Production Of Corticotropin-releasing Hormone Research Articles

Glucocorticoid receptors regulate hypothalamic CRH neuron activity in primary hypertension

The hypothalamic-pituitary-adrenal axis is important in maintaining homeostasis in response to physical and psychological stressors. The corticotropin-releasing hormone (CRH) is a neuropeptide synthesized by CRH neurons in brain regions including paraventricular nucleus (PVN) of the hypothalamus. The glucocorticoids synthesized and released in adrenal gland act on hypothalamic CRH-expressing neurons inhibit the CRH production and maintain the level of glucocorticoids. The glucocorticoid receptor (GR) is critical for this negative feedback to regulate CRH synthesis and release. Hypertension is associated with high stress response and CRH mRNA levels. The number of CRH-expression neurons are significantly increased in PVN of the hypothalamus in primary hypertension patients. this study determined if the HPA axis negative feedback is altered and contribute to maintaining hypertension. We measured mRNA expression levels of GRs and MR in PVN tissue obtained from adult Wistar-Kyoto normotensive rats (WKYs) and spontaneously hypertensive rats (SHRs) and found that the GR mRNA expression level was significantly lower in SHRs that in WKY rats, while the MR gene expression did not differ between WKY rats and SHRs. Furthermore, we found that acute perfusion of dexamethasone (DEX), a synthetic glucocorticoid, significantly decreased frequency of spontaneous excitatory postsynaptic synaptic currents (EPSCs) in identified PVN-CRH expressing neurons in brain slices prepared from WKY and SHRs. DEX caused a greater reduction of frequency of EPSCs in SHRs was than in WKY rats. Acute perfusion of DEX significantly increased the firing rate of PVN-CRH neurons in WKY rats but did not change the firing rate in SHRs. In addition, incubation of brain slices with DEX for 1 hr significantly inhibited the firing activity of PVN-CRH neurons in WKY rats but did not change the firing activity of PVN CRH neurons in SHRs. These data suggested that the glucocorticoid excites PVN-CRH neurons in acute phase while inhibits these neurons in chronic phase in normotensive rat. In hypertension, downregulated GR may be responsible for impaired the HPA axis feedback and contribute to hypertension. HL139523, HL142133, and HL159157. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Clinical Approach to Adrenal Insufficiency

Adrenal insufficiency refers to inadequate production of glucocorticoids, mineralocorticoids, or both by the adrenal glands. This may result from dysfunction or complete destruction of the adrenal cortex (primary adrenal insufficiency), inadequate adrenocorticotropic hormone production by the pituitary (secondary adrenal insufficiency), or inadequate corticotropin-releasing hormone production by the hypothalamus (tertiary adrenal insufficiency). Diagnosis of adrenal insufficiency requires a high index of suspicion because of its nonspecific signs and symptoms. It is associated with a high morbidity and low quality of life even in patients on treatment. When it presents as adrenal crisis it has a high mortality. Glucocorticoid replacement is the mainstay of management, and this may be combined with mineralocorticoids in the case of primary adrenal insufficiency. Health care personnel must be reminded of this condition, to improve rates of early diagnosis and improve outcomes in management. In this review, we also look at the management of adrenal insufficiency in special populations and the potential role of newer long-acting steroids in the management of adrenal insufficiency is briefly discussed.

Changes in Cortisol Secretion and Corticosteroid Receptors in COVID-19 and Non COVID-19 Critically Ill Patients with Sepsis/Septic Shock and Scope for Treatment.

Sepsis is associated with dysregulated cortisol secretion, leading to abnormal levels of cortisol in the blood. In the early stages of the condition, cortisol levels are typically elevated due to increased secretion from the adrenal glands. However, as the disease progresses, cortisol levels may decline due to impaired adrenal function, leading to relative adrenal insufficiency. The latter is thought to be caused by a combination of factors, including impaired adrenal function, decreased production of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) by the hypothalamus and pituitary gland, and increased breakdown of cortisol. The dysregulation of cortisol secretion in sepsis is thought to contribute to the pathophysiology of the disease by impairing the body's ability to mount an appropriate inflammatory response. Given the dysregulation of cortisol secretion and corticosteroid receptors in sepsis, there has been considerable interest in the use of steroids as a treatment. However, clinical trials have yielded mixed results and corticosteroid use in sepsis remains controversial. In this review, we will discuss the changes in cortisol secretion and corticosteroid receptors in critically ill patients with sepsis/septic shock. We will also make special note of COVID-19 patients, who presented a recent challenge for ICU management, and explore the scope for corticosteroid administration in both COVID-19 and non-COVID-19 septic patients.

