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1.
Commun Biol ; 7(1): 345, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38509283

RESUMO

The scaffolding A-kinase anchoring protein 150 (AKAP150) is critically involved in kinase and phosphatase regulation of synaptic transmission/plasticity, and neuronal excitability. Emerging evidence also suggests that AKAP150 signaling may play a key role in brain's processing of rewarding/aversive experiences, however its role in the lateral habenula (LHb, as an important brain reward circuitry) is completely unknown. Using whole cell patch clamp recordings in LHb of male wildtype and ΔPKA knockin mice (with deficiency in AKAP-anchoring of PKA), here we show that the genetic disruption of PKA anchoring to AKAP150 significantly reduces AMPA receptor-mediated glutamatergic transmission and prevents the induction of presynaptic endocannabinoid-mediated long-term depression in LHb neurons. Moreover, ΔPKA mutation potentiates GABAA receptor-mediated inhibitory transmission while increasing LHb intrinsic excitability through suppression of medium afterhyperpolarizations. ΔPKA mutation-induced suppression of medium afterhyperpolarizations also blunts the synaptic and neuroexcitatory actions of the stress neuromodulator, corticotropin releasing factor (CRF), in mouse LHb. Altogether, our data suggest that AKAP150 complex signaling plays a critical role in regulation of AMPA and GABAA receptor synaptic strength, glutamatergic plasticity and CRF neuromodulation possibly through AMPA receptor and potassium channel trafficking and endocannabinoid signaling within the LHb.


Assuntos
Hormônio Liberador da Corticotropina , Habenula , Animais , Masculino , Camundongos , Proteínas de Ancoragem à Quinase A/genética , Proteínas de Ancoragem à Quinase A/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Endocanabinoides , Habenula/metabolismo , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Receptores de GABA-A/metabolismo , Transmissão Sináptica/fisiologia
2.
J Integr Neurosci ; 23(2): 41, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38419452

RESUMO

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.


Assuntos
Hormônio Liberador da Corticotropina , Serotonina , Humanos , Ratos , Animais , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/metabolismo , Serotonina/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Depressão/etiologia , Privação Materna , Sistema Hipófise-Suprarrenal/metabolismo , Encéfalo/metabolismo , Hiperfagia/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Estresse Psicológico
3.
PLoS One ; 19(2): e0294918, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38408050

RESUMO

BACKGROUND: Variation of circulating concentrations of putative biomarkers of intestinal barrier function over the day and after acute physiological interventions are poorly documented on humans. This study aimed to examine the stability and pharmacokinetics of changes in plasma concentrations of intestinal Fatty-acid -binding -protein (IFABP), Lipopolysaccharide-binging-protein (LBP), soluble CD14, and Syndecan-1 after acute stress and high fat-high-carbohydrate meal. METHODS: In a single-blinded, cross-over, randomised study, healthy volunteers received on separate days corticotropin-releasing hormone (CRH, 100 µg) or normal saline (as placebo) intravenously in random order, then a HFHC meal. Participants were allowed low caloric food. Markers of intestinal barrier function were measured at set timed intervals from 30 minutes before to 24 hours after interventions. RESULTS: 10 participants (50% female) completed all three arms of the study. IFABP decreased by median 3.6 (IQR 1.4-10)% from -30 minutes to zero time (p = 0.001) and further reduced by 25 (20-52)% at 24 hours (p = 0.01) on the low caloric diet, but did not change in response to the meal. Syndecan-1, LBP and sCD14 were stable over a 24-hour period and not affected acutely by food intake. LBP levels 2 hours after CRH reduced by 0.61 (-0.95 to 0.05) µg/ml compared with 0.16 (-0.3 to 0.5) µg/ml post placebo injection (p = 0.05), but other markers did not change. CONCLUSION: Concentrations of IFABP, but not other markers, are unstable over 24 hours and should be measured fasting. A HFHC meal does not change intestinal permeability. Transient reduction of LPB after CRH confirms acute barrier dysfunction during stress.


