Hypothalamic-pituitary-adrenal Research Articles

The neurobiological link between prayer, breath control and serotonin release

The relationship between spirituality, physical well-being, and mental health has long intrigued researchers, with growing interest in understanding the neurobiological mechanisms underlying practices such as prayer and breath control. This review explores the neurobiological link between prayer, controlled breathing, and the release of serotonin, a neurotransmitter essential for regulating mood, emotional balance, and overall mental well-being. Emerging evidence suggests that specific prayer practices, particularly those involving rhythmic breathing patterns, activate key brain regions associated with emotional regulation and serotonin synthesis. By engaging the parasympathetic nervous system, breath control during prayer induces a relaxation response, potentially modulating the hypothalamic-pituitary-adrenal (HPA) axis and enhancing serotonin production. Additionally, the meditative aspects of prayer may further support neurochemical balance by reducing stress and promoting feelings of inner peace. Through an interdisciplinary examination of neurophysiology, psychology, and spirituality, this review highlights how prayer combined with breath control can serve as a non-invasive, holistic method for enhancing serotonin release and improving mental health outcomes. Future research directions are proposed to deepen the understanding of these practices within both clinical and everyday settings.

Personality and Psychoneuroimmunology: A Systems Biology Perspective.

Research in psychoneuroimmunology (PNI) underscores the intricate connections within the "whole mind-body system." Personality plays a pivotal role, with specific traits linked to stress influencing neural behavior and psychophysiological disorders. Gene expression networks associated with personality affect neuronal plasticity, epigenetic processes, and adaptive behaviors, highlighting the importance of systems biology mechanisms. Systemic inflammation correlates with key personality traits. Understanding the roles of inflammatory and oxidative biomarkers in personality traits and disorders can help identify diagnostic and therapeutic targets for various diseases. Neurobiological features contribute to our understanding of personality disorders and related conditions. Personality traits are linked to distributed neuroendocrine networks, particularly the hypothalamic-pituitary-adrenal (HPA) axis, rather than localized brain areas. Correlations have also been identified between personality traits and thyroid hormones. Disrupted hypothalamic-pituitary-thyroid (HPT) axis functions may be associated with disease severity, depression, and distress, highlighting the need for comprehensive endocrinological and psychopathological evaluations. The gut-brain axis influences personality traits, emotions, stress, and social behaviors. Altered gut microbiota is common in psychiatric conditions, suggesting potential treatments targeting the microbiota. Chronic stress impacts cognitive functions and correlates with personality and mental health, emphasizing the need for comprehensive, multi-dimensional patient profiles for effective prevention and therapy. A biopsychosocial model integrating personality traits will advance personalized and systems medicine.

Personality, Aging, and Alzheimer's Disease: Implications for Psychoneuroimmunology and Personalized Medicine.

Psychoneuroimmunology (PNI) advancements may revolutionize personalized medicine by identifying systemic biomarkers that enhance diagnosis and treatment. Inflammatory pathways connect personality traits with cognitive performance, aging-related disorders, and mortality risks. Studies have demonstrated the critical interactions between personality and various biological systems like the hypothalamic-pituitary-adrenal (HPA) axis. The gut-brain axis also affects behaviors and psychological states in older adults, with specific gut microbiota influencing cognition, mood, and personality. These findings underscore the practical implications of understanding personality-biology interactions. They can support preventive and personalized medicine for aging-associated disorders. Specifically, personality changes are prevalent in Alzheimer's disease (AD) patients, impacting clinical management and caregiver stress. Non-cognitive factors, such as personality traits and psychiatric symptoms, may serve as early markers of AD. Traits like high Neuroticism and low Openness can predict initial AD stages, often before a formal diagnosis. Personality alterations in AD are also linked to cerebrospinal fluid (CSF) and vascular imaging biomarkers, which can track AD pathology and serve as predictors. Dynamic personality assessment can aid in timely diagnosis, monitoring progression, and evaluating treatmentsof AD. Understanding personality traits is crucial for predicting burnout, lifespan, and intervention success. Integrating personality and PNI biomarkers into patient profiles will support the development of personalized and systems medicine.

Physiological and Psychological Stress Reactivity in Narcolepsy Type 1.