A Review Article of Corticotrophin-Releasing Hormone and Preterm Birth: A Placental Clock

Preterm Birth is one of the main causes of infant mortality and morbidity worldwide. An estimated 15 million preterm births are birthed each year. Preterm Birth is not a single disease but a complex syndrome. The placenta's production of Corticotrophin-Releasing Hormone (CRH) is one theory for Preterm Birth. The peptide hormone CRH, which levels rise exponentially during pregnancy, has been linked to preterm Birth due to its endocrine, autocrine, and paracrine functions. It has been suggested that CRH functions as a component of the placental clock, with preterm Birth occurring when the placental clock is activated too early. In this review article, we will discuss Preterm Birth and the role of CRH in Preterm Birth. Keywords: Preterm Birth, Corticotrophin-Releasing Hormone (CRH), Placental clock

Local production of corticotropin-releasing hormone in prefrontal cortex modulates male-specific novelty exploration

Neuromodulatory substances can be released from distal afferents for communication between brain structures or produced locally to modulate neighboring circuit elements. Corticotropin-releasing hormone (CRH) from long-range neurons in the hypothalamus projecting to the medial prefrontal cortex (mPFC) has been shown to induce anxiety-like behaviors. However, the role of CRH produced in the mPFC has not been investigated. Here we demonstrate that a specific class of mPFC interneurons that express CRH (CrhINs) releases CRH upon high-frequency stimulation to enhance excitability of layer 2/3 pyramidal cells (L2/3 PCs) expressing the CRH receptors. When stimulated at low frequency, CrhINs release GABA resulting in the inhibition of oxytocin receptor-expressing interneurons (OxtrINs) and L2/3 PCs. Conditional deletion of CRH in mPFC CrhINs and chemogenetic activation of CrhINs have opposite effects on novelty exploration in male but not in female mice, and do not affect anxiety-related behaviors in either males or females. Our data reveal that CRH produced by local interneurons in the mPFC is required for sex-specific novelty exploration and suggest that our understanding of complex behaviors may require knowledge of local and remote neuromodulatory action.

Differential Expression of Hypothalamic and Gill-crh System With Osmotic Stress in the Euryhaline Black Porgy, Acanthopagrus schlegelii.

The local gill production of corticotropin releasing hormone (crh) and crh-receptor (crhr) is hypothesized to play important roles during seawater (SW) and freshwater (FW) acclimation in euryhaline black porgy (Acanthopagrus schlegelii). The mRNA expression of crh, crhr, and Na+/K+-ATPase (a-nka) was examined in SW and FW diencephalon (Dien) and in the gills at different exposure time by Q-PCR analysis. The in situ hybridization results indicate that crh mRNA hybridization signals were more abundant in FW fish in the gigantocellular (PMgc) and parvocellular (PMpc) part of the magnocellular preoptic nucleus versus SW fish. The crh and crhr-expressing cells were located in basal cells of gill filament. Furthermore, in vitro dexamethasone (DEX) treatment could increase the crh-system in the gill. Increased transcripts of the crh-system in the gill via in vitro and in vivo CRH treatments suggest that CRH may regulate the system in a local manner. The a-Nka cells were localized in the filament and secondary lamellae mitochondria rich cells (MRCs) of FW fish at 8 h and 1 day. a-Nka cells were seen in both filament and lamellae in the FW but much less in SW fish indicating that gills play key roles in black porgy osmoregulation. Gill crh and crhr play important roles in the response to salinity stress.

Parity-related variation in cortisol concentrations in hair during pregnancy.

