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Nerve terminals are the final point of regulation before neurosecretion. As such, neuromodulators acting on nerve terminals can exert significant influence on neural signaling. Hypothalamic corticotropin-releasing hormone (CRH) neurons send axonal projections to the median eminence where CRH is secreted to stimulate the hypothalamic-pituitary-adrenal (HPA) axis. Noradrenaline and corticosterone are two of the most important neuromodulators of HPA axis function; noradrenaline excites CRH neurons and corticosterone inhibits CRH neurons by negative feedback. Here, we used GCaMP6f Ca2+ imaging and measurement of nerve terminal CRH secretion using sniffer cells to determine whether these neuromodulators act directly on CRH nerve terminals in male mice. Contrary to expectations, noradrenaline inhibited action potential-dependent Ca2+ elevations in CRH nerve terminals and suppressed evoked CRHsecretion. This inhibitory effect was blocked by a2-adrenoreceptor antagonism. Corticosterone also suppressed evoked CRH peptide secretion from nerve terminals, independent of action potential-dependent Ca2+ levels. This inhibition was prevented by the glucocorticoid receptor antagonist, RU486, and indicates that CRH nerve terminals may be a site of fast glucocorticoid negative feedback. Together these findings establish median eminence nerve terminals as a key site for regulation of the HPA axis. [ABSTRACT FROM AUTHOR]

Background: Stress is an aversive stimulus that disrupts the organism's biological balance. Formononetin, an isoflavone, has been implicated in anxiolytic responses. However, the intra-hypothalamic molecular mechanisms by which formononetin controls stress remain unknown. Objectives: This study aimed to investigate the impact of formononetin on hypothalamic Mch and Crh gene expression in a rat model of stress. Methods: Male Wistar rats (200 - 220 g) were used. Thirty minutes before exposure to stress, the rats were injected with either saline or formononetin. Two hours after stress induction, hypothalamic samples were dissected and stored at -70°C until the measurement of Mch and Crh gene expression using real-time PCR. Results: Stress induction led to a significant increase in Mch and Crh mRNA levels. However, animals receiving formononetin showed a significant reduction in Mch and Crh mRNA levels compared to the stressed rats. Conclusions: Formononetin may exert anxiolytic effects by down-regulating intra-hypothalamic CRH and MCH signaling pathways. [ABSTRACT FROM AUTHOR]

Introduction: To investigate whether synthetic (s) glucocorticoids (GCs) administered between the 24th and the 34th gestational weeks in pre-term labor might precipitate labor, studies on sGCs administration were reviewed. The physiology of endogenous glucocorticoid-related increase in fetal–maternal circulation and its association with labor, followed by a scoping review of studies on exogenous sGCs administered for fetal lung maturation and the timing of labor, were included. Materials and methods: The methodology of systematic reviews was followed. MEDLINE, Cochrane Library, and Google Scholar databases were searched until October 2023, for original studies investigating the administration of sGCs in pregnancies risking pre-term labor. Duplicates were removed, and 1867 abstracts were excluded as irrelevant. Six controlled and four non-controlled studies were included. The index group consisted of 6001 subjects and 7691 controls in the former, while in the latter, the index group consisted of 2069 subjects. Results: In three out of the six controlled studies, gestational age at labor was significantly lower in sGC-treated women than in controls, while in three studies, gestational age at labor was lower in sGC-treated women than in controls, with a trend toward statistical significance. In one study, gestational age at labor was significantly lower in controls than in sGC-treated women. In the non-controlled studies, the majority of women delivered less than 1 week from the day of sGC administration. Conclusions: In this scoping review, studies lack homogeneity. However, in the controlled studies, a pattern of earlier labor emerges among sGC-treated pregnant women. The use of multiple courses of antenatal sGCs appears to be associated with precipitated labor. Their use should be carefully weighed. Carefully designed trials should examine this ongoing scientific query.

Rationale: Alcohol consumption despite negative consequences is a core symptom of Alcohol Use Disorder. In animal models, this is studied by pairing aversive stimuli with alcohol access, and continuation of drinking under these conditions is known as aversion resistance. Previously, we found that female mice are more aversion resistant than males. Corticotropin releasing hormone (Crh) and the Crh receptor 1 (Crhr1) regulate stress-induced reinstatement, alcohol dependence, and binge-like drinking. However, the role of the Crh system in aversion resistance has not been assessed. Objectives: We aimed to identify sex differences in the Crh system during quinine-adulterated alcohol intake. Methods: We used two-bottle choice and adulterated the alcohol solution with quinine. Next, we measured Crh and Crhr1 levels in brain tissue using real-time polymerase chain reaction (RT-qPCR) and RNAscope in situ hybridization. We then infused a Crhr1 antagonist into the medial prefrontal cortex (mPFC) prior to quinine-alcohol intake. Results: After quinine-alcohol consumption, females exhibited increased mPFC Crhr1 mRNA levels as measured by RT-qPCR. This was confirmed with greater anatomical specificity using RNAscope, with females exhibiting an increased number of Crhr1 + cells in the dorsomedial PFC and the ventromedial PFC. mPFC Crhr1 antagonist treatment reduced quinine-alcohol consumption in females but did not impact consumption in males. Quinine-free alcohol intake was unaffected by Crhr1 antagonist treatment. Conclusions: Our findings suggest that Crhr1 in mPFC plays a role in aversion resistant alcohol intake in females. Future experiments will examine the sources of Crh innervation to the mPFC and their distinct roles in alcohol seeking. [ABSTRACT FROM AUTHOR]

Research confirms that stress is associated with alcohol drinking and relapse in males and females and that there are sex differences in the alcohol-related adaptations of stress pathways. The predator stress (PS) model of traumatic stress produces an increase in alcohol drinking or self-administration in a subpopulation of rodents, so it is utilized as an animal model of comorbid alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD). Previous work determined that sensitivity to PS-enhanced drinking produced sex differences in proteins related to stress-regulating systems in the medial prefrontal cortex and hippocampus. The present studies examined whether male and female C57BL/6J mice differ in sensitivity to the ability of the corticotropin releasing factor receptor 1 antagonist CP-376395 to decrease PS-enhanced drinking. In control studies, CP-376395 doses of 5, 10, and 20 mg/kg dose-dependently decreased 4-h ethanol drinking. Next, CP-376395 doses of 5 and 10 mg/kg were tested for effects on ethanol drinking in mice with differential sensitivity to PS-enhanced drinking. Subgroups of "Sensitive" and "Resilient" male and female mice were identified based on changes in ethanol intake in an unrestricted-access ethanol-drinking procedure following four exposures to PS (dirty rat bedding). During the first 2 h post-injection of CP-376395, both doses significantly decreased ethanol licks versus vehicle in the females, with no significant interaction between subgroups, whereas the 10 mg/kg dose significantly decreased ethanol licks versus vehicle in the "Resilient" males. Thus, sensitivity to the suppressive effect of CP-376395 on stress-induced ethanol intake was greater in females versus males, whereas sensitivity and resilience to PS-enhanced drinking produced differential sensitivity to the ability of CP-376395 to decrease ethanol drinking only in male mice. Our results argue against greater efficacy of CRF-R1's ability to decrease ethanol intake in subjects with traumatic stress-enhanced ethanol drinking. • CRF-R1 antagonist CP-376395 decreased alcohol intake in control male and female mice. • This decrease was less alcohol-selective in male than in female mice. • CP-376395 decreased alcohol intake in female mice following repeated predator stress. • CP-376395 decreased such intake only in males resistant to stress-enhanced drinking. • Predator stress-enhanced alcohol drinking does not increase CRF-R1 sensitivity. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) is a common endocrine disorder and a leading cause of infertility in women. Studies suggest that naringenin may improve ovarian function; however, its molecular mechanism within the hypothalamus-pituitary-gonad (HPG) axis remains unclear. Objectives: This study investigated the role of naringenin on the expression of corticotropin-releasing hormone (CRH) and nesfatin-1 genes in the hypothalamus of PCOS rats. Methods: Twenty rats, each weighing 180 - 200 g, were divided into four groups (n = 5). Polycystic ovary syndrome was induced by administering estradiol valerate (2 mg per rat). The control and PCOS groups received saline, while the other two PCOS groups received intraperitoneal injections of naringenin at doses of 20 and 50 mg/kg for 14 days. Hypothalamic samples were collected to measure gene expression via real-time PCR. Results: The PCOS group showed a significant decrease in CRH and nesfatin-1 gene expression compared to the control group (P ≤ 0.05). Naringenin treatment significantly increased the expression of CRH and nesfatin-1 genes in comparison to the PCOS group (P ≤ 0.05). Conclusions: Naringenin appears to have therapeutic potential in improving ovarian function in PCOS. Its effects are mediated through up-regulation of hypothalamic neuropeptides upstream of GnRH neurons. [ABSTRACT FROM AUTHOR]

