Hippocampal Over-Expression of Cyclooxygenase-2 (COX-2) Is Associated with Susceptibility to Stress-Induced Anhedonia in Mice.

The phenomenon of individual variability in susceptibility/resilience to stress and depression, in which the hippocampus plays a pivotal role, is attracting increasing attention. We investigated the potential role of hippocampal cyclooxygenase-2 (COX-2), which regulates plasticity, neuroimmune function, and stress responses that are all linked to this risk dichotomy. We used a four-week-long chronic mild stress (CMS) paradigm, in which mice could be stratified according to their susceptibility/resilience to anhedonia, a key feature of depression, to investigate hippocampal expression of COX-2, a marker of microglial activation Iba-1, and the proliferation marker Ki67. Rat exposure, social defeat, restraints, and tail suspension were used as stressors. We compared the effects of treatment with either the selective COX-2 inhibitor celecoxib (30 mg/kg/day) or citalopram (15 mg/kg/day). For the celecoxib and vehicle-treated mice, the Porsolt test was used. Anhedonic (susceptible) but not non-anhedonic (resilient) animals exhibited elevated COX-2 mRNA levels, increased numbers of COX-2 and Iba-1-positive cells in the dentate gyrus and the CA1 area, and decreased numbers of Ki67-positive cells in the subgranular zone of the hippocampus. Drug treatment decreased the percentage of anhedonic mice, normalized swimming activity, reduced behavioral despair, and improved conditioned fear memory. Hippocampal over-expression of COX-2 is associated with susceptibility to stress-induced anhedonia, and its pharmacological inhibition with celecoxib has antidepressant effects that are similar in size to those of citalopram.

Competitive anxiety or Coronavirus anxiety? The psychophysiological responses of professional football players after returning to competition during the COVID-19 pandemic.

OBJECTIVE: This study aimed to examine the relationship between competitive anxiety, fear/anxiety of COVID-19, and autonomic and endocrine stress responses in professional football players after returning to competition during the COVID-19 pandemic. METHODS: Ninety male professional football players (age: 26.33 ± 2.48 yr) volunteered to participate in this study, which included an official competition. Psychophysiological responses, including the Fear of COVID-19 Scale, the Coronavirus Anxiety Scale, and the Competitive State Anxiety Inventory-2 Revised, were collected 30 min before the competition. In addition, salivary alpha-amylase (sAA) and salivary cortisol (sCort) were collected at 8 a.m. and 15 min before the competition. RESULTS: The main findings, based on the Pearson correlation, showed significant positive correlations between COVID-19 anxiety and somatic competitive anxiety (p = 0.01), cognitive competitive anxiety (p = 0.01), and competition response of sCort and sAA (p = 0.01). Moreover, fear of COVID-19 was positively correlated with COVID-19 anxiety (p = 0.01). On the contrary, the awakening response of sCort and sAA was not found to be correlated with psychological parameters (all p > 0.05). The analysis also indicated that there was no significant correlation between self-confidence with other psychological and physiological variables (all p > 0.05). The regression analysis showed that cognitive anxiety was a relevant predictor for the competition response of sCort and sAA (p < 0.05). Moreover, COVID-19 anxiety was the only predictor of somatic and cognitive anxiety (p < 0.05). CONCLUSIONS: The present study provides the first preliminary evidence that COVID-19 anxiety and competitive anxiety might pose a negative impact on the athletic performance of professional football players during COVID-19 pandemic competitions. Thus, research is needed to build a strategy to reduce the psychophysiological stress related to COVID-19 and competition response.

Social isolation stress facilitates chemically induced oral carcinogenesis.

Social isolation has affected a large number of people and may lead to impairment of physical and mental health. Although stress resulting from social isolation may increase cancer progression, its interference on tumorigenesis is poorly known. In this study, we used a preclinical model to evaluate the effects of social isolation stress on chemically induced oral carcinogenesis. Sixty-two 21-day-old male Wistar rats were divided into isolated and grouped groups. After 90 days of age, the rats from both groups underwent oral carcinogenesis with 4-nitroquinoline 1-oxide (4NQO) for 20 weeks. All rats were assessed for depressive-like behavior and euthanized for oral squamous cell carcinoma (OSCC) diagnosis and measurement of inflammatory mediators in the tumor microenvironment. Social isolation stress increased the OSCC occurrence by 20.4% when compared to control. Isolated rats also showed higher tumor volume and cachexia than the grouped rats. Social isolation did not induce changes in the depressive-like behavior after carcinogenic induction. Tumors from stressed rats had increased levels of the inflammatory mediators, TNF-alpha, IL1-beta and MCP-1. The concentrations of TNF-alpha and MCP-1 were significantly increased in the large tumors from isolated animals. Higher tumor levels of TNF-alpha, IL-6, IL1-beta and MCP-1 were positively correlated with OSCC growth. This study provides the first evidence that social isolation stress may facilitate OSCC occurrence and tumor progression, an event accompanied by increased local levels of inflammatory mediators.