ObjectiveTo investigate hair cortisol concentrations (HCC) monthly in pregnant women and to explore the effect of parity.DesignProspective cohort study from gestational week (GW) 26, at childbirth and postpartum.SettingAn antenatal care clinic in southeast Sweden.Sample390 pregnant women.MethodsCortisol was measured using radioimmunoassay in methanol extracts of ground hair samples.Main outcome measuresHair cortisol concentrations.ResultsBoth primi‐ and multiparae exhibited an increase in HCC throughout pregnancy. Primiparae had significantly higher HCC in the latter part of the last trimester compared with multiparae (1 month P = 0.003, 2 months P = 0.038). The use of psychotropic medication in the first trimester correlated to HCC postpartum (P < 0.001). HCC in GW 14–17 was associated with HCC in GW 18–21 (primiparae and multiparae, P < 0.001), GW 22–25 (primiparae P = 0.036, multiparae P = 0.033), and 2 months postpartum (primiparae P = 0.049). HCC in GW 18–21 was associated with GW 22–25 in both primiparae (P < 0.001) and multiparae (P < 0.001) as well as 2 months prior to childbirth among primiparae (<0.037). In general, all estimates of HCC in pregnancy and postpartum showed a significant association between HCC for a specific month and the HCC in the previous month (all P < 0.001), except for the association of HCC among primiparae in GW 22–25 and 3 months prior to childbirth.ConclusionsIncreased cortisol concentrations in hair were observed during pregnancy, which decreased 3 months prior to childbirth in multiparae. The results indicate a quicker suppression of the hypothalamic CRH (corticotropin‐releasing hormone) production by placenta CRH in multiparous women.Tweetable abstractMultiparae have a quicker suppression of hypothalamic CRH production by placenta CRH during pregnancy compared to primiparae.

Perbedaan Jumlah Sel Neuron Cerebrum dan Cerebellum Mus musculus pada Kehamilan Remaja dan Dewasa

Teenage pregnancy contributes to emotional stress higher than adult women Pregnancy in adolescents will trigger negative thoughts and feelings of fear that become the root cause of stress reactions. The onset of stress will trigger the occurrence of Axis HPA activity and the release of corticotrophin releasing hormone (CRH) by the paraventricular nucleus of the hypothalamus, then stimulate the production of adrenencorticotropic hormone (ACTH) by the anterior pituitary gland. ACTH will stimulate glucocorticoids (cortisol) from the adrenal gland cortex to increase the production of CRH in the placenta and give an effect of increasing cortisol in the maternal, as well as the amount of cortisol in the fetus will also increase because it follows the blood placenta barrier. This affects the growth and development of the fetal brain, so that the process of proliferation and differentiation, migration, organization and synaptogenesis and myelination in brain cells. The growth of the brain decreases which affects the number of neuron cells. This study aims to analyze the differences in the number of neuron cells in the cerebrum and cerebellum Mus musculus newly born in adolescent and adult pregnancy. The division of the study group consisted of two groups, namely the adolescent and adult pregnancy groups each of 16 individuals. Taking the examination sample is by taking each of the 3 children from the parent with the heaviest, medium and lowest weights. Then the Mus musculus children were sacrificed by anesthesia and decapitation, then Hematoxilin-Eosin preparations were made from the child's brain. The next step is to examine Hematoxilin-Eosin to calculate the number of neuron cells in the cerebrum and cerebellum with the analysis of the Independent T test showing significant differences between the control and treatment groups with a value of p = 0,000 (p &lt;0.05). Then the analysis of the number of brain neuron cells using the Mann Whitney test showed a difference that the control group was higher than the adolescent group.

The Difference of Brain Derivat Neutrophic Factor of Mus Musculus Newborn from Adolescent and Adult Pregnancy

Background: The brain is the main organ involved in stress adaptation, while being the target of stress. Stress activates the hypothalamic-pituitary-adrenal (HPA) axis and the system is adrenomedular Simpato thereby increasing the production of corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP) resulting in lower levels of Brain Derived Neurotrophic Factor (BDNF) in the hippocampus. Objective: The study aims to find out the difference of BDNFof Mus musculus newborn brain fromadolescents and adults pregnancy. Method: The samples on this study were 32 mice that divided by 2 groups were adolescent pregnancy mice group and adult pregnancy mice group. Mus musculus newborn were born by sectio and selected three with the heaviest, medium and lightest of each mothers to sacrificed their brains did decapitated and made immunohypochemical preparations and continued examination of the Immunoreactive Score to calculate Brain Derived Neurotrophic Factor expression. Result: BDNF expression of adolescent pregnancy mice group had higher (5.65±1.044) than adult pregnancy mice group (4.15±1,049). Test results showed that there was differences of BDNF expression in the brain p = 0,000 (p< 0.05) with details, there were differences in the cerebrum p = 0,015 and the cerebellum p = 0,000 between adolescent pregnancy mice group and adult pregnancy mice group. Conclusion: BDNF expression in brain of Mus musculus newborn from adolescent pregnancy lower than Mus musculus newborn from adult pregnancy.