Assuntos
Hormônio Liberador da Corticotropina , Sindecana-1 , Humanos , Feminino , Masculino , Hormônio Liberador da Corticotropina/metabolismo , Lipopolissacarídeos , Biomarcadores
4.
Int J Mol Sci ; 25(3)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38339042

RESUMO

We have previously proven the involvement of transient receptor potential ankyrin 1 (TRPA1) in stress adaptation. A lack of TRPA1 affects both urocortin 1 (member of the corticotropin-releasing hormone (CRH) family) content of the Edinger-Westphal nucleus. The noradrenergic locus ceruleus (LC) is also an important player in mood control. We aimed at investigating whether the TRPA1 is expressed in the LC, and to test if the response to chronic variable mild stress (CVMS) is affected by a lack of TRPA1. The TRPA1 expression was examined via RNAscope in situ hybridization. We investigated TRPA1 knockout and wildtype mice using the CVMS model of depression. Tyrosine hydroxylase (TH) and FOSB double immunofluorescence were used to test the functional neuromorphological changes in the LC. No TRPA1 expression was detected in the LC. The TH content was not affected by CVMS exposure. The CVMS-induced FOSB immunosignal did not co-localize with the TH neurons. TRPA1 is not expressed in the LC. A lack of functional TRPA1 receptor neither directly nor indirectly affects the TH content of LC neurons under CVMS.


Assuntos
Locus Cerúleo , Estresse Psicológico , Canal de Cátion TRPA1 , Animais , Camundongos , Hormônio Liberador da Corticotropina/metabolismo , Expressão Gênica , Locus Cerúleo/fisiopatologia , Urocortinas/metabolismo , Canal de Cátion TRPA1/genética , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologia , Tirosina 3-Mono-Oxigenase/metabolismo
5.
Biomed Res Int ; 2024: 8322844, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38327803

RESUMO

Neuroimaging data in humans and neurobiological studies in rodents have suggested an involvement of the insular cortex (IC) in anxiety manifestations. However, the local neurochemical mechanisms involved are still poorly understood. Corticotropin-releasing factor (CRF) neurotransmission has been described as a prominent neurochemical mechanism involved in the expression of anxiety-like behaviors, but the brain sites related are poorly understood. Additionally, several findings indicate that control of physiological and behavioral responses by the IC occurs in a site-specific manner along its rostrocaudal axis. Thus, this study is aimed at evaluating the effect of CRF receptor agonism and antagonism within the anterior and posterior subregions of the IC in controlling anxiety-related behaviors in the elevated plus maze (EPM). For this, independent groups (six groups) of animals received bilateral microinjections of vehicle, the selective CRF1 receptor antagonist CP376395, or CRF into either the anterior or posterior subregions of the IC. Ten minutes later, the behavior in the EPM was evaluated for five minutes. Treatment of the anterior IC with CP376395, but not with CRF, increased the time and number of entries into the open arms of the EPM. CRF, but not the CRF1 receptor antagonist, microinjected into the posterior IC also increased exploration of the EPM open arms. Taken together, these data indicate that CRFergic neurotransmission in the anterior IC is involved in the expression of anxiety-related behaviors in the EPM. This neurochemical mechanism does not seem to be activated within the posterior IC during exposure to the EPM, but the effects caused by CRF microinjection indicate that activation of CRF receptors in this IC subregion might evoke anxiolytic-like effects.


Assuntos
Aminopiridinas , Ansiolíticos , Receptores de Hormônio Liberador da Corticotropina , Humanos , Ratos , Animais , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Hormônio Liberador da Corticotropina/farmacologia , Hormônio Liberador da Corticotropina/metabolismo , Teste de Labirinto em Cruz Elevado , Córtex Insular , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Ansiolíticos/farmacologia
6.
Psychoneuroendocrinology ; 163: 106994, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38387218