Narcolepsy type 1 (NT1) is a chronic sleep-wake disorder, characterized by a loss of hypocretin production. Unexpectedly, in post-mortem tissue of people with NT1 there is a loss of corticotrophin-releasing hormone (CRH) in the paraventricular nucleus. CRH is known as activator of the hypothalamic-pituitary-adrenal (HPA) axis in response to stress. This activation results in the release of the stress hormones adrenocorticotropic hormone (ACTH) and cortisol. We hypothesize an altered physiological and psychological stress response in NT1. Participants were people with NT1 (n=14) and matched healthy controls (n=12). The Trier Social Stress Test for Groups (TSST-G), a validated socially evaluated stress test in controlled settings, induced acute stress. We measured ACTH and cortisol levels in blood before and at three timepoints after the TSST-G. We also measured subjective stress and heart rate levels. In both groups, acute stress led to increases in ACTH (p=0.006), cortisol (p<0.001), heart rate (p<0.001) and subjective stress (p<0.001). Subjectively, people with NT1 experienced more stress than controls (p<0.001). No differences were found in heart rate, cortisol, and ACTH between people with NT1 and controls at any timepoint. Secondary analyses showed that men with NT1 had lower cortisol levels immediately after stress induction than men in the control group (p=0.002). People with NT1 show an increased subjective stress response, but no changes in their endocrine or cardiovascular stress reactivity. Further research is required to determine the impact of reduced CRH production and gender in NT1.

Depression, stress, and tryptophan metabolism through the kynurenine pathway: treatment strategies from the perspective of Chinese herbal medicine.

The pathogenesis of depression is complex, involving abnormalities in tryptophan (TRP) metabolism through the kynurenine pathway (KP). Moreover, depression is closely related to the hypothalamic-pituitary-adrenal (HPA) axis, the gut-brain axis, neuroinflammation, and stress. These factors collectively influence the multidimensional pathological mechanisms of depression. TRP, a fundamental amino acid, serves as a precursor for neuroactive metabolites vital to physiological functions. Central to TRP metabolism is the KP, and the imbalance between neurotoxic and neuroprotective metabolites is closely related to the onset and progression of depression. Therefore, maintaining the balance of KP metabolites is important. In this review, we have investigated the role of the KP in depression and explored the complexity of KP dysregulation and its therapeutic importance. Here, we highlight how a deeper understanding of the KP and its regulation can pave the way for new treatment strategies. Specifically, we have summarized the latest advances in elucidating the key mechanisms of rate-limiting enzyme inhibitors, providing insights into their potential therapeutic efficacy. In addition, we have explored the emerging field of Chinese herbal medicine, discussing its potential to regulate KP metabolites and alleviate depressive symptoms, thereby expanding the treatment options for depression. Our findings emphasize the multifaceted nature of depression and the necessity of interdisciplinary research to fully utilize KP regulation and Chinese herbal medicine as strategies to advance the treatment of depression.

HOW THE ENDOCRINE SYSTEM AND MICROBIOTA EXPLAIN THE EMOTIONS BIOCHEMISTRY AND THEIR IMPACT IN HEALTH

Emotional reactions stimulate neural circuits and biological pathways that produce neurotransmitters, affecting homeostasis and promoting disease. Health and emotions communicate, establishing a bidirectional cause-and-effect pathway. The composition of the microbiota also affects health and emotions, interacting through metabolites, such as short-chain fatty acids (SCFA), with the host's biochemistry. Certain genera of bacteria act in different ways on the host's homeostasis, keeping the immune system constantly vigilant and acting on the synthesis of neurotransmitters, such as serotonin and dopamine, which are responsible for well-being. When the host is in homeostasis, the synthesis of neurotransmitters is normal, which keeps the intestinal microbiota in balance. However, when the organism is out of balance, this synthesis is impaired; decreasing the concentration of the initial compounds for the production of neurotransmitters, which leads to a reduction in the concentration of neurotransmitters and exaggerated activation of the HPA axis, inducing an imbalance in the intestinal microbiota, generating dysbiosis. Due to dysbiosis, the synthesis of neurotransmitters is impaired, leading the host to develop mental disorders such as depression, anxiety and chronic stress; which contributes to the state of imbalance of the organism, harming mental and physical health. By adequately restoring the intestinal microbiota, the hyperactivation of the HPA axis decreases, returning the body to homeostasis, resulting in the improvement of symptoms of depression, anxiety and chronic stress; leaving the organism healthy, both mentally and physically. Therefore, in this study we contextualize emotional research from a historical and descriptive perspective and present the main models of emotional identification. Focusing on basic emotions, we research the relationship of emotional states with the HPA axis and the microbiota, as well as how the bacteria present in the intestine affect the well-being of the host. Finally, we discuss our analysis presenting the bidirectional relationship between the endocrine system, microbiota and emotions.