Local secretion of stress hormones increases in alopecia areata lesions after treatment with UVA-1 phototherapy.

Alopecia areata (AA) is an autoimmune disease of the hair follicle. Keratinocytes of the hair follicle generate an immunosuppressive environment by the local secretion of hormones of the hypothalamic-pituitary-adrenal axis of the skin (skin HPA analog). Our objective was to measure the local production of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and α-melanocyte-stimulating hormone (α-MSH) in the scalp tissue of patients with AA before and after ultraviolet A1 (UVA-1) phototherapy to determine their role in the pathogenesis of AA and the effect of UVA-1 on the AA hormonal environment. This was a retrospective and descriptive study of skin samples from 22 patients with AA before and after UVA-1 treatment. We compared the changes in the local hormonal environment by measuring CRH, ACTH, type 2 melanocortin receptor (ACTH receptor) and α-MSH with immunohistochemical stains. The positivity of MSH was significantly higher (P=.037) in the post-treatment samples compared with the baseline value. ACTH was significantly higher in intensity (P=.032) in the post-treatment samples compared with the initial value. CRH was significantly higher in intensity (P=.013) in baseline samples compared with the final biopsies. The positivity of the ACTH receptor MC2R was not different between the two groups (P=.626). In AA, an interruption in the signalling of CRH could decrease the local concentration of ACTH and MSH, and consequently, the immunosuppressive effect of these hormones. This phenomenon is normalized in the skin treated with UVA-1. A defective signalling system in the cutaneous HPA axis may be involved in the pathogenesis of AA.

Impact of mast cells in fibromyalgia and low-grade chronic inflammation: Can IL-37 play a role?

Fibromyalgia (FM) is a disease characterized by chronic widespread pain, fatigue, aches, joint stiffness, depression, cognitive dysfunction, and nonrestorative sleep. In FM, neurotransmission and glial activation can occur with an increase in inflammatory cytokines and involvement of mast cells (MCs) in the skin. FM skin biopsies show an increase in the number of MCs, as well as the production of corticotropin releasing hormone and substance P (SP) by the neurons, which in turn activate MCs to release neurosensitizing proinflammatory substances, such as cytokines, secreted preformed mediators, and lipids, which can exacerbate low-grade inflammation. In fact, certain proinflammatory cytokines are higher in FM and mediate muscle pain, the mechanism of which is not yet clear. MC-derived tumor necrosis factor (TNF) induces nerve growth factor (NGF) and participates in nerve fiber elongation in skin hypersensitivity. IL-37 is an inhibitor of proinflammatory IL-1 family members, which are generated and released by MCs. The goal of this article is to demonstrate that inflammatory cytokines and MC products play a role in FM and that inflammation may be inhibited by IL-37. Here, we propose IL-37 as a cytokine that contributes to improve the pathogenesis of FM by blocking IL-1 family members.

Pre‐autonomic corticotropin‐releasing hormone neurons in the paraventricular nucleus of the hypothalamus may contribute to chronic unpredictable stress‐induced blood pressure hyperreactivity

Exposure to chronic unpredictable stress (CUS) has been shown to augment the pressor response to novel stress. The neural circuits mediating the CUS induced blood pressure hyperreactivity are not fully understood. Exposure to CUS is known to increase the production of corticotropin‐releasing hormone (CRH) in the paraventricular nucleus of the hypothalamus (PVN). A subpopulation of PVN CRH neurons project to the rostroventral medulla (RVLM), a key nucleus regulating sympathetic outflow and blood pressure. To study how CUS exposure affect RVLM‐projecting CRH neurons in the PVN, we injected retrograde AAV expressing Cre‐inducible mCherry into the RVLM of CRH‐Cre mice. We then exposed mice to the a CUS paradigm. The CUS paradigm included the following stressors: hot air stream (10 min), cold temperature (4°C, 1h), fox urine exposure (10 min), hypoxia (10% oxygen, 20 min), shaker (100 oscillations/min, 1h), forced swimming (10 min). These stressors were randomly assigned to the mice twice daily for 14 days. We found that mice exposed to the CUS had significantly increased number of RVLM‐projecting CRH neurons in the PVN compared to mice that were not exposed to the CUS (CON, 32 ± 4 vs CUS 81 ± 9; p = 0.003). To study whether RVLM‐projecting CRH neurons in the PVN regulates blood pressure, we expressed Channelrhodopsin 2 (ChR2) specifically into the PVN CRH neurons by injecting AAV expressing Cre‐inducible ChR2 into the PVN of CRH‐Cre mice. Optogenetic activation of CRH fibers in the RVLM significantly increased blood pressure (7 ± 1 mmHg). These results indicate that CUS can induce CRH production in a large population of PVN preautonomic neurons that do not produce CRH in basal condition. This population of plastic RVLM‐projecting CRH neurons in the PVN may contribute to CUS induced blood pressure hyperreactivity.Support or Funding InformationThis work was supported by American Heart Association Postdoctoral Fellowship 18POST34050013 and National Heart, Lung, and Blood Institute PO1 Grant HL‐088052.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Screening a small molecule library to identify inhibitors of NF-\u03baB inducing kinase and pro-labor genes in human placenta

