Corticotropin-releasing Hormone Secretion Research Articles

Investigating the Role of CART/GPR160 Signaling in Stress-Induced Anorexia

Stress-induced anorexia represents a conserved adaptive response across diverse species. While this response can be crucial for survival in specific situations, it may become detrimental when prolonged stress exposure leads to unhealthy eating patterns, contributing to eating disorders like anorexia nervosa and bulimia. Feeding behavior is intricately connected to the stress response, as stress levels can influence appetite and energy expenditure. Central to the stress response are corticotropin-releasing hormone (CRH)-producing neurons, which secrete CRH, stimulating the production of ACTH in the pituitary gland and subsequently triggering the release of cortisol, a stress hormone, from the adrenal glands. The presence of CRH in the hypothalamus, a brain region involved in controlling feeding, suggests a complex interplay where stress and metabolic signals converge. One such signal is the peptide cocaine- and amphetamine-regulated transcript (CART) which has been shown to regulate feeding behavior, satiety, and metabolic function by signaling through its receptor GPR160 and downstream glucagon-like peptide (GLP)-1 signaling. In this study, we hypothesize that CART/GPR160 signals within CRH-producing neurons to control feeding behavior and stress responses. To test this hypothesis, we used a multifaceted approach, utilizing both wild type and GPR160-floxed rats in which GPR160 was knocked down specifically in CRH neurons using an AAV-Cre under the control of the CRH promoter injected bilaterally into the paraventricular nucleus. We monitored food and water intake, investigated CRH secretion from hypothalamic explants treated with CART, and assessed physiological changes in GPR160, CART, and other related molecules in various brain regions following acute stress. We also examined the effects of GPR160 knockdown in PVN neurons on plasma cortisol levels in response to restraint stress. While further studies are necessary to fully define the roles of CART and GPR160 in stress responses and feeding behavior control, our preliminary findings indicate that this ligand-receptor pair could serve as a novel therapeutic target for treating psychiatric diseases related to eating disorders. NIH. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Pathogenetic and clinical rationale for syntropic pathology based on metabolic syndrome, coronary heart disease and type 2 diabetes mellitus

Pathogenetic and clinical rationale for syntropic pathology based on metabolic syndrome, coronary heart disease and type 2 diabetes mellitus

THU624 Opioid Induced Adrenal Insufficiency (OIAI) Presenting With Altered Mental Status

Abstract Disclosure: D. Bondarenko: None. M. Ahmad: None. G.A. McGrath: None. Background: Opioid suppression of the hypothalamic-pituitary-adrenal (HPA) axis via inhibition of corticotropin releasing hormone secretion leading to secondary adrenal insufficiency (AI) has been described in literature. Biochemical secondary AI is evident in 6-50% of patients on chronic opioids; fewer cases are reported presenting with clinical AI.1 We present a rare case of symptomatic opioid-induced AI (OIAI) with clinical improvement on initiation of hydrocortisone. Clinical Case: A 49-year-old female on daily buprenorphine (20 mg) and naltrexone (5 mg) presented to the hospital with syncope and hypotension (79/49 mmHg). AM cortisol was 6.2 mcg/dL, a cosyntropin stimulation test was performed, but there was technical difficulty with the results. She was started on midodrine 2.5 mg three times daily and referred to outpatient endocrinology for follow up. Weeks later, outpatient cosyntropin stimulation test showed baseline cortisol of 18 mcg/dL with increase to 26 mcg/dL. Simultaneous adrenocorticotrophic hormone (ACTH) was 16.9 pg/mL. AI was ruled out. Seven years later she presented with acute lethargy, confusion, and memory loss over several days. AM cortisol was 1.6 mcg/dL and cosyntropin stimulation test increased cortisol to 15.1 mcg/dL (normal response being 18 mcg/dL or greater). ACTH was 24 pg/mL. The abnormal cosyntropin stimulation test results are consistent with AI, and lack of elevation of morning ACTH is consistent with secondary AI.2 Hydrocortisone therapy was started and midodrine was held due to elevated blood pressure after initiation of steroids. She was discharged on hydrocortisone 15 mg each morning and 5 mg each afternoon. Within 10 days of initiation of glucocorticoid replacement therapy her neurologic symptoms improved and midodrine discontinued. Prescription Drug Monitoring Program (PDMP) review shows reduction of buprenorphine (16 mg) and naltrexone (4 mg). Conclusion: Data on management of OIAI and recovery of the HPA axis with or without cessation of opioid therapy is limited. This case highlights that opioids should be considered as a potential cause of secondary AI. Further follow-up of this case and other OIAI cases would provide insight into management of opioid therapy, continuation of glucocorticoid therapy, and recovery of HPA axis. This data could provide basis for OIAI management recommendations. Reference: (1) Fountas, A., Prof, S.V.U., Karavitaki, N. Opioid-induced endocrinopathies. Lancet Diabetes Endocrinol. 2020;8(1);68-80. (2) Bornstein, S.R., Allolio, B., Arlt, W., et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J. Clin. Endocr. 2016;101(2);364-389. Presentation: Thursday, June 15, 2023

