Actions Of Corticotropin-releasing Hormone Research Articles

Corticotropin-releasing hormone neurons control trigeminal neuralgia-induced anxiodepression via a hippocampus-to-prefrontal circuit.

Anxiety and depression are frequently observed in patients suffering from trigeminal neuralgia (TN), but neural circuits and mechanisms underlying this association are poorly understood. Here, we identified a dedicated neural circuit from the ventral hippocampus (vHPC) to the medial prefrontal cortex (mPFC) that mediates TN-related anxiodepression. We found that TN caused an increase in excitatory synaptic transmission from vHPCCaMK2A neurons to mPFC inhibitory neurons marked by the expression of corticotropin-releasing hormone (CRH). Activation of CRH+ neurons subsequently led to feed-forward inhibition of layer V pyramidal neurons in the mPFC via activation of the CRH receptor 1 (CRHR1). Inhibition of the vHPCCaMK2A-mPFCCRH circuit ameliorated TN-induced anxiodepression, whereas activating this pathway sufficiently produced anxiodepressive-like behaviors. Thus, our studies identified a neural pathway driving pain-related anxiodepression and a molecular target for treating pain-related psychiatric disorders.

Corticotropin-Releasing Hormone: A Novel Stimulator of Somatolactin in Teleost Pituitary Cells.

Corticotropin-releasing hormone (CRH) is known for its crucial role in the stress response system, which could induce pituitary adrenocorticotropic hormone (ACTH) secretion to promote glucocorticoid release in the adrenal gland. However, little is known about other pituitary actions of CRH in teleosts. Somatolactin is a fish-specific hormone released from the neurointermediate lobe (NIL) of the posterior pituitary. A previous study has reported that ACTH was also located in the pituitary NIL region. Interestingly, our present study found that CRH could significantly induce two somatolactin isoforms' (SLα and SLβ) secretion and synthesis in primary cultured grass carp pituitary cells. Pharmacological analysis further demonstrated that CRH-induced pituitary somatolactin expression was mediated by the AC/cAMP/PKA, PLC/IP3/PKC, and Ca2+/CaM/CaMK-II pathways. Finally, transcriptomic analysis showed that both SLα and SLβ should play an important role in the regulation of lipid metabolism in primary cultured hepatocytes. These results indicate that CRH is a novel stimulator of somatolactins in teleost pituitary cells, and somatolactins may participate in the stress response by regulating energy metabolism.

Sleep-Disturbance-Induced Microglial Activation Involves CRH-Mediated Galectin 3 and Autophagy Dysregulation.

Chronic sleep disturbances (CSDs) including insomnia, insufficient sleep time, and poor sleep quality are major public health concerns around the world, especially in developed countries. CSDs are major health risk factors linked to multiple neurodegenerative and neuropsychological diseases. It has been suggested that CSDs could activate microglia (Mg) leading to increased neuroinflammation levels, which ultimately lead to neuronal dysfunction. However, the detailed mechanisms underlying CSD-mediated microglial activation remain mostly unexplored. In this study, we used mice with three-weeks of sleep fragmentation (SF) to explore the underlying pathways responsible for Mg activation. Our results revealed that SF activates Mg in the hippocampus (HP) but not in the striatum and prefrontal cortex (PFc). SF increased the levels of corticotropin-releasing hormone (CRH) in the HP. In vitro mechanism studies revealed that CRH activation of Mg involves galectin 3 (Gal3) upregulation and autophagy dysregulation. CRH could disrupt lysosome membrane integrity resulting in lysosomal cathepsins leakage. CRHR2 blockage mitigated CRH-mediated effects on microglia in vitro. SF mice also show increased Gal3 levels and autophagy dysregulation in the HP compared to controls. Taken together, our results show that SF-mediated hippocampal Mg activation involves CRH mediated galectin 3 and autophagy dysregulation. These findings suggest that targeting the hippocampal CRH system might be a novel therapeutic approach to ameliorate CSD-mediated neuroinflammation and neurodegenerative diseases.