The non-canonical NF-κB signaling (RelB/p52) pathway drives pro-labor genes in the human placenta, including corticotropin-releasing hormone (CRH) and cyclooxygenase-2 (COX-2), making this a potential therapeutic target to delay onset of labor. Here we sought to identify small molecule compounds from a pre-existing chemical library of orally active drugs that can inhibit this NF-κB signaling, and in turn, human placental CRH and COX-2 production. We used a cell-based assay coupled with a dual-luciferase reporter system to perform an in vitro screening of a small molecule library of 1,120 compounds for inhibition of the non-canonical NF-κB pathway. Cell toxicity studies and drug efflux transport MRP1 assays were used to further characterize the lead compounds. We have found that 14 drugs have selective inhibitory activity against lymphotoxin beta complex-induced activation of RelB/p52 in HEK293T cells, several of which also inhibited expression of CRH and COX-2 in human term trophoblast. We identified sulfapyridine and propranolol with activity against CRH and COX-2 that deserve further study. These drugs could serve as the basis for development of orally active drugs to affect length of gestation, first in an animal model, and then in clinical trials to prevent preterm birth during human pregnancy.

Molecular diversity of corticotropin-releasing hormone mRNA-containing neurons in the hypothalamus.

Hormonal responses to acute stress rely on the rapid induction of corticotropin-releasing hormone (CRH) production in the mammalian hypothalamus, with subsequent instructive steps culminating in corticosterone release at the periphery. Hypothalamic CRH neurons in the paraventricular nucleus of the hypothalamus are therefore considered as 'stress neurons'. However, significant morphological and functional diversity among neurons that can transiently produce CRH in other hypothalamic nuclei has been proposed, particularly as histochemical and molecular biology evidence associates CRH to both GABA and glutamate neurotransmission. Here, we review recent advances through single-cell RNA sequencing and circuit mapping to suggest that CRH production reflects a state switch in hypothalamic neurons and thus confers functional competence rather than being an identity mark of phenotypically segregated neurons. We show that CRH mRNA transcripts can therefore be seen in GABAergic, glutamatergic and dopaminergic neuronal contingents in the hypothalamus. We then distinguish 'stress neurons' of the paraventricular nucleus that constitutively express secretagogin, a Ca2+ sensor critical for the stimulus-driven assembly of the molecular machinery underpinning the fast regulated exocytosis of CRH at the median eminence. Cumulatively, we infer that CRH neurons are functionally and molecularly more diverse than previously thought.

Skin Exposure to Ultraviolet B Rapidly Activates Systemic Neuroendocrine and Immunosuppressive Responses.

The back skin of C57BL/6 mice was exposed to a single 400 mJ cm-2 dose of ultraviolet B (UVB), and parameters of hypothalamic-pituitary-adrenal (HPA) axis in relation to immune activity were tested after 30-90 min following irradiation. Levels of brain and/or plasma corticotropin-releasing hormone (CRH), β-endorphin, ACTH and corticosterone (CORT) were enhanced by UVB. Hypophysectomy had no effect on UVB-induced increases of CORT. Mitogen-induced IFNγ production by splenocytes from UVB-treated mice was inhibited at 30, 90 min and after 24 h. UVB also led to inhibition of IL-10 production indicating an immunosuppressive effect on both Th1 and Th2 cytokines. Conditioned media from splenocytes isolated from UVB-treated animals had no effect on IFNγ production in cultured normal splenocytes; however, IFNγ increased with conditioned media from sham-irradiated animals. Sera from UVB-treated mice suppressed T-cell mitogen-induced IFNγ production as compared to sera from sham-treated mice. IFNγ production was inhibited in splenocytes isolated from UVB-treated animals with intact pituitary, while stimulated in splenocytes from UVB-treated hypophysectomized mice. Thus, cutaneous exposure to UVB rapidly stimulates systemic CRH, ACTH, β-endorphin and CORT production accompanied by rapid immunosuppressive effects in splenocytes that appear to be independent of the HPA axis.