Repeated Experience of Aggression Changes Gene Expression in Hypothalamus in Male Mice of Two Strains

Repeated positive fighting experience can lead to changes in the neurophysiology and behavior of animals and to the formation of pathological aggression. Mechanisms of adaptation to repeated aggression are thought to be controlled through hypothalamus and HPA axis. In this work, we studied the effect of repeated (30 days) experience of aggression on gene expression in the hypothalamus in male mice of two strains – C57BL/6J and CD1. We measured expression levels of the HPA axis genes (Crh, Crhr1, Crhbp, Fkbp5, Nr3c1), as well as early response gene (Fos) and dopamine receptor D1 gene (Drd1). Repeated experience of aggression led to prolongation of Fos activation in C57BL/6J, although the expression of other studied genes remained unchanged. CD1 aggressors are characterized by decreased expression level of Crhr1 and Crhbp genes, whose products inhibit the secretion of corticotropin-releasing hormone. Most of the studied genes showed strain variation in gene expression that is probably associated with different levels of locomotor activity and anxiety in mice of these strains. The basal expression level of Crh gene was higher in C57BL/6J mice, while Crhr1, Crhbp, Fkbp5, Fos, and Drd1 genes were higher in CD1 mice. Thus, the repeated experience of aggression leads to gene expression changes in the hypothalamus of male mice, that depend on the genetic background and related psychophysiological features of individuals.

Ectopic Cushing's syndrome from a corticotropin-releasing hormone-secreting medullary thyroid carcinoma: a rare pitfall of inferior petrosal sinus sampling.

This case report describes a rare presentation of ectopic Cushing's syndrome (CS) due to ectopic corticotropin-releasing hormone (CRH) production from a medullary thyroid carcinoma (MTC). The patient, a 69-year-old man, presented with symptoms of muscle weakness, facial plethora, and easy bruising. An inferior petrosal sinus sampling test (IPSS) demonstrated pituitary adrenocorticotrophic hormone (ACTH) secretion, but a whole-body somatostatin receptor scintigraphy (68Ga-DOTATOC PET/CT) revealed enhanced uptake in the right thyroid lobe which, in addition to a grossly elevated serum calcitonin level, was indicative of an MTC. A 18F-DOPA PET/CT scan supported the diagnosis, and histology confirmed the presence of MTC with perinodal growth and regional lymph node metastasis. On immunohistochemical analysis, the tumor cell stained positively for calcitonin and CRH but negatively for ACTH. Distinctly elevated plasma CRH levels were documented. The patient therefore underwent thyroidectomy and bilateral adrenalectomy. This case shows that CS caused by ectopic CRH secretion may masquerade as CS due to a false positive IPSS test. It also highlights the importance of considering rare causes of CS when diagnostic test results are ambiguous. Medullary thyroid carcinoma may secrete CRH and cause ectopic CS. Ectopic CRH secretion entails a rare pitfall of inferior petrosal sinus sampling yielding a false positive test. Plasma CRH measurements can be useful in selected cases.

Salt-inducible kinase 1-CREB-regulated transcription coactivator 1 signalling in the paraventricular nucleus of the hypothalamus plays a role in depression by regulating the hypothalamic-pituitary-adrenal axis.

Elucidating the molecular mechanism underlying the hyperactivity of the hypothalamic-pituitary-adrenal axis during chronic stress is critical for understanding depression and treating depression. The secretion of corticotropin-releasing hormone (CRH) from neurons in the paraventricular nucleus (PVN) of the hypothalamus is controlled by salt-inducible kinases (SIKs) and CREB-regulated transcription co-activators (CRTCs). We hypothesised that the SIK-CRTC system in the PVN might contribute to the pathogenesis of depression. Thus, the present study employed chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression, various behavioural tests, virus-mediated gene transfer, enzyme-linked immunosorbent assay, western blotting, co-immunoprecipitation, quantitative real-time reverse transcription polymerase chain reaction, and immunofluorescence to investigate this connection. Our results revealed that both CSDS and CUMS induced significant changes in SIK1-CRTC1 signalling in PVN neurons. Both genetic knockdown of SIK1 and genetic overexpression of CRTC1 in the PVN simulated chronic stress, producing a depression-like phenotype in naive mice, and the CRTC1-CREB-CRH pathway mediates the pro-depressant actions induced by SIK1 knockdown in the PVN. In contrast, both genetic overexpression of SIK1 and genetic knockdown of CRTC1 in the PVN protected against CSDS and CUMS, leading to antidepressant-like effects in mice. Moreover, stereotactic infusion of TAT-SIK1 into the PVN also produced beneficial effects against chronic stress. Furthermore, the SIK1-CRTC1 system in the PVN played a role in the antidepressant actions of fluoxetine, paroxetine, venlafaxine, and duloxetine. Collectively, SIK1 and CRTC1 in PVN neurons are closely involved in depression neurobiology, and they could be viable targets for novel antidepressants.

