Publications by authors named "Bruce McEwen"

429 Publications

Genes, Environments, and Time: The Biology of Adversity and Resilience.

Pediatrics 2021 Feb;147(2)

Center on the Developing Child and

Exposures to adverse environments, both psychosocial and physicochemical, are prevalent and consequential across a broad range of childhood populations. Such adversity, especially early in life, conveys measurable risk to learning and behavior and to the foundations of both mental and physical health. Using an interactive gene-environment-time (GET) framework, we survey the independent and interactive roles of genetic variation, environmental context, and developmental timing in light of advances in the biology of adversity and resilience, as well as new discoveries in biomedical research. Drawing on this rich evidence base, we identify 4 core concepts that provide a powerful catalyst for fresh thinking about primary health care for young children: (1) all biological systems are inextricably integrated, continuously "reading" and adapting to the environment and "talking back" to the brain and each other through highly regulated channels of cross-system communication; (2) adverse environmental exposures induce alterations in developmental trajectories that can lead to persistent disruptions of organ function and structure; (3) children vary in their sensitivity to context, and this variation is influenced by interactions among genetic factors, family and community environments, and developmental timing; and (4) critical or sensitive periods provide unmatched windows of opportunity for both positive and negative influences on multiple biological systems. These rapidly moving frontiers of investigation provide a powerful framework for new, science-informed thinking about health promotion and disease prevention in the early childhood period.
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http://dx.doi.org/10.1542/peds.2020-1651DOI Listing
February 2021

Leveraging the Biology of Adversity and Resilience to Transform Pediatric Practice.

Pediatrics 2021 Feb 25;147(2). Epub 2021 Jan 25.

The Rockefeller University, New York, New York.

Advances in science are fundamentally changing the way we understand how inextricable interactions among genetic predispositions, physical and social environments, and developmental timing influence early childhood development and the foundations of health and how significant early adversity can lead to a lifetime of chronic health impairments. This article and companion article illustrate the extent to which differential outcomes are shaped by ongoing interactive adaptations to context that begin at or even before conception and continue throughout life, with increasing evidence pointing to the importance of the prenatal period and early infancy for the developing brain, the immune system, and metabolic regulation. Although new discoveries in the basic sciences are transforming tertiary medical care and producing breakthrough outcomes in treating disease, this knowledge is not being leveraged effectively to inform new approaches to promoting whole-child development and preventing illness. The opportunity for pediatrics to serve as the leading edge of science-based innovation across the early childhood ecosystem has never been more compelling. In this article, we present a framework for leveraging the frontiers of scientific discovery to inform new strategies in pediatric practice and advocacy to protect all developing biological systems from the disruptive effects of excessive early adversity beyond providing information on child development for parents and enriched learning experiences for young children.
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http://dx.doi.org/10.1542/peds.2019-3845DOI Listing
February 2021

Chronic stress differentially alters mRNA expression of opioid peptides and receptors in the dorsal hippocampus of female and male rats.

J Comp Neurol 2021 Jan 22. Epub 2021 Jan 22.

Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York, USA.

Chronic immobilization stress (CIS) results in sex-dependent changes in opioid peptide levels and receptor subcellular distributions within the rat dorsal hippocampus, which are paralleled with an inability for males to acquire conditioned place preference (CPP) to oxycodone. Here, RNAScope in situ hybridization was used to determine the expression of hippocampal opioid peptides and receptors in unstressed (US) and CIS estrus female and male adult (∼2.5 months old ) Sprague Dawley rats. In all groups, dentate granule cells expressed PENK and PDYN; additionally, numerous interneurons expressed PENK. OPRD1 and OPRM1 were primarily expressed in interneurons, and to a lesser extent, in pyramidal and granule cells. OPRK1-was expressed in sparsely distributed interneurons. There were few baseline sex differences: US females compared to US males had more PENK-expressing and fewer OPRD1-expressing granule cells and more OPRM1-expressing CA3b interneurons. Several expression differences emerged after CIS. Both CIS females and males compared to their US counterparts had elevated: (1) PENK-expressing dentate granule cells and interneurons in CA1 and CA2/3a; (2) OPRD1 probe number and cell expression in CA1, CA2/3a and CA3b and the dentate gyrus; and (3) OPRK1-expressing interneurons in the dentate hilus. Also, CIS males compared to US males had elevated: (1) PDYN expression in granule cells; (2) OPRD1 probe and interneuron expression in CA2/3a; (3) OPRM1 in granule cells; and (4) OPRK1 interneuron expression in CA2/3a. The sex-specific changes in hippocampal opioid gene expression may impact network properties and synaptic plasticity processes that may contribute to the attenuation of oxycodone CPP in CIS males.
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http://dx.doi.org/10.1002/cne.25115DOI Listing
January 2021

Sex and chronic stress alter delta opioid receptor distribution within rat hippocampal CA1 pyramidal cells following behavioral challenges.

Neurobiol Stress 2020 Nov 22;13:100236. Epub 2020 Jun 22.

Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, United States.

Following oxycodone (Oxy) conditioned place preference (CPP), delta opioid receptors (DORs) differentially redistribute in hippocampal CA3 pyramidal cells in female and male rats in a manner that would promote plasticity and opioid-associative learning processes. However, following chronic immobilization stress (CIS), males do not acquire Oxy-CPP and the trafficking of DORs in CA3 pyramidal neurons is attenuated. Here, we examined the subcellular distribution of DORs in CA1 pyramidal cells using electron microscopy in these same cohorts.

Cpp: Saline (Sal)-females compared to Sal-males have more cytoplasmic and total DORs in dendrites and more DOR-labeled spines. Following Oxy-CPP, DORs redistribute from near-plasmalemma pools in dendrites to spines in males.

Cis: Control females compared to control males have more near-plasmalemmal dendritic DORs. Following CIS, dendritic DORs are elevated in the cytoplasm in females and near-plasmalemma in males.