Comparison of the effects of lockdown due to COVID-19 on glucose patterns among children, adolescents, and adults with type 1 diabetes: CGM study.

INTRODUCTION: The COVID-19 pandemic forced the Italian government to issue extremely restrictive measures on daily activities since 11 March 2020 ('lockdown'), which may have influenced the metabolic control of type 1 diabetes mellitus (T1D). The aims of the study were to investigate continuous glucose monitoring (CGM) metrics in children and adults with T1D during lockdown and to identify their potentially related factors. RESEARCH DESIGN AND METHODS: We enrolled 130 consecutive patients with T1D (30 children (≤12 years), 24 teenagers (13-17 years), and 76 adults (≥18 years)) using either Dexcom or FreeStyle LibreCGM>70% during the study period, without hybrid closed-loop insulin pump. CGM metrics during the 20 days before and the 20 days after lockdown were calculated. By telephonic contact, we performed validated physical activity and perceived stress questionnaires. RESULTS: In children, significantly lower glucose SD (SDglu) (p=0.029) and time below range (TBR)<54 mg/dL (TBR2) (p=0.029) were detected after lockdown. CGM metrics were comparable in teenagers before and during lockdown. After lockdown, adults improved significantly time in range (TIR) 70-180 mg/dL (p<0.001) and remaining metrics, except percent coefficient of variation and TBR2. In adults, considering the changes in SDglu and TIR occurred before and during lockdown, we identified a group with improved TIR and SDglu who performed more physical activity, one with improved glucose variability who was younger than the other patients, and one with worsened glucose variability who showed higher perceived stress than others. CONCLUSION: In patients with T1D during lockdown, CGM metrics mostly improved in children and adults, whereas it was unchanged in teenagers. In adults, age, physical activity, and perceived stress may be relevant contributing factors.

Putative COVID- 19 Induction of Reward Deficiency Syndrome (RDS) and Associated Behavioral Addictions with Potential Concomitant Dopamine Depletion: Is COVID-19 Social Distancing a Double Edged Sword?

BACKGROUND: The overwhelming fatalities of the global COVID-19 Pandemic will have daunting epigenetic sequala that can translate into an array of mental health issues, including panic, phobia, health anxiety, sleep disturbances to dissociative like symptoms including suicide. Method: We searched PUBMED for articles listed using the search terms "COVID 19 Pandemic", COVID19 and genes," "stress and COVID 19", Stress and Social distancing: Results: Long-term social distancing may be neurologically harmful, the consequence of epigenetic insults to the gene encoding the primary receptor for SARS-CoV2, and COVID 19. The gene is Angiotensin I Converting-Enzyme 2 (ACE2). According to the multi-experiment matrix (MEM), the gene exhibiting the most statistically significant co-expression link to ACE2 is Dopa Decarboxylase (DDC). DDC is a crucial enzyme that participates in the synthesis of both dopamine and serotonin. SARS-CoV2-induced downregulation of ACE2 expression might reduce dopamine and serotonin synthesis, causing hypodopaminergia. Discussion: Indeed, added to the known reduced dopamine function during periods of stress, including social distancing the consequence being both genetic and epigenetic vulnerability to all Reward Deficiency Syndrome (RDS) addictive behaviors. Stress seen in PTSD can generate downstream alterations in immune functions by reducing methylation levels of immune-related genes. Conclusion: Mitigation of these effects by identifying subjects at risk and promoting dopaminergic homeostasis to help regulate stress-relative hypodopaminergia, attenuate fears, and prevent subsequent unwanted drug and non-drug RDS type addictive behaviors seems prudent.

Current methods for stress marker detection in saliva.

Stress and stress-related diseases are leading to drastic consequences in private and professional life. Therefore, the need for stress prevention strategies is of personal and economic interest. Especially during the recent period related to covid-19 outbreak and lock-down, an ongoing discussion of increasing stress etiology is reported. Biomarker analysis may help to assist diagnosis and classification of stress-related diseases and therefore support therapeutical decisions. Due to its non-invasive sampling, the analysis of saliva has become highly attractive compared to the detection methods in other specimen. This review article summarizes the status of research, innovative approaches, and trends. Scientific literature published since 2011 was excerpted with concentration on the detection of up to seven promising marker substances. Most often reported cortisol represents the currently best evaluated stress marker, while norepinephrine (noradrenaline) or its metabolite 3-methoxy-4-hydroxyphenylglycol is also a quite commonly considered stress marker. Other complementary stress marker candidates are testosterone, dehydroepiandrosterone (DHEA) and its sulfonated analogue DHEA-S, alpha-amylase, secretory immunoglobulin A, and chromogranin A. Several working groups are researching in the field of stress marker detection to develop reliable, fast, and affordable methods. Analytical methods reported mainly focused on immunological and electrochemical as well as chromatographic methods hyphenated to mass spectrometric detection to yield the required detection limits.