinatal psychosocial stressors, the microbiota, and the immune system that have significant additional effects on both physical and psychiatric wellbeing in subsequent adulthood.This article is part of a Special Issue entitled Neuroimmunology in Health And Disease

Consequences of Post-Weaning Social Isolation on Anxiety Behavior and Related Neural Circuits in Rodents

Exposure to adverse experiences in early-life is implicated in the later vulnerability to development of psychiatric disorders, including anxiety and affective disorders in humans. Adverse early-life experiences likely impart their long-term consequences on mental health by disrupting the normal development of neural systems involved in stress responses, emotional behavior and emotional states. Neural systems utilizing the neurotransmitters serotonin, dopamine and the neuropeptide corticotropin-releasing factor (CRF) are implicated in mediating emotive behaviors, and dysfunction of these neurochemical systems is associated with mood/anxiety disorders. These neural systems continue maturing until early or mid-adolescence in humans, thus alterations to their development are likely to contribute to the long-term consequences of adverse early-life experiences. A large body of literature suggests that post-weaning isolation rearing of rodents models the behavioral consequences of adverse early-life experiences in humans. Overall, the majority findings suggest that post-weaning social isolation that encompasses pre-adolescence produces long-lasting alterations to anxiety behavior, while measures of monoaminergic activity in various limbic regions during social isolation suggest alterations to dopamine and serotonin systems. The goal of this review is to evaluate and integrate findings from post-weaning social isolation studies specifically related to altered fear and anxiety behaviors and associated changes in neuroendocrine function and the activity of monoaminergic systems