A large body of evidence indicates that vasopressin (AVP) and steroid hormones are frequently secreted together and closely cooperate in the regulation of blood pressure, metabolism, water–electrolyte balance, and behavior, thereby securing survival and the comfort of life. Vasopressin cooperates with hormones of the hypothalamo–pituitary–adrenal axis (HPA) at several levels through regulation of the release of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and multiple steroid hormones, as well as through interactions with steroids in the target organs. These interactions are facilitated by positive and negative feedback between specific components of the HPA. Altogether, AVP and the HPA cooperate closely as a coordinated functional AVP-HPA system. It has been shown that cooperation between AVP and steroid hormones may be affected by cellular stress combined with hypoxia, and by metabolic, cardiovascular, and respiratory disorders; neurogenic stress; and inflammation. Growing evidence indicates that central and peripheral interactions between AVP and steroid hormones are reprogrammed in cardiovascular and metabolic diseases and that these rearrangements exert either beneficial or harmful effects. The present review highlights specific mechanisms of the interactions between AVP and steroids at cellular and systemic levels and analyses the consequences of the inappropriate cooperation of various components of the AVP-HPA system for the pathogenesis of cardiovascular and metabolic diseases. [ABSTRACT FROM AUTHOR]

Suppression of the hypothalamic–pituitary–adrenal (HPA) axis is a well‐characterised maternal adaptation that limits the exposure of the offspring to maternally‐derived stress hormones. This current study has investigated the possible involvement of the lactogenic hormone, prolactin, in this physiologically important adaptation. As expected, circulating prolactin levels were higher in unstressed lactating mice compared to their virgin counterparts. Interestingly however, the ability of an acute period of restraint stress to further elevate prolactin levels was diminished in the former group. The stress‐induced rise in prolactin levels in the virgin animals was concurrent with an increase in prolactin receptor activation within the adrenal cortical cells. This adrenal response was not seen in either the stressed or control lactation group, an observation that may be in part explained by the observed downregulation of prolactin receptor mRNA expression within this tissue. Further evidence of suppression of the HPA axis during lactation was revealed using in situ hybridisation to demonstrate that while acute restraint stress increased corticotrophin releasing hormone (CRH) mRNA expression in the hypothalamic paraventricular nucleus in both virgin and lactating mice, the magnitude of this response was reduced in the latter group. This potentially adaptive response did not, however, appear to result from the altered prolactin profile during lactation because it was not affected by the pharmacological suppression of prolactin secretion from the pituitary. This study therefore suggests that during lactation the response of the HPA axis to stress is suppressed at multiple physiological levels which are mediated by both prolactin‐dependent and prolactin‐independent mechanisms. [ABSTRACT FROM AUTHOR]

Cushing's syndrome (CS) is a rare disorder, once exogenous causes have been excluded. However, when diagnosed, the majority of cases are adrenocorticotropic hormone (ACTH)‐dependent, of which a substantial minority are due to a source outside of the pituitary, ectopic ACTH syndrome (EAS). Differentiating among pituitary‐dependent CS, Cushing's disease (CD) and an ectopic source can be problematic. Because non‐invasive tests in the evaluation of CS patients often lack adequate sensitivity and specificity, bilateral inferior petrosal sinus sampling (BIPSS), a minimally invasive procedure performed during the investigation of ACTH‐dependent CS, can be extremely helpful. BIPSS is considered to be the gold standard for differentiating CD from the EAS. Furthermore, although such differentiation may indeed be challenging, BIPSS is itself a complex investigation, especially in recent times due to the widespread withdrawal of corticotrophin‐releasing hormone and its replacement by desmopressin. We review current published data on this investigation and, in the light of this and our own experience, discuss its appropriate use in diagnostic algorithms. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) increases the risk of type 2 diabetes (T2D) by 60% in untreated patients, and hypercortisolism is common in MDD as well as in some patients with T2D. Patients with MDD, despite hypercortisolism, show inappropriately normal levels of corticotropin-releasing hormone (CRH) and plasma adrenocorticotropin (ACTH) in the cerebrospinal fluid, which might implicate impaired negative feedback. Also, a positive feedback loop of the CRH–norepinephrine (NE)–CRH system may be involved in the hypercortisolism of MDD and T2D. Dysfunctional CRH receptor 1 (CRHR1) and CRH receptor 2 (CRHR2), both of which are involved in glucose regulation, may explain hypercortisolism in MDD and T2D, at least in a subgroup of patients. CRHR1 increases glucose-stimulated insulin secretion. Dysfunctional CRHR1 variants can cause hypercortisolism, leading to serotonin dysfunction and depression, which can contribute to hyperglycemia, insulin resistance, and increased visceral fat, all of which are characteristics of T2D. CRHR2 is implicated in glucose homeostasis through the regulation of insulin secretion and gastrointestinal functions, and it stimulates insulin sensitivity at the muscular level. A few studies show a correlation of the CRHR2 gene with depressive disorders. Based on our own research, we have found a linkage and association (i.e., linkage disequilibrium [LD]) of the genes CRHR1 and CRHR2 with MDD and T2D in families with T2D. The correlation of CRHR1 and CRHR2 with MDD appears stronger than that with T2D, and per our hypothesis, MDD may precede the onset of T2D. According to the findings of our analysis, CRHR1 and CRHR2 variants could modify the response to prolonged chronic stress and contribute to high levels of cortisol, increasing the risk of developing MDD, T2D, and the comorbidity MDD-T2D. We report here the potential links of the CRH system, NE, and their roles in MDD and T2D. [ABSTRACT FROM AUTHOR]