Cis Plus Cpp: CIS Sal-females compared to CIS Sal-males have more DORs on the plasmalemma of dendrites and in spines. After Oxy, the distribution of DORs does not change in either females or males.

Conclusion: Following Oxy-CPP, DORs within CA1 pyramidal cells remain positioned in naïve female rats to enhance sensitivity to DOR agonists and traffic to dendritic spines in naïve males where they can promote plasticity processes. Following CIS plus behavioral enrichment, DORs are redistributed within CA1 pyramidal cells in females in a manner that could enhance sensitivity to DOR agonists. Conversely, CIS plus behavioral enrichment does not alter DORs in CA1 pyramidal cells in males, which may contribute to their diminished capacity to acquire Oxy-CPP.
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http://dx.doi.org/10.1016/j.ynstr.2020.100236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739044PMC
November 2020

Framework for a Community Health Observing System for the Gulf of Mexico Region: Preparing for Future Disasters.

Front Public Health 2020 15;8:578463. Epub 2020 Oct 15.

Emerging Pathogens Institute, University of Florida, Gainesville, FL, United States.

The Gulf of Mexico (GoM) region is prone to disasters, including recurrent oil spills, hurricanes, floods, industrial accidents, harmful algal blooms, and the current COVID-19 pandemic. The GoM and other regions of the U.S. lack sufficient baseline health information to identify, attribute, mitigate, and facilitate prevention of major health effects of disasters. Developing capacity to assess adverse human health consequences of future disasters requires establishment of a comprehensive, sustained community health observing system, similar to the extensive and well-established environmental observing systems. We propose a system that combines six levels of health data domains, beginning with three existing, national surveys and studies plus three new nested, longitudinal cohort studies. The latter are the unique and most important parts of the system and are focused on the coastal regions of the five GoM States. A statistically representative sample of participants is proposed for the new cohort studies, stratified to ensure proportional inclusion of urban and rural populations and with additional recruitment as necessary to enroll participants from particularly vulnerable or under-represented groups. Secondary data sources such as syndromic surveillance systems, electronic health records, national community surveys, environmental exposure databases, social media, and remote sensing will inform and augment the collection of primary data. Primary data sources will include participant-provided information via questionnaires, clinical measures of mental and physical health, acquisition of biological specimens, and wearable health monitoring devices. A suite of biomarkers may be derived from biological specimens for use in health assessments, including calculation of allostatic load, a measure of cumulative stress. The framework also addresses data management and sharing, participant retention, and system governance. The observing system is designed to continue indefinitely to ensure that essential pre-, during-, and post-disaster health data are collected and maintained. It could also provide a model/vehicle for effective health observation related to infectious disease pandemics such as COVID-19. To our knowledge, there is no comprehensive, disaster-focused health observing system such as the one proposed here currently in existence or planned elsewhere. Significant strengths of the GoM Community Health Observing System (CHOS) are its longitudinal cohorts and ability to adapt rapidly as needs arise and new technologies develop.
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http://dx.doi.org/10.3389/fpubh.2020.578463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593336PMC
October 2020

The bed nucleus of the stria terminalis and functionally linked neurocircuitry modulate emotion processing and HPA axis dysfunction in posttraumatic stress disorder.

Neuroimage Clin 2020 24;28:102442. Epub 2020 Sep 24.

Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Background: The bed nucleus of the stria terminalis (BNST) plays an important role in rodent posttraumatic stress disorder (PTSD), but evidence to support its relevance to human PTSD is limited. We sought to understand the role of the BNST in human PTSD via fMRI, behavioral, and physiological measurements.

Methods: 29 patients with PTSD (childhood sexual abuse) and 23 healthy controls (HC) underwent BOLD imaging with an emotional word paradigm. Symptom severity was assessed using the Clinician-Administered PTSD Scale and HPA-axis dysfunction was assessed by measuring the diurnal cortisol amplitude index (DCAI). A data-driven multivariate analysis was used to determine BNST task-based functional co-occurrence (tbFC) across individuals.

Results: In the trauma-versus-neutral word contrast, patients showed increased activation compared to HC in the BNST, medial prefrontal cortex (mPFC), posterior cingulate gyrus (PCG), caudate heads, and midbrain, and decreased activation in dorsolateral prefrontal cortex (DLPFC). Symptom severity positively correlated with activity in the BNST, caudate head, amygdala, hippocampus, dorsal anterior cingulate gyrus (dACG), and PCG, and negatively with activity in the medial orbiotofrontal cortex (mOFC) and DLPFC. Patients and HC showed marked differences in the relationship between the DCAI and BOLD activity in the BNST, septal nuclei, dACG, and PCG. Patients showed stronger tbFC between the BNST and closely linked limbic and subcortical regions, and a loss of negative tbFC between the BNST and DLPFC.

Conclusions: Based upon novel data, we present a new model of dysexecutive emotion processing and HPA-axis dysfunction in human PTSD that incorporates the role of the BNST and functionally linked neurocircuitry.
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http://dx.doi.org/10.1016/j.nicl.2020.102442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569227PMC
September 2020

Environmental epigenetics of sex differences in the brain.

Handb Clin Neurol 2020 ;175:209-220

Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, Rockefeller University, New York, NY, United States.

Experiences throughout the life course lead to unique phenotypes even among those with the same genotype. Genotype sets the substrate on which physiologic processes, which communicate with the brain, mediate the effects of life experiences via epigenetics. Epigenetics modify the expression of genes in the brain and body in response to circulating hormones and other mediators, which are activated to facilitate survival responses through a process called allostasis. Epigenetic signatures can even be inherited, resulting in transgenerational effects. This chapter addresses epigenetics in the context of sex differences, discussing the intersection between genetics and gonadal hormones and their effect in the brain at discrete developmental periods.
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http://dx.doi.org/10.1016/B978-0-444-64123-6.00015-1DOI Listing
January 2020

Behavioral and neurobiological effects of GnRH agonist treatment in mice-potential implications for puberty suppression in transgender individuals.

