Intertwined associations between oxytocin, immune system and major depressive disorder.

Major depressive disorder (MDD) is a prominent psychiatric disorder with a high prevalence rate. The recent COVID-19 pandemic has exacerbated the already high prevalence of MDD. Unfortunately, a significant proportion of patients are unresponsive to conventional treatments, necessitating the exploration of novel therapeutic strategies. Oxytocin, an endogenous neuropeptide, has emerged as a promising candidate with anxiolytic and antidepressant properties. Oxytocin has been shown to alleviate emotional disorders by modulating the hypothalamic-pituitary-adrenal (HPA) axis and the central immune system. The dysfunction of the immune system has been strongly linked to the onset and progression of depression. The central immune system is believed to be a key target of oxytocin in ameliorating emotional disorders. In this review, we examine the evidence regarding the interactions between oxytocin, the immune system, and depressive disorder. Moreover, we summarize and speculate on the potential roles of the intertwined association between oxytocin and the central immune system in treating emotional disorders.

SARS-CoV-2 (COVID-19) as a possible risk factor for neurodevelopmental disorders.

Pregnant women constitute one of the most vulnerable populations to be affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the cause of coronavirus disease 2019. SARS-CoV-2 infection during pregnancy could negatively impact fetal brain development via multiple mechanisms. Accumulating evidence indicates that mother to fetus transmission of SARS-CoV-2 does occur, albeit rarely. When it does occur, there is a potential for neuroinvasion via immune cells, retrograde axonal transport, and olfactory bulb and lymphatic pathways. In the absence of maternal to fetal transmission, there is still the potential for negative neurodevelopmental outcomes as a consequence of disrupted placental development and function leading to preeclampsia, preterm birth, and intrauterine growth restriction. In addition, maternal immune activation may lead to hypomyelination, microglial activation, white matter damage, and reduced neurogenesis in the developing fetus. Moreover, maternal immune activation can disrupt the maternal or fetal hypothalamic-pituitary-adrenal (HPA) axis leading to altered neurodevelopment. Finally, pro-inflammatory cytokines can potentially alter epigenetic processes within the developing brain. In this review, we address each of these potential mechanisms. We propose that SARS-CoV-2 could lead to neurodevelopmental disorders in a subset of pregnant women and that long-term studies are warranted.

Hormonal trends in patients suffering from long COVID symptoms.

Symptoms of long COVID are complex and long-lasting, and endocrine dysfunction might be involved in the underlying mechanisms. In this study, to clarify the hormonal characteristics of long COVID patients, laboratory data for patients who visited the outpatient clinic for long COVID were evaluated. A retrospective analysis was performed for patients who visited Okayama University Hospital during the period from Feb 2021 to Dec 2021 with focus on the interrelationships between major symptoms and endocrine data. Information and laboratory data were obtained from medical records for 186 patients. The patients had various symptoms, and the most frequent symptoms were general malaise, dysosmia/dysgeusia, hair loss, headache, dyspnea, and sleeplessness. Patients who were suffering from fatigue and dysosmia/dysgeusia were younger, while hair loss was more frequent in older and female patients. As for the characteristics of patients suffering from general fatigue, the scores of depression and fatigue were positively correlated with serum levels of cortisol and free thyroxin (FT4), respectively. Also, patients suffering from general fatigue had lower levels of serum growth hormone and higher levels of serum FT4, while patients with dysosmia/dysgeusia had a significantly lower level of serum cortisol. Serum thyrotropin (TSH) levels were higher and the ratios of FT4/TSH were lower in the initially severe cases, suggesting occult hypothyroidism. In addition, the ratios of plasma adrenocorticotropin to serum cortisol were decreased in patients with relatively high titers of serum SARS-CoV-2 antibody. Thus, hormonal changes seem to be, at least in part, involved in the persistent symptoms of long COVID.

Prenatal hair cortisol concentrations during the COVID-19 outbreak: Associations with maternal psychological stress and infant temperament.