The Interaction of Polygenic Susceptibility to Stress and Childhood Adversity Dimensions Predicts Longitudinal Trajectories of Stress-Sensitivity.

Stress-sensitivity (SS) is considered a psychobiological trait possibly resulting from the interaction of genetic and environmental factors (GxE). This study examined whether the interaction of SS-related genetic markers with interview-based dimensions of childhood adversity predicted longitudinal trajectories of low versus high SS. Participants were nonclinically-ascertained young adults comprising normative and elevated scores on schizotypy. SS trajectories were defined in a previous report based on three prospective assessments (23.5, 25, 28 years-old) of both retrospective (Perceived Stress Scale; PSS) and momentary (Experience Sampling Methodology; ESM) stress ratings. A total of n=177 and n=165 participants with PSS and ESM stress-sensitivity trajectories, respectively, as well as genetic data, were included in the study. GxE effects between a SS Polygenic Risk Score (PRS-SS) and a Genetic Risk Score of the Hypothalamic Pituitary Adrenal axis (GRS-HPA) with childhood adversity dimensions (Intrafamilial Adversity, Threat and Deprivation) on SS trajectories were examined. Threat was the most consistent predictor of persistently high SS. PRS-SS moderated the association of Threat with high-PSS. GRS-HPA moderated the effects of all adversity dimensions on high-PSS. The interaction of PRS-SS with Deprivation and GRS-HPA with Intrafamilial Adversity predicted trajectories of momentary social stress, but the effects were driven by those with lower genetic susceptibility. Genetic-HPA-axis moderates the effects of all adversity dimensions on persistent SS trajectories, as well as PRS-SS and Threat, particularly for retrospective stress measure. The findings highlight the complex interplay between GxE factors and suggest that PSS may better capture SS trait. Including biologically-meaningful GRS indexing SS and adversity dimensions in future studies using comprehensive stress measures would enhance our knowledge on high SS susceptibility and its relationship with diverse psychopathological outcomes.

Neurobiological and Anti-Inflammatory Effects of a DeepDiaphragmatic Breathing Technique Based on Neofunctional Psychotherapy: A Pilot RCT.

We examined the feasibility of using the neofunctional deep breathing (NDB) technique to reduce the allostatic load following the Trier Social Stress Test (TSST). Forty-four healthy subjects were randomised into experimental and control groups. Following the TSST procedure, participants underwent either a single session of NDB or an attention control intervention. The Procomp Infinity Biofeedback system measured breath per minute (BPM), respiratory amplitude, HRV linear domains, skin conductance, and trapezius muscle electromyographic activity. Cortisol and cytokine salivary concentrations, perceived stress, and anxiety levels were also assessed. These parameters were combined into an allostatic load index (ALI) to measure the intervention's effect. This pilot RCT demonstrated the feasibility of the study design and practicality of the intervention. The NDB group showed reduced ALI, increased respiratory abdominal amplitude, decreased BPM, increased HRV indicating parasympathetic activation, and decreased cortisol and inflammatory cytokines. This study highlighted the feasibility of testing the NDB technique in reducing allostatic load through a neurobiological and anti-inflammatory response after exposure to psychosocial stress. This protocol can represent a non-invasive therapeutic adjutant in disorders related to a dysregulation of the HPA axis or to an inflammatory state. Trial Registration: NCT04102813.