Trivariate compound generalized poisson model for corticotropin-releasing hormone effects on human pregnant and nonpregnant

In this paper, we apply a new approach to uterine contractions to a large panel of human pregnant non pregnant myometrial strips, treated or not by corticotropin releasing hormone (CRH). This model is based on a fine analysis of the contraction curves.This analysis yield four mathematical parameters beta, theta, tau1 and tau2 related to excitability, duration of plateau phase, and time constants for relaxation describing respectively, the different portions of the contraction cycle. This leads to specific differences in spontaneous contractile activity between pregnant and nonpregnant states. In the present study, we compare nonpregant and pregnant women close to the term vitro CRH myometrial responsiveness, to describe uterine contractile activity during a parturition. We have a Trivariate compound generalized Poisson model for uterine contraction to a pregnant and nonpregnant myometrial strips, treated or not treated by corticotrophin- releasing hormone (CRH). Although, the biochemical signification of these results remains to be elucidated, we contribute to emphasize CRH action at the myometrical level. The results reveal highly significant differences between pregnant and nonpregnant myometrium as well as in their response to CRH.

The role of inflammatory cytokines in anemia and gastrointestinal mucosal injury induced by foot electric stimulation

Foot electrical stimulation (FES) has been considered as a classic stressor that can disturb homeostasis. Acute anemia was observed in the model induced by FES. The aim of this study was to explore the role of inflammatory cytokines underlying the acute anemia and gastrointestinal (GI) mucosal injury in the FES. Twenty-four male Kunming mice (20 ± 2 g) were randomly divided into control group and experimental group. The mice were placed in a footshock chamber that can generate 0.5 mA electrical impulse periodically for 0.5 h. After the process, red blood cell count, hemoglobin concentration and hematocrit, the levels of corticotropin releasing hormone (CRH) in serum and hypothalamus, and adrenocorticotropic hormone (ACTH) in serum and pituitary were detected separately. In addition, we investigated the expressions of inflammatory cytokines (IL-1, IL-6, TNF-α, iNOS, and IL-10) in the hypothalamus and duodenum by Polymerase Chain Reaction (PCR). Results showed that this FES model induced anemia, increased CRH and ACTH activity in the serum after the FES. Moreover, the expressions of IL-1β, IL-6, TNF-α, and iNOS were significantly increased following the process, while IL-10 was not activated. These findings suggest that anemia, the inflammatory cytokines in the hypothalamus and duodenum of the mice in the model induced by FES is closely related to GI mucosal injury/bleeding. Taken together, these results underscore the importance of anemia, GI mucosal injury/bleeding and stress, future studies would be needed to translate these findings into the benefit of affected patients.

Macrophage-activating lipopeptide-2 and corticotropin-releasing hormone stimulate the inflammatory signalling in human sebocytes through activation of stearoyl-CoA desaturase and fatty acid desaturase 2.

The macrophage-activating lipopeptide-2 (MALP-2) activates cells carrying a functional Toll-like receptor (TLR)-2/6. Human sebocytes express functional TLR-2, TLR-4 and CD14. Upregulation of stearoyl-CoA desaturase (SCD) and fatty acid desaturase-2 (FADS2) expression induces pro-inflammatory sebaceous activity. On the other hand, corticotropin-releasing hormone (CRH) is likely to serve as an autocrine stress hormone in human sebocytes. In addition to its antiproliferative, lipogenetic and androgen-activating functions, CRH exhibits a pro-inflammatory action and its expression is upregulated in acne-involved sebaceous glands. Determination of the pro-inflammatory function of MALP-2 and CRH and clarification of the option that MALP-2 and/or CRH activity on human sebocytes might be mediated through SCD and/or FADS2. SZ95 sebocytes were treated with MALP-2, CRH and the SCD inhibitor/ligand FPCA. SCD, FADS2, TLR-2 mRNA and protein levels and IL-6 and IL-8 secretion were investigated. Intracellular CRH levels were assessed under treatment with CRH, MALP-2, linoleic acid and arachidonic acid. Phorbol 12-myristate 13-acetate and dexamethasone served as positive and negative controls, respectively. MALP-2 upregulated SCD, FADS2, TLR-2 mRNA and protein levels and IL-6 and IL-8 secretion from SZ95 sebocytes. Co-incubation of SZ95 sebocytes with MALP-2/FPCA did not affect the MALP-2-induced SCD mRNA upregulation but reduced FADS2 mRNA levels and inhibited IL-8 secretion. CRH induced an early, low-level SCD and FADS2 upregulation and TLR-2 and IL-8 secretion. High intracellular CRH concentrations could be detected early after CRH treatment and persisted up to 24h. MALP-2 stimulated intracellular CRH levels. MALP-2 stimulates the inflammatory signalling in human sebocytes through SCD and FADS2 activation. Inhibition of FADS2 mRNA levels and IL-8 secretion through MALP-2/FCPA co-incubation and diminution of fatty acid unsaturation might lead to a reduction of pro-inflammatory sebaceous lipids. CRH upregulates inflammatory signalling via the SCD/FADS2 pathway, and MALP-2 selectively enhances CRH levels in human sebocytes.

