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1.
Mol Psychiatry ; 27(2): 896-906, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34697452

RESUMEN

Neuroplasticity in the medial prefrontal cortex (mPFC) is essential for fear extinction, the process of which forms the basis of the general therapeutic process used to treat human fear disorders. However, the underlying molecules and local circuit elements controlling neuronal activity and concomitant induction of plasticity remain unclear. Here we show that sustained plasticity of the parvalbumin (PV) neuronal network in the infralimbic (IL) mPFC is required for fear extinction in adult male mice and identify the involvement of neuregulin 1-ErbB4 signalling in PV network plasticity-mediated fear extinction. Moreover, regulation of fear extinction by basal medial amygdala (BMA)-projecting IL neurons is dependent on PV network configuration. Together, these results uncover the local molecular circuit mechanisms underlying mPFC-mediated top-down control of fear extinction, suggesting alterative therapeutic approaches to treat fear disorders.


Asunto(s)
Extinción Psicológica , Miedo , Animales , Extinción Psicológica/fisiología , Miedo/fisiología , Masculino , Ratones , Neurregulina-1 , Plasticidad Neuronal/fisiología , Parvalbúminas , Corteza Prefrontal/fisiología , Receptor ErbB-4
2.
Biotechnol Lett ; 37(2): 475-81, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25312921

RESUMEN

Embryoid bodies (EBs) with large starting numbers of embryonic stem cells (ESCs) have a greater degree of cardiac differentiation than from low numbers of EBs. However, the biological roles of signaling molecules in these effects are not well understood. Here, we show that groups of EBs with different starting numbers of ESCs had differential gene expression patterns for Wnt5a and Wnt11. Wnt11 significantly increased the percentage of beating EBs by up-regulating the expression of the cardiac-specific genes. Wnt5a did not show these effects. Moreover, Wnt11 significantly increased the level of phosphorylated Jun N-terminal kinase. The inhibition of the JNK pathway by SP600125 blocked the effects of Wnt11. Thus, enrichment of cardiac differentiation in groups of EBs with a larger starting number of ESCs is mediated by the Wnt11-JNK pathway.


Asunto(s)
Diferenciación Celular/fisiología , Cuerpos Embrioides/fisiología , Células Madre Embrionarias/fisiología , Sistema de Señalización de MAP Quinasas/fisiología , Miocitos Cardíacos/metabolismo , Proteínas Wnt/metabolismo , Animales , Línea Celular , Ratones , Miocitos Cardíacos/citología , Proteínas Wnt/genética
3.
Neuropsychopharmacology ; 49(9): 1468-1480, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38734818

RESUMEN

The ventral subiculum (vSUB), the major output structure of the hippocampal formation, regulates motivation, stress integration, and anxiety-like behaviors that rely on heightened arousal. However, the roles and underlying neural circuits of the vSUB in wakefulness are poorly known. Using in vivo fiber photometry and multichannel electrophysiological recordings in mice, we found that the vSUB glutamatergic neurons exhibited high activities during wakefulness. Moreover, activation of vSUB glutamatergic neurons caused an increase in wakefulness and anxiety-like behaviors and induced a rapid transition from sleep to wakefulness. In addition, optogenetic stimulation of vSUB glutamatergic terminals and retrograde-targeted chemogenetic activation of vSUB glutamatergic neurons revealed that vSUB promoted arousal by innervating the lateral hypothalamus (LH), nucleus accumbens (NAc) shell, and prefrontal cortex (PFC). Nevertheless, local microinjection of dopamine D1 or D2/D3 receptor antagonist blocked the wake-promoting effect induced by chemogenetic activation of vSUB pathways. Finally, chemogenetic inhibition of vSUB glutamatergic neurons decreased arousal. Altogether, our findings reveal a prominent contribution of vSUB glutamatergic neurons to the control of wakefulness through several pathways.