Emerging role of microglia in the developing dopaminergic system: perturbation by early life stress

Early life stress correlates with a higher prevalence of neurological disorders, including autism, attention-deficit/hyperactivity disorder, schizophrenia, depression, and Parkinson's disease. These conditions, primarily involving abnormal development and damage of the dopaminergic system, pose significant public health challenges. Microglia, as the primary immune cells in the brain, are crucial in regulating neuronal circuit development and survival. From the embryonic stage to adulthood, microglia exhibit stage-specific gene expression profiles, transcriptome characteristics, and functional phenotypes, enhancing the susceptibility to early life stress. However, the role of microglia in mediating dopaminergic system disorders under early life stress conditions remains poorly understood. This review presents an up-to-date overview of preclinical studies elucidating the impact of early life stress on microglia, leading to dopaminergic system disorders, along with the underlying mechanisms and therapeutic potential for neurodegenerative and neurodevelopmental conditions. Impaired microglial activity damages dopaminergic neurons by diminishing neurotrophic support (e.g., insulin-like growth factor-1) and hinders dopaminergic axon growth through defective phagocytosis and synaptic pruning. Furthermore, blunted microglial immunoreactivity suppresses striatal dopaminergic circuit development and reduces neuronal transmission. Furthermore, inflammation and oxidative stress induced by activated microglia can directly damage dopaminergic neurons, inhibiting dopamine synthesis, reuptake, and receptor activity. Enhanced microglial phagocytosis inhibits dopamine axon extension. These long-lasting effects of microglial perturbations may be driven by early life stress–induced epigenetic reprogramming of microglia. Indirectly, early life stress may influence microglial function through various pathways, such as astrocytic activation, the hypothalamic–pituitary–adrenal axis, the gut–brain axis, and maternal immune signaling. Finally, various therapeutic strategies and molecular mechanisms for targeting microglia to restore the dopaminergic system were summarized and discussed. These strategies include classical antidepressants and antipsychotics, antibiotics and anti-inflammatory agents, and herbal-derived medicine. Further investigations combining pharmacological interventions and genetic strategies are essential to elucidate the causal role of microglial phenotypic and functional perturbations in the dopaminergic system disrupted by early life stress.

Sex-dependent effects of early life sensory overstimulation on later life behavioral function in rats.

Children today are immersed in electronic technology shortly after birth as they now begin regularly watching television earlier than they did in the past. Many new programs geared towards infants contain lots of lights, color, and sounds, which may constitute a form of sensory overstimulation (SOS) that leads to cognitive and behavioral changes in children and adolescents. Here, we examined the impact of early life SOS exposure on later life behavioral and cognitive function in rodents by exposing developing male and female rats to excessive audiovisual stimulation from postnatal days (PND) 10-40 and assessing anxiety-like behavior, social motivation, compulsive behavior, and spatial learning/cognition from PND 50-60. To evaluate potential SOS effects on hypothalamic-pituitary-adrenal (HPA)-axis function, levels of the stress hormone corticosterone (CORT) were measured at 3 timepoints (e.g., PND 23, 41, 61) post-SOS exposure. Sensory overstimulated males exhibited reduced anxiety-like and compulsive behavior compared to controls, whereas females exhibited reduced social motivation but enhanced spatial learning/cognition compared to controls. No differences in baseline CORT levels were found at any age tested, suggesting no impact of early life SOS on later life basal HPA-axis function. Our results demonstrate sex-specific effects of early life SOS on distinct behavioral domains in early adult rats.

Who and how to screen for endogenous hypercortisolism in patients with mood disorders.

A strict association exists between mood disorders and endogenous hypercortisolism, namely Cushing's syndrome (CS). Indeed, CS is characterized by a wide range of mood disorders, such as major depression, generalized anxiety, panic disorders, bipolar disorders up to psychosis, with major depression being the most frequent, with a prevalence of 50-80%, and potentially representing the clinical onset of disease. Despite this observation, the exact prevalence of hypercortisolism in patients with mood disorders is unknown and who/how to screen for endogenous hypercortisolism among patients with mood disorders is still unclear. In this context, an accurate anamnestic and clinical examination are crucial in order to identify those patients who may benefit from CS screening. In particular, the presence of specific signs and symptoms of CS, comorbidities typically associated with CS, and lack of improvement of depressive symptoms with standard treatments can further guide the decision to screen for CS. Anyhow, it is noteworthy that mood disorders represent a cause of functional activation of hypothalamic-pituitary-adrenal (HPA) axis, a condition formerly known as non-neoplastic hypercortisolism (NNH). The differential diagnosis between CS and NNH is challenging. Beyond anamnestic and clinical features, various tests, including measurement of daily urinary cortisol and late-night salivary cortisol, together with low dose-dexamethasone suppression test, are used for initial screening. However, considering their low accuracy, a definitive diagnosis may require a longitudinal follow-up along with second-line dynamic tests like combined dexamethasone-CRH test and desmopressin test. In conclusion, available data suggest the need for a comprehensive assessment and follow-up of individuals with mood disorders to detect possible underlying CS, considering the pitfalls in diagnosis and the overlap of symptoms with other conditions like NNH. Specialized centers with expertise in CS diagnosis and differential testing are recommended for accurate evaluation and management of these patients.

