Deficiency in the cell-adhesion molecule dscaml1 impairs hypothalamic CRH neuron development and perturbs normal neuroendocrine stress axis function.

The corticotropin-releasing hormone (CRH)-expressing neurons in the hypothalamus are critical regulators of the neuroendocrine stress response pathway, known as the hypothalamic-pituitary-adrenal (HPA) axis. As developmental vulnerabilities of CRH neurons contribute to stress-associated neurological and behavioral dysfunctions, it is critical to identify the mechanisms underlying normal and abnormal CRH neuron development. Using zebrafish, we identified Down syndrome cell adhesion molecule like-1 (dscaml1) as an integral mediator of CRH neuron development and necessary for establishing normal stress axis function. In dscaml1 mutant animals, hypothalamic CRH neurons had higher crhb (the CRH homolog in zebrafish) expression, increased cell number, and reduced cell death compared to wild-type controls. Physiologically, dscaml1 mutant animals had higher baseline stress hormone (cortisol) levels and attenuated responses to acute stressors. Together, these findings identify dscaml1 as an essential factor for stress axis development and suggest that HPA axis dysregulation may contribute to the etiology of human DSCAML1-linked neuropsychiatric disorders.

Estrogen receptor beta in the central amygdala regulates the deleterious behavioral and neuronal consequences of repeated social stress in female rats.

While over 95% of the population has reported experiencing extreme stress or trauma, females of reproductive age develop stress-induced neuropsychiatric disorders at twice the rate of males. This suggests that ovarian hormones may facilitate neural processes that increase stress susceptibility and underlie the heightened rates of these disorders, like depression and anxiety, that result from stress exposure in females. However, there is contradicting evidence in the literature regarding estrogen's role in stress-related behavioral outcomes. Estrogen signaling through estrogen receptor beta (ERß) has been traditionally thought of as anxiolytic, but recent studies suggest estrogen exhibits distinct effects in the context of stress. Furthermore, ERß is found abundantly in many stress-sensitive brain loci, including the central amygdala (CeA), in which transcription of the vital stress hormone, corticotropin releasing factor (CRF), can be regulated by an estrogen response element. Therefore, these experiments sought to identify the role of CeA ERß activity during stress on behavioral outcomes in naturally cycling, adult, female Sprague-Dawley rats. Rats were exposed to an ethological model of vicarious social stress, witness stress (WS), in which they experienced the sensory and psychological aspects of an aggressive social defeat encounter between two males. Following WS, rats exhibited stress-induced anxiety-like behaviors in the marble burying taskand brain analysis revealed increased ERß and CRF specifically within the CeA following exposure to stress cues. Subsequent experiments were designed to target this receptor in the CeA using microinjections of the ERß antagonist, PHTPP, prior to each stress session. During WS, estrogen signaling through ERß was responsible for the behavioral sensitization to repeated social stress. Sucrose preference, acoustic startle, and marble burying tasks determined that blocking ERß in the CeA during WS prevented the development of depressive-, anxiety-like, and hypervigilant behaviors. Additionally, brain analysis revealed a long-term decrease of intra-CeA CRF expression in PHTPP-treated rats. These experiments indicate that ERß signaling in the CeA, likely through its effects on CRF, contributes to the development of negative valence behaviors that result from exposure to repeated social stress in female rats.

Prolonged efavirenz exposure reduces peripheral oxytocin and vasopressin comparable to known drugs of addiction in male Sprague Dawley rats.

INTRODUCTION: Several drugs of abuse (DOA) are capable of modulating neurohypophysial hormones, such as oxytocin (OT) and vasopressin (VP), potentially resulting in the development of psychological abnormalities, such as cognitive dysfunction, psychoses, and affective disorders. Efavirenz (EFV), widely used in Africa and globally to treat HIV, induces diverse neuropsychiatric side effects while its abuse has become a global concern. The actions of EFV may involve neurohypophysial system (NS) disruption like that of known DOA. This study investigated whether sub-chronic EFV exposure, at a previously-determined rewarding dose, alters peripheral OT and VP levels versus that of a control, ∆9-tetrahydrocannabinol (∆9-THC), methamphetamine (MA) and cocaine. MATERIALS AND METHODS: To simulate the conditions under which reward-driven behavior had previously been established for EFV, male Sprague Dawley rats (n = 16/exposure) received intraperitoneal vehicle (control) or drug administration across an alternating sixteen-day dosing protocol. Control administration (saline/olive oil; 0.2 ml) occurred on odd-numbered and drug administration (EFV: 5 mg/kg, ∆9-THC: 0.75 mg/kg, MA: 1 mg/kg, or cocaine: 20 mg/kg) on even-numbered days followed by euthanasia, trunk blood collection and plasma extraction for neuropeptide assay. Effect of drug exposure on peripheral OT and VP levels was assessed versus controls and quantified using specific ELISA kits. Statistical significance was determined by Kruskal-Wallis ANOVA, with p < 0.05. Ethics approval: NWU-00291-17-A5. RESULTS: Delta-9-THC reduced OT and VP plasma levels (p < 0.0001, p = 0.0141; respectively), cocaine reduced plasma OT (p = 0.0023), while MA reduced plasma VP levels (p = 0.0001), all versus control. EFV reduced OT and VP plasma levels (p < 0.0001; OT and VP) versus control, and similar to ∆9-THC. CONCLUSION: EFV markedly affects the NS in significantly reducing both plasma OT and VP equivalent to DOA. Importantly, EFV has distinct effects on peripheral OT and VP levels when assessed within the context of drug dependence. The data highlights a possible new mechanism underlying previously documented EFV-induced effects in rats, and whereby EFV may induce neuropsychiatric adverse effects clinically; also providing a deeper understanding of the suggested abuse-potential of EFV.