Influence of labor on direct and indirect determinants of placental 11beta-hydroxysteroid dehydrogenase activity

PurposeLabor is a complex process involving multiple para-, auto- and endocrine cascades. The interaction of cortisol, corticotropin-releasing hormone (CRH) and progesterone is essential. The action of cortisol on the human feto-placental unit is regulated by 11beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2/HSD11B2) that converts cortisol into inactive cortisone. The majority of studies on the assessment of placental 11β-HSD2 function determined indirect activity parameters. It remains elusive if indirect measurements correlate with enzymatic function and if these parameters are affected by potential confounders (e.g., mode of delivery). Thus, we compared determinants of indirect 11β-HSD2 tissue activity with its direct enzymatic turnover rate in placental samples from spontaneous births and cesarean (C)-sections.MethodsUsing LC–MS/MS, we determined CRH, cortisol, cortisone, progesterone and 17-hydroxy(OH)-progesterone in human term placentas (spontaneous birth vs. C-section, n = 5 each) and measured the enzymatic glucocorticoid conversion rates in placental microsomes. Expression of HSD11B1, 2 and CRH was determined via qRT-PCR in the same samples.ResultsCortisol–cortisone ratio correlated with direct microsomal enzymatic turnover. While this observation seemed independent of sampling site, a strong influence of mode of delivery on tissue steroids was observed. The mRNA expression of HSD11B2 correlated with indirect and direct cortisol turnover rates in C-section placentas only. In contrast to C-sections, CRH, cortisol and cortisone levels were significantly increased in placental samples following spontaneous birth.ConclusionLabor involves a series of complex hormonal processes including activation of placental CRH and glucocorticoid metabolism. This has to be taken into account when selecting human cohorts for comparative analysis of placental steroids.

0071 A Medullary Circuit Controlling REM Sleep

Abstract Introduction Rapid eye movement (REM) sleep is a distinct brain state known for its association with vivid dreaming in humans, though it is also crucial for other mental processes such as memory consolidation and emotion regulation. REM sleep is punctuated by phasic neurophysiological events known as pontine (P)-waves, which are thought to contribute to the cognitive functions of REM sleep. However, little is known about the neural circuits regulating these P-waves, or those responsible for initiating REM sleep itself. Here, we show that a yet unstudied population of medullary neurons expressing corticotropin-releasing-hormone (CRH) are important for controlling both the induction of REM sleep and its phasic events. Methods To measure the endogenous activity of CRH+ neurons in the dorsomedial medulla (dmM), we injected the calcium indicator GCaMP6 in the dmM of CRH-Cre mice. To optogenetically manipulate dmM CRH+ neuron activity, we delivered either an excitatory (ChR2) or inhibitory (iC++) opsin to the dmM of CRH-Cre mice. To record P-waves, we implanted microelectrodes to record local field potentials in the subcoeruleus region of the pons. Results Fiber photometry recordings showed that dmM CRH+ neurons are selectively active during REM sleep, and optogenetic stimulation and inhibition of this population is sufficient to promote and reduce REM sleep, respectively. Additionally, dmM CRH+ neuron activity is correlated with P-waves in the pons, and optogenetic activation of dmM CRH+ cells reliably triggers P-waves during REM sleep. Finally, histological examination of fluorescently labeled dmM CRH+ axons revealed strong projections to several pontine areas involved in P-wave generation as well as modulation of the theta rhythm during REM sleep. Conclusion Our results suggest that dmM CRH+ neurons are involved in controlling REM sleep initiation as well as phasic events within REM sleep. These neurons thus constitute an important component of the brainstem circuitry regulating REM sleep. Support National Institutes of Health (R01 HL149133)

Paraventricular nucleus CRH neurons encode stress controllability and regulate defensive behavior selection.