PSAT053 An Unusual Case of Central Adrenal Insufficiency Following the Diagnosis of Presumed Neuro-Sarcoidosis

Abstract Background Central adrenal insufficiency develops due to inadequate ACTH secretion by the pituitary gland (secondary) or decreased corticotropin-releasing hormone (CRH) secretion by the hypothalamus (tertiary).1 The hallmark of central adrenal insufficiency is inappropriately low levels of ACTH in the setting of low cortisol levels.1 Central adrenal insufficiency can be caused by CNS processes affecting the hypothalamus or pituitary gland, such as infection, autoimmune disease, malignancy, or the abrupt cessation of steroids.1 Here we present a rare case of central adrenal insufficiency following the diagnosis of presumed neuro-sarcoidosis. Clinical Case A 69-year-old female presents with fatigue, weight loss, and diffuse bilateral weakness. Vital signs were within normal with a physical exam significant for 3/5 strength in bilateral upper and lower extremities. MRI brain revealed leptomeningeal and pituitary stalk enhancement. CSF studies showed CSF lymphocytic pleocytosis and an elevated CSF ACE level 5.8 U/L. The most common etiologies of an elevated CSF ACE level are neuro-sarcoidosis or malignancy, and patient had no imaging findings of malignancy. With the elevated CSF ACE level along with imaging findings, she was given a presumptive diagnosis of neuro-sarcoidosis. She was treated with three days of IV methylprednisolone with mild improvement in symptoms. After discharge, she continued to have symptoms of diffuse weakness, fatigue, nausea and was re-admitted a few weeks later. Vitals on this admission revealed hypotension to 93/55, heart rate 66, SpO2 99%. Repeat MRI brain revealed resolution of leptomeningeal and pituitary enhancements. Due to the hypotension, morning cortisol levels were drawn and returned low at 0.4 ug/dL. ACTH stimulation test showed cortisol at 0 minutes low at 0.5 ug/dL and cortisol at 60 minutes at 9.7 ug/dL. ACTH prior to stimulation test returned low at 1.6 pg/mL. With reduced ACTH levels in the setting of low cortisol levels, the patient was diagnosed with central adrenal insufficiency. She began hydrocortisone treatment with complete resolution of symptoms. Further pituitary hormones were tested with TSH returning low at 0.04 uIU/mL; free T4 normal at 0.8 ng/dL; T3 low-normal at 39 ng/dL; FSH low for a post-menopausal female at 2.8 mIU/mL. This multi-hormonal insufficiency suggested the presence of an intracranial process contributing to hypothalamic-pituitary dysfunction. With initial neuro-imaging findings and elevated CSF ACE, the intracranial process causing her central adrenal insufficiency was presumed to be neuro-sarcoidosis. Due to resolution of symptoms on hydrocortisone therapy, definitive histologic evidence of neuro-sarcoidosis was not pursued. Conclusion This is a case demonstrating a rare presentation of central adrenal insufficiency following the diagnosis of presumed isolated neuro-sarcoidosis, with symptoms and radiographic findings responding rapidly to steroid therapy. References Nicolaides, N. C., Chrousos, G. P., & Charmandari, E. Adrenal Insufficiency. [Updated 2017]. In: Feingold KR, Anawalt B, Boyce A, et al., editors Endotext [Internet]. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Immunologic aspects of migraine: A review of literature.

Migraine headaches are highly prevalent, affecting 15% of the population. However, despite many studies to determine this disease's mechanism and efficient management, its pathophysiology has not been fully elucidated. There are suggested hypotheses about the possible mediating role of mast cells, immunoglobulin E, histamine, and cytokines in this disease. A higher incidence of this disease in allergic and asthma patients, reported by several studies, indicates the possible role of brain mast cells located around the brain vessels in this disease. The mast cells are more specifically within the dura and can affect the trigeminal nerve and cervical or sphenopalatine ganglion, triggering the secretion of substances that cause migraine. Neuropeptides such as calcitonin gene-related peptide (CGRP), neurokinin-A, neurotensin (NT), pituitary adenylate-cyclase-activating peptide (PACAP), and substance P (SP) trigger mast cells, and in response, they secrete pro-inflammatory and vasodilatory molecules such as interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) as a selective result of corticotropin-releasing hormone (CRH) secretion. This stress hormone contributes to migraine or intensifies it. Blocking these pathways using immunologic agents such as CGRP antibody, anti-CGRP receptor antibody, and interleukin-1 beta (IL-1β)/interleukin 1 receptor type 1 (IL-1R1) axis-related agents may be promising as potential prophylactic migraine treatments. This review is going to summarize the immunological aspects of migraine.