Asunto(s)
Hipocampo , Ratones Endogámicos C57BL , Vías Nerviosas , Optogenética , Vigilia , Animales , Vigilia/fisiología , Vigilia/efectos de los fármacos , Masculino , Ratones , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Vías Nerviosas/fisiología , Vías Nerviosas/efectos de los fármacos , Neuronas/fisiología , Neuronas/efectos de los fármacos , Corteza Prefrontal/fisiología , Corteza Prefrontal/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/fisiología , Ácido Glutámico/metabolismo , Ansiedad/fisiopatología , Nivel de Alerta/fisiología , Nivel de Alerta/efectos de los fármacos
4.
Fitoterapia ; 175: 105881, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38438054

RESUMEN

Two previously undescribed cholestanol saponins, parpetiosides F - G (1-2), and six known analogs (3-8) were isolated from the rhizomes of Paris fargesii var. petiolata. Their structures were elucidated by extensive spectroscopic data analysis and chemical methods. Compound 1 was a rare 6/6/6/5/5 fused-rings cholestanol saponin with disaccharide moiety linked at C-26 of aglycone which was hardly seen in genus Paris. All of these compounds were discovered in this plant for the first time. In addition, the cytotoxicities of saponins (1-8) against three human cancer cell lines (U87, HepG2 and SGC-7901) were evaluated by CCK-8 method, and saponins 5-8 displayed certain cytotoxicities. The strong interactions between saponins 5-8 and SCUBE3, an oncogene for glioma cells, were displayed by molecular docking.


Asunto(s)
Antineoplásicos Fitogénicos , Colestanol , Simulación del Acoplamiento Molecular , Rizoma , Saponinas , Rizoma/química , Humanos , Saponinas/aislamiento & purificación , Saponinas/farmacología , Saponinas/química , Estructura Molecular , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Línea Celular Tumoral , Colestanol/farmacología , Colestanol/química , Colestanol/aislamiento & purificación , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Melanthiaceae/química , China , Liliaceae/química
5.
Mol Cell Biochem ; 380(1-2): 67-72, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23606057

RESUMEN

Neuregulin-1ß (NRG-1ß)/ErbB signaling plays crucial roles in the cardiac differentiation of mouse embryonic stem cells (ESCs), but its roles and the underlying mechanisms in cardiac differentiation are incompletely understood. This study showed that NRG-1ß significantly increased the percentage of beating embryoid bodies (EBs) and up-regulated the gene expressions of Nkx2.5, GATA4, α-actin, MLC-2v, and ANF in a time-dependent manner, with no effect on the gene expressions of HCN4 and Tbx3. Inhibition of ErbB receptors with AG1478 significantly decreased the percentage of beating EBs; down-regulated the gene expressions of Nkx2.5, GATA4, MLC-2v, ANF, and α-actin; and concomitantly up-regulated the gene expressions of HCN4 and Tbx3 in a time-dependent manner. Moreover, the up-regulation of transcripts for Nkx2.5 and GATA4 by NRG-1ß was blocked by the extracellular signal-related kinases (ERK) 1/2 inhibitor, U0126. However, U0126 could not inhibit the transcript up-regulations of MLC-2v and ANF by NRG-1ß. The protein quantitation results were consistent with those of gene quantitation. Our results suggest that NRG-1ß/ErbB signaling plays critical roles in the cardiac differentiation of mouse ESCs and in the subtype specification of cardiomyocytes in a time-dependent manner. The ERK1/2 pathway may be involved in the early cardiogenesis, but not in the subtype specification of cardiomyocytes.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Células Madre Embrionarias/efectos de los fármacos , Receptores ErbB/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Neurregulina-1/farmacología , Transducción de Señal/efectos de los fármacos , Actinas/genética , Animales , Factor Natriurético Atrial/genética , Butadienos/farmacología , Diferenciación Celular/genética , Línea Celular , Cuerpos Embrioides/citología , Cuerpos Embrioides/efectos de los fármacos , Cuerpos Embrioides/metabolismo , Células Madre Embrionarias/citología , Células Madre Embrionarias/metabolismo , Receptores ErbB/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Factor de Transcripción GATA4/genética , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Proteína Homeótica Nkx-2.5 , Proteínas de Homeodominio/genética , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/genética , Ratones , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Cadenas Ligeras de Miosina/genética , Nitrilos/farmacología , Fosforilación/efectos de los fármacos , Quinazolinas/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas de Dominio T Box/genética , Factores de Tiempo , Factores de Transcripción/genética , Tirfostinos/farmacología
6.
Int J Mol Sci ; 14(1): 1370-82, 2013 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-23344047