In humans and rodents, the perception of control during stressful events has lasting behavioral consequences. These consequences are apparent even in situations that are distinct from the stress context, but how the brain links prior stressful experience to subsequent behaviors remains poorly understood. By assessing innate defensive behavior in a looming-shadow task, we show that the initiation of an escape response is preceded by an increase in the activity of corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus (CRHPVN neurons). This anticipatory increase is sensitive to stressful stimuli that have high or low levels of outcome control. Specifically, experimental stress with high outcome control increases CRHPVN neuron anticipatory activity, which increases escape behavior in an unrelated context. By contrast, stress with no outcome control prevents the emergence of this anticipatory activity and decreases subsequent escape behavior. These observations indicate that CRHPVN neurons encode stress controllability and contribute to shifts between active and passive innate defensive strategies.

Molecular Basis for Hormone Recognition and Activation of Corticotropin-Releasing Factor Receptors.

Corticotropin-releasing factor (CRF) and the three related peptides urocortins 1-3 (UCN1-UCN3) are endocrine hormones that control the stress responses by activating CRF1R and CRF2R, two members of class B G-protein-coupled receptors (GPCRs). Here, we present two cryoelectron microscopy (cryo-EM) structures of UCN1-bound CRF1R and CRF2R with the stimulatory G protein. In both structures, UCN1 adopts a single straight helix with its N terminus dipped into the receptor transmembrane bundle. Although the peptide-binding residues in CRF1R and CRF2R are different from other members of class B GPCRs, the residues involved in receptor activation and G protein coupling are conserved. In addition, both structures reveal bound cholesterol molecules to the receptor transmembrane helices. Our structures define the basis of ligand-binding specificity in the CRF receptor-hormone system, establish a common mechanism of class B GPCR activation and G protein coupling, and provide a paradigm for studying membrane protein-lipid interactions for class B GPCRs.

Serotonergic Plasticity in the Dorsal Raphe Nucleus Characterizes Susceptibility and Resilience to Anhedonia.

Chronic stress induces anhedonia in susceptible but not resilient individuals, a phenomenon observed in humans as well as animal models, but the molecular mechanisms underlying susceptibility and resilience are not well understood. We hypothesized that the serotonergic system, which is implicated in stress, reward, and antidepressant therapy, may play a role. We found that plasticity of the serotonergic system contributes to the differential vulnerability to stress displayed by susceptible and resilient animals. Stress-induced anhedonia was assessed in adult male rats using social defeat and intracranial self-stimulation, while changes in serotonergic phenotype were investigated using immunohistochemistry and in situ hybridization. Susceptible, but not resilient, rats displayed an increased number of neurons expressing the biosynthetic enzyme for serotonin, tryptophan-hydroxylase-2 (TPH2), in the ventral subnucleus of the dorsal raphe nucleus (DRv). Further, a decrease in the number of DRv glutamatergic (VGLUT3+) neurons was observed in all stressed rats. This neurotransmitter plasticity is activity-dependent, as was revealed by chemogenetic manipulation of the central amygdala, a stress-sensitive nucleus that forms a major input to the DR. Activation of amygdalar corticotropin-releasing hormone (CRH)+ neurons abolished the increase in DRv TPH2+ neurons and ameliorated stress-induced anhedonia in susceptible rats. These findings show that activation of amygdalar CRH+ neurons induces resilience, and suppresses the gain of serotonergic phenotype in the DRv that is characteristic of susceptible rats. This molecular signature of vulnerability to stress-induced anhedonia and the active nature of resilience could be targeted to develop new treatments for stress-related disorders like depression.SIGNIFICANCE STATEMENT Depression and other mental disorders can be induced by chronic or traumatic stressors. However, some individuals are resilient and do not develop depression in response to chronic stress. A complete picture of the molecular differences between susceptible and resilient individuals is necessary to understand how plasticity of limbic circuits is associated with the pathophysiology of stress-related disorders. Using a rodent model, our study identifies a novel molecular marker of susceptibility to stress-induced anhedonia, a core symptom of depression, and a means to modulate it. These findings will guide further investigation into cellular and circuit mechanisms of resilience, and the development of new treatments for depression.