Effect of Listening Music on Nulliparous Singleton Pregnancies Who Underwent Induction of Labor: A Randomized Clinical Trial.

A recent randomized clinical trial (RCT) showed that listening to music reduces the pain level and anxiety levels in women with spontaneous labor at term. The effect on pregnant women undergoing induction of labor is still unclear.This study aimed to test the hypothesis that in nulliparous women with singleton pregnancies, undergoing induction of labor at term, listening to music would reduce the pain level during labor. Parallel group, non-blinded, RCT conducted at a single center in Italy. Nulliparous women with singleton pregnancies and vertex presentation, admitted for induction of labor with either oral or vaginal prostaglandins, between 370/7 and 420/7 weeks, were randomized in a 1:1 ratio to receive music during induction of labor or no music during induction. The endpoints of the trials were the pain level during induction, and in the active phase of labor, recorded using the visual analog scale for pain, ranging from 0 (no pain) to 10 (unbearable pain). The effect of music use on each outcome was quantified as the mean difference (MD) with a 95% confidence interval (CI). During the study period, 30 women agreed to take part in the study, underwent randomization, and were enrolled and followed up. Fifteen women were randomized in the music group and 15 in the control group. No patients were lost to follow-up for the primary outcome. Pain level during the induction procedure was 8.8 ± 0.9 in the music group, and 9.8 ± 0.3 in the control group (MD -2.60 points, 95% CI -3.94 to -1.26; p < 0.01). Music during labor and delivery was also associated with decreased anxiety during the induction procedure (MD -3.80 points, 95% CI -5.53 to -2.07; p < 0.01). In nulliparous women, listening to music during the induction of labor reduces pain and anxiety levels. · Music listening has a modulatory effect on the human stress response.. · Music listening may generate beneficial changes in the autonomic nervous system and the HPA axis activity that should be conducive to the stress recovery process.. · Listening to music during induction of labor resulted in a significant lower pain..

TMIC-44. ANDROGEN LOSS WEAKENS ANTI-TUMOR IMMUNITY AND ACCELERATES BRAIN TUMOR GROWTH

Abstract Many cancers, including glioblastoma (GBM), exhibit a male-biased incidence and outcome disparity. The underlying reasons for this sex bias are unclear but likely involve differences in tumor cell state and immune response. This effect is further influenced by sex hormones, including androgens, which have been shown to inhibit anti-tumor T cell immunity in other solid tumors. Using a series of pre-clinical models, we observed that androgens drive anti-tumor immunity in brain tumors, contrasting with their effect in other tumor types. Upon castration, tumor growth was accelerated in GBM and brain tumor models, while the opposite effect was observed when tumors were located outside the brain. This castration effect could be reversed by testosterone administration. Flow cytometry revealed decreased T cell function, indicated by reduced anti-tumor cytokines (IFNγ and TNFα), and increased T cell exhaustion in both tumors and peripheral tissues in castrated mice, suggesting systemic immunosuppression. Indeed, the survival difference was completely abrogated in T cell deficient mice (RAG1 knockout). Mechanistically, increased hypothalamus-pituitary-adrenal (HPA) axis activity in castrated mice was responsible for the observed systemic immunosuppression, particularly in those with brain tumors. Blocking glucocorticoid receptors reversed the accelerated tumor growth in castrated mice, indicating that elevated glucocorticoid signaling mediated the castration effect. This mechanism was brain-specific rather than GBM-specific, as hyperactivation of the HPA axis was also observed with intracranial implantation of non-GBM tumors. Neuroinflammation caused by brain tumors was stronger in castrated mice, and proinflammatory cytokines like IL-1 and TNF induced HPA axis hyperactivation. Together, these findings highlight that brain tumors drive distinct endocrine-mediated mechanisms in the androgen-deprived setting and highlight the importance of organ-specific effects on anti-tumor immunity.