Neuropsychopharmacology 2021 Apr 12;46(5):882-890. Epub 2020 Sep 12.

Division of Systems Neuroscience, Research Foundation for Mental Hygiene, Inc. (RFMH)/New York State Psychiatric Institute (NYSPI), New York, NY, 10032, USA.

In the United States, ~1.4 million individuals identify as transgender. Many transgender adolescents experience gender dysphoria related to incongruence between their gender identity and sex assigned at birth. This dysphoria may worsen as puberty progresses. Puberty suppression by gonadotropin-releasing hormone agonists (GnRHa), such as leuprolide, can help alleviate gender dysphoria and provide additional time before irreversible changes in secondary sex characteristics may be initiated through feminizing or masculinizing hormone therapy congruent with the adolescent's gender experience. However, the effects of GnRH agonists on brain function and mental health are not well understood. Here, we investigated the effects of leuprolide on reproductive function, social and affective behavior, cognition, and brain activity in a rodent model. Six-week-old male and female C57BL/6J mice were injected daily with saline or leuprolide (20 μg) for 6 weeks and tested in several behavioral assays. We found that leuprolide increases hyperlocomotion, changes social preference, and increases neuroendocrine stress responses in male mice, while the same treatment increases hyponeophagia and despair-like behavior in females. Neuronal hyperactivity was found in the dentate gyrus (DG) of leuprolide-treated females, but not males, consistent with the elevation in hyponeophagia and despair-like behavior in females. These data show for the first time that GnRH agonist treatment after puberty onset exerts sex-specific effects on social- and affective behavior, stress regulation, and neural activity. Investigating the behavioral and neurobiological effects of GnRH agonists in mice will be important to better guide the investigation of potential consequences of this treatment for youth experiencing gender dysphoria.
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http://dx.doi.org/10.1038/s41386-020-00826-1DOI Listing
April 2021

Oxycodone injections not paired with conditioned place preference have little effect on the hippocampal opioid system in female and male rats.

Synapse 2021 01 29;75(1):e22182. Epub 2020 Jul 29.

Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.

Oxycodone (Oxy) conditioned place preference (CPP) in Sprague Dawley rats results in sex-specific alterations in hippocampal opioid circuits in a manner that facilitates opioid-associative learning processes, particularly in females. Here, we examined if Oxy (3 mg/kg, I.P.) or saline (Sal) injections not paired with behavioral testing similarly affect the hippocampal opioid system. Sal-injected females compared to Sal-injected males had: (1) higher densities of cytoplasmic delta opioid receptors (DOR) in GABAergic hilar dendrites suggesting higher baseline reserve DOR pools and (2) elevated phosphorylated DOR levels, but lower phosphorylated mu opioid receptor (MOR) levels in CA3a suggesting that the baseline pools of activated opioid receptors vary in females and males. In contrast to CPP studies, Oxy-injections in the absence of behavioral tests resulted in few changes in the hippocampal opioid system in either females or males. Specifically, Oxy-injected males compared to Sal-injected males had fewer DORs near the plasma membrane of CA3 pyramidal cell dendrites and in CA3 dendritic spines contacted by mossy fibers, and lower pMOR levels in CA3a. Oxy-injected females compared to Sal-injected females had higher total DORs in GABAergic dendrites and lower total MORs in parvalbumin-containing dendrites. Thus, unlike Oxy CPP, Oxy-injections redistributed opioid receptors in hippocampal neurons in a manner that would either decrease (males) or not alter (females) excitability and plasticity processes. These results indicate that the majority of changes within hippocampal opioid circuits that would promote opioid-associative learning processes in both females and males do not occur with Oxy administration alone, and instead must be paired with CPP.
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http://dx.doi.org/10.1002/syn.22182DOI Listing
January 2021

Corticosterone after acute stress prevents the delayed effects on the amygdala.

Neuropsychopharmacology 2020 12 6;45(13):2139-2146. Epub 2020 Jul 6.

National Centre for Biological Sciences, Bangalore, 560065, India.

Even a single 2-hour episode of immobilization stress is known to trigger anxiety-like behavior and increase spine-density in the basolateral amygdala (BLA) of rats 10 days later. This delayed build-up of morphological and behavioral effects offers a stress-free time window of intervention after acute stress, which we used to test a protective role for glucocorticoids against stress. We observed that post-stress corticosterone, given 1 day after acute stress in drinking water, reversed enhanced anxiety-like behavior 10 days later. Quantification of spine-density on Golgi-stained BLA principal neurons showed that the same intervention also prevented the increase in spine numbers in the amygdala, at the same delayed time-point. Further, stress elevated serum corticosterone levels in rats that received vehicle in the drinking water. However, when stress was followed 24 h later by corticosterone in the drinking water, the surge in corticosterone was prevented. Together, these observations suggest that corticosterone, delivered through drinking water even 24 h after acute stress, is capable of reversing the delayed enhancing effects on BLA synaptic connectivity and anxiety-like behavior. Strikingly, although the immobilization-induced surge in corticosterone by itself has delayed detrimental effects on amygdalar structure and function, there exists a window of opportunity even after stress to mitigate its impact with a second surge of exogenously administered corticosterone. This provides a framework in the amygdala for analyzing how the initial physiological and endocrine processes triggered by traumatic stress eventually give rise to debilitating emotional symptoms, as well as the protective effects of glucocorticoids against their development.
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http://dx.doi.org/10.1038/s41386-020-0758-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784883PMC
December 2020

Insulin receptor substrate in brain-enriched exosomes in subjects with major depression: on the path of creation of biosignatures of central insulin resistance.

Mol Psychiatry 2020 Jun 15. Epub 2020 Jun 15.

Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA.