Loss of hypothalamic corticotropin-releasing hormone markedly reduces anxiety behaviors in mice.

A long-standing paradigm posits that hypothalamic corticotropin-releasing hormone (CRH) regulates neuroendocrine functions such as adrenal glucocorticoid release, while extra-hypothalamic CRH plays a key role in stressor-triggered behaviors. Here we report that hypothalamus-specific Crh knockout mice (Sim1CrhKO mice, created by crossing Crhflox with Sim1Cre mice) have absent Crh mRNA and peptide mainly in the paraventricular nucleus of the hypothalamus (PVH) but preserved Crh expression in other brain regions including amygdala and cerebral cortex. As expected, Sim1CrhKO mice exhibit adrenal atrophy as well as decreased basal, diurnal and stressor-stimulated plasma corticosterone secretion and basal plasma ACTH, but surprisingly, have a profound anxiolytic phenotype when evaluated using multiple stressors including open field, elevated plus maze, holeboard, light-dark box, and novel object recognition task. Restoring plasma corticosterone did not reverse the anxiolytic phenotype of Sim1CrhKO mice. Crh-Cre driver mice revealed that PVHCrh fibers project abundantly to cingulate cortex and the nucleus accumbens shell, and moderately to medial amygdala, locus coeruleus, and solitary tract, consistent with the existence of PVHCrh-dependent behavioral pathways. Although previous, nonselective attenuation of CRH production or action, genetically in mice and pharmacologically in humans, respectively, has not produced the anticipated anxiolytic effects, our data show that targeted interference specifically with hypothalamic Crh expression results in anxiolysis. Our data identify neurons that express both Sim1 and Crh as a cellular entry point into the study of CRH-mediated, anxiety-like behaviors and their therapeutic attenuation.

Alterations in the corticotropin-releasing hormone (CRH) neurocircuitry: Insights into post stroke functional impairments.

Although it is well accepted that changes in the regulation of the hypothalamic-pituitary adrenal (HPA) axis may increase susceptibility to affective disorders in the general population, this link has been less examined in stroke patients. Yet, the bidirectional association between depression and cardiovascular disease is strong, and stress increases vulnerability to stroke. Corticotropin-releasing hormone (CRH) is the central stress hormone of the HPA axis pathway and acts by binding to CRH receptors (CRHR) 1 and 2, which are located in several stress-related brain regions. Evidence from clinical and animal studies suggests a role for CRH in the neurobiological basis of depression and ischemic brain injury. Given its importance in the regulation of the neuroendocrine, autonomic, and behavioral correlates of adaptation and maladaptation to stress, CRH is likely associated in the pathophysiology of post stroke emotional impairments. The goals of this review article are to examine the clinical and experimental data describing (1) that CRH regulates the molecular signaling brain circuit underlying anxiety- and depression-like behaviors, (2) the influence of CRH and other stress markers in the pathophysiology of post stroke emotional and cognitive impairments, and (3) context and site specific interactions of CRH and BDNF as a basis for the development of novel therapeutic targets. This review addresses how the production and release of the neuropeptide CRH within the various regions of the mesocorticolimbic system influences emotional and cognitive behaviors with a look into its role in psychiatric disorders post stroke.

MID-PREGNANCY CORTICOTROPIN-RELEASING HORMONE LEVELS IN ASSOCIATION WITH POSTPARTUM DEPRESSIVE SYMPTOMS.