RESUMEN

The traditional Chinese medicine bufalin, extracted from toad's skin, has been demonstrated to exert anticancer activities in various kinds of human cancers. The mechanisms of action lie in its capacity to induce apoptosis, or termed type I programmed cell death (PCD). However, type II PCD, or autophagy, participates in cancer proliferation, progression, and relapse, as well. Recent studies on autophagy seem to be controversial because of the dual roles of autophagy in cancer survival and death. In good agreement with previous studies, we found that 100 nM bufalin induced extensive HepG2 cell apoptosis. However, we also noticed bufalin triggered autophagy and enhanced Beclin-1 expression, LC3-I to LC3-II conversion, as well as decreased p62 expression and mTOR signaling activation in HepG2 cells. Blockage of autophagy by selective inhibitor 3-MA decreased apoptotic ratio in bufalin-treated HepG2 cells, suggesting a proapoptotic role of bufalin-induced autophagy. Furthermore, we investigated the underlying mechanisms of bufalin-induced autophagy. Bufalin treatment dose-dependently promoted AMPK phosphorylation while AMPK inhibition by compound C significantly attenuated bufalin-induced autophagy. Taken together, we report for the first time that bufalin induces HepG2 cells PCD, especially for autophagy, and the mechanism of action is, at least in part, AMPK-mTOR dependent.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Bufanólidos/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Antineoplásicos/química , Proteínas Reguladoras de la Apoptosis/metabolismo , Beclina-1 , Western Blotting , Bufanólidos/química , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/ultraestructura , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/ultraestructura , Proteínas de la Membrana/metabolismo , Microscopía Confocal , Microscopía Electrónica de Transmisión , Proteínas Asociadas a Microtúbulos/metabolismo , Estructura Molecular , Fosforilación/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo
7.
Phytochemistry ; 207: 113577, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36587887

RESUMEN

Paris polyphylla var. yunnanensis (Franch.) Hand.-Mazz. (Melanthiaceae), an important specie of the genus Paris, has long been in a traditional Chinese medicine (TCM) for a long time. This study aimed to isolate and identify the structures of bioactive saponins from the rhizomes of P. polyphylla var. yunnanensis and evaluate their cytotoxicity against BxPC-3, HepG2, U373 and SGC-7901 carcinoma cell lines. Seven previously undescribed and seven known saponins were identified, and Paris saponins VII (PSVII) showed significant cytotoxicity against the BxPC-3 cell line with IC50 values of 3.59 µM. Furthermore, flow cytometry, transmission electron microscopy and western-bolt analysis revealed that PSVII inhibited the proliferation of BxPC-3 cells and might be involved in inducing apoptosis and pyroptosis by activating caspase-3, -7 and caspase-1, respectively.


Asunto(s)
Antineoplásicos , Liliaceae , Melanthiaceae , Saponinas , Rizoma/química , Saponinas/farmacología , Liliaceae/química , Melanthiaceae/química
8.
Neuropharmacology ; 201: 108842, 2021 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-34678375

RESUMEN

The posttraumatic stress disorder is marked by an impaired ability to extinct fear memory acquired in trauma. Although previous studies suggest that fear extinction depends on the function of the amygdala, the underlying mechanisms are unclear. We found that NRG1 receptors (ErbB4) were abundantly expressed in the intercalated cells mass of amygdala (ITC). The NRG1-ErbB4 pathway in the ITC promotes fear extinction. The NRG1