Hypothalamic-Pituitary-Adrenal Axis Activity and Metabolic Disorders in Kidney Transplant Recipients on Long-Term Glucocorticoid Therapy

Background/Objectives: Glucocorticoids are commonly used for maintenance immunosuppressive therapy in kidney transplant recipients (KTRs). We aimed to investigate the prevalence of hypothalamic-pituitary-adrenal (HPA) axis suppression and its association with metabolic disorders in stable KTRs on low-dose glucocorticoids. Methods: This cross-sectional study included adult KTRs on low-dose glucocorticoids. HPA axis suppression was defined as baseline morning cortisol &lt; 5 μg/dL. Adrenocorticotropic hormone (ACTH), dehydroepiandrosterone-sulphate (DHEAS) and 24 h urinary free cortisol (UFC) levels were also assessed. Examined metabolic disorders included hypertension, dyslipidemia, central obesity and post-transplant diabetes mellitus (PTDM). Results: Eighty adult KTRs with a median 57 months (IQR 24–102) since transplantation were included in the study. The mean prednisolone dose was 5.0 ± 1.3 mg/day. Baseline cortisol &lt; 5.0 μg/dL was observed in 27.5% of the KTRs. Participants with baseline cortisol &lt; 5.0 μg/dL were older (55.1 vs. 47.4 years, p = 0.023) and had had a transplant for a longer time (101.4 vs. 67.0 months, p = 0.043), compared with the rest of the cohort. Baseline cortisol correlated positively with ACTH (rho = 0.544, p &lt; 0.001), DHEAS (rho:0.459, p &lt; 0.001) and UFC (rho: 0.377, p = 0.002). The area under the receiver-operating characteristic curve for ACTH as a predictor of baseline cortisol &gt; 5.0 μg/dL was 0.79 [95% confidence interval (CI): 0.68–0.89]. After adjustment for covariates, HPA axis suppression was not associated with the examined metabolic disorders. Conclusions: Our study showed that stable KTRs on chronic low-dose glucocorticoids exhibited an increased prevalence of HPA axis suppression. ACTH may serve as a surrogate biomarker for HPA axis activity in this population. Further research could evaluate the association of glucocorticoid-induced HPA axis inhibition with metabolic disorders.

Altered Steroidome in Women with Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) mainly afflicting young women. Various steroids can influence the onset and development of the disease or, on the contrary, mitigate its course; however, a systematic review of steroidomic changes in MS patients is lacking. Based on the gas chromatography tandem mass spectrometry (GC-MS/MS) platform and, in the case of estradiol, also using immunoassay, this study performed a comprehensive steroidomic analysis in 25 female MS patients aged 39(32, 49) years compared to 15 female age-matched controls aged 38(31, 46) years. A significant trend towards higher ratios of conjugated steroids to their unconjugated counterparts was found in patients, which is of particular interest in terms of the balance between excitatory and inhibitory steroid modulators of ionotropic receptors. Patients showed altered metabolic pathway to cortisol with decreased conversion of pregnenolone to 17-hydroxypregnenolone and 17-hydroxypregnenolone to 17-hydroxyprogesterone and increased conversion of 17-hydroxypregnenolone to dehydroepiandrosterone (DHEA), resulting in lower levels of 17-hydroxyprogesterone, as well as indications of impaired conversion of 11-deoxy-steroids to 11β-hydroxy-steroids but reduced conversion of cortisol to cortisone. Due to over-activation of hypothalamic-pituitary-adrenal axis (HPAA), however, cortisol and cortisone levels were higher in patients with indications of depleted cortisol synthesizing enzymes. Patients showed lower conversion of DHEA to androstenedione, androstenedione to testosterone, androstenedione to estradiol in the major pathway, and testosterone to estradiol in the minor pathway for estradiol synthesis at increased conversion of androstenedione to testosterone. They also showed lower conversion of immunoprotective Δ5 androstanes to their more potent 7α/β-hydroxy metabolites and had lower circulating allopregnanolone and higher ratio 3β-hydroxy-steroids to their neuroprotective 3α-hydroxy-counterparts.