SAT-415 Action of Neurotensin, CRH, And RFRP-3 in E2-Induced Negative Feedback Control: Studies Using a Mouse Arc Hypothalamic Cell Model

The recently established immortalized hypothalamic cell model mHypoA-55 possesses characteristics similar to those of Kiss-1 neurons in the arcuate nucleus (ARC) region of the hypothalamus. Here, we show that Kiss-1 gene expression in these cells was downregulated by 17β-estradiol (E2) under certain conditions. Both neurotensin (NT) and corticotropin-releasing hormone (CRH) were expressed in these cells and upregulated by E2. Stimulation of mHypoA-55 cells with NT and CRH significantly decreased Kiss-1 mRNA expression. A mammalian gonadotropin-inhibitory hormone homolog, RFamide-related peptide-3 (RFRP-3), was also found to be expressed in mHypoA-55 cells, and RFRP-3 expression in these cells was increased by exogenous melatonin stimulation. E2 stimulation also upregulated RFRP-3 expression in these cells. Stimulation of mHypoA-55 cells with RFRP-3 significantly increased the expression of NT and CRH. Furthermore, melatonin stimulation resulted in the increase of both NT and CRH mRNA expression in mHypoA-55 cells. On the other hand, in experiments using mHypoA-50 cells, which were originally derived from hypothalamic neurons in the anteroventral periventricular nucleus, Kiss-1 gene expression was upregulated by both NT and CRH, although E2 increased both NT and CRH expression, similarly to the mHypoA-55 cells. Our observations using the hypothalamic ARC cell model mHypoA-55 suggest that NT and CRH have inhibitory effects on Kiss-1 gene expression under the influence of E2 in association with RFRP-3 expression. Thus, these neuropeptides might be involved in E2-induced negative feedback mechanisms.

New viral-genetic mapping uncovers an enrichment of corticotropin-releasing hormone-expressing neuronal inputs to the nucleus accumbens from stress-related brain regions.

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.

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.

Corticotropin-releasing hormone projections from the paraventricular nucleus of the hypothalamus to the nucleus of the solitary tract increase blood pressure.

Activation of corticotropin-releasing hormone (CRH) type 2 receptors (CRHR2) in the nucleus of the solitary tract (NTS) contributes to the development of hypertension, but the source of CRH inputs to the NTS that increases blood pressure remains unknown. This study tested the hypothesis that activation of CRH-containing projections from the paraventricular nucleus of the hypothalamus (PVN) to the NTS increase blood pressure. We expressed channelrhodopsin 2 (ChR2), a light-sensitive ion channel, into CRH-containing neurons in the PVN. This was achieved by injecting Cre-inducible virus expressing ChR2 into the PVN of CRH-Cre mice. CRH-Cre mice are genetically modified mice expressing Cre recombinase only in neurons producing CRH. We found that optogenetic stimulation of CRH-containing somas in the PVN or CRH-containing fibers in the NTS originating from the PVN significantly increased blood pressure and heart rate. Microinjection of K-41498 (CRHR2 antagonist) into the NTS attenuated the pressor and tachycardiac responses induced by optogenetic stimulation of CRH-containing somas in the PVN. In vitro loose-patch recordings revealed that optogenetic stimulation of CRH-containing fibers in the NTS originating from the PVN significantly increased the discharge frequency of NTS neurons. This effect was attenuated by pretreatment of K-41498 and was abolished by pretreatment of kynurenic acid (nonselective glutamate receptor antagonist). These results suggest that activation of PVN-NTS CRH-containing projections increases blood pressure and heart rate. The cardiovascular responses may be mediated at least in part by the corelease of CRH and glutamate from NTS CRH-containing axons originating from the PVN. NEW & NOTEWORTHY Optogenetic stimulation of paraventricular nucleus of the hypothalamus (PVN) corticotropin-releasing hormone (CRH)-containing somas or nucleus of the solitary tract (NTS) CRH-containing fibers originating from the PVN increased blood pressure and heart rate. Corelease of CRH and glutamate from NTS CRH-containing axons originating from the PVN may contribute to the pressor and tachycardiac responses elicited by optogenetic stimulation of PVN CRH-containing somas.