BACKGROUND: Maternal psychological stress during pregnancy, including stress resulting from disasters and trauma, has been linked to temperamental difficulties in offspring. Although heightened cortisol concentrations are often hypothesized as an underlying mechanism, evidence supporting this mechanism is not consistent, potentially because of methodological issues and low stress in the population. AIM: To address these issues, this preregistered study investigated the following associations between: 1) prenatal psychological stress and hair cortisol, as a biomarker for chronic stress, during the COVID-19 outbreak (i.e., as a major worldwide psychological stressor), and 2) maternal hair cortisol during the COVID-19 outbreak and later infant temperamental negative affectivity and orienting/regulation. Additionally, we explored whether associations were different for women with low versus high socioeconomic status (SES; maternal education and annual household income) and at different stages of pregnancy. METHOD: Pregnant women (N = 100) filled out online questionnaires during the first COVID-19 lockdown. Six months later, when most mothers were still pregnant or had just given birth, maternal hair samples were collected during home visits. When infants were six months old, mothers reported on their infant's temperament. RESULTS: Although hierarchical regression analyses revealed no associations between prenatal COVID-19 psychological stress and hair cortisol during the COVID-19 outbreak, SES proved to be a moderator in this association. Only pregnant women with higher levels of SES, not lower levels, showed a positive association between work-related and social support-related COVID-19 worries and hair cortisol. Finally, prenatal hair cortisol was not associated with later infant temperamental negative affectivity and orienting/regulation. CONCLUSION: Although the COVID-19 outbreak proved to be a major psychological stressor worldwide, the physiological impact of the crisis might be different for pregnant women with higher SES as compared to lower SES.

Pedicularis resupinata Extract Prevents Depressive-like Behavior in Repeated Corticosterone-Induced Depression in Mice: A Preliminary Study.

Excessive corticosterone (CORT), resulting from a dysregulated hypothalamic-pituitary-adrenal (HPA) axis, is associated with cognitive impairment and behavioral changes, including depression. In Korean oriental medicine, Pedicularis resupinata is used for the treatment of inflammatory diseases such as rheumatoid arthritis. However, the antidepressant properties of P. resupinata have not been well characterized. Here, the antidepressant-like effects of P. resupinata extract (PRE) were evaluated in terms of CORT-induced depression using in vivo models. HPLC confirmed that acteoside, a phenylethanoid glycoside, was the main compound from PRE. Male ICR mice (8 weeks old) were injected with CORT (40 mg/kg, i.p.) and orally administered PRE daily (30, 100, and 300 mg/kg) for 21 consecutive days. Depressive-like behaviors were evaluated using the open-field test, sucrose preference test, passive avoidance test, tail suspension test, and forced swim test. Treatment with a high dose of PRE significantly alleviated CORT-induced, depressive-like behaviors in mice. Additionally, repeated CORT injection markedly reduced brain-derived neurotrophic factor levels, whereas total glucocorticoid receptor (GR) and GR phosphorylation at serine 211 were significantly increased in the mice hippocampus but improved by PRE treatment. Thus, our findings suggest that PRE has potential antidepressant-like effects in CORT-induced, depressive-like behavior in mice.

Exploring Daily Salivary Cortisol Patterns as Biomarkers of Chronic Chemotherapy-Induced Peripheral Neuropathy Pain.

OBJECTIVES: Little is known about the biologic mechanisms of chronic chemotherapy-induced peripheral neuropathy (CIPN) pain. The purpose of this secondary analysis was to explore salivary cortisol patterns among cancer survivors with chronic CIPN pain to provide preliminary data regarding the role of hypothalamic-pituitary-adrenal axis dysregulation in the pathophysiology of this condition. SAMPLE & SETTING: 13 cancer survivors with chronic CIPN pain recruited from the breast, gastrointestinal, and gynecologic cancer centers at Dana-Farber Cancer Institute in Boston, Massachusetts. METHODS & VARIABLES: Salivary cortisol was collected on awakening, 30 minutes after awakening, and before going to bed on two consecutive days. Cortisol awakening response and diurnal cortisol slope were calculated by averaging results across two days. RESULTS: Cortisol was available from 13 participants. The median cortisol awakening response was -0.03 mcg/dl, and the average diurnal cortisol slope was -0.24 mcg/dl. IMPLICATIONS FOR NURSING: Mechanism-based treatments are needed for cancer survivors with chronic CIPN pain. Nurse scientists may use study results to explore stress-related mechanisms of chronic CIPN pain.