Improvements in sleep indices during exam stress due to consumption of a Bifidobacterium longum.

Targeting the gut microbiome as an effective therapeutic strategy for psychological disorders has shown promise in recent years. Variation in the composition of the microbiota and restoration of a stable microbiome using targeted interventions (psychobiotics) including Bifidobacteria have shown promise in pre-clinical studies, but more human data is required on the potential health benefits of these live microorganisms. Bifidobacterium including Bif. longum 1714 has been shown to dampen the effects of acute stress in humans. However, its effects over a period of prolonged stress have not been examined. A randomised, placebo-controlled, repeated measures, cross-over intervention study was conducted to examine the effects of a probiotic intervention on measures of stress, cognitive performance, and mood in healthy human volunteers. Twenty male students participated in this crossover study. Post-intervention assessments took place during the university exam period, which was used as a naturalistic chronic stressor. Self-reported measures of stress, depression, sleep quality, physical activity, gastrointestinal symptoms, cognition, and mood were assessed by questionnaire. In addition, tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) were administered to all participants. Stress and depression scores increased in both placebo and probiotic treated groups during the exam period. While overall sleep quality and duration of sleep improved significantly in the probiotic treated group during exam stress compared with the placebo treated group, B. longum 1714, similar to placebo treatment, showed no efficacy in improving measures of working memory, visual memory, sustained attention or perception. Overall, while B. longum 1714 shows promise in improving sleep quality and duration, it did not alleviate symptoms of chronic stress, depression, or any measure of cognitive assessment. Thus, further mechanistic studies into the ability of B. longum 1714 to modulate sleep during prolonged periods of stress are now warranted.

Understanding stress: Insights from rodent models.

Through incorporating both physical and psychological forms of stressors, a variety of rodent models have provided important insights into the understanding of stress physiology. Rodent models also have provided significant information with regards to the mechanistic basis of the pathophysiology of stress-related disorders such as anxiety disorders, depressive illnesses, cognitive impairment and post-traumatic stress disorder. Additionally, rodent models of stress have served as valuable tools in the area of drug screening and drug development for treatment of stress-induced conditions. Although rodent models do not accurately reproduce the biochemical or physiological parameters of stress response and cannot fully mimic the natural progression of human disorders, yet, animal research has provided answers to many important scientific questions. In this review article, important studies utilizing a variety of stress models are described in terms of their design and apparatus, with specific focus on their capabilities to generate reliable behavioral and biochemical read-out. The review focusses on the utility of rodent models by discussing examples in the literature that offer important mechanistic insights into physiologically relevant questions. The review highlights the utility of rodent models of stress as important tools for advancing the mission of scientific research and inquiry.

Higher Perceived Stress and Poor Glycemic Changes in Prediabetics and Diabetics Among Indian Population.

Diabetes mellitus (DM) is a chronic metabolic disorder with significant co-morbidities and healthcare burdens. Many large studies have investigated the association between perceived stress and DM; however, none investigated this in a larger Indian population. We hypothesized stress as one of the reasons for the progression of people with prediabetes into DM. The present study was, therefore, planned to report on associations between perceived stress and blood glucose markers stratified by diabetic status. The current descriptive study was a subset analysis of the nationwide cross-sectional survey, conducted in all Indian zones under the National Multicentric Diabetes Control Program. The study examined the perceived stress levels using a perceived stress scale (PSS-10) in people with prediabetes (n=649) and DM (n=485) and then segregated them into three categories (minimum, moderate, and severe). Blood glucose markers (fasting blood glucose, postprandial blood glucose, and HbA1c) were evaluated to report their association with the perceived stress. The study revealed a significantly higher HbA1c level in people with prediabetes, particularly those with severe perceived stress (6.12 ± 0.27) compared to other categories. Those with DM had a higher fasting blood glucose level, particularly with severe perceived stress (239.28 ± 99.52). An increased HbA1c level is noted in severely stressed people with prediabetes, requiring a comprehensive analysis with a longitudinal study of the role of perceived stress in the progression of prediabetes into DM. Additionally, higher fasting blood glucose levels in patients with DM and severe perceived stress suggests the need for establishing comprehensive diabetic care inclusive of stress management.