Corticotropin-releasing factor family peptides (CRF peptides) comprise corticotropin releasing hormone (CRH), urocortin (UCN1), UCN2 and UCN3. CRH is first isolated in the brain and later with UCNs found in many peripheral cells/tissues including the colon. CRH and UCNs function via the two types of receptors, CRF1 and CRF2, with CRH mainly acting on CRF1, UCN1 on both CRF1 &CRF2 and UCN2-3 on CRF2. Compiling evidence shows that CRH participates in inflammation and cancers via both indirect central effects related to stress response and direct peripheral influence. CRH, as a stress-response mediator, plays a significant central role in promoting the development of colitis involving colon motility, immunity and gut flora, while a few anti-colitis results of central CRH are also reported. Moreover, CRH is found to directly influence the motility and immune/inflammatory cells in the colon. Likewise, CRH is believed to be greatly related to tumorigenesis of many kinds of cancers including colon cancer via the central action during chronic stress while the peripheral effects on colitisassociated-colon cancer (CAC) are also proved. We and others observe that CRH/CRF1 plays a significant peripheral role in the development of colitis and CAC in that CRF1 deficiency dramatically suppresses the colon inflammation and CAC. However, up to date, there still exist not many relevant experimental data on this topic, and there seems to be no absolute clearcut between the central and direct peripheral effects of CRH in colitis and colon cancer. Taken together, CRH, as a critical factor in stress and immunity, may participate in colitis and CAC as a centrally active molecule; meanwhile, CRH has direct peripheral effects regulating the development of colitis and CAC, both of which will be summarized in this review. [ABSTRACT FROM AUTHOR]

Background: Chrysin is a natural flavonoid with several demonstrated neuro-pharmacological effects in brain areas related to anxiety. However, the intra-hypothalamic molecular mechanisms underlying the anxiolytic effects of chrysin remain unclear. Objectives: The current study revealed the effects of chrysin on hypothalamic corticotrophin-releasing hormone (CRH) and calcitonin gene-related peptide (CGRP) gene expression levels in a rat model of stress. Methods: Thirty male Wistar rats weighing 200 ± 10 g were divided into six groups for this investigation. Acute restraint stress was induced in the animals for 2 hours. Intact or stress-induced rats received 20 or 40 µg of chrysin via the third cerebral ventricle, respectively. Open-field and forced swimming tests were performed to evaluate stress-related behaviors. Hypothalamic samples were then removed, and real-time polymerase chain reaction (PCR) was used to measure relative gene expression. Results: The results showed that in the rats receiving chrysin, CRH and CGRP gene expression levels were significantly decreased compared to the stress group. Additionally, chrysin injection reduced anxiogenic behaviors. Conclusions: Chrysin decreased the expression of hypothalamic CRH and CGRP genes in stressed rats. [ABSTRACT FROM AUTHOR]

Urocortin 3 (UCN3) is a peptide hormone expressed in pancreatic islets of Langerhans of both human alpha and human beta cells and solely in murine beta cells. UCN3 signaling acts locally within the islet to activate its cognate receptor, corticotropin releasing hormone receptor 2 (CRHR2), which is expressed by delta cells, to potentiate somatostatin (SST) negative feedback to reduce islet cell hormone output. The functional importance of UCN3 signaling in the islet is to modulate the amount of SST tone allowing for finely tuned regulation of insulin and glucagon secretion. UCN3 signaling is a hallmark of functional beta cell maturation, increasing the beta cell glucose threshold for insulin secretion. In doing so, UCN3 plays a relevant functional role in accurately maintaining blood glucose homeostasis. Additionally, UCN3 acts as an indicator of beta cell maturation and health, as UCN3 is not expressed in immature beta cells and is downregulated in dedifferentiated and dysfunctional beta cell states. Here, we review the mechanistic underpinnings of UCN3 signaling, its net effect on islet cell hormone output, as well as its value as a marker for beta cell maturation and functional status.

The aim of this systematic review is to investigate the impact of corticotropin-releasing hormone (CRH) family peptides and their corresponding receptors on human physiology and disease onset, with a specific focus on gynaecological malignancies such as breast, endometrial, ovarian, vulvar, and cervical cancer. A comprehensive systematic review of 3 medical databases was conducted by 2 independent reviewers. We reviewed studies that explored the expression and role of CRH peptides in various aspects of cancer biology, in the context of breast, endometrial, ovarian, vulvar, and cervical cancer. Our findings reveal that CRH family peptides and their receptors, CRHR1 and CRHR2, are expressed in diverse gynaecological tissues, including cancer cells. Notably, we observed differential expression patterns among different gynaecological cancer types and stages, indicating potential associations with tumour aggressiveness and patient prognosis. Furthermore, CRH peptides were found to exert significant influences on critical cellular processes, such as cell proliferation, migration, invasion, and immune response, in gynaecological cancers. These findings highlight the multifaceted roles of CRH family peptides in gynaecological malignancies and emphasize the need for further research in this field. Therefore, understanding the mechanisms underlying the involvement of CRH family peptides in tumourigenesis may open new avenues for targeted therapeutic strategies in gynaecological malignancies.

Background Preterm birth before 37 th wk of gestation is called premature birth. Corticotropin-releasing hormone (CRH) and CRH-binding protein (BP) act on various maternal and fetal tissues during pregnancy, such as the myometrium, which regulates the transition from the dormant phase of the uterus to the active phase. Studies have shown that mir-200c and mir-181a interact with CRH and CRH-BP. Objective The present study aimed to investigate the expression of mir-200c, mir-181a, CRH, and CRH-BP in women with a history of preterm birth. Materials and Methods In this case-control study, the gene expression level of mir-200c, mir-181a, CRH, and CRH-BP in placental tissue samples obtained from 48 women with a history of preterm labor was assessed in the Mojibian hospital of Yazd, Iran, from January to March 2023. Differences between mir-200c, mir-181a CRH, and CRH-BP gene expressions among cases and controls were assessed. Results The outcomes indicated that the expression of CRH increased with going on to the regular parturition time (p < 0.001). While outcomes indicated, CRH-BP decreased with going on to the regular parturition time (p < 0.001). In addition, the results showed that the expression of mir-181a increased and mir-200c decreased with approaching the normal delivery time (p < 0.001). Conclusion In conclusion, the expressions of mir-200c, mir-181a, CRH, and CRH-BP were dissimilar in different weeks of gestation. It could be proposed to use mir-200c, mir-181a, CRH, and CRH-BP as biomarkers to weigh the exact delivery time, which could minimize the side effects of preterm labor for the mother and fetus.

Background: Different types of stress inflicted in early stages of life elevate the risk, among adult animals and humans, to develop disturbed emotional-associated behaviors, such as hyperphagia or depression. Early-life stressed (ELS) adults present hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis, which is a risk factor associated with mood disorders. However, the prevalence of hyperphagia (17%) and depression (50%) is variable among adults that experienced ELS, suggesting that the nature, intensity, and chronicity of the stress determines the specific behavioral alteration that those individuals develop. Methods: We analyzed corticosterone serum levels, Crh, GR, Crhr1 genes expression in the hypothalamic paraventricular nucleus, amygdala, and hippocampus due to their regulatory role on HPA axis in adult rats that experienced maternal separation (MS) or limited nesting material (LNM) stress; as well as the serotonergic system activity in the same regions given its association with the corticotropin-releasing hormone (CRH) pathway functioning and with the hyperphagia and depression development. Results: Alterations in dams' maternal care provoked an unresponsive or hyper-responsive HPA axis function to an acute stress in MS and LNM adults, respectively. The differential changes in amygdala and hippocampal CRH system seemed compensating alterations to the hypothalamic desensitized glucocorticoids receptor (GR) in MS or hypersensitive in LNM. However, both adult animals developed hyperphagia and depression-like behavior when subjected to the forced-swimming test, which helps to understand that both hypo and hypercortisolemic patients present those disorders. Conclusion: Different ELS types induce neuroendocrine, brain CRH and 5-hydroxytriptamine (5-HT) systems' alterations that may interact converging to develop similar maladaptive behaviors. [ABSTRACT FROM AUTHOR]