Sex Differences in the Neuroendocrine Stress Response: A View from a CRH-Reporting Mouse Line

Corticotropin-releasing hormone (CRH) neurons within the paraventricular hypothalamic nucleus (PVH) play a crucial role in initiating the neuroendocrine response to stress and are also pivotal in coordination of autonomic, metabolic, and behavioral stress reactions. Although the role of parvocellular CRHPVH neurons in activation of the hypothalamic–pituitary–adrenal (HPA) axis is well established, the distribution and function of CRH-expressing neurons across the whole central nervous system are less understood. Stress responses activate complex neural networks, which differ depending on the type of stressor and on the sex of the individual. Because of the technical difficulties of localizing CRH neurons throughout the rodent brain, several CRH reporter mouse lines have recently been developed. In this study, we used Crh-IRES-Cre;Ai9 reporter mice to examine whether CRH neurons are recruited in a stressor- or sex-specific manner, both within and outside the hypothalamus. In contrast to the clear sexual dimorphism of CRH-mRNA-expressing neurons, quantification of CRH-reporting, tdTomato-positive neurons in different stress-related brain areas revealed only subtle differences between male and female subjects. These results strongly imply that sex differences in CRH mRNA expression occur later in development under the influence of sex steroids and reflects the limitations of using genetic reporter constructs to reveal the current physiological/transcriptional status of a specific neuron population. Next, we compared the recruitment of stress-related, tdTomato-expressing (putative CRH) neurons in male and female Crh-IRES-Cre;Ai9 reporter mice that had been exposed to predator odor. In male mice, fox odor triggered more c-Fos in the CRH neurons of the paraventricular hypothalamic nucleus, central amygdala, and anterolateral bed nucleus of the stria terminalis compared to females. These results indicate that male mice are more sensitive to predator exposure due to a combination of hormonal, environmental, and behavioral factors.

Protective Strategies for Pituitary Function During Endoscopic Transnasal Pituitary Adenoma Surgery: A Single-center Experience.

This study investigated the impact of endoscopic transnasal pituitary adenoidectomy on function and discussed the factors that contribute to postoperative pituitary function. To provide a foundation for protecting pituitary function and improving the curative effect of pituitary adenoma neuroendoscope resection. From January 2019 to January 2022, in the Neurosurgery Pituitary Tumor Diagnosis and Treatment Research Center, the First Affiliated Hospital of Shenzhen University, the clinical data of 306 patients who underwent endoscopic transnasal pituitary adenoma surgery were analyzed retrospectively. The surgical treatment strategy was discussed and explored, while the factors related to pituitary function were examined based on tumor size and Knosp grade. There were 40 cases (67.8%) of pituitary-thyroid axis, 18 cases (60%) of pituitary-adrenal axis, 25 cases (45.4%) of pituitary-gonad axis, 5 cases (62.5%) of pituitary-growth hormone axis, and 8 cases (72.7%) of diabetes insipidus with postoperative improves of hypopituitarism. Postoperative newly developed hypopituitarism occurred in 20 cases (8.1%) of pituitary-thyroid axis, 15 cases (5.4%) of pituitary-adrenal axis, 10 cases (4.0%) of pituitary-gonad axis, 5 cases (1.7%) of pituitary-growth hormone axis, and 8 cases (2.7%) of new diabetes insipidus. The incidence of pituitary-adrenal axis hypofunction in giant pituitary adenomas was significantly higher than that in microadenomas and macroadenomas (P<0.05). The incidence of hypopituitarism of Knosp grade 4 pituitary adenoma before operation was higher than that of other groups (P<0.05), but there was no significant difference in the incidence of new hypopituitarism after operation (P>0.05). In endoscopic transnasal pituitary adenoma surgery, the incidence of hypothyroidism and adrenal gland dysfunction is higher than in other hormone axes, but the recovery rate is also higher, and the recovery rate of sex hormones is lower. The incidence of postoperative hypothyroidism increases dramatically with tumor size and tumor invasiveness.