Effects of corticotropin-releasing hormone on the expression of adenosine triphosphate-sensitive potassium channels (Kir6.1/SUR2B) in human term pregnant myometrium.

ObjectiveCorticotropin-releasing hormone (CRH) is a crucial regulator of human pregnancy and parturition. Adenosine triphosphate (ATP)-sensitive potassium (KATP) channels are important for regulating myometrial quiescence during pregnancy. We investigated regulatory effects of different concentrations of CRH on KATP channel expression in human myometrial smooth muscle cells (HSMCs) in in vitro conditions.MethodsAfter treating HSMCs with different concentrations of CRH (1, 10, 102, 103, 104 pmol/L), mRNA and protein expression of KATP channel subunits (Kir6.1 and SUR2B) was analyzed by reverse transcription-polymerase chain reaction and western blot. We investigated which CRH receptor was involved in the reaction and measured the effects of CRH on intracellular Ca2+ concentration when oxytocin was administered in HSMCs using Fluo-8 AM ester.ResultsWhen HSMCs were treated with low (1 pmol/L) and high (103, 104 pmol/L) CRH concentrations, KATP channel expression significantly increased and decreased, respectively. SUR2B mRNA expression at low and high CRH concentrations was significantly antagonized by antalarmin (CRH receptor-1 antagonist) and astressin 2b (CRH receptor-2 antagonist), respectively; however, Kir6.1 mRNA expression was not affected. After oxytocin treatment, the intracellular Ca2+ concentration in CRH-treated HSMCs was significantly lowered in low concentration of CRH (1 pmol/L), but not in high concentration of CRH (103 pmol/L), compared to control.ConclusionOur data demonstrated the regulatory effect was different when HSMCs were treated with low (early pregnancy-like) and high (labor-like) CRH concentrations and the KATP channel expression showed significant increase and decrease. This could cause inhibition and activation, respectively, of uterine muscle contraction, demonstrating opposite dual actions of CRH.

Thyrotropic activity of corticotropin-releasing hormone in an altricial bird species, the zebra finch (Taeniopygia guttata)

In chicken, corticotropin-releasing hormone (CRH) acts as a thyrotropin (TSH)-releasing factor, mediated by the type 2 CRH receptor (CRHR2) on the thyrotropes of the pituitary gland. It is not known whether CRH also controls TSH release in non-precocial avian species that have a different pattern of thyroidal activity during their life cycle. Therefore, we investigated the TSH-releasing capacity of CRH in an altricial species, the zebra finch (Taeniopygia guttata). Cellular localisation of type 1 CRH receptor (CRHR1) and CRHR2 mRNA in the pituitary was determined by in situ hybridisation, combined with immunohistochemical staining of pituitary thyrotropes. In addition, isolated pituitary glands were stimulated with CRH to determine the effect on TSH release. Lastly, the mRNA levels of hormones and receptors involved in the control of thyroidal and adrenal function were measured by qPCR in zebra finch chicks between hatching and fledging, and in adults. Most of the hypophyseal CRHR2 mRNA co-localised with thyrotropes, whereas CRHR1 mRNA was found inbetween thyrotropes. Pituitary glands stimulated in vitro with CRH showed increased secretion of TSH-like activity. Pituitary CRHR2 mRNA expression decreased while pituitary TSHB mRNA and brain CRH mRNA levels increased towards fledging, similar as seen in chicken hatching. These results suggest that CRHR2 expressed on thyrotropes is likely mediating CRH-induced TSH release in altricial avian species like it does in precocial species, and that the increased thyroid hormone levels towards fledging in altricial birds are the result of increased hypothalamic stimulation, in which the thyrotropic activity of CRH may initially play a role.