Peripartum depression is a common cause of pregnancy- and postpartum-related morbidity. The production of corticotropin-releasing hormone (CRH) from the placenta alters the profile of hypothalamus-pituitary-adrenal axis hormones and may be associated with postpartum depression. The purpose of this study was to assess, in nondepressed pregnant women, the possible association between CRH levels in pregnancy and depressive symptoms postpartum. A questionnaire containing demographic data and the Edinburgh Postnatal Depression Scale (EPDS) was filled in gestational weeks 17 and 32, and 6 week postpartum. Blood samples were collected in week 17 for assessment of CRH. A logistic regression model was constructed, using postpartum EPDS score as the dependent variable and log-transformed CRH levels as the independent variable. Confounding factors were included in the model. Subanalyses after exclusion of study subjects with preterm birth, newborns small for gestational age (SGA), and women on corticosteroids were performed. Five hundred thirty-five women without depressive symptoms during pregnancy were included. Logistic regression showed an association between high CRH levels in gestational week 17 and postpartum depressive symptoms, before and after controlling for several confounders (unadjusted OR = 1.11, 95% CI 1.01-1.22; adjusted OR = 1.13, 95% CI 1.02-1.26; per 0.1 unit increase in log CRH). Exclusion of women with preterm birth and newborns SGA as well as women who used inhalation corticosteroids during pregnancy did not alter the results. This study suggests an association between high CRH levels in gestational week 17 and the development of postpartum depressive symptoms, among women without depressive symptoms during pregnancy.

The Nutrient and Energy Sensor Sirt1 Regulates the Hypothalamic-Pituitary-Adrenal (HPA) Axis by Altering the Production of the Prohormone Convertase 2 (PC2) Essential in the Maturation of Corticotropin-releasing Hormone (CRH) from Its Prohormone in Male Rats

Understanding the role of hypothalamic neuropeptides and hormones in energy balance is paramount in the search for approaches to mitigate the obese state. Increased hypothalamic-pituitary-adrenal axis activity leads to increased levels of glucocorticoids (GC) that are known to regulate body weight. The axis initiates the production and release of corticotropin-releasing hormone (CRH) from the paraventricular nucleus (PVN) of the hypothalamus. Levels of active CRH peptide are dependent on the processing of its precursor pro-CRH by the action of two members of the family of prohormone convertases 1 and 2 (PC1 and PC2). Here, we propose that the nutrient sensor sirtuin 1 (Sirt1) regulates the production of CRH post-translationally by affecting PC2. Data suggest that Sirt1 may alter the preproPC2 gene directly or via deacetylation of the transcription factor Forkhead box protein O1 (FoxO1). Data also suggest that Sirt1 may alter PC2 via a post-translational mechanism. Our results show that Sirt1 levels in the PVN increase in rats fed a high fat diet for 12 weeks. Furthermore, elevated Sirt1 increased PC2 levels, which in turn increased the production of active CRH and GC. Collectively, this study provides the first evidence supporting the hypothesis that PVN Sirt1 activates the hypothalamic-pituitary-adrenal axis and basal GC levels by enhancing the production of CRH through an increase in the biosynthesis of PC2, which is essential in the maturation of CRH from its prohormone, pro-CRH.

Variation in the corticotropin-releasing hormone receptor 1 (CRHR1) gene modulates age effects on working memory

Decline in working memory (WM) functions during aging has been associated with hippocampal dysfunction mediated by age-related changes to the corticotropin-releasing hormone (CRH) system. Recent reports suggest that GG-homozygous individuals of single nucleotide polymorphisms (rs110402 and rs242924) in the CRH receptor 1 (CRHR1) gene show increased stress vulnerability and decreased BOLD responses in WM relevant regions. However, until now, no study investigated the interaction effects of variation in the CRHR1 gene and age on individual differences in WM.Here, young, middle-aged and old subjects (N = 466) were genotyped for rs110402 and rs242924 within the CRHR1 gene and an n-back task was used to investigate the hypothesis that vulnerable genotypes (GG-homozygotes) would show impaired WM functions that might be magnified by increased CRH production with advancing age. Our results show an impact of genotype already in middle-age with significantly better performance in AT-carriers. Working memory performance in AT-carriers did not differ between young and middle-aged subjects, but was significantly impaired in old age. In GG-homozygotes, severe working memory dysfunction occurred already in middle age. Our data indicate that GG-homozygotes of CRHR1 rs110402 and rs242924 represent a genetically driven subtype of early WM impairments due to alterations in hippocampal CRHR1 activation. Early interventions that have proven effective in delaying cognitive decline appear to be particularly important for these subjects at risk for premature memory decline, who are in the prime of their personal and professional lives.