Background: Insulin-like growth factor-1 (IGF-1) is involved in the pathology of non-alcoholic fatty liver disease (NAFLD) and ameliorates fatty infiltration in the liver. It is activated by growth hormone (GH); however, the role of GH–IGF-1 axis in NAFLD developmental phase has not been well identified. Therefore, in this study, we focused on the effect of IGF-1 in NAFLD pathology and GH excretion activation from the pituitary gland by peripheral autonomic neural pathways relaying liver–brain–gut pathway and by central neuropeptides. Methods: GH and IGF-1 levels were assessed in wild-type and melanocortin-4 receptor knockout mice upon the development of diet-induced NAFLD. The contribution of the peripheral autonomic nervous system connecting the liver–brain–gut axis was assessed by its blockade using capsaicin and that of the central nervous system was assessed by the expression of hypothalamic brain-derived neurotrophic factor (BDNF) and corticotropin-releasing factor (CRH), which activates GH release from the pituitary gland. Results: In the NAFLD mouse models, the levels of GH and IGF-1 increased (p <.05). Further, hepatic fatty infiltration was suppressed even under peripheral autonomic nervous system blockade (p <.001), which inhibited gastric ghrelin expression. In mice with peripheral autonomic nervous blockade, hypothalamic BDNF and CRH were inhibited (p <.05), resulting in GH and IGF-1 excretion, whereas other neuropeptides of somatostatin and cortistatin showed no changes. These complementary effects were canceled in melanocortin-4 receptor knockout mice, which diminished BDNF and CRH release control. Conclusions: Our study demonstrates that the release of IGF-1 by the nervous system is a key factor in maintaining the pathological homeostasis of NAFLD, suggesting its therapeutic potential. [ABSTRACT FROM AUTHOR]

Introduction: The impact of stress on reproductive function is significant. Hypothalamic paraventricular nucleus (PVN) corticotrophin-releasing hormone (CRH) plays a major role in regulating the stress response. Understanding how the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitarygonadal (HPG) axis interact is crucial for comprehending how stress can lead to reproductive dysfunction. However, whether stress influences reproductive function via modulating PVN CRH or HPA sequelae is not fully elucidated. Methods: In this study, we investigated the impact of chemogenetic activation of PVN CRH neurons on reproductive function. We chronically and selectively stimulated PVN CRH neurons in female CRH-Cre mice using excitatory designer receptor exclusively activated by designer drugs (DREADDs) viral constructs, which were bilaterally injected into the PVN. The agonist compound-21 (C21) was delivered through the drinking water. We determined the effects of DREADDs activation of PVN CRH neurons on the estrous cycles, LH pulse frequency in diestrus and metestrus and LH surge in proestrus mice. The effect of long-term C21 administration on basal corticosterone secretion and the response to acute restraint stress during metestrus was also examined. Additionally, computer simulations of a mathematical model were used to determine the effects of DREADDs activation of PVN CRH neurons, simulating chronic stress, on the physiological parameters examined experimentally. Results: As a result, and consistent with our mathematical model predictions, the length of the estrous cycle was extended, with an increase in the time spent in estrus and metestrus, and a decrease in proestrus and diestrus. Additionally, the frequency of LH pulses during metestrus was decreased, but unaffected during diestrus. The occurrence of the preovulatory LH surge during proestrus was disrupted. The basal level of corticosterone during metestrus was not affected, but the response to acute restraint stress was diminished after long-term C21 application. Discussion: These data suggest that PVN CRH neurons play a functional role in disrupting ovarian cyclicity and the preovulatory LH surge, and that the activity of the GnRH pulse generator remains relatively robust during diestrus but not during metestrus under chronic stress exposure in accordance with our mathematical model predictions. [ABSTRACT FROM AUTHOR]

Background: Melatonin is a key hormone in regulation of circadian rhythms, and involved in many rhythmic functions, such as feeding and locomotor activity. Melatonin reportedly counteracts stress responses in many vertebrates, including fish. However, targets for this action of melatonin and underlying mechanisms remain unknown. Results: This study reports potential anti-stress properties of melatonin in goldfish (Carassius auratus), with a focus on its effect on plasma cortisol, food intake, and locomotor activity, all of them involved in the responses to stress exposure. Indeed, acute injection of melatonin counteracted stress-induced hypercortisolinemia and reduced food intake. The reduced locomotor activity following melatonin treatment suggests a possible sedative role in fish. To assess whether this anti-stress effects of melatonin involve direct actions on interrenal tissue, in vitro cultures of head kidney (containing the interrenal cortisolproducing tissue) were carried out in presence of ACTH, melatonin, and luzindole, an antagonist of melatonin receptors. Melatonin in vitro reduced ACTH-stimulated cortisol release, an effect attenuated by luzindole; this suggests the presence of specific melatonin receptors in interrenal tissue. Conclusions: Our data support a role for melatonin as an anti-stress signal in goldfish, and suggest that the interrenal tissue of teleosts may be a plausible target for melatonin action decreasing cortisol production. [ABSTRACT FROM AUTHOR]

Background: To address geographic barriers to specialty care access for services such as cardiology, the Veterans Health Administration (VA) has implemented a novel, regionalized telehealth care hub. The Clinical Resource Hub (CRH) model extends care, including cardiology services, to individuals in low-access communities across the region. Little is known, however, about the reach of such programs. Objective: This study aimed to describe the initial CRH program implementation in terms of growth in users and clinical encounters, as well as the association between user characteristics and the use of CRH cardiology care, in VA's Sierra Pacific region (Northern California, Nevada, and the Pacific Islands). Methods: We compared patients who used CRH cardiology services (CRH users) to those using non-CRH cardiology services (CRH nonusers) in the Sierra Pacific region between July 15, 2021, and March 31, 2023. After characterizing changes in the numbers of CRH users and nonusers and clinical encounters over the study period, we used multivariable logistic regression to estimate the association between patient-level factors and the odds of being a CRH user. Results: There were 804 CRH users over the study period, with 1961 CRH encounters concentrated at 3 main CRH sites. The CRH program comprised a minority of cardiology users and encounters in the region, with 19,583 CRH nonusers with 83,489 encounters. The numbers of CRH patients and encounters both increased at a steady-to-increasing rate over the study period, with increases of 37% (n=292 vs n=213) in users and 64% (n=584 vs n=356) in encounters in the first quarter of 2023 compared with the last quarter of 2022. Among CRH users, 8.3% (67/804) were female and 41.4% (333/804) were aged ≥75 years, compared with 4.3% (840/19,583) and 49% (9600/19,583), respectively, among CRH nonusers. The proportions of rural (users: 205/804, 25.5%; nonusers: 4936/19,583, 25.2%), highly disabled (users: 387/804, 48.1%; nonusers: 9246/19,583, 47.2%), and low-income (users: 165/804, 20.5%; nonusers: 3941/19,583, 20.1%) veterans in both groups were similar. In multivariable logistic models, adjusted odds ratios of using CRH were higher for female veterans (1.70, 95% CI 1.29-2.24) and lower for older veterans (aged ≥75 years; 0.33, 95% CI 0.23-0.47). Rural veterans also had a higher adjusted odds ratio of using CRH (1.19, 95% CI 1.00-1.42; P =.046). Conclusions: The VA's Sierra Pacific CRH cardiology program grew substantially in its first 2 years of operation, serving disproportionately more female and rural veterans and similar proportions of highly disabled and low-income veterans compared to conventional VA care. This model appears to be effective for overcoming specialty care access barriers for certain individuals, although targeted efforts may be required to reach older veterans. While this study focuses on a single region, specialty, and health care system, lessons from implementing regionalized telehealth hub models may be applicable to other settings. [ABSTRACT FROM AUTHOR]