Polysaccharides From Abrus cantoniensis Hance Modulate Intestinal Microflora and Improve Intestinal Mucosal Barrier and Liver Oxidative Damage Induced by Heat Stress.

The protective effects of polysaccharides from Abrus cantoniensis Hance (ACP) on antioxidant capacity, immune function, the hypothalamus-pituitary-adrenal (HPA) axis balance, the intestinal mucosal barrier, and intestinal microflora in heat stress (HS)-induced heat-injured chickens are rarely reported. The purpose of this study was to investigate the protective effects of ACP on HS-injured chickens by enhancing antioxidant capacity and immune function, repairing the intestinal mucosal barrier, and regulating intestinal microflora. A total of 120 native roosters in Guangxi were randomly divided into 5 groups to evaluate the protective effect of ACP on chickens injured by HS (33 ± 2°C). The results showed that ACP increased the body weight and the immune organ index of heat-injured chickens, regulated the oxidative stress kinase secretion, and restored the antioxidant level of heat-injured birds. ACP significantly inhibited the secretion of corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and corticosterone (COR) and reversed the disorder of hormone levels caused by HS. ACP significantly regulated the secretion levels of immune cytokines and restored the immune function of the body. ACP significantly improved the intestinal morphology and increased the expression levels of tight junction proteins, which had a positive effect on protecting intestinal health. The results of high-throughput sequencing of the 16S rRNA gene showed that HS led to an increase in the abundance of harmful bacteria and an abnormal increase in the abundance of intestinal microflora and that ACP restored the HS-induced intestinal microflora imbalance. In conclusion, this study provides a scientific basis for ACP as an antioxidant activity enhancer to reduce liver injury, regulate intestinal microflora, and protect intestinal mucosal damage in chickens.

GluN2A/ERK/CREB Signaling Pathway Involved in Electroacupuncture Regulating Hypothalamic-Pituitary-Adrenal Axis Hyperactivity.

The hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis caused by stress will inevitably disrupt the homeostasis of the neuroendocrine system and damage physiological functions. It has been demonstrated that electroacupuncture (EA) can modulate HPA axis hyperactivity during the perioperative period. As the initiating factor of the HPA axis, hypothalamic corticotrophin-releasing hormone (CRH) is the critical molecule affected by EA. However, the mechanism by which EA reduces CRH synthesis and secretion remains unclear. Activated N-methyl-D-aspartate receptor (NMDAR) has been linked to over-secretion of hypothalamic CRH induced by stress. To determine whether NMDAR is involved in EA regulating the over-expression of CRH, a surgical model of partial hepatectomy (HT) was established in our experiment. The effect of EA on hypothalamic NMDAR expression in HT mice was examined. Then, we investigated whether the extracellular regulated protein kinases (ERK)/cyclic adenosine monophosphate response element-binding protein (CREB) signaling pathway mediated by NMDAR was involved in EA regulating HPA axis hyperactivity. It was found that surgery enhanced the expression of hypothalamic CRH and caused HPA axis hyperactivity. Intriguingly, EA effectively suppressed the expression of CRH and decreased the activation of GluN2A (NMDAR subunit), ERK, and CREB in HT mice. GluN2A, ERK, and CREB antagonists had similar effects on normalizing the expression of CRH and HPA axis function compared with EA. Our findings suggested that surgery enhanced the activation of the hypothalamic GluN2A/ERK/CREB signaling pathway, thus promoting the synthesis and secretion of CRH. EA suppressed the phosphorylation of GluN2A, ERK, and CREB in mice that had undergone surgery, indicating that the GluN2A/ERK/CREB signaling pathway was involved in EA alleviating HPA axis hyperactivity.