Corticotropin-Releasing Hormone As the Homeostatic Rheostat of Feto-Maternal Symbiosis and Developmental Programming In Utero and Neonatal Life

A balanced interaction between the homeostatic mechanisms of mother and the developing organism during pregnancy and in early neonatal life is essential in order to ensure optimal fetal development, ability to respond to various external and internal challenges, protection from adverse programming, and safeguard maternal care availability after parturition. In the majority of pregnancies, this relationship is highly effective resulting in successful outcomes. However, in a number of pathological settings, perturbations of the maternal homeostasis disrupt this symbiosis and initiate adaptive responses with unpredictable outcomes for the fetus or even the neonate. This may lead to development of pathological phenotypes arising from developmental reprogramming involving interaction of genetic, epigenetic, and environmental-driven pathways, sometimes with acute consequences (e.g., growth impairment) and sometimes delayed (e.g., enhanced susceptibility to disease) that last well into adulthood. Most of these adaptive mechanisms are activated and controlled by hormones of the hypothalamo-pituitary adrenal axis under the influence of placental steroid and peptide hormones. In particular, the hypothalamic peptide corticotropin-releasing hormone (CRH) plays a key role in feto-maternal communication by orchestrating and integrating a series of neuroendocrine, immune, metabolic, and behavioral responses. CRH also regulates neural networks involved in maternal behavior and this determines efficiency of maternal care and neonate interactions. This review will summarize our current understanding of CRH actions during the perinatal period, focusing on the physiological roles for both mother and offspring and also how external challenges can alter CRH actions and potentially impact on fetus/neonate health.

The Endogenous Stress Hormone CRH Modulates Excitatory Transmission and Network Physiology in Hippocampus.

Memory is strongly influenced by stress but underlying mechanisms are unknown. Here, we used electrophysiology, neuroanatomy, and network simulations to probe the role of the endogenous, stress-related neuropeptide corticotropin-releasing hormone (CRH) in modulating hippocampal function. We focused on neuronal excitability and the incidence of sharp waves (SPWs), a form of intrinsic network activity associated with memory consolidation. Specifically, we blocked endogenous CRH using 2 chemically distinct antagonists of the principal hippocampal CRH receptor, CRHR1. The antagonists caused a modest reduction of spontaneous excitatory transmission onto CA3 pyramidal cells, mediated, in part by effects on IAHP. This was accompanied by a decrease in the incidence but not amplitude of SPWs, indicating that the synaptic actions of CRH are sufficient to alter the output of a complex hippocampal network. A biophysical model of CA3 described how local actions of CRH produce macroscopic consequences including the observed changes in SPWs. Collectively, the results provide a first demonstration of the manner in which subtle synaptic effects of an endogenously released neuropeptide influence hippocampal network level operations and, in the case of CRH, may contribute to the effects of acute stress on memory.

Modeling the diversity of spontaneous and agonist-induced electrical activity in anterior pituitary corticotrophs

Pituitary corticotrophs fire action potentials spontaneously and in response to stimulation with corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), and such electrical activity is critical for calcium signaling and calcium-dependent adrenocorticotropic hormone secretion. These cells typically fire tall, sharp action potentials when spontaneously active, but a variety of other spontaneous patterns have also been reported, including various modes of bursting. There is variability in reports of the fraction of corticotrophs that are electrically active, as well as their patterns of activity, and the sources of this variation are not well understood. The ionic mechanisms responsible for CRH- and AVP-triggered electrical activity in corticotrophs are also poorly characterized. We use electrophysiological measurements and mathematical modeling to investigate possible sources of variability in patterns of spontaneous and agonist-induced corticotroph electrical activity. In the model, variation in as few as two parameters can give rise to many of the types of patterns observed in electrophysiological recordings of corticotrophs. We compare the known mechanisms for CRH, AVP, and glucocorticoid actions and find that different ionic mechanisms can contribute in different but complementary ways to generate the complex time courses of CRH and AVP responses. In summary, our modeling suggests that corticotrophs have several mechanisms at their disposal to achieve their primary function of pacemaking depolarization and increased electrical activity in response to CRH and AVP.NEW & NOTEWORTHY We and others recently demonstrated that the electrical activity and calcium dynamics of corticotrophs are strikingly diverse, both spontaneously and in response to the agonists CRH and AVP. Here we demonstrate this diversity with electrophysiological measurements and use mathematical modeling to investigate its possible sources. We compare the known mechanisms of agonist-induced activity in the model, showing how the context of ionic conductances dictates the effects of agonists even when their target is fixed.