Longitudinal associations between stress and sleep disturbances during COVID-19.

The psychological consequences of COVID-19 pandemic may include the activation of stress systems, that involve the hypothalamic-pituitary-adrenal axis which influences many physiological functions, including sleep. Despite epidemiological studies evidenced greater prevalence of stress symptoms and sleep disturbances during COVID-19, longitudinal evidence investigating the effects of stress on sleep disturbances during the pandemic is lacking. We collected measures of perceived stress and sleep disturbances during the first wave of COVID-19 (March 2020) and at 8-10 months follow up in a sample of 648 adults (M = 33.52, SD = 12.98 years). Results showed that 39.4% of participants reported moderate to extremely severe stress in March 2020. Prevalence of sleep disturbances was 54.8% in March 2020 and 57.4% at follow-up. Structural equation modelling highlighted that perceived stress in March 2020 significantly predicted sleep disturbances at follow up (ß = 0.203; p < 0.001), even after controlling for baseline sleep disturbances. Results remained significant even after controlling for the effects of covariates including age, sex, depression and anxiety symptoms, and referring to psychological services (ß = 0.179; p < 0.05). Findings confirm the high prevalence of stress symptoms during the COVID-19 pandemic and provide first longitudinal evidence for the effects of perceived stress on sleep disturbances during the pandemic.

Neuroimaging a cytokine storm by transducing IL-1α to hippocampal cornu ammonis: COVID-19 SARS-CoV-2

Concerning the matter of depression, its full understanding pushes the envelope beyond clinical psychology and moves the subject further into the areas of Neuropsychopharmacology and Neuromolecular Imaging (NMI). Here, we studied, with the BRODERICK PROBE® acute and chronic stress-induced depression via the hypothalamic-pituitary-adrenal (HPA) axis. The “axis” is responsible for the emission of glucocorticoids during sympathetic nervous system activation. Negative feedback systems within areas of the hippocampus (HPC) and prefrontal cortex (PFC) prevent excessive amounts of glucocorticoids in the neurochemical environment and regulate the HPA axis production of these hormones. In depression, whether or not stress-induced, an increased concentration of glucocorticoids is present. In fact, when released by psychological or physical insult, glucocorticoids are accompanied by cytokines. The purpose of this work is to neuroimage a cytokine storm in the brain as it relates to COVID-19 SARS-CoV-2 patients. The advanced sensor nanobiotechnology, BRODERICK PROBE® transduced a small, protein cytokine, interleukin 1 alpha (IL-1α) to hippocampal Cornu Ammonis (CA-1) in two groups of animal subjects who are walking during neurotransmitter signaling. One genetically normal group was devoid of comorbidity to depression and indeed was also bred without viruses. The other genetic group was bred genetically depressed having platelet storage pool deficiency of the neurotransmitter, serotonin (5-HT);this group presented with Chediak-Higashi Syndrome and are Fawn-Hooded. Microdosing the pro-inflammatory IL-1α showed inherent neuroprotection of the hippocampal cytokine storm during real-time video tracking in Cornu Ammonis neurons in both nondepressed and depressed freely moving and walking subjects. The depressed subjects showed that the cytokine-induced storm began earlier than in nondepressed subjects while walking was increased in addition to enhanced stereotypy. Longer term studies in the same freely moving, walking subjects showed that the nondepressed were adapted to this cytokine brainstorm according to reliable sensor signaling signatures whereas the depressed subjects remained depressed. Thus, at the same time that we watched the brain immune derived cytokine storm directly coming to us online from HPC (CA-1) neurons, we monitored these motor skills with infrared photocell beams. Stereotypic grooming, nasopharyngeal systems were carefully assessed. These skills are important as they are related to respiratory SARS-CoV-2 insults and trauma. We watched online as the feared “hippocampal cytokine storm” was imaged in the depressed subject while immune T cell ratio CD4/CD8 was reversed. Tracking cytokine neuroinflammation transduced to HPC CA-1 neurons directly online while the subject is walking enables direct extrapolation to immune brain dysfunction in SARS-CoV-2 virus (Covid 19) patient data. © 2021 Elsevier Inc. All rights reserved.