RESUMO

Placental corticotropin-releasing hormone (pCRH) is a neuroactive peptide produced in high concentrations in mid-late pregnancy, during key periods of fetal brain development. Some evidence suggests that higher pCRH exposure during gestation is associated with adverse neurodevelopment, particularly in female offspring. In 858 mother-child dyads from the sociodemographically diverse CANDLE cohort (Memphis, TN), we examined: (1) the slope of pCRH rise in mid-late pregnancy and (2) estimated pCRH at delivery as a measure of cumulative prenatal exposure. When children were 4 years-old, mothers reported on problem behaviors using the Child Behavior Checklist (CBCL) and cognitive performance was assessed by trained psychologists using the Stanford-Binet Intelligence Scales. We fitted linear regression models examining pCRH in relation to behavioral and cognitive performance measures, adjusting for covariates. Using interaction models, we evaluated whether associations differed by fetal sex, breastfeeding, and postnatal neighborhood opportunity. In the full cohort, log-transformed pCRH measures were not associated with outcomes; however, we observed sex differences in some models (interaction p-values≤0.01). In male offspring, an interquartile (IQR) increase in pCRH slope (but not estimated pCRH at delivery), was positively associated with raw Total (ß=3.06, 95%CI: 0.40, 5.72), Internalizing (ß=0.89, 95%CI: 0.03, 1.76), and Externalizing (ß=1.25, 95%CI: 0.27, 2.22) Problem scores, whereas, in females, all associations were negative (Total Problems: ß=-1.99, 95%CI: -3.89, -0.09; Internalizing: ß=-0.82, 95%CI: -1.42, -0.23; Externalizing: ß=-0.56, 95%CI: -1.34, 0.22). No associations with cognitive performance were observed nor did we observe moderation by breastfeeding or postnatal neighborhood opportunity. Our results provide further evidence that prenatal pCRH exposure may impact subsequent child behavior in sex-specific ways, however in contrast to prior studies suggesting adverse impacts in females, steeper mid-gestation pCRH rise was associated with more problem behaviors in males, but fewer in females.


Assuntos
Efeitos Tardios da Exposição Pré-Natal , Comportamento Problema , Humanos , Gravidez , Feminino , Masculino , Pré-Escolar , Hormônio Liberador da Corticotropina , Placenta , Desenvolvimento Fetal , Cuidado Pré-Natal
7.
Zhongguo Zhong Yao Za Zhi ; 49(1): 208-215, 2024 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-38403353

RESUMO

This study aimed to investigate the regulatory effects of Zuogui Jiangtang Jieyu Formula(ZJJ) on the intestinal flora, short chain fatty acids(SCFAs), and neuroinflammation in rats with diabetes mellitus complicated depression(DD). The DD model was established in rats and model rats were randomly divided into a model group, a positive drug(metformin + fluoxetine) group, a ZJJ low-dose group, and a ZJJ high-dose group, with eight rats in each group. Another eight rats were assigned to the blank group. Subsequently, depressive-like behavior test was conducted on the rats, and cerebrospinal fluid samples were collected to measure pro-inflammatory cytokines [interleukin-1ß(IL-1ß), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α)]. Blood serum samples were collected to measure proteins related to the hypothalamic-pituitary-adrenal axis(HPA axis), including corticotropin-releasing hormone(CRH), adrenocorticotropic hormone(ACTH), and cortisol(CORT), as well as glucose metabolism. Gut contents were collected from each group for 16S rRNA sequencing analysis of intestinal flora and SCFAs sequencing. The results indicated that ZJJ not only improved glucose metabolism in DD rats(P<0.01) but also alleviated depressive-like behavior(P<0.05) and HPA axis hyperactivity(P<0.05 or P<0.01). Besides, it also improved the neuroinflammatory response in the brain, as evidenced by a significant reduction in pro-inflammatory cytokines in cerebrospinal fluid(P<0.05 or P<0.01). Additionally, ZJJ improved the intestinal flora, causing the intestinal flora in DD rats to resemble that of the blank group, characterized by an increased Firmicutes abundance. ZJJ significantly increased the levels of SCFAs(acetic acid, butyric acid, valeric acid, and isovaleric acid)(P<0.01). Therefore, it is deduced that ZJJ can effectively ameliorate intestinal flora dysbiosis, regulate SCFAs, and thereby improve both glucose metabolism disturbances and depressive-like behavior in DD.