Rathke’s Cyst and Adrenal Insufficiency: A Rare Case of Hyponatremia

Abstract Background: Hyponatremia is the most common electrolyte abnormality encountered in clinical practice, the diagnosis of which can be challenging. A holistic approach with appropriate investigations is imperative to its diagnosis and management. We report this peculiar case of a patient with hypopituitarism secondary to Rathke’s cyst resulting in secondary Adrenal Insufficiency, thus causing Hyponatremia. Case Details: A 32 year male was admitted to hospital with an intractable headache and deterioration in his general wellbeing. His admission parameters revealed a GCS of 15 with normal observations. He had no evidence of meningism and examination of all other systems was unremarkable. He was not on any regular medications and there was no history of trauma. Bloods revealed a Sodium of 122mmol/l, the rest being normal. Investigations including a CT brain, CXR, paired serum & urine osmolality, urinary sodium, Thyroid functions and a 9am cortisol were conducted. Radiological imaging was unremarkable. Subsequently, he was fluid restricted due to a euvolemic fluid status. Serum osmolality was 246 mmol/kg (275-295 mmol/kg), Urine osmolality 847 mmol/kg, urine sodium 85 mmol/l and a 9 am serum cortisol of 29 nmol/L, in keeping with Adrenal Insufficiency. A further decline in his Sodium to 116 mmol/L resulted in Hyponatremic Encephalopathy. In view of impending Adrenal crisis, IV hydrocortisone was commenced in conjunction with hypertonic Saline. This was followed by strict monitoring with cautious correction. An anterior Pituitary profile, serum testosterone and Prolactin were requested. Serum Testosterone levels were 0.4nmol/L (10.0-36nmol/L), FSH- 2.5 IU/L (1.0-11.0 IU/L) and LH- 1.9 IU/L (1.5-9.3 IU/L). Serum prolactin was 85mU/L (45-375 mU/L), TSH- 0.59 mU/L (0.30-6.00 mU/L), Free T4- 13.0 pmol/L (10.4-24.5 pmol/L), IGF1-135 ug/L (60-197 ug/L). This was suggestive of partial hypopituitarism. An MRI Pituitary revealed appearances in keeping with a Rathke’s cyst occupying the pituitary fossa without compromise of the Optic Chiasma. Once stable, he was safely discharged with follow-up appointments planned with the Endocrine and Neurosurgical teams. Discussion: Rathke cleft cysts are non-neoplastic cysts arising from the embryological remnants of Rathke’s pouch in the pituitary gland. Hormonal and visual manifestations can occur if these cysts enlarge and interfere with the Pituitary production and optic chiasma. A proposed mechanism causing Hyponatremia in the context of Cortisol deficiency is increased hypothalamic secretion of Corticotropin releasing hormone (CRH), a Vasopressin secretagogue. Cortisol feeds back negatively on CRH, which is removed with adrenal insufficiency. Hyponatremia is thus often seen in patients with adrenal insufficiency, caused by an inappropriate increase in vasopressin due to cortisol deficiency and inability to excrete free water.

MON-018 Fertility Rates in Rats Characterized by Increased Hypothalamic CRH Secretion

Certain strains of rats are characterized by hyperactive Hypothalamic-Pituitary-Adrenal axis responses to stress, increased hypothalamic Corticotropin-Releasing Hormone (CRH) production and decreased fertility rates. Activation of the HPA-axis and CRH secretion has been associated with suppression of the Hypothalamic-Pituitary-Ovarian axis primarily as a result of glucocorticoids. Here we examined the hypothesis that Fischer rats have decreased fertility rates because of hypothalamic CRH hypersecretion. Antalarmin, a CRH receptor type 1 antagonist, is known to suppress adrenocorticotropin hormone secretion and other CRH receptor type 1-mediated responses. Adult female Fischer rats were injected with antalarmin or placebo, twice a day, for 16 days. Mating was evidenced by the presence of spermatozoa in the vaginal smear performed every morning. After 16 days, 20% of rats (20%) treated with placebo became pregnant and 55% rats treated with antalarmin became pregnant. We have previously reported that administration of antalarmin after the first day of pregnancy does not affect blastocyst implantation in Fischer rats. Our data suggest that antalarmin improves fertility rates in Fischer rats by antagonizing the direct antireproductive role of hypothalamic CRH.

Dopaminergic afferents from midbrain to dorsolateral bed nucleus of stria terminalis inhibit release and expression of corticotropin-releasing hormone in paraventricular nucleus.

Dopaminergic (DAergic) neurons of the midbrain ventral tegmental area (VTA) are known to regulate the hypothalamic-pituitary-adrenal (HPA) axis but have no direct projections to the paraventricular nucleus (PVN) of the hypothalamus. This study investigated whether VTA DAergic afferents modulate glutamatergic transmission-dependent GABAergic neurons in dorsolateral bed nucleus of stria terminalis (dlBNST) to affect the activity of the HPA-axis. Herein, we demonstrate that systemic administration of the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or the VTA-injection of 1-methyl-4-phenylpyridinium ion (MPP+) in male mice (MPTP-mice and MPP+mice) caused a decline of tyrosine hydroxylase positive (TH+) cells in VTA with a reduction in TH+fibers in the dlBNST. MPTP-mice and MPP+mice displayed a clear increase in serum levels of corticosterone (CORT) and adrenocorticotropic hormone, corticotropin-releasing hormone (CRH) expression, and CRH neuron activity in PVN. The presynaptic glutamate release, glutamatergic synaptic transmission and induction of long-term potentiation in dlBNST of MPTP-mice were suppressed, and these effects were rescued by a D1-like DAergic receptor (D1R) agonist and mimicked in control dlBNST by blockade of D1R. MPTP-mice exhibited low expression of glutamic acid decarboxylase and dysfunction of the excitatory-dependent GABAergic circuit in dlBNST, and these effects were recovered by the administration of D1R agonist. Furthermore, either dlBNST-injection of D1R agonist or PVN-injection of GABAA receptor (GABAA R) agonist could correct the increased secretion and expression of CRH in MPTP-mice. The results indicate that the DAergic afferents from VTA enhance excitatory-dependent activation of GABAergic neurons in dlBNST, which suppress the activity of the HPA-axis.