Ashwagandha and stress

Ashwagandha, also known as Withania somnifera, is an adaptogen gaining popularity as a natural stress reducer. Stress is a common phenomenon caused by factors such as lifestyle, work pressure or social conflict, and has a negative impact on both mental and physical health. In response to these challenges, more and more people are looking for natural solutions, and adaptogens such as ashwagandha offer support in dealing with stress without significant side effects. Scientific research shows that ashwagandha can lower levels of the stress hormone cortisol and improve results on tests assessing stress, anxiety and depression. Numerous studies conducted on both animals and humans confirm its beneficial effects on mental and physical health, including improvement of cognitive functions, sleep quality and emotional well-being. The mechanism of action of ashwagandha includes regulation of the HPA axis, reduction of glucocorticoids and modulation of the immune system. Despite promising results, further research is needed to fully understand its mechanism of action, assess long-term effects, and investigate possible interactions with other drugs. Ashwagandha seems to be a safe and effective agent in the fight against stress, but it is recommended to consult a doctor before starting supplementation.

A glucocorticoid-mediated immunoregulatory circuit integrated at brain levels: our early studies and a present view.

Background It was known since the 1940's that pharmacological administration of glucocorticoids can inhibit inflammatory and immune processes, and these hormones are still today among the most widely used therapeutic tools to treat diseases with immune components. However, it became clear later that endogenous glucocorticoids can either support or restrain immune processes. Summary Early studies showed that: a) endogenous levels of glucocorticoids can modulate immune cell activity; b) the immune response itself can stimulate the hypothalamus-pituitary-adrenal (HPA) axis to release glucocorticoids to levels that can exert immunoregulatory effects; c) immune products, later identified as cytokines, mediate this effect. On these bases, the existence of a glucocorticoid-mediated immunoregulatory circuit was proposed. It was also shown that increased levels of endogenous glucocorticoids exert protective effects during infections and other diseases with immune components. However, it was found in animal models and in humans that these effects can be blunted in several immune-linked diseases by defects at several levels, for example by glucocorticoid resistance or by adrenal insufficiency. Evidence was later provided that the glucocorticoid-mediated immunoregulatory circuit can also be activated by cytokines produced not only as consequence of immune stimulation but also following psycho/sensorial and physical stimuli. Thus, this circuit can be integrated at brain levels and, besides stimulating the HPA axis, cytokines can also affect synaptic plasticity, most likely via a tripartite synapse, with astrocytes as neuro-immune cells acting as the third component. Key Messages It is now well established that the glucocorticoid-mediated immunoregulatory circuit plays a central role in maintaining health. However, several variables can condition the efficacy of the effect of endogenous glucocorticoids. Furthermore, since cytokines and other immune products have many other neuro-endocrine and metabolic effects, other neuro-endocrine-immune circuits could simultaneously operate or become predominant during different pathologies. The consideration of these aspects might help to implement strategies to eventually decrease therapeutic doses of exogenous glucocorticoids.

Optimizing Chronotherapy in Psychiatric Care: The Impact of Circadian Rhythms on Medication Timing and Efficacy

In many medical settings, medications are typically administered in the morning or evening, aligning with patients’ daily routines. This practice does not stem from chronotherapy, which involves scheduling drug administration to enhance its effectiveness, but rather from the way clinical operations are structured. The timing of drug administration can significantly affect a medication’s effectiveness and side effects, with the impact varying by up to ten times based on circadian rhythms. Disorders such as major depression, bipolar disorder, and schizophrenia are linked to disruptions in these rhythms. Recent studies have found that circadian dysfunctions, including genetic and neurohumoral changes, underlie many psychiatric conditions. Issues such as an altered glucocorticoid rhythm due to impaired HPA axis function, disturbed melatonin balance, and sleep disturbances have been noted in psychotic disorders. Furthermore, mood disorders have been associated with changes in the expression of circadian rhythm genes such as Clock, Bmal1, and Per. Considering that the absorption, biodistribution, effects on target organs, half-life, metabolism, and elimination of drugs are all influenced by the body’s circadian rhythms, this narrative review explores the optimal timing of medication administration to maximize efficacy and minimize side effects in the treatment of psychiatric disorders. By closely monitoring circadian variations in cortisol, melatonin, and key clock genes, as well as by deepening our understanding of the metabolisms and pharmacokinetics of antipsychotic medications, we propose a chronotherapy approach for psychiatric patients that could significantly enhance patient care.