Assuntos
Diabetes Mellitus , Medicamentos de Ervas Chinesas , Microbioma Gastrointestinal , Ratos , Animais , Sistema Hipotálamo-Hipofisário/metabolismo , Depressão/tratamento farmacológico , RNA Ribossômico 16S , Sistema Hipófise-Suprarrenal/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Citocinas/genética , Citocinas/metabolismo , Glucose/metabolismo , Ácidos Graxos Voláteis/metabolismo , Ácidos Graxos Voláteis/farmacologia
8.
J Affect Disord ; 351: 870-877, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38341156

RESUMO

The hypothalamus is a well-established core structure in the sleep-wake cycle. While previous studies have not consistently found whole hypothalamus volume changes in chronic insomnia disorder (CID), differences may exist at the smaller substructural level of the hypothalamic nuclei. The study aimed to investigate the differences in total and subfield hypothalamic volumes, between CID patients and healthy controls (HCs) in vivo, through an advanced deep learning-based automated segmentation tool. A total of 150 patients with CID and 155 demographically matched HCs underwent T1-weighted structural magnetic resonance scanning. We utilized FreeSurfer v7.2 for automated segmentation of the hypothalamus and its five nuclei. Additionally, correlation and causal mediation analyses were performed to investigate the association between hypothalamic volume changes, insomnia symptom severity, and hypothalamus-pituitary-adrenal (HPA) axis-related blood biomarkers. CID patients exhibited larger volumes in the right anterior inferior, left anterior superior, and left posterior subunits of the hypothalamus compared to HCs. Moreover, we observed a positive association between blood corticotropin-releasing hormone (CRH) levels and insomnia severity, with anterior inferior hypothalamus (a-iHyp) hypertrophy mediating this relationship. In conclusion, we found significant volume increases in several hypothalamic subfield regions in CID patients, highlighting the central role of the HPA axis in the pathophysiology of insomnia.


Assuntos
Hormônio Liberador da Corticotropina , Distúrbios do Início e da Manutenção do Sono , Humanos , Hormônio Liberador da Corticotropina/metabolismo , Distúrbios do Início e da Manutenção do Sono/diagnóstico por imagem , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Hipotálamo/diagnóstico por imagem
9.
Int J Mol Sci ; 25(3)2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38338760

RESUMO

Tobacco smoking is the leading cause of preventable death and disease. Although there are some FAD-approved medicines for controlling smoking, the relapse rate remains very high. Among the factors that could induce nicotine relapse, stress might be the most important one. In the last decades, preclinical studies have generated many new findings that lead to a better understanding of stress-induced relapse of nicotine-seeking. Several molecules such as α3ß4 nicotinic acetylcholine receptor, α2-adrenergic receptors, cannabinoid receptor 1, trace amine-associated receptor 1, and neuropeptide systems (corticotropin-releasing factor and its receptors, dynorphine and kappa opioid receptor) have been linked to stress-induced nicotine relapse. In this review, we discuss recent advances in the neurobiology, treatment targets, and potential therapeutics of stress-induced nicotine relapse. We also discuss some factors that may influence stress-induced nicotine relapse and that should be considered in future studies. In the final section, a perspective on some research directions is provided. Further investigation on the neurobiology of stress-induced nicotine relapse will shed light on the development of new medicines for controlling smoking and will help us understand the interactions between the stress and reward systems in the brain.


Assuntos
Receptores Nicotínicos , Tabagismo , Humanos , Nicotina/uso terapêutico , Tabagismo/tratamento farmacológico , Recompensa , Hormônio Liberador da Corticotropina/farmacologia , Recidiva
10.
Curr Biol ; 34(2): 389-402.e5, 2024 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-38215742