Objectives: To examine the relation of corticotropin-releasing hormone (CRH) family peptides with inflammatory processes and oncogenesis, emphasizing in vulvar inflammatory, premalignant and malignant lesions, as well as to investigate the possibility of lesion cells immunoescaping, utilizing FAS/FAS-L complex. Methods: Immunohistochemical expression of CRH, urocortin (UCN), FasL and their receptors CRHR1, CRHR2 and Fas was studied in vulvar tissue sections obtained from patients with histologically confirmed diagnosis of lichen, vulvar intraepithelial neoplasia (VIN) and vulvar squamous cell carcinoma (VSCC). The patient cohort was selected from a tertiary teaching Hospital in Greece, between 2005 and 2015. For each of the disease categories, immunohistochemical staining was evaluated and the results were statistically compared. Results: A progressive increase of the cytoplasmic immunohistochemical expression of CRH and UCN, from precancerous lesions to VSCC was observed. A similar increase was detected for Fas and FasL expression. Nuclear localization of UCN was demonstrated in both premalignant and VSCC lesions, with staining being significantly intensified in carcinomas, particularly in the less differentiated tumor areas or in the areas at invasive tumor front. Conclusions: Stress response system and CRH family peptides seem to have a role in inflammation maintenance and progression of vulvar premalignant lesions to malignancy. It seems that stress peptides may locally modulate the stroma through Fas/FasL upregulation, possibly contributing to vulvar cancer development. [ABSTRACT FROM AUTHOR]

BackgroundMelatonin is a key hormone in regulation of circadian rhythms, and involved in many rhythmic functions, such as feeding and locomotor activity. Melatonin reportedly counteracts stress responses in many vertebrates, including fish. However, targets for this action of melatonin and underlying mechanisms remain unknown.ResultsThis study reports potential anti-stress properties of melatonin in goldfish (Carassius auratus), with a focus on its effect on plasma cortisol, food intake, and locomotor activity, all of them involved in the responses to stress exposure. Indeed, acute injection of melatonin counteracted stress-induced hypercortisolinemia and reduced food intake. The reduced locomotor activity following melatonin treatment suggests a possible sedative role in fish. To assess whether this anti-stress effects of melatonin involve direct actions on interrenal tissue, in vitro cultures of head kidney (containing the interrenal cortisol-producing tissue) were carried out in presence of ACTH, melatonin, and luzindole, an antagonist of melatonin receptors. Melatonin in vitro reduced ACTH-stimulated cortisol release, an effect attenuated by luzindole; this suggests the presence of specific melatonin receptors in interrenal tissue.ConclusionsOur data support a role for melatonin as an anti-stress signal in goldfish, and suggest that the interrenal tissue of teleosts may be a plausible target for melatonin action decreasing cortisol production.

Background and Purpose: Endocannabinoid (eCB) signalling gates many aspects of the stress response, including the hypothalamic--pituitary--adrenal (HPA) axis. The HPA axis is controlled by corticotropin releasing hormone (CRH) producing neurons in the paraventricular nucleus of the hypothalamus (PVN). Disruption of eCB signalling increases drive to the HPA axis, but the mechanisms subserving this process are poorly understood. Experimental Approach: Using an array of cellular, endocrine and behavioural readouts associated with activation of CRH neurons in the PVN, we evaluated the contributions of tonic eCB signalling to the generation of a stress response. Key Results: The CB1 receptor antagonist/inverse agonist AM251, neutral antagonist NESS243 and NAPE PLD inhibitor LEI401 all uniformly increased Fos in the PVN, unmasked stress-linked behaviours, such as grooming, and increased circulating CORT, recapitulating the effects of stress. Similar effects were also seen after direct administration of AM251 into the PVN, while optogenetic inhibition of PVN CRH neurons ameliorated stress-like behavioural changes produced by disruption of eCB signalling. Conclusions and Implications: These data indicate that under resting conditions, constitutive eCB signalling restricts activation of the HPA axis through local regulation of CRH neurons in the PVN. [ABSTRACT FROM AUTHOR]

The advent of railways and especially highspeed railways marks great strides in human transportation history. To guarantee exclusive right-of-way, highspeed railways are often built on equal simply supported beams resting on piers. In this paper, a historical review will be given of the resonance and cancellation phenomena observed for simply supported beams traveled by a set of moving loads, as they are typical of highspeed railways. The phenomenon of resonance was observed by early investigators including Timoshenko, Bolotin, Frýba, Matsuura, etc. However, the phenomenon of cancellation was noted lately in 1997 by Yang et al. By letting the conditions of resonance and cancellation coincident, they proposed the optimal span length for suppressing the resonance of simple beams, which is equal to 1.5 times the car length. This 1.5 times rule has been verified and adopted in the design of some highspeed railways. In this article, the theoretical solution for the problem will be revisited for unveiling the key parameters such as the resonance speed (in temporal domain) and resonance wavelength (in spatial domain). Then a rather in-depth review will be given of existing works on the resonance and cancellation of railway bridges from the waves perspective. Some new developments along these lines will also be identified. [ABSTRACT FROM AUTHOR]

Hindlimb unloading (HU), widely used to simulate microgravity effects, is known to induce a stress response. However, as single-housed animals are usually used in such experiments, social isolation (SI) stress can affect experimental results. In the present study, we aimed to delineate stressful effects of 3-day HU and SI in mice. Three animal groups, HU, SI, and group-housed (GH) control mice, were recruited. A comprehensive analysis of stress-related markers was performed using ELISA, western blotting, and immunohistochemistry. Our results showed that blood corticosterone and activity of glucocorticoid receptors and cAMP response element-binding protein (CREB) in the hippocampus of SI and HU animals did not differ from GH control. However, SI mice demonstrated upregulation of the hippocampal corticotropin-releasing hormone (CRH), inducible NO synthase (iNOS), vesicular glutamate transporter 1 (VGLUT1), and glutamate decarboxylases 65/67 (GAD65/67) along with activation of Fos-related antigen 1 (Fra-1) in the amygdala confirming the expression of stress. In HU mice, the same increase in GAD65/67 and Fra-1 indicated the contribution of SI. The special HU effect was expressed only in neurogenesis attenuation. Thus, our data indicated that 3-day HU could not be characterized as physiological stress, but SI stress contributed to the negative effects of HU. [ABSTRACT FROM AUTHOR]

The aim of this systematic review is to investigate the impact of corticotropin-releasing hormone (CRH) family peptides and their corresponding receptors on human physiology and disease onset, with a specific focus on gynaecological malignancies such as breast, endometrial, ovarian, vulvar, and cervical cancer. A comprehensive systematic review of 3 medical databases was conducted by 2 independent reviewers. We reviewed studies that explored the expression and role of CRH peptides in various aspects of cancer biology, in the context of breast, endometrial, ovarian, vulvar, and cervical cancer. Our findings reveal that CRH family peptides and their receptors, CRHR1 and CRHR2, are expressed in diverse gynaecological tissues, including cancer cells. Notably, we observed differential expression patterns among different gynaecological cancer types and stages, indicating potential associations with tumour aggressiveness and patient prognosis. Furthermore, CRH peptides were found to exert significant influences on critical cellular processes, such as cell proliferation, migration, invasion, and immune response, in gynaecological cancers. These findings highlight the multifaceted roles of CRH family peptides in gynaecological malignancies and emphasize the need for further research in this field. Therefore, understanding the mechanisms underlying the involvement of CRH family peptides in tumourigenesis may open new avenues for targeted therapeutic strategies in gynaecological malignancies. [ABSTRACT FROM AUTHOR]