The Neural Response of Deep Brain Structures to Odorant Stimulations: A Manganese-Enhanced MRI Study

An increased understanding of how odors are processed in the central nervous system may provide comprehensive information about the neural basis of odor-related behavior and learning. In this study, we investigated how different odors are processed from the olfactory bulb to the deep cerebral structures through various olfactory pathways. To do this, we employed a novel manganese-enhanced magnetic resonance imaging (MEMRI) method to map the activity-dependent functional connectivity of the olfactory and non-olfactory pathways associated with various odorants. Our MEMRI data revealed odor-specific neural pathways that correspond to different odorant stimulations, suggesting that different neural circuits may process different odorants. Among the odorants tested, formic acid, an alarm pheromone, stimulated not only the primary and secondary olfactory pathways but also the mesolimbic neural circuit, which overlaps with the dopaminergic neural pathway. Linalool, which is a major component of aroma oils, showed high Mn2+ uptake in the hypothalamus, which plays a role in the stress response through the secretion of corticotropin-releasing hormone (CRH), and consequently, the stimulation of corticotropin secretion. Acetone mainly activated the primary olfactory pathway, whereas saline acted as a non-odorous trigeminal stimulus. Taken together, our functional MEMRI using anatomic standardization and statistical analyses could be a promising in vivo imaging method to map neural connectivity, enabling further understanding of the neural processing of different odorants.

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder.

The mood disorders, major depression (MD) and bipolar disorder (BD), have a high lifetime prevalence in the human population and accordingly generate huge costs for health care. Efficient, rapidly acting, and side-effect-free pharmaceuticals are hitherto not available, and therefore, the identification of new therapeutic targets is an imperative task for (pre)clinical research. Such a target may be the purinergic P2X7 receptor (P2X7R), which is localized in the central nervous system (CNS) at microglial and neuroglial cells mediating neuroinflammation. MD and BD are due to neuroinflammation caused in the first line by the release of the pro-inflammatory cytokine interleukin-1β (IL-1β) from the microglia. IL-1β in turn induces the secretion of corticotropin-releasing hormone (CRH) and in consequence the secretion of adrenocorticotropic hormone (ACTH) and cortisol, which together with a plethora of further cytokines/chemokines lead to mood disorders. A number of biochemical/molecular biological measurements including the use of P2X7R- or IL-1β-deficient mice confirmed this chain of events. More recent studies showed that a decrease in the astrocytic release of ATP in the prefrontal cortex and hippocampus is a major cause of mood disorders. It is an attractive hypothesis that compensatory increases in P2X7Rs in these areas of the brain are the immediate actuators of MD and BD. Hence, blood-brain barrier-permeable P2X7R antagonists may be promising therapeutic tools to improve depressive disorders in humans.

Intermittent hypobaric hypoxia and neuroendocrine reaction of the parvocellular neurons of the paraventricular hypothalamic nucleus