Insulin signaling is critical for neuroplasticity, cerebral metabolism as well as for systemic energy metabolism. In rodent studies, impaired brain insulin signaling with resultant insulin resistance (IR) modulates synaptic plasticity and the corresponding behavioral functions. Despite discoveries of central actions of insulin, in vivo molecular mechanisms of brain IR until recently have proven difficult to study in the human brain. In the current study, we leveraged recent technological advances in molecular biology and herein report an increased number of exosomes enriched for L1CAM, a marker predominantly expressed in the brain, in subjects with major depressive disorder (MDD) as compared with age- and sex-matched healthy controls (HC). We also report increased concentration of the insulin receptor substrate-1 (IRS-1) in L1CAM exosomes in subjects with MDD as compared with age- and sex-matched HC. We found a relationship between expression of IRS-1 in L1CAM exosomes and systemic IR as assessed by homeostatic model assessment of IR in HC, but not in subjects with MDD. The increased IRS-1 levels in L1CAM exosomes were greater in subjects with MDD and were associated with suicidality and anhedonia. Finally, our data suggested sex differences in serine-312 phosphorylation of IRS-1 in L1CAM exosomes in subjects with MDD. These findings provide a starting point for creating mechanistic framework of brain IR in further development of personalized medicine strategies to effectively treat MDD.
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http://dx.doi.org/10.1038/s41380-020-0804-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787430PMC
June 2020

Determining the Optimal Outcome Measures for Studying the Social Determinants of Health.

Int J Environ Res Public Health 2020 04 27;17(9). Epub 2020 Apr 27.

Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

Americans have significantly poorer health outcomes and shorter longevity than citizens of other industrialized nations. Poverty is a major driver of these poor health outcomes in the United States. Innovative anti-poverty policies may help reduce economic malaise thereby increasing the health and longevity of the most vulnerable Americans. However, there is no consensus framework for studying the health impacts of anti-poverty social policies. In this paper, we describe a case study in which leading global experts systematically: (1) developed a conceptual model that outlines the potential pathways through which a social policy influences health, (2) fits outcome measures to this conceptual model, and (3) estimates an optimal time frame for collection of the selected outcome measures. This systematic process, called the Delphi method, has the potential to produce estimates more quickly and with less bias than might be achieved through expert panel discussions alone. Our case study is a multi-component randomized-controlled trial (RCT) of a workforce policy called MyGoals for Healthy Aging.
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http://dx.doi.org/10.3390/ijerph17093028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246501PMC
April 2020

The untapped power of allostasis promoted by healthy lifestyles.

Authors:
Bruce S McEwen

World Psychiatry 2020 Feb;19(1):57-58

Harold and Margaret Milliken Hatch, Laboratory of Neuroendocrinology, Rockefeller University, New York, NY, USA.

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http://dx.doi.org/10.1002/wps.20720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953580PMC
February 2020

Metabolic signature in nucleus accumbens for anti-depressant-like effects of acetyl-L-carnitine.

Elife 2020 01 10;9. Epub 2020 Jan 10.

Laboratory of Behavioral Genetics, Brain and Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

Emerging evidence suggests that hierarchical status provides vulnerability to develop stress-induced depression. Energy metabolic changes in the nucleus accumbens (NAc) were recently related to hierarchical status and vulnerability to develop depression-like behavior. Acetyl-L-carnitine (LAC), a mitochondria-boosting supplement, has shown promising antidepressant-like effects opening therapeutic opportunities for restoring energy balance in depressed patients. We investigated the metabolic impact in the NAc of antidepressant LAC treatment in chronically-stressed mice using H-magnetic resonance spectroscopy (H-MRS). High rank, but not low rank, mice, as assessed with the tube test, showed behavioral vulnerability to stress, supporting a higher susceptibility of high social rank mice to develop depressive-like behaviors. High rank mice also showed reduced levels of several energy-related metabolites in the NAc that were counteracted by LAC treatment. Therefore, we reveal a metabolic signature in the NAc for antidepressant-like effects of LAC in vulnerable mice characterized by restoration of stress-induced neuroenergetics alterations and lipid function.
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http://dx.doi.org/10.7554/eLife.50631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970538PMC
January 2020

Revisiting the Stress Concept: Implications for Affective Disorders.

J Neurosci 2020 01;40(1):12-21

University of Michigan Medical School, Ann Arbor, Michigan 48109

Over the last 50 years, the concept of stress has evolved significantly, and our understanding of the underlying neurobiology has expanded dramatically. Rather than consider stress biology to be relevant only under unusual and threatening conditions, we conceive of it as an ongoing, adaptive process of assessing the environment, coping with it, and enabling the individual to anticipate and deal with future challenges. Though much remains to be discovered, the fundamental neurocircuitry that underlies these processes has been broadly delineated, key molecular players have been identified, and the impact of this system on neuroplasticity has been well established. More recently, we have come to appreciate the critical interaction between the brain and the rest of the body as it pertains to stress responsiveness. Importantly, this system can become overloaded due to ongoing environmental demands on the individual, be they physical, physiological, or psychosocial. The impact of this overload is deleterious to brain health, and it results in vulnerability to a range of brain disorders, including major depression and cognitive deficits. Thus, stress biology is one of the best understood systems in affective neuroscience and is an ideal target for addressing the pathophysiology of many brain-related diseases. The story we present began with the discovery of glucocorticoid receptors in hippocampus and has extended to other brain regions in both animal models and the human brain with the further discovery of structural and functional adaptive plasticity in response to stressful and other experiences.
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http://dx.doi.org/10.1523/JNEUROSCI.0733-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939488PMC
January 2020

Stress-induced modulation of endocannabinoid signaling leads to delayed strengthening of synaptic connectivity in the amygdala.

Proc Natl Acad Sci U S A 2020 01 16;117(1):650-655. Epub 2019 Dec 16.