RESUMO

Aversive stimuli activate corticotropin-releasing factor (CRF)-expressing neurons in the paraventricular nucleus of hypothalamus (PVNCRF neurons) and other brain stress systems to facilitate avoidance behaviors. Appetitive stimuli also engage the brain stress systems, but their contributions to reward-related behaviors are less well understood. Here, we show that mice work vigorously to optically activate PVNCRF neurons in an operant chamber, indicating a reinforcing nature of these neurons. The reinforcing property of these neurons is not mediated by activation of the hypothalamic-pituitary-adrenal (HPA) axis. We found that PVNCRF neurons send direct projections to the ventral tegmental area (VTA), and selective activation of these projections induced robust self-stimulation behaviors, without activation of the HPA axis. Similar to the PVNCRF cell bodies, self-stimulation of PVNCRF-VTA projection was dramatically attenuated by systemic pretreatment of CRF receptor 1 or dopamine D1 receptor (D1R) antagonist and augmented by corticosterone synthesis inhibitor metyrapone, but not altered by dopamine D2 receptor (D2R) antagonist. Furthermore, we found that activation of PVNCRF-VTA projections increased c-Fos expression in the VTA dopamine neurons and rapidly triggered dopamine release in the nucleus accumbens (NAc), and microinfusion of D1R or D2R antagonist into the NAc decreased the self-stimulation of these projections. Together, our findings reveal an unappreciated role of PVNCRF neurons and their VTA projections in driving reward-related behaviors, independent of their core neuroendocrine functions. As activation of PVNCRF neurons is the final common path for many stress systems, our study suggests a novel mechanism underlying the positive reinforcing effect of stressful stimuli.


Assuntos
Hormônio Liberador da Corticotropina , Hormônios Liberadores de Hormônios Hipofisários , Camundongos , Animais , Hormônio Liberador da Corticotropina/metabolismo , Hormônios Liberadores de Hormônios Hipofisários/metabolismo , Hormônios Liberadores de Hormônios Hipofisários/farmacologia , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Hipotálamo/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Neurônios Dopaminérgicos/metabolismo
11.
Pflugers Arch ; 476(3): 351-364, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38228895

RESUMO

Despite the importance of physiological responses to stress in a short-term, chronically these adjustments may be harmful and lead to diseases, including cardiovascular diseases. The lateral hypothalamus (LH) has been reported to be involved in expression of physiological and behavioral responses to stress, but the local neurochemical mechanisms involved are not completely described. The corticotropin-releasing factor (CRF) neurotransmission is a prominent brain neurochemical system implicated in the physiological and behavioral changes induced by aversive threats. Furthermore, chronic exposure to aversive situations affects the CRF neurotransmission in brain regions involved in stress responses. Therefore, in this study, we evaluated the influence of CRF neurotransmission in the LH on changes in cardiovascular function and baroreflex activity induced by chronic variable stress (CVS). We identified that CVS enhanced baseline arterial pressure and impaired baroreflex function, which were followed by increased expression of CRF2, but not CRF1, receptor expression within the LH. Local microinjection of either CRF1 or CRF2 receptor antagonist within the LH inhibited the baroreflex impairment caused by CVS, but without affecting the mild hypertension. Taken together, the findings documented in this study suggest that LH CRF neurotransmission participates in the baroreflex impairment related to chronic stress exposure.


Assuntos
Hormônio Liberador da Corticotropina , Região Hipotalâmica Lateral , Ratos , Animais , Hormônio Liberador da Corticotropina/metabolismo , Hormônio Liberador da Corticotropina/farmacologia , Região Hipotalâmica Lateral/metabolismo , Barorreflexo , Encéfalo/metabolismo , Transmissão Sináptica
12.
Curr Biol ; 34(2): R64-R67, 2024 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-38262362

RESUMO

The brain has long been known to control stress and reward through complex and interconnected circuitry. A new study now reveals a group of hypothalamic neurons that paradoxically mediate both reward and aversion.


Assuntos
Hormônio Liberador da Corticotropina , Neurociências , Recompensa , Afeto , Hormônio Adrenocorticotrópico
13.
J Affect Disord ; 349: 244-253, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38199409