The neuroendocrine system occupies an important place in the systemic mechanisms of the body response to stress. The paraventricular nuclei of the hypothalamus (PVH) are one of the most important links of the brain`s neuroendocrine system which determine the reactivity of the hypothalamic-pituitary-adrenal axis (HPA) in response to the various stressors and thereby ensure the development of adaptive reactions by the formation of body resistance to the stress. The aim of the research was to study the functional state of the peptidergic neurons of the medial parvocellular nuclei of the paraventricular hypothalamic nucleus (PVHmp) during the multi-day action of intermittent hypobaric hypoxia and in the posthypoxic period. Materials and methods. The research was conducted on 24 male Wistar rats. Intermittent hypoxia was modeled by a daily 6-hour stay of rats at an altitude of 6000 m (pO 2 = 9.8 %) for 15 days, the posthypoxic period lasted for 10 days. The distribution of corticotropin-releasing hormone (CRH), [Arg 8 ]-vasopressin (AVP), β-endorphin, cFos and HIF-1α proteins was studied by quantitative immunofluorescence methods in serial frontal sections of the hypothalamus. Results. The intermittent hypobaric hypoxia stimulated the developing of mild hypertrophy of PVHmp neurons and increased the concentration of RNA in the cytoplasm by 37 %. An indicator of PVHmp neurons response to hypoxia was 2.5-fold increase in the concentration of the HIF-1α protein in them. IHH elevated the concentration of cFos protein in PVHmp by 37 %, increased the area of immunoreactivity to AVP by 2.5 times, to CRH and β-endorphin by 3 times. There was an increase in the synthesis of neuropeptides in response to hypoxia, which led to the elevation in the concentration of AVP in PVHmp by 6.6 times, β-endorphin by 7 times, and CRH by 8.5 times. The immunoreactivity indicators for the HIF-1α protein and its concentration in PVHmp remained at a high level in the posthypoxic period. At the same time, high immunoreactivity to CRH and β-endorphin in PVHmp was noted, as well as a high concentration of these neuropeptides in neurons against the background of AVP synthesis inhibition in neurons. It is possible that high rates of neurosecretory activity of PVHmp in the posthypoxic period may indicate the formation of neuroendocrine mechanisms of adaptation of the HPA axis to the long-term effect of hypoxia. Conclusions. Intermittent hypobaric hypoxia stimulates the neurosecretory activity of the PVHmp neurons, increases the synthesis and secretion of CRH and AVP hormones that activate the HPA axis. Synthesis of the secretory response indicator cFos protein and a central regulator of hypoxic responses HIF‑1α protein is also increasing in the peptidergic neurons of the PVHmp. High levels of the PVHmp neurosecretory activity at the posthypoxic period are preserved and indicate the formation of neuroendocrine mechanisms of the HPA axis adaptation to the long term intermittent hypoxia exposures.

Hyponatremia in a Patient With Cancer

Hyponatremia in a Patient With Cancer

Особенности функционального состояния гипоталамо-гипофизарно-адренокортикальной системы у крыс линии Крушинского–Молодкиной

The aim of present work was to evaluate functional state of the hypothalamic–pituitary–adrenal axis (HPA) in both naive control Wistar rats and Krushinsky-Molodkina (KM) rats, genetically prone to audiogenic epilepsy, and analyzed the changes of activity of HPA in KM rats during and after expression of audiogenic seizure (AGS). Obtained data demonstrated that the activity of corticotropin-releasing hormone (CRH) neurons in KM rats was reduced, due to the increased inhibitory effect of GABAergic neurons. In the anterior pituitary, we observed accumulation of proopiomelanocortin and adrenocorticotropic hormone (ACTH). However, basal levels of ACTH and corticosterone were equal in the blood in both naive KM rats and Wistar rats. Thus, the data indicate the disturbances in the interaction between the hypothalamus and the pituitary gland in KM rats, which can be one of the regulatory mechanisms for maintaining hormone concentrations in the blood. Analysis of AGS effects on HPA demonstrated increasing secretion of CRH and vasopressin into the portal system of KM rats and ACTH in the blood at clonus-tonus stages, which expresses in 6-10 seconds after sound stimulation. Therein corticosterone level was increased in KM rats during 24 hours. In Wistar rats, the sound stimulation did not change the levels of ACTH and corticosterone in the blood. Thus, we demonstrated specific activation of HPA in KM rats by AGS as a result of epileptiform activity overspreading in the brain that revealed participation of HPA is the expression of seizure activity.

Endocannabinoid hydrolase and cannabinoid receptor 1 are involved in the regulation of hypothalamus-pituitary-adrenal axis in type 2 diabetes.

Hypothalamus-pituitary-adrenal (HPA) axis, as the key moderator in energy metabolism, plays an important role in diabetes. The endogenous cannabinoid system (eCBs) involves in neuronal functions, and simultaneously cannabinoid receptors are almost expressed in all regions of the hypothalamus according to a spate of reports. However, few data investigate the changes of eCBs and HPA axis in type 2 diabetes. In this study, five diabetes mellitus rhesus monkeys, five prediabetes rhesus monkeys and five healthy rhesus monkeys were observed. In the present study, we detected cell swelling and necrosis extensively in the paraventricular nucleus (PVN) and neurohypophysis in prediabetes and overt diabetes monkeys. The adrenocorticotropic hormone in the pituitary gland, adrenocorticotropic hormone receptor, and 11β-hydroxysteroid dehydrogenase in the adrenal gland were all hyper-secreted and expressed from healthy to overt diabetes. Meanwhile, the cortisol concentration in the adrenal gland was increased along with the progress of diabetes. It could be concluded that hyperfunction of the HPA axis exists in the type 2 Diabetes pathogenesis. However, we also found a weakened expression and secretion of corticotrophin releasing hormone and glucocorticoids receptor in PVN. The expression of corticotropin releasing hormone receptor 1 in pituitary gland decreased in prediabetes monkeys, but increased in overt diabetes monkeys. The downregulation of cannabinoid receptor 1 and upregulation of monoglycerol lipase and fatty acid amide hydrolase in PVN was involved in the pathogenesis of type 2 diabetes. Collectively, we can conclude that changes in endocannabinoid hydrolase and cannabinoid receptor might indicate the effect of downregulation of eCBs. It can be assumed that hyper-function of the HPA axis from healthy to overt diabetes is due to the undermining inhibition of eCBs. However, the regulatory mechanism of eCBs targets on the HPA axis need to be further explored.