Dream Recall/Affect and the Hypothalamic-Pituitary-Adrenal Axis.

In this concise review, we present an overview of research on dream recall/affect and of the hypothalamic-pituitary-adrenal (HPA) axis, discussing caveats regarding the action of hormones of the HPA axis (mainly cortisol and its free form, cortisol-binding globulin and glucocorticoid receptors). We present results of studies regarding dream recall/affect and the HPA axis under physiological (such as waking) or pathological conditions (such as in Cushing's syndrome or stressful situations). Finally, we try to integrate the effect of the current COVID-19 situation with dream recall/affect vis-à-vis the HPA axis.

Chronic circadian phase advance in male mice induces depressive-like responses and suppresses neuroimmune activation.

Altered working and sleeping schedules during the COVID-19 pandemic likely impact our circadian systems. At the molecular level, clock genes form feedback inhibition loops that control 24-hr oscillations throughout the body. Importantly, core clock genes also regulate microglia, the brain resident immune cell, suggesting circadian regulation of neuroimmune function. To assess whether circadian disruption induces neuroimmune and associated behavioral changes, we mimicked chronic jetlag with a chronic phase advance (CPA) model. 32 adult male C57BL/6J mice underwent 6-hr light phase advance shifts every 3 light/dark cycles (CPA) 14 times or were maintained in standard light/dark cycles (control). CPA mice showed higher behavioral despair but not anhedonia in forced swim and sucrose preferences tests, respectively. Changes in behavior were accompanied by altered hippocampal circadian genes in CPA mice. Further, CPA suppressed expression of brain-derived neurotrophic factor (BDNF) and pro-inflammatory cytokine interleukin-1 beta in the hippocampus. Plasma corticosterone concentrations were elevated by CPA, suggesting that CPA may suppress neuroimmune pathways via glucocorticoids. These results demonstrate that chronic circadian disruption alters mood and neuroimmune function, which may have implications for shift working populations such as frontline health workers.

Lung-brain axis.

The appreciation of human microbiome is gaining strong grounds in biomedical research. In addition to gut-brain axis, is the lung-brain axis, which is hypothesised to link pulmonary microbes to neurodegenerative disorders and behavioural changes. There is a need for analysis based on emerging studies to map out the prospects for lung-brain axis. In this review, relevant English literature and researches in the field of 'lung-brain axis' is reported. We recommend all the highlighted prospective studies to be integrated with an interdisciplinary approach. This might require conceptual research approaches based on physiology and pathophysiology. Multimodal aspects should include experimental animal units, while exploring the research gaps and making reference to the already existing human data. The overall microbiome medicine is gaining more ground. Aetiological paths and experimental recommendations as per prospective studies in this review will be an important guideline to develop effective treatments for any lung induced neurodegenerative diseases. An in-depth knowledge of the bi-directional communication between host and microbiome in the lung could help treatment to respiratory infections, alleviate stress, anxiety and enhanced neurological effects. The timely prevention and treatment of neurodegenerative diseases requires paradigm shift of the aetiology and more innovative experimentation.Impact statementThe overall microbiome medicine is gaining more ground. An in-depth knowledge of the bi-directional communication between host and microbiome in the lung could confer treatment to respiratory infections, alleviate stress, anxiety and enhanced neurological effects. Based on this review, we recommend all the highlighted prospective studies to be integrated and be given an interdisciplinary approach. This might require conceptual research approaches based on physiology and pathophysiology. Multimodal aspects should include experimental animal units; while exploring the research gaps and making reference to the already existing human data.