RESUMO

BACKGROUND: While depression has been associated with alterations in the hypothalamic-pituitary adrenal (HPA) axis function, there is still controversy regarding the nature and extent of the dysfunction, such as in the debate about hypercortisolism vs. hypocortisolism. It may therefore be necessary to understand whether and how HPA axis function in depression is linked to mRNA expression of key genes regulating this system. METHODS: We studied 163 depressed outpatients, most of whom were chronically ill, and 181 healthy controls. Blood mRNA expression levels of NR3C1 (including GRα, GRß, and GR-P isoforms), FKBP4, and FKBP5 were measured at baseline. HPA axis feedback sensitivity was measured by the dexamethasone (Dex)/corticotropin-releasing hormone (CRH) test. The association between mRNA expression levels and HPA axis feedback sensitivity was examined. RESULTS: Compared to controls, patients showed significantly higher expression of GRα and lower expression of FKBP5, and higher post-Dex cortisol levels, even after controlling for age and sex. FKBP5 expression was significantly positively correlated with cortisol levels in patients, while GRα expression was significantly negatively correlated with cortisol levels in controls. LIMITATIONS: Most patients were taking psychotropic medications. The large number of correlation tests may have caused type I errors. CONCLUSIONS: The tripartite relationship between depression, mRNA expression of GR and FKBP5, and HPA axis function suggests that the altered gene expression affects HPA axis dysregulation and, as a result, impacts the development and/or illness course of depressive disorder. The combination of increased GRα expression and decreased FKBP5 expression may serve as a biomarker for chronic depression.


Assuntos
Transtorno Depressivo , Receptores de Glucocorticoides , Humanos , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/metabolismo , Transtorno Depressivo/tratamento farmacológico , Dexametasona/farmacologia , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Receptores de Glucocorticoides/metabolismo , RNA Mensageiro/metabolismo
15.
Vascul Pharmacol ; 154: 107275, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38184094

RESUMO

Corticotropin releasing factor family peptides (CRF peptides) include 4 members, corticotropin releasing hormone (CRH), Urocortin (UCN1), UCN2 and UCN3. CRF peptides function via the two distinct receptors, CRF1 and CRF2. Among them, CRH/CRF1 has been recognized to influence immunity/inflammation peripherally. Both pro- and anti-inflammatory effects of CRH are reported. Likewise, UCNs, peripherally in cardiovascular system have been documented to have both potent protective and harmful effects, with UCN1 acting on both CRF1 & CRF2 and UCN2 & UCN3 on CRF2. We and others also observe protective and detrimental effects of CRF peptides/receptors on vasculature, with the latter of predominantly higher incidence, i.e., they play an important role in the development of vasculitis while in some cases they are found to counteract vascular inflammation. The pro-vasculitis effects of CRH & UCNs include increasing vascular endothelial permeability, interrupting endothelial adherens & tight junctions leading to hyperpermeability, stimulating immune/inflammatory cells to release inflammatory factors, and promoting angiogenesis by VEGF release while the anti-vasculitis effects may be just the opposite, depending on many factors such as different CRF receptor types, species and systemic conditions. Furthermore, CRF peptides' pro-vasculitis effects are found to be likely related to cPLA2 and S1P receptor signal pathway. This minireview will focus on summarizing the peripheral effects of CRF peptides on vasculature participating in the processes of vasculitis.


Assuntos
Hormônio Liberador da Corticotropina , Vasculite , Humanos , Hormônio Liberador da Corticotropina/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Peptídeos , Inflamação , Urocortinas/metabolismo , Urocortinas/farmacologia
16.
Neuron ; 112(1): 1-3, 2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-38176389

RESUMO

Negative affective aspects of alcohol withdrawal and pain involve converging brain circuits. In this issue of Neuron, Son et al.1 identify a peripheral mechanism of an alcohol-withdrawal-induced headache-like condition, which is centered on mast-cell-specific receptor MrgprB2 activated by corticotropin-releasing factor (CRF) in dura mater to drive nociception.