Deletion of CRH From GABAergic Forebrain Neurons Promotes Stress Resilience and Dampens Stress-Induced Changes in Neuronal Activity.

Dysregulation of the corticotropin-releasing hormone (CRH) system has been implicated in stress-related psychopathologies such as depression and anxiety. Although most studies have linked CRH/CRH receptor 1 signaling to aversive, stress-like behavior, recent work has revealed a crucial role for distinct CRH circuits in maintaining positive emotional valence and appetitive responses under baseline conditions. Here we addressed whether deletion of CRH, specifically from GABAergic forebrain neurons (Crh CKO-GABA mice) differentially affects general behavior under baseline and chronic stress conditions. Expression mapping in Crh CK O-GABA mice revealed absence of Crh in GABAergic neurons of the cortex and limbic regions including the hippocampus, central nucleus of the amygdala and the bed nucleus of the stria terminals, but not in the paraventricular nucleus of hypothalamus. Consequently, conditional CRH knockout animals exhibited no alterations in circadian and stress-induced corticosterone release compared to controls. Under baseline conditions, absence of Crh from forebrain GABAergic neurons resulted in social interaction deficits but had no effect on other behavioral measures including locomotion, anxiety, immobility in the forced swim test, acoustic startle response and fear conditioning. Interestingly, following exposure to chronic social defeat stress, Crh CKO-GABA mice displayed a resilient phenotype, which was accompanied by a dampened, stress-induced expression of immediate early genes c-fos and zif268 in several brain regions. Collectively our data reveals the requirement of GABAergic CRH circuits in maintaining appropriate social behavior in naïve animals and further supports the ability of CRH to promote divergent behavioral states under baseline and severe stress conditions.

Clinical Validation of Nebulized Budesonide and Effect of Nebulized Budesonide on the Hypothalamic-Pituitary-Adrenal Axis in Adult Patients Admitted with Acute Asthmatic Attack / 결핵

BACKGROUND: Many clinicians are reluctant to prescribe systemic corticosteroids to manage and asthmatic attack because of many complications such as osteoporosis, cushing's syndrome, diabetes, hypertension and blee ding tendency. The use of nebulized budesonide may be of value in some infants, old men, and in particular adult asthmatic patients who complain of severe dyspnea. A clinical validation and steroid-sparing effect of nebulized budesonide in asthmatic adults and COPD were evaluated, and the short-term effects of budesonide use on the HPA axis were assessed. METHODS: Study A was propectively done with 41 patients diagnosed with pure asthma and 30 patients diagnosed wit COPD (including asthmatic component) in Soonchunhyang Hospital, Chunan from June. 2000 to Sep. 2001. They were treated with nebulized budesonide including sytemic steroids (Group 1), a budesonide tubuhaler including a sytemic steroid (Group 2), or only the systemic steroid (Group3). The peak flow rate, arterial blood gas in room air, pulmonary function test, symptom scoring, steroid amount and hospital stay were analyzed. Study B was conducted with 19 patients to evaluate the short-term effects on the HPA axis of treatment with nebulized budesonide 1mg twice daily and a budesonide turbuhaler 5 puffs twice daily. The adrenal function was assessed prior to budesonide inhalation and after 7 days of budesonide inhalation. RESULTS: In the pure asthmatic patients, the mean value of the symptoms (dyspnea, wheezing, cough, night asthma) or the arterial BGAs, total amounts of steroid or hospital stay and the difference in the results of the pulmonary function tests or peak expiratory flow rate were similar in the three groups. In COPD with an asthmatic component, there were no significant differences among the three groups. Although nebulized budesonide suppressed HPA function, (p=0.006) the HPA responses from the nebulized budesonide and turbuhaler budesonide were similar (p=0.288). CONCLUSION: This result suggests that systemic steroid should only be made available for acute asthmatic patients irrespective of the inhaled budesonides. Nebulized budesonide at the therapeutic dose has similar effects on the HPA axis compared to that of turbuhaler budesonide.