Disrupted operation of the reward circuitry underlies many aspects of affective disorders. Such disruption may manifest as aberrant behavior including risk taking, depression, anhedonia, and addiction. Early-life adversity is a common antecedent of adolescent and adult affective disorders involving the reward circuitry. However, whether early-life adversity influences the maturation and operations of the reward circuitry, and the potential underlying mechanisms, remain unclear. Here, we present novel information using cutting-edge technologies in animal models to dissect out the mechanisms by which early-life adversity provokes dysregulation of the complex interactions of stress and reward circuitries. We propose that certain molecularly defined pathways within the reward circuitry are particularly susceptible to early-life adversity. We examine regions and pathways expressing the stress-sensitive peptide corticotropin-releasing factor (CRF), which has been identified in critical components of the reward circuitry and interacting stress circuits. Notably, CRF is strongly modulated by early-life adversity in several of these brain regions. Focusing on amygdala nuclei and their projections, we provide evidence suggesting that aberrant CRF expression and function may underlie augmented connectivity of the nucleus accumbens with fear/anxiety regions, disrupting the function of this critical locus of pleasure and reward.

Abstract THE1-family retrovirus invaded the primate genome more than 40 million years ago. Dunn-Fletcher et al. reported one THE1B element upstream of CRH gene alters gestation length by upregulating corticotropin-releasing hormone expression in transgenic mice and concluded it has the same role in human as well. However, no promoter or enhancer mark has been detected around this CRH-proximal element in any human tissue or cell, so probably some anti-viral factor exists in primates to prevents it from wreaking havoc. Here I report two paralogous zinc finger genes, ZNF430 and ZNF100, that emerged during the simian lineage to specifically silence THE1B and THE1A, respectively. Contact residue changes in one finger confers each ZNF the unique ability to preferentially repress one THE1 sub-family over the other. The reported THE1B element contains an intact ZNF430 binding site, thus under the repression of ZNF430 in most tissues including placenta, it is questionable whether or not this retrovirus has any role in human pregnancy. Overall, this analysis highlights the need to study human retroviruses’ functions in suitable model system.

Objective To study the mechanism of learning and memory impairment in aged female mice caused by chronic stress. Methods Twenty-month-old ICR mice were randomly divided into four groups: control females, control males, stressed females, and stressed males. Chronic stress was applied to the stress group for 30 days. The learning and memory ability was measured by novel object recognition test and Morris water maze test. Damage to hippocampal neurons was observed with Nissl staining, and dendrites of hippocampal neurons were observed with Golgi-Cox staining microscopy, the expression of the mammalian target of rapamycin (mTOR) and p-mTOR in hippocampal tissue was measured by Western blot, and the level of serum corticotropin-releasing hormone (CRH) was measured by ELISA. Results There was a significant decrease in the learning and memory ability only in the stressed female group after applied stress. In the Morris water maze, after a 6-day swimming training, the escape latency decreased in the control female group, the control male group and in the stressed male group(P＜0.001, P＜0.001, P＜0.05), but not in the stressed female group. The swimming speed was consistent across groups, but the number of platform crossings and the number of target quadrant crossings were significantly lower in the stressed female group than those in the control female and stressed male groups(P＜0.001).There was significant damage to neurons in the hippocampal CA3, CA1, and DG regions of mice in the stressed female group. The expression of hippocampal m-TOR and p-mTOR protein was significantly decreased in the stressed female group of mice(P＜0.05). In addition, chronic stress caused a significant increase in serum CRH levels in aged female mice(P＜0.05). Conclusions Chronic stress caused learning and memory impairment and pathological damage of the hippocampus in aged female mice, but not in aged male mice, which may be related to a fact that chronic stress elevates CRH and inhibits the hippocampal m-TOR signaling pathway in aged female mice.

Background Schizophrenia spectrum disorder (SSD) is a common mental disorder causing severe and chronic disability. Epigenetic changes in genes related to the hypothalamic–pituitary–adrenal (HPA) axis are believed to play an important role in SSD pathogenesis. The methylation status of the corticotropin-releasing hormone (CRH) gene, which is central to the HPA axis, has not been investigated in patients with SSD. Aim We investigated the methylation status of the coding region of the CRH gene (hereafter, CRH methylation) using peripheral blood samples from patients with SSD. Subjects and methods We used sodium bisulphite and MethylTarget to determine CRH methylation after collecting peripheral blood samples from 70 patients with SSD who had positive symptoms and 68 healthy controls. Results CRH methylation was significantly increased in patients with SSD, especially in male patients. Conclusions Differences in CRH methylation were detectable in the peripheral blood of patients with SSD. Epigenetic abnormalities in the CRH gene were closely related to positive symptoms of SSD, suggesting that epigenetic processes may mediate the pathophysiology of SSD.

An impaired intestinal barrier function can be detrimental to the host as it may allow the translocation of luminal antigens and toxins into the subepithelial tissue and bloodstream. In turn, this may cause local and systemic immune responses and lead to the development of pathologies. In vitro and animal studies strongly suggest that psychosocial stress is one of the factors that can increase intestinal permeability via mast-cell dependent mechanisms. Remarkably, studies have not been able to yield unequivocal evidence that such relation between stress and intestinal permeability also exists in (healthy) humans. In the current Review, we discuss the mechanisms that are involved in stress-induced intestinal permeability changes and postulate factors that influence these alterations and that may explain the translational difficulties from in vitro and animal to human studies. As human research differs highly from animal research in the extent to which stress can be applied and intestinal permeability can be measured, it remains difficult to draw conclusions about the presence of a relation between stress and intestinal permeability in (healthy) humans. Future studies should bear in mind these difficulties, and more research into in vivo methods to assess intestinal permeability are warranted.

Purpose: In women with Polycystic Ovarian Syndrome (PCOS), an increased risk of disordered eating has been described. There is growing interest regarding a possible interconnection between psychological states and increased appetite in women with PCOS. Acute stress is characterized by increased Corticotropin Releasing Hormone (CRH) secretion. The aim was to estimate the ghrelin concentrations during CRH test. Methods: Twenty postmenopausal women with PCOS and twenty age- and BMI- matched postmenopausal control women were recruited at Aretaieion University Hospital. In the morning (9 am) all subjects had anthropometric measurements (weight, height, waist circumference) and a fasting sample for hormonal measurements. An intravenous (iv) CRH stimulation test conducted over 1 min. Serum active ghrelin levels were measured at 0, 15, 30, 60, 90, 120 min after iv CRH administration. Results: The postmenopausal PCOS group had a higher waist circumference compared to postmenopausal controls. Active ghrelin concentrations increased significantly from 0 to 15 min, to 30 min, to 60 min, to 90 min and then decreased to 120 min. However, within the postmenopausal control group there were no significant changes in serum active ghrelin levels. Serum active ghrelin concentrations were significantly greater in the postmenopausal control group at 0, 15 and 120 min compared to the postmenopausal PCOS group. At 90 min active ghrelin concentrations were significantly greater in the postmenopausal PCOS group. Delta Area Under the Curve of active ghrelin (ΔAUCghr) was significantly greater in the postmenopausal PCOS group compared to controls. Conclusions: In postmenopausal PCOS, but not in postmenopausal controls, iv CRH administration induces increased serum active ghrelin secretion, suggesting a possible anti-stress adaptive mechanism. An increase in serum active ghrelin may induce hunger as a side-effect of this presumed adaptive mechanism. [ABSTRACT FROM AUTHOR]