Assuntos
Alcoolismo , Síndrome de Abstinência a Substâncias , Humanos , Síndrome de Abstinência a Substâncias/psicologia , Receptores de Hormônio Liberador da Corticotropina/fisiologia , Hormônio Liberador da Corticotropina , Dor
17.
Transl Psychiatry ; 14(1): 8, 2024 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-38191479

RESUMO

Impaired motivational drive is a key feature of depression. Chronic stress is a known antecedent to the development of depression in humans and depressive-like states in animals. Whilst there is a clear relationship between stress and motivational drive, the mechanisms underpinning this association remain unclear. One hypothesis is that the endocrine system, via corticotropin-releasing hormone (CRH) in the paraventricular nucleus of the hypothalamus (PVN; PVNCRH), initiates a hormonal cascade resulting in glucocorticoid release, and that excessive glucocorticoids change brain circuit function to produce depression-related symptoms. Another mostly unexplored hypothesis is that the direct activity of PVNCRH neurons and their input to other stress- and reward-related brain regions drives these behaviors. To further understand the direct involvement of PVNCRH neurons in motivation, we used optogenetic stimulation to activate these neurons 1 h/day for 5 consecutive days and showed increased acute stress-related behaviors and long-lasting deficits in the motivational drive for sucrose. This was associated with increased Fos-protein expression in the lateral hypothalamus (LH). Direct stimulation of the PVNCRH inputs in the LH produced a similar pattern of effects on sucrose motivation. Together, these data suggest that PVNCRH neuronal activity may be directly responsible for changes in motivational drive and that these behavioral changes may, in part, be driven by PVNCRH synaptic projections to the LH.


Assuntos
Hormônio Adrenocorticotrópico , Hormônio Liberador da Corticotropina , Animais , Humanos , Motivação , Hormônios Liberadores de Hormônios Hipofisários , Optogenética , Hipotálamo , Glucocorticoides , Neurônios , Sacarose
18.
Zhen Ci Yan Jiu ; 49(1): 47-56, 2024 Jan 25.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-38239138

RESUMO

OBJECTIVES: To observe the effect of moxibustion intervention on the hypothalamus-spinal cord-colon axis of rats with irritable bowel syndrome with diarrhea (IBS-D) and explore the mechanism of moxibustion in improving visceral hypersensitivity in rats with IBS-D. METHODS: A total of 36 SD rats were randomly divided into normal, model, and moxibustion groups, with 12 rats in each group. The IBS-D model was established by maternal separation + acetic acid stimulation + chronic restraint. Rats of the moxibustion group received bilateral moxibustion on "Tianshu" (ST25) and "Shangjuxu" (ST37) for 15 min, once a day for 7 consecutive days. The body weight, loose stool rate, and minimum threshold volume of abdominal withdrawal reflex (AWR) were measured before and after moxibustion intervention, respectively. The histopathological changes in the colon tissue were observed after HE staining. The number of colonic mucosal mast cells (MCs) was measured by toluidine blue staining. The activation of MCs was determined by tryptase positive expression level and examined by immunohistochemical staining. The content, protein and mRNA expression levels and positive expression levels of corticotropin releasing factor (CRF), substance P (SP), and calcitonin gene-related peptide (CGRP) in the hypothalamus, spinal cord and colon tissues were measured by ELISA, Western blot, real-time fluorescent quantitative PCR and immunofluorescence staining, respectively. RESULTS: Compared with the normal group, the loose stool rate was increased (P<0.01);the body weight and minimum threshold volume of AWR were decreased (P<0.01);the inflammatory infiltration of colon tissues was obvious;the number of MCs and positive expression level of tryptase in the colon tissue were increased (P<0.01);the contents, positive expression le-vels, protein and mRNA expression levels of CRF, SP and CGRP in the hypothalamus, spinal cord and colon tissues were increased (P<0.01, P<0.05) in the model group. After the intervention, compared with the model group, all these indicators showed opposite trends (P<0.01, P<0.05) in the moxibustion group. CONCLUSIONS: Moxibustion can improve visceral hypersensitivity in rats with IBS-D, and its mechanism may be related to regulating the hypothalamic-spinal-colon axis to reduce the release of CRF, SP and CGRP, and thus to inhibite MC in colon tissue.