How Does COVID-19 Affect the Neurobiology of Suicide?

PURPOSE OF REVIEW: The aim of this review was to analyze COVID-19 effect on the biological features of suicidal vulnerability and its interaction with suicide-related biological pathways. We carried out a narrative review of international publications on the interactions of COVID-19 with the biological bases of suicide. RECENT FINDINGS: We hypothesize that SARS-CoV-2 interacts with multiple biological processes that underlie suicidal behavior, such as the renin-angiotensin system, nicotinic receptors, and central and systemic inflammation. Social distancing measures may also worsen subjective or objective social disconnection, thus increasing the risk of suicide. Interestingly, the drugs used to prevent suicide could be promising options to counteract brain damage caused by this coronavirus. SARS-CoV-2 interacts with multiple biological pathways involved in suicide and opens a new window for understanding the suicidal process. The development of suicide prevention treatments in the context of a pandemic may benefit from knowledge on these interactions.

Cortisol level dysregulation and its prevalence-Is it nature's alarm clock?

This review examines the stress hormone cortisol which plays an important role in regulating and supporting different bodily functions. Disruption in cortisol production has an impact on health and this review looks at a wide range of papers where cortisol has been indicated as a factor in numerous chronic conditions-especially those which are classed as "noncommunicable diseases" (NCDs). Timely detection, screening, and treatment for NCDs are vital to address the growing problem of NCDs worldwide-this would have health and socioeconomic benefits. Interestingly, many of the papers highlight the pro-inflammatory consequences of cortisol dysregulation and its deleterious effects on the body. This is particularly relevant given the recent findings concerning COVID-19 where pro-inflammatory cytokines have been implicated in severe inflammation.

Chronic exposure to air pollution implications on COVID-19 severity.

Populations in areas with higher levels of air pollution both indoors and outdoors show increased mortality rates when infected with coronavirus disease 2019 (COVID-19). The association between air quality and COVID-19 is commonly attributed to the risk of transmission. Although controlled transmission is crucial, further investigation into air quality traits that contribute to the lethality of COVID-19 in infected persons enables risk stratification and optimization of the allocation of resources. There is a need for a valid basis for the proactive identification of indicators of COVID-19 severity in air quality that allow for the implementation of systematic environmental improvements aimed at preventing COVID-19 mortality. In this paper, chronic exposure to fine particulate matter (PM) is identified as a source of disrupted activation of the hypothalamic-pituitary-adrenal (HPA) axis; it is therefore, a contributable variable to COVID-19 mortality.

Psycho-Neuroendocrine-Immune Interactions in COVID-19: Potential Impacts on Mental Health.

Coronavirus disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The impacts of the disease may be beyond the respiratory system, also affecting mental health. Several factors may be involved in the association between COVID-19 and psychiatric outcomes, such as fear inherent in the pandemic, adverse effects of treatments, as well as financial stress, and social isolation. Herein we discuss the growing evidence suggesting that the relationship between SARS-CoV-2 and host may also trigger changes in brain and behavior. Based on the similarity of SARS-CoV-2 with other coronaviruses, it is conceivable that changes in endocrine and immune response in the periphery or in the central nervous system may be involved in the association between SARS-CoV-2 infection and impaired mental health. This is likely to be further enhanced, since millions of people worldwide are isolated in quarantine to minimize the transmission of SARS-CoV-2 and social isolation can also lead to neuroendocrine-immune changes. Accordingly, we highlight here the hypothesis that neuroendocrine-immune interactions may be involved in negative impacts of SARS-CoV-2 infection and social isolation on psychiatric issues.