Department of Neurobiology, National Centre for Biological Sciences, 560065 Bangalore, India;

Even a brief exposure to severe stress strengthens synaptic connectivity days later in the amygdala, a brain area implicated in the affective symptoms of stress-related psychiatric disorders. However, little is known about the synaptic signaling mechanisms during stress that eventually culminate in its delayed impact on the amygdala. Hence, we investigated early stress-induced changes in amygdalar synaptic signaling in order to prevent its delayed effects. Whole-cell recordings in basolateral amygdala (BLA) slices from rats revealed higher frequency of miniature excitatory postsynaptic currents (mEPSCs) immediately after 2-h immobilization stress. This was replicated by inhibition of cannabinoid receptors (CBR), suggesting a role for endocannabinoid (eCB) signaling. Stress also reduced -arachidonoylethanolamine (AEA), an endogenous ligand of CBR. Since stress-induced activation of fatty acid amide hydrolase (FAAH) reduces AEA, we confirmed that oral administration of an FAAH inhibitor during stress prevents the increase in synaptic excitation in the BLA soon after stress. Although stress also caused an immediate reduction in synaptic inhibition, this was not prevented by FAAH inhibition. Strikingly, FAAH inhibition during the traumatic stressor was also effective 10 d later on the delayed manifestation of synaptic strengthening in BLA neurons, preventing both enhanced mEPSC frequency and increased dendritic spine-density. Thus, oral administration of an FAAH inhibitor during a brief stress prevents the early synaptic changes that eventually build up to hyperexcitability in the amygdala. This framework is of therapeutic relevance because of growing interest in targeting eCB signaling to prevent the gradual development of emotional symptoms and underlying amygdalar dysfunction triggered by traumatic stress.
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http://dx.doi.org/10.1073/pnas.1910322116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955336PMC
January 2020

Sex and age differentially affect GABAergic neurons in the mouse prefrontal cortex and hippocampus following chronic intermittent hypoxia.

Exp Neurol 2020 03 16;325:113075. Epub 2019 Dec 16.

Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065, United States of America; Department of Neurology, Icahn School of Medicine, Mount Sinai, New York, NY 10029, United States of America; Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States of America. Electronic address:

Obstructive sleep apnea (OSA), a chronic sleep disorder characterized by repetitive reduction or cessation of airflow during sleep, is widely prevalent and is associated with adverse neurocognitive sequelae including increased risk of Alzheimer's disease (AD). In humans, OSA is more common in elderly males. OSA is characterized by sleep fragmentation and chronic intermittent hypoxia (CIH), and recent epidemiological studies point to CIH as the best predictor of neurocognitive sequelae associated with OSA. The sex- and age- specific effects of OSA-associated CIH on specific cell populations such as γ-aminobutyric acid (GABA)-ergic neurons in the hippocampus and the medial prefrontal cortex (mPFC), regions important for cognitive function, remain largely unknown. The present study examined the effect of 35 days of either moderate (10% oxygen) or severe (5% oxygen) CIH on GABAergic neurons in the mPFC and hippocampus of young and aged male and female mice as well as post-accelerated ovarian failure (AOF) female mice. In the mPFC and hippocampus, the number of GABA-labeled neurons increased in aged and young severe CIH males compared to controls but not in young moderate CIH males. This change was not representative of the individual GABAergic cell subpopulations, as the number of parvalbumin-labeled neurons decreased while the number of somatostatin-labeled neurons increased in the hippocampus of severe CIH young males only. In all female groups, the number of GABA-labeled cells was not different between CIH and controls. However, in the mPFC, CIH increased the number of parvalbumin-labeled neurons in young females and the number of somatostatin-labeled cells in AOF females but decreased the number of somatostatin-labeled cells in aged females. In the hippocampus, CIH decreased the number of somatostatin-labeled neurons in young females. CIH decreased the density of vesicular GABA transporter in the mPFC of AOF females only. These findings suggest sex-specific changes in GABAergic neurons in the hippocampus and mPFC with males showing an increase of this cell population as compared to their female counterparts following CIH. Age at exposure and severity of CIH also differentially affect the GABAergic cell population in mice.
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http://dx.doi.org/10.1016/j.expneurol.2019.113075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050962PMC
March 2020

Hormones and behavior and the integration of brain-body science.

Authors:
Bruce S McEwen

Horm Behav 2020 03 26;119:104619. Epub 2019 Dec 26.

Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, United States of America. Electronic address:

The investigation of hormones, brain function and behavior over the past 50 years has played a major role in elucidating how the brain and body communicate reciprocally via hormones and other mediators and how this impacts brain and body health both positively and negatively. This is illustrated here for the hippocampus, a uniquely sensitive and vulnerable brain region, study of which as a hormone target has provided a gateway into the rest of the brain. Hormone actions on the brain and hormones generated within the brain are now recognized to include not only steroid hormones but also metabolic hormones and chemical signals from bone and muscle. Moreover, steroid hormones, and some metabolic hormones, and their receptors, are generated by the brain for specific functions that synergize with effects of those circulating hormones. Hormone actions in hippocampus have revealed its capacity, and that of other brain regions, for adaptive plasticity, loss of which needs external intervention in, for example, mood disorders. Early life experiences as well as in utero and transgenerational effects are now appreciated for their lasting effects at the level of gene expression affecting the capacity for adaptive plasticity. Moreover sex differences are recognized as affecting the whole brain via both genetic and epigenetic mechanisms. The demonstrated plasticity of a healthy brain gives hope that interventions throughout the life course can ameliorate negative effects by reactivating that plasticity and the underlying epigenetic activity to produce compensatory changes in the brain with more positive consequences for the body.
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http://dx.doi.org/10.1016/j.yhbeh.2019.104619DOI Listing
March 2020

During infant maltreatment, stress targets hippocampus, but stress with mother present targets amygdala and social behavior.

Proc Natl Acad Sci U S A 2019 11 21;116(45):22821-22832. Epub 2019 Oct 21.