Neuroendocrine responses to early life stress and trauma and susceptibility to disease

ABSTRACTThe term ‘early life stress’ has been used to describe a broad spectrum of adverse exposures during foetal life, childhood and adolescence. Early life stress and trauma are associated with a higher risk for later mental and physical health disorders, such as anxiety, depression, and post-traumatic stress disorder (P.T.S.D.) as well as cardiometabolic and inflammatory diseases and chronic pain syndromes. The objective of this brief review is to investigate the neuroendocrine responses to early life stress and their role as biological predisposing factors for later disease.Stress-related neuroendocrine alterations in response to early adversity include hyper- or hypo-activation of the stress system and may persist or worsen in later life, acting as biological vulnerability factors for the development of later disease. A key effect of stress during foetal life, childhood, and adolescence is that it programmes the developing brain, especially brain structures involved in stress reactions, such as the prefrontal cortex, the hippocampus, and the amygdala, to hyper- or hypo-react to ensuing stressors. Animal studies have shown that chronically elevated stress mediators may lead to alterations in brain development through mechanisms of accelerated loss of neurons, delays in myelination, or abnormalities in developmentally appropriate neural synaptic pruning. Critical periods of brain development represent time-windows of elevated synaptic plasticity, mediating vulnerability, or establishing resilience to stress.Stress is generally associated with acute activation of the hypothalamic-pituitary-adrenal (H.P.A.) axis and the arousal/sympathetic nervous system, as evidenced, in most studies, by elevated cortisol and catecholamine concentrations in the periphery. However, the chronic and/or intense experience of stress may be associated with chronic hyper- or hypo-activation of mediators of the stress system. This chronic condition represents dyshomeostasis, also called allostasis or cacostasis, which is related to further morbidity, such as obesity and the metabolic syndrome, diabetes mellitus type 2, atherosclerosis, osteoporosis, and immune dysfunction (Pervanidou & Chrousos, 2012).P.T.S.D., the most common stress-related disorder, is typically associated with increased secretion of corticotropin-releasing hormone centrally, with paradoxically decreased cortisol secretion peripherally, and elevated circulating catecholamine concentrations. Stress-related neuroendocrine alterations during early life might result in conditions characterized by chronic hypo-activation of the H.P.A. axis, as typically observed in P.T.S.D. and atypical depression. Scarce data exist on the longitudinal course of P.T.S.D. development and maintenance, beginning from the exposure to the traumatic event. We investigated the natural history of neuroendocrine changes in relation to P.T.S.D. development in children and adolescents experiencing a motor vehicle accident. This longitudinal study provided evidence for an initial elevation of evening salivary cortisol and an alteration in cortisol circadian secretion in response to the experience of an intense stressor. This initial alteration was followed by a gradual normalization of cortisol with time, leading potentially to decreased cortisol concentrations in the periphery, months or years after the traumatic exposure. At the same time, a progressive elevation of circulating norepinephrine (N.E.) was noted in children that continued to exhibit P.T.S.D. This longitudinal interaction of peripheral cortisol and NE concentrations seems to characterize those that develop and maintain P.T.S.D. (Pervanidou et al., 2007). Thus, low cortisol, together with high N.E. concentrations, that characterize adult P.T.S.D., may be the end stage of the disorder. These data are also in accordance with findings in adults, showing hypocortisolism in the aftermath of a stressful experience to predict P.T.S.D. development.Several parameters affect the direction of the H.P.A. axis (increased or decreased cortisol production) in P.T.S.D., and among them, previous trauma and time since the trauma occurred seem to be crucial determinants of hyper- or hypo- activation of the H.P.A. axis. Other parameters include: genetic and epigenetic vulnerability; transgenerational actions; environmental influences in the management of early life stress; the nature, severity, and duration of the traumatic event; the developmental stage, age at the time of trauma; and comorbidities (Pervanidou, 2008).In conclusion, early life stress exposures result in neuroendocrine alterations and programming of the neuronal networks of the brain, acting as predisposing factors for further mental and physical health problems.