Assuntos
Síndrome do Intestino Irritável , Moxibustão , Ratos , Animais , Síndrome do Intestino Irritável/genética , Síndrome do Intestino Irritável/terapia , Síndrome do Intestino Irritável/metabolismo , Ratos Sprague-Dawley , Hormônio Liberador da Corticotropina/metabolismo , Triptases/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Privação Materna , Diarreia/genética , Diarreia/terapia , Hipotálamo/metabolismo , Substância P/metabolismo , Medula Espinal , Peso Corporal , RNA Mensageiro/metabolismo
19.
Psychoneuroendocrinology ; 162: 106953, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38232531

RESUMO

BACKGROUND: Evidence suggests that early life adversity is associated with maladaptive behaviors and is commonly an antecedent of stress-related psychopathology. This is particularly relevant to rearing in primate species as infant primates depend on prolonged, nurturant rearing by caregivers for normal development. To further understand the consequences of early life rearing adversity, and the relation among alterations in behavior, physiology and brain function, we assessed young monkeys that had experienced maternal separation followed by peer rearing with behavioral, endocrine and multimodal neuroimaging measures. METHODS: 50 young rhesus monkeys were studied, half of which were rejected by their mothers and peer reared, and the other half were reared by their mothers. Assessments were performed at approximately 1.8 years of age and included: threat related behavioral and cortisol responses, cerebrospinal fluid (CSF) measurements of oxytocin and corticotropin releasing hormone (CRH), and multimodal neuroimaging measures (anatomical scans, resting functional connectivity, diffusion tensor imaging, and threat-related regional glucose metabolism). RESULTS: The results demonstrated alterations across behavioral, endocrine, and neuroimaging measures in young monkeys that were reared without their mothers. At a behavioral level in response to a potential threat, peer reared animals engaged in significantly less freezing behavior (p = 0.022) along with increased self-directed behaviors (p < 0.012). Levels of oxytocin in the CSF, but not plasma, were significantly reduced in the peer reared animals (p = 0.019). No differences in plasma cortisol or CSF CRH were observed. Diffusion tensor imaging revealed significantly decreased white matter density across the brain. Exploratory correlational and permutation analyses suggest that the impact of peer rearing on behavior, endocrine and brain structural alterations are mediated by separate parallel mechanisms. CONCLUSIONS: Taken together, these results demonstrate in NHPs the importance of maternal rearing on the development of brain, behavior and hormonal systems that are linked to social functioning and adaptive responses. The findings suggest that the effects of maternal deprivation are mediated via multiple independent pathways which may account for the heterogeneity in behavioral and biological alterations observed in individuals that have experienced this early life adversity.


Assuntos
Experiências Adversas da Infância , Humanos , Animais , Lactente , Feminino , Imagem de Tensor de Difusão , Hidrocortisona , Privação Materna , Ocitocina , Hormônio Liberador da Corticotropina , Macaca mulatta , Mães
20.
Transl Psychiatry ; 14(1): 29, 2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38233378

RESUMO

The neuropeptide corticotropin-releasing factor (CRF) exerts a pivotal role in modulating neuronal activity in the mammalian brain. The effects of CRF exhibit notable variations, depending on factors such as duration of exposure, concentration, and anatomical location. In the CA1 region of the hippocampus, the impact of CRF is dichotomous: chronic exposure to CRF impairs synapse formation and dendritic integrity, whereas brief exposure enhances synapse formation and plasticity. In the current study, we demonstrate long-term effects of acute CRF on the density and stability of mature mushroom spines ex vivo. We establish that both CRF receptors are present in this hippocampal region, and we pinpoint their precise subcellular localization within synapses by electron microscopy. Furthermore, both in vivo and ex vivo data collectively demonstrate that a transient surge of CRF in the CA1 activates the cyclin-dependent kinase 5 (Cdk5)-pathway. This activation leads to a notable augmentation in CRF-dependent spine formation. Overall, these data suggest that upon acute release of CRF in the CA1-SR synapse, both CRF-Rs can be activated and promote synaptic plasticity via activating different downstream signaling pathways, such as the Cdk5-pathway.


Assuntos
Hormônio Liberador da Corticotropina , Espinhas Dendríticas , Animais , Hormônio Liberador da Corticotropina/metabolismo , Espinhas Dendríticas/metabolismo , Quinase 5 Dependente de Ciclina/metabolismo , Quinase 5 Dependente de Ciclina/farmacologia , Hipocampo/metabolismo , Receptores de Hormônio Liberador da Corticotropina , Sinapses/metabolismo , Mamíferos/metabolismo
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