Corticotropin-releasing hormone expressing (CRH+) neurons are distributed throughout the brain and play a crucial role in shaping the stress responses. Mouse models expressing site-specific recombinases (SSRs) or reporter genes are important tools providing genetic access to defined cell types and have been widely used to address CRH+ neurons and connected brain circuits. Here, we investigated a recently generated CRH-FlpO driver line expanding the CRH system-related tool box. We directly compared it to a previously established and widely used CRH-Cre line with respect to the FlpO expression pattern and recombination efficiency. In the brain, FlpO mRNA distribution fully recapitulates the expression pattern of endogenous Crh. Combining both Crh locus driven SSRs driver lines with appropriate reporters revealed an overall coherence of respective spatial patterns of reporter gene activation validating CRH-FlpO mice as a valuable tool complementing existing CRH-Cre and reporter lines. However, a substantially lower number of reporter-expressing neurons was discerned in CRH-FlpO mice. Using an additional CRH reporter mouse line (CRH-Venus) and a mouse line allowing for conversion of Cre into FlpO activity (CAG-LSL-FlpO) in combination with intersectional and subtractive mouse genetic approaches, we were able to demonstrate that the reduced number of tdTomato reporter expressing CRH+ neurons can be ascribed to the lower recombination efficiency of FlpO compared to Cre recombinase. This discrepancy particularly manifests under conditions of low CRH expression and can be overcome by utilizing homozygous CRH-FlpO mice. These findings have direct experimental implications which have to be carefully considered when targeting CRH+ neurons using CRH-FlpO mice. However, the lower FlpO-dependent recombination efficiency also entails advantages as it provides a broader dynamic range of expression allowing for the visualization of cells showing stress-induced CRH expression which is not detectable in highly sensitive CRH-Cre mice as Cre-mediated recombination has largely been completed in all cells generally possessing the capacity to express CRH. These findings underscore the importance of a comprehensive evaluation of novel SSR driver lines prior to their application. [ABSTRACT FROM AUTHOR]

Background: The adrenocortical system and copeptin as prognostic markers were intensively investigated in critical illness. The potential predictive power of apelin-13 as a biomarker is largely unknown. We aimed to investigate the prognostic role of apelin-13 in relation to free cortisol, aldosterone, CRH, and copeptin in critically ill patients. Methods: In this prospective observational study, 124 critically ill patients (64 men, 60 women, median age: 70 (59–78) years) were consecutively enrolled at the time of admission. All routinely available clinical and laboratory parameters were evaluated and correlated to hormonal changes. Results: Serum apelin-13 was 1161 (617–2967) pg/mL in non-survivors vs. 2477 (800–3531) pg/mL in survivors (p = 0.054). The concentrations of apelin-13 and CRH had strong positive correlations (r = 0.685, p < 0.001) and were significantly higher in surviving non-septic patients (Apelin-13 (pg/mL): 2286 (790–3330) vs. 818 (574–2732) p < 0.05; CRH (pg/mL) 201 (84–317) vs. 89 (74–233) p < 0.05). Apelin-13 and free cortisol were independent determinants of survival in the multivariate Cox regression analysis, while copeptin, CRH, or aldosterone were not. Conclusions: Beyond free cortisol, serum apelin-13 may also help refine prognostic predictions in the early phase of critical illness, especially in non-septic patients. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) increases the risk of type 2 diabetes (T2D) by 60% in untreated patients, and hypercortisolism is common in MDD as well as in some patients with T2D. Patients with MDD, despite hypercortisolism, show inappropriately normal levels of corticotropin-releasing hormone (CRH) and plasma adrenocorticotropin (ACTH) in the cerebrospinal fluid, which might implicate impaired negative feedback. Also, a positive feedback loop of the CRH–norepinephrine (NE)–CRH system may be involved in the hypercortisolism of MDD and T2D. Dysfunctional CRH receptor 1 (CRHR1) and CRH receptor 2 (CRHR2), both of which are involved in glucose regulation, may explain hypercortisolism in MDD and T2D, at least in a subgroup of patients. CRHR1 increases glucose-stimulated insulin secretion. Dysfunctional CRHR1 variants can cause hypercortisolism, leading to serotonin dysfunction and depression, which can contribute to hyperglycemia, insulin resistance, and increased visceral fat, all of which are characteristics of T2D. CRHR2 is implicated in glucose homeostasis through the regulation of insulin secretion and gastrointestinal functions, and it stimulates insulin sensitivity at the muscular level. A few studies show a correlation of the CRHR2 gene with depressive disorders. Based on our own research, we have found a linkage and association (i.e., linkage disequilibrium [LD]) of the genes CRHR1 and CRHR2 with MDD and T2D in families with T2D. The correlation of CRHR1 and CRHR2 with MDD appears stronger than that with T2D, and per our hypothesis, MDD may precede the onset of T2D. According to the findings of our analysis, CRHR1 and CRHR2 variants could modify the response to prolonged chronic stress and contribute to high levels of cortisol, increasing the risk of developing MDD, T2D, and the comorbidity MDD-T2D. We report here the potential links of the CRH system, NE, and their roles in MDD and T2D.

Stress is well-known to inhibit a variety of reproductive processes, including the suppression of episodic Gonadotropin releasing hormone (GnRH) secretion, typically measured via downstream luteinizing hormone (LH) secretion. Since pulsatile secretion of GnRH and LH are necessary for proper reproductive function in both males and females, and stress is common for both human and animals, understanding the fundamental mechanisms by which stress impairs LH pulses is of critical importance. Activation of the hypothalamic-pituitary-adrenal axis, and its corresponding endocrine factors, is a key feature of the stress response, so dissecting the role of stress hormones, including corticotrophin releasing hormone (CRH) and corticosterone, in the inhibition of LH secretion has been one key research focus. However, some evidence suggests that these stress hormones alone are not sufficient for the full inhibition of LH caused by stress, implicating the additional involvement of other hormonal or neural signaling pathways in this process (including inputs from the brainstem, amygdala, parabrachial nucleus, and dorsomedial nucleus). Moreover, different stress types, such as metabolic stress (hypoglycemia), immune stress, and psychosocial stress, appear to suppress LH secretion via partially unique neural and endocrine pathways. The mechanisms underlying the suppression of LH pulses in these models offer interesting comparisons and contrasts, including the specific roles of amygdaloid nuclei and CRH receptor types. This review focuses on the most recent and emerging insights into endocrine and neural mechanisms responsible for the suppression of pulsatile LH secretion in mammals, and offers insights in important gaps in knowledge.