Emotional Brain Institute, Nathan Kline Institute, Orangeburg, NY 10962;

Infant maltreatment increases vulnerability to physical and mental disorders, yet specific mechanisms embedded within this complex infant experience that induce this vulnerability remain elusive. To define critical features of maltreatment-induced vulnerability, rat pups were reared from postnatal day 8 (PN8) with a maltreating mother, which produced amygdala and hippocampal deficits and decreased social behavior at PN13. Next, we deconstructed the maltreatment experience to reveal sufficient and necessary conditions to induce this phenotype. Social behavior and amygdala deficits (volume, neurogenesis, c-Fos, local field potential) required combined chronic high corticosterone and maternal presence (not maternal behavior). Hippocampal deficits were induced by chronic high corticosterone regardless of social context. Causation was shown by blocking corticosterone during maltreatment and suppressing amygdala activity during social behavior testing. These results highlight (1) that early life maltreatment initiates multiple pathways to pathology, each with distinct causal mechanisms and outcomes, and (2) the importance of social presence on brain development.
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http://dx.doi.org/10.1073/pnas.1907170116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842629PMC
November 2019

Epigenetic impact of the social and physical environment on brain and body.

Metabolism 2019 11;100S:153941

Laboratory of Neuroendocrinology and Neuroimmunology and Inflammation Program The Rockefeller University, 1230 York Ave, New York, N.Y. 10065, United States of America.

Modern biomedical scientists are often trapped in silos of knowledge and practice, such as those who study brain structure, function and behavior, on the one hand, and body systems and disorders, on the other. Scientists and physicians in each of those silos have not often paid attention to the brain-body communication that leads to multi-morbidity of systemic and brain-related disorders [eg. depression with diabetes or cardiovascular disease]. Outside of biomedicine, social scientists have long recognized the impact of the social and physical environment on individuals and populations but have not usually connected these effects with changes in underlying biology. However, with the rise of epigenetics, science and the public understanding of science is leaving an era in which the DNA sequence was thought to be "destiny" and entering an era where the environment shapes the biology and behavior of individuals and groups through its interactive effects on brain and body. It does so, at least in part, by shaping epigenetically the structure and function of brain and body systems that show a considerable amount of adaptive plasticity throughout development and adult life. This results in substantial individual differences even between identical twins. These individual differences are produced epigenetically by the two-way interaction between the brain and hormones, immune system mediators and the autonomic nervous system. Disorders, then, are often multimorbid involving both brain and body, such as depression with diabetes and cardiovascular disease. It is therefore imperative to incorporate into "precision medicine" a better understanding of how these differences affect the efficacy of pharmacological, behavioral and psychosocial interventions. This article presents an overview of this new synthesis, using as an example emerging evidence about the linkages between systemic inflammation, insulin resistance and mental health and neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.metabol.2019.07.005DOI Listing
November 2019

What Is the Confusion With Cortisol?

Authors:
Bruce S McEwen

Chronic Stress (Thousand Oaks) 2019 Jan-Dec;3. Epub 2019 Feb 27.

Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA.

Cortisol has many roles not only in mediating the response to stress but also in the circadian rhythm, and it does so by both genomic and nongenomic cellular and molecular mechanisms. Yet, it is common to associate cortisol only with stress and, in particular, with the negative aspects of stress even though we would not survive without it. This commentary provides a brief overview not only of the diverse roles of cortisol but also of how to measure it to get meaningful information in the context of other mediators of stress and adaptation and the concepts of allostasis and allostatic load and overload. In particular, the adaptive plasticity of the brain mediated by glucocorticoids and excitatory amino acids is discussed in relation to misconceptions about what constitutes brain damage. Thus the confusion with cortisol is that it does too many important things both positive and negative!
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http://dx.doi.org/10.1177/2470547019833647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788742PMC
February 2019

Divergent roles of astrocytic versus neuronal EAAT2 deficiency on cognition and overlap with aging and Alzheimer's molecular signatures.

Proc Natl Acad Sci U S A 2019 10 7;116(43):21800-21811. Epub 2019 Oct 7.

Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029;

The excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the brain expressed predominantly in astrocytes and at low levels in neurons and axonal terminals. EAAT2 expression is reduced in aging and sporadic Alzheimer's disease (AD) patients' brains. The role EAAT2 plays in cognitive aging and its associated mechanisms remains largely unknown. Here, we show that conditional deletion of astrocytic and neuronal EAAT2 results in age-related cognitive deficits. Astrocytic, but not neuronal EAAT2, deletion leads to early deficits in short-term memory and in spatial reference learning and long-term memory. Neuronal EAAT2 loss results in late-onset spatial reference long-term memory deficit. Neuronal EAAT2 deletion leads to dysregulation of the kynurenine pathway, and astrocytic EAAT2 deficiency results in dysfunction of innate and adaptive immune pathways, which correlate with cognitive decline. Astrocytic EAAT2 deficiency also shows transcriptomic overlaps with human aging and AD. Overall, the present study shows that in addition to the widely recognized astrocytic EAAT2, neuronal EAAT2 plays a role in hippocampus-dependent memory. Furthermore, the gene expression profiles associated with astrocytic and neuronal EAAT2 deletion are substantially different, with the former associated with inflammation and synaptic function similar to changes observed in human AD and gene expression changes associated with inflammation similar to the aging human brain.
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http://dx.doi.org/10.1073/pnas.1903566116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815169PMC
October 2019

Sex and chronic stress differentially alter phosphorylated mu and delta opioid receptor levels in the rat hippocampus following oxycodone conditioned place preference.

Neurosci Lett 2019 11 24;713:134514. Epub 2019 Sep 24.

Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, United States; Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, United States. Electronic address:

Following oxycodone conditioned place preference (CPP) in naïve female and male Sprague Dawley rats, delta- and mu-opioid receptors (DORs and MORs) redistribute in hippocampal CA3 pyramidal cells and GABAergic interneurons in a manner that would promote opioid-associative learning processes, particularly in females. MORs and DORs similarly redistribute in CA3 and hilar neurons following chronic immobilization stress (CIS) in females, but not males, essentially "priming" the opioid system for oxycodone-associative learning. Following CIS, only females acquire oxycodone CPP. The present study determined whether sex and CIS differentially affect the levels of phosphorylated MORs and DORs (pMORs and pDORs) in the hippocampus following oxycodone CPP as phosphorylation is important for opioid receptor internationalization and trafficking. In naïve oxycodone-injected (Oxy) female rats, the density of pMOR-immunoreactivity (ir) was increased in CA1 stratum oriens and CA3a,b strata lucidum and radiatum compared to saline-injected (Sal)-females. Additionally, the density of pDOR-ir increased in the pyramidal cell layer and stratum radiatum of CA2/3a in Oxy-males compared to Sal-males. In CIS females that acquire CPP, pDOR-ir levels were increased in the CA2/3a. These findings indicate only rats that acquire oxycodone CPP have activated MORs and DORs in the hippocampus but that the subregion containing activated opioid receptors differs in females and males. These results are consistent with previously observed sex differences in the hippocampal opioid system following Oxy-CPP.
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http://dx.doi.org/10.1016/j.neulet.2019.134514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768632PMC
November 2019

Multidimensional Predictors of Susceptibility and Resilience to Social Defeat Stress.

Biol Psychiatry 2019 09 29;86(6):483-491. Epub 2019 Jul 29.

Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.

Background: Previous studies identified several separate risk factors for stress-induced disorders. However, an integrative model of susceptibility versus resilience to stress including measures from brain-body domains is likely to yield a range of multiple phenotypic information to promote successful adaptation to stress.

Methods: We used computational and molecular approaches to test whether 1) integrative brain-body behavioral, immunological, and structural domains characterized and predicted susceptibility or resilience to social defeat stress (SDS) in mice and 2) administration of acetyl-L-carnitine promoted resilience at the SDS paradigm.

Results: Our findings identified multidimensional brain-body predictors of susceptibility versus resilience to SDS. The copresence of anxiety, decreased hippocampal volume, and elevated systemic interleukin-6 characterized a susceptible phenotype that developed behavioral and neurobiological deficits after exposure to SDS. The susceptible phenotype showed social withdrawal and impaired transcriptomic-wide changes in the ventral dentate gyrus after SDS. At the individual level, a computational approach predicted whether a given animal developed SDS-induced social withdrawal, or remained resilient, based on the integrative in vivo measures of anxiety and immune system function. Finally, we provide initial evidence that administration of acetyl-L-carnitine promoted behavioral resilience at the SDS paradigm.

Conclusions: The current findings of multidimensional brain-body predictors of susceptibility versus resilience to stress provide a starting point for in vivo models of mechanisms predisposing apparently healthy individuals to develop the neurobiological and behavioral deficits resulting from stress exposure. This framework can lead to novel therapeutic strategies to promote resilience in susceptible phenotypes.
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http://dx.doi.org/10.1016/j.biopsych.2019.06.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730655PMC
September 2019

Midlife reversibility of early-established biobehavioral risk factors: A research agenda.

Dev Psychol 2019 Oct 1;55(10):2203-2218. Epub 2019 Aug 1.

Laboratory of Comparative Ethology, Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Epidemiological evidence links exposure to early life adversities-such as childhood maltreatment-with impaired health and well-being in adulthood. Since these effects are usually unrecognized or untreated in childhood, preventive and remediating interventions in adults are needed. Our focus on adulthood prompted three major questions. First, does our increased understanding of mechanisms accounting for the long-term effects of early life adversities help delineate underlying dimensions that underscore key similarities and differences among these adversities? Second, can adults accurately report on adversities they experienced in childhood? Third, can we identify malleable risk processes in adulthood that might be targets for preventive intervention? Supported by the National Institute on Aging, the U.K. Economic and Social and the Biotechnology and Biological Sciences Research Councils, a network of researchers in human and animal development addressed these questions through meetings and literature review. A small number of dimensions may adequately distinguish among a range of co-occurring childhood adversities. Widely used adult ascertainments of childhood adversity are poorly related to prospective ascertainment. Strategies for preventive interventions should be aimed both at adults who were actually exposed to adversity as well as those who recall adversity, but the targeted risk processes may be different. Now is an opportune time to support research on adult interventions based on unfolding research on critical periods of sensitivity to adversity in fetal and child development, on improved understanding of risk mechanisms that may persist across the life span, and on new insights on enhancing neuroplasticity in adults. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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http://dx.doi.org/10.1037/dev0000780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907692PMC
October 2019

Early Life Stress Restricts Translational Reactivity in CA3 Neurons Associated With Altered Stress Responses in Adulthood.

Front Behav Neurosci 2019 11;13:157. Epub 2019 Jul 11.

Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, United States.

Early life experiences program brain structure and function and contribute to behavioral endophenotypes in adulthood. Epigenetic control of gene expression by those experiences affect discrete brain regions involved in mood, cognitive function and regulation of hypothalamic-pituitary-adrenal (HPA) axis. In rodents, acute restraint stress increases the expression of the repressive histone H3 lysine 9 tri-methylation (H3K9me3) in hippocampal fields, including the CA3 pyramidal neurons. These CA3 neurons are crucially involved in cognitive function and mood regulation as well as activation of glucocorticoid (CORT) secretion. CA3 neurons also exhibit structural and functional changes after early-life stress (ELS) as well as after chronic stress in adulthood. Using a protocol of chronic ELS induced by limited bedding and nesting material followed by acute-swim stress (AS) in adulthood, we show that mice with a history of ELS display a blunted CORT response to AS, despite exhibiting activation of immediate early genes after stress similar to that found in control mice. We find that ELS induced persistently increased expression of the repressive H3K9me3 histone mark in the CA3 subfield at baseline that was subsequently decreased following AS. In contrast, AS induced a transient increase of this mark in control mice. Using translating ribosome affinity purification (TRAP) method to isolate CA3 translating mRNAs, we found that expression of genes of the epigenetic gene family, GABA/glutamate family, and glucocorticoid receptors binding genes were decreased transiently in control mice by AS and showed a persistent reduction in ELS mice. In most cases, AS in ELS mice did not induce gene expression changes. A stringent filtering of genes affected by AS in control and ELS mice revealed a noteworthy decrease in gene expression change in ELS mice compared to control. Only 18 genes were selectively regulated by AS in ELS mice and encompassed pathways such as circadian rhythm, inflammatory response, opioid receptors, and more genes included in the glucocorticoid receptor binding family. Thus, ELS programs a restricted translational response to stress in stress-sensitive CA3 neurons leading to persistent changes in gene expression, some of which mimic the transient effects of AS in control mice, while leaving in operation the immediate early gene response to AS.
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http://dx.doi.org/10.3389/fnbeh.2019.00157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637287PMC
July 2019

Clinical characterization of allostatic overload.