Corticotropin-releasing hormone (CRH) is an essential, evolutionarily-conserved stress neuropeptide. In addition to hypothalamus, CRH is expressed in brain regions including amygdala and hippocampus where it plays crucial roles in modulating the function of circuits underlying emotion and cognition. CRH+ fibers are found in nucleus accumbens (NAc), where CRH modulates reward/motivation behaviors. CRH actions in NAc may vary by the individual's stress history, suggesting roles for CRH in neuroplasticity and adaptation of the reward circuitry. However, the origin and extent of CRH+ inputs to NAc are incompletely understood. We employed viral genetic approaches to map both global and CRH+ projection sources to NAc in mice. We injected into NAc variants of a new designer adeno-associated virus that permits robust retrograde access to NAc-afferent projection neurons. Cre-dependent viruses injected into CRH-Cre mice enabled selective mapping of CRH+ afferents. We employed anterograde AAV1-directed axonal tracing to verify NAc CRH+ fiber projections and established the identity of genetic reporter-labeled cells via validated antisera against native CRH. We quantified the relative contribution of CRH+ neurons to total NAc-directed projections. Combined retrograde and anterograde tracing identified the paraventricular nucleus of the thalamus, bed nucleus of stria terminalis, basolateral amygdala, and medial prefrontal cortex as principal sources of CRH+ projections to NAc. CRH+ NAc afferents were selectively enriched in NAc-projecting brain regions involved in diverse aspects of the sensing, processing and memory of emotionally salient events. These findings suggest multiple, complex potential roles for the molecularly-defined, CRH-dependent circuit in modulation of reward and motivation behaviors.

Abstract Background Recent studies suggest that the incidence of small for gestational age (SGA) birth related to maternal depression, but the mechanism is unclear. The aim of this study was to explore the changes of promoter methylation in the placenta which may be involved in the relationship between prenatal depression and SGA. Methods Three hundred forty-five pregnant women were enrolled in this prospective cohort study. Perinatal emotion and sleep quality in the second and third trimesters were assessed using self-rating depression scale, self-rating anxiety scale, and Pittsburgh sleep quality index. According to the exposure (depressed emotion of mother) and outcome (SGA), the placentas were divided into four groups. Methylation of the promoter regions of the placental CRH, HSD11β2, SLA16A10, DIO3, and MTNR1B genes was determined using next generation sequencing based on bisulfite sequencing PCR. Results There were 97 (28.1%) and 95 (27.5%) pregnant women who had depression in the second trimester and third trimester, respectively. Thirty-five pregnant women had an SGA birth. The incidence of SGA births in this prospective cohort was 10.1%. The risk factors of SGA birth were low BMI of pregnancy women (RR = 0.71, 95%CI = 0.54 ~ 0.92), hypertensive disorder complicating pregnancy (HDCP, RR = 4.7, 95%CI = 1.18 ~ 18.72), and maternal depression in the second trimester (RR = 3.71, 95%CI = 1.31 ~ 12.16). We found that the CRH and HSD11β2 methylation levels were higher in the depression group than those in the non-depression group. Methylation levels of DIO3 were higher in SGA group than that in the non-SGA group. Higher methylation levels of CRH correlated with higher methylation levels of DIO3 in the placenta. Conclusions Maternal depression in the second trimester may lead to the changes of methylation levels in the promoter region of CRH and HSD11β2 gene, while the changes of methylation of DIO3 in subsequent could related to SGA. This study suggests that maternal depressed emotion during pregnancy may result in SGA due to the epigenetic changes of placenta.

Total sleep deprivation (TSD) causes several harmful changes including anxiety, inflammation, and increased expression of extracellular signal-regulated kinase (ERK) and tropomyosin receptor kinase B (TrkB) genes in the hippocampus. The current study was conducted to explain the possible effects of exogenous GH against the above parameters caused by TSD and the possible mechanisms involved. Male Wistar rats were divided into 1) control, 2) TSD and 3) TSD + GH groups. To induce TSD, the rats received a mild repetitive electric shock (2 mA, 3 s) to their paws every 10 min for 21 days. Rats in the third group received GH (1 ml/kg, sc) for 21 days as treatment for TSD. The motor coordination, locomotion, the level of IL-6, and expression of ERK and TrkB genes in hippocampal tissue were measured after TSD. The motor coordination (p < 0.001) and locomotion indices (p < 0.001) were impaired significantly by TSD. The concentrations of serum corticotropin-releasing hormone (CRH) (p < 0.001) and hippocampal interleukin-6 (IL-6) (p < 0.001) increased. However, there was a significant decrease in the interleukin-4 (IL-4) concentration and expression of ERK (p < 0.001) and TrkB (p < 0.001) genes in the hippocampus of rats with TSD. Treatment of TSD rats with GH improved motor balance (p < 0.001) and locomotion (p < 0.001), decreased serum CRH (p < 0.001), IL-6 (p < 0.01) but increased the IL-4 and expression of ERK (p < 0.001) and TrkB (p < 0.001) genes in the hippocampus. Results show that GH plays a key role in modulating the stress hormone, inflammation, and the expression of ERK and TrkB genes in the hippocampus following stress during TSD. [ABSTRACT FROM AUTHOR]

Corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) are central to the stress response. Chemogenetic activation of PVN CRH neurons decreases LH pulse frequency but the mechanism is unknown. In the present study, optogenetic stimulation of PVN CRH neurons suppressed LH pulse frequency in estradiol-replaced ovariectomized CRH-cre mice, and this effect was augmented or attenuated by intra-PVN GABAA or GABAB receptor antagonism, respectively. PVN CRH neurons signal to local GABA neurons, which may provide a possible indirect mechanism by which PVN CRH neurons suppress LH pulse frequency. Optogenetic stimulation of potential PVN GABAergic projection terminals in the hypothalamic arcuate nucleus in ovariectomized estradiol-replaced Vgat-cre-tdTomato mice via an optic fiber implanted in the arcuate nucleus suppressed LH pulse frequency. To further determine whether PVN CRH neurons signal through PVN GABA neurons to suppress LH pulsatility, we combined recombinase mice with intersectional vectors to selectively target these neurons. CRH-cre::Vgat-FlpO mice expressing the stimulatory opsin ChRmine in non-GABAergic CRH neurons alone or in combination with the inhibitory opsin NpHR3.3 in non-CRH-expressing GABA neurons in the PVN were used. Optogenetic stimulation of non-GABAergic CRH neurons suppressed pulsatile LH secretion; however, LH pulse frequency was not affected when CRH neurons were stimulated and PVN GABA neurons were simultaneously inhibited. Together, these studies demonstrate that suppression of LH pulse frequency in response to PVN CRH neuronal activation is mediated by GABAergic signalling intrinsic to the PVN and may incorporate PVN GABAergic projection to the hypothalamic GnRH pulse generator. [ABSTRACT FROM AUTHOR]

THE1-family retrovirus invaded the primate genome more than 40 million years ago. Dunn-Fletcher et al. reported one THE1B element upstream of CRH gene alters gestation length by upregulating corticotropin-releasing hormone expression in transgenic mice and concluded it has the same role in human as well. However, no promoter or enhancer mark has been detected around this CRH-proximal element in any human tissue or cell, so probably some anti-viral factor exists in primates to prevents it from wreaking havoc. Here I report two paralogous zinc finger genes, ZNF430 and ZNF100, that emerged during the simian lineage to specifically silence THE1B and THE1A, respectively. Contact residue changes in one finger confers each ZNF the unique ability to preferentially repress one THE1 sub-family over the other. The reported THE1B element contains an intact ZNF430 binding site, thus under the repression of ZNF430 in most tissues including placenta, it is questionable whether or not this retrovirus has any role in human pregnancy. Overall, this analysis highlights the need to study human retroviruses' functions in suitable model system. [ABSTRACT FROM AUTHOR]