Psychoneuroendocrinology 2019 10 31;108:94-101. Epub 2019 May 31.

Department of Psychiatry, State University of New York at Buffalo, Buffalo, NY, USA; Department of Statistical Sciences, University of Padova, Padova, Italy.

Allostatic load reflects the cumulative effects of stressful experiences in daily life and may lead to disease over time. When the cost of chronic exposure to fluctuating or heightened neural and systemic physiologic responses exceeds the coping resources of an individual, this is referred to as "toxic stress" and allostatic overload ensues. Its determination has initially relied on measurements of an interacting network of biomarkers. More recently, clinical criteria for the determination of allostatic overload, that provide information on the underlying individual experiential causes, have been developed and used in a number of investigations. These clinimetric tools can increase the number of people screened, while putting the use of biomarkers in a psychosocial context. The criteria allow the personalization of interventions to prevent or decrease the negative impact of toxic stress on health, with particular reference to lifestyle modifications and cognitive behavioral therapy.
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http://dx.doi.org/10.1016/j.psyneuen.2019.05.028DOI Listing
October 2019

The good side of "stress".

Authors:
Bruce S McEwen

Stress 2019 09 25;22(5):524-525. Epub 2019 Jun 25.

a Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University , New York , NY , USA.

Stress has both a good and bad side which are discussed in terms of the concepts of allostasis and allostatic load and overload. Stressful experiences can cause health damaging behaviors which lead to allostatic load and overload and accelerate disease processes.
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http://dx.doi.org/10.1080/10253890.2019.1631794DOI Listing
September 2019

Systemic and Local Corticosteroid Use Is Associated with Reduced Executive Cognition, and Mood and Anxiety Disorders.

Neuroendocrinology 2020 21;110(3-4):282-291. Epub 2019 Jun 21.

Department of Internal Medicine, Division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands,

Background: Use of local corticosteroids, especially the inhaled types, has increasingly been associated with systemic uptake and consequent adverse effects. In this study, we assessed the associations between the use of different corticosteroid types with cognitive and neuropsychiatric adverse effects related to high glucocorticoid exposure.

Methods: In 83,592 adults (mean age 44 years, 59% women) of the general population (Lifelines Cohort Study), we analyzed the relationship between corticosteroid use with executive cognitive functioning (Ruff Figural Fluency Test), and presence of mood and anxiety disorders (Mini-International Neuropsychiatric Interview survey). We performed additional exploration for effects of physical quality of life (QoL; RAND-36), and inflammation (high-sensitive C-reactive protein [CRP]).

Results: Cognitive scores were lower among corticosteroid users, in particular of systemic and inhaled types, when compared to nonusers. Users of inhaled types showed lower cognitive scores irrespective of physical QoL, psychiatric disorders, and high-sensitive CRP. Overall corticosteroid use was also associated with higher likelihood for mood and anxiety disorders. Users of inhaled corticosteroids were more likely to have mood disorders (OR 1.40 [95% CI 1.19-1.65], p < 0.001) and anxiety disorders (OR 1.19 [95% CI 1.06-1.33], p = 0.002). These findings were independent of physical QoL. A higher likelihood for mood disorders was also found for systemic users whereas nasal and dermal corticosteroid users were more likely to have anxiety disorders.

Conclusions: Commonly used local corticosteroids, in particular inhaled types, and systemic corticosteroids are associated with reduced executive cognitive functioning and a higher likelihood of mood and anxiety disorders in the general adult population.
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http://dx.doi.org/10.1159/000501617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7114901PMC
February 2021

Leptin in hippocampus mediates benefits of mild exercise by an antioxidant on neurogenesis and memory.

Proc Natl Acad Sci U S A 2019 05 13;116(22):10988-10993. Epub 2019 May 13.

Laboratory of Exercise Biochemistry and Neuroendocrinology, Faculty of Health and Sport Sciences, University of Tsukuba, 305-8574 Tsukuba, Ibaraki, Japan;

Regular exercise and dietary supplements with antioxidants each have the potential to improve cognitive function and attenuate cognitive decline, and, in some cases, they enhance each other. Our current results reveal that low-intensity exercise (mild exercise, ME) and the natural antioxidant carotenoid astaxanthin (AX) each have equivalent beneficial effects on hippocampal neurogenesis and memory function. We found that the enhancement by ME combined with AX in potentiating hippocampus-based plasticity and cognition is mediated by leptin (LEP) made and acting in the hippocampus. In assessing the combined effects upon wild-type (WT) mice undergoing ME with or without an AX diet for four weeks, we found that, when administrated alone, ME and AX separately enhanced neurogenesis and spatial memory, and when combined they were at least additive in their effects. DNA microarray and bioinformatics analyses revealed not only the up-regulation of an antioxidant gene, , but also that the up-regulation of gene expression in the hippocampus of WT mice with ME alone is further enhanced by AX. Together, they also increased hippocampal LEP (h-LEP) protein levels and enhanced spatial memory mediated through AKT/STAT3 signaling. AX treatment also has direct action on human neuroblastoma cell lines to increase cell viability associated with increased LEP expression. In LEP-deficient mice (), chronic infusion of LEP into the lateral ventricles restored the synergy. Collectively, our findings suggest that not only h-LEP but also exogenous LEP mediates effects of ME on neural functions underlying memory, which is further enhanced by the antioxidant AX.
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http://dx.doi.org/10.1073/pnas.1815197116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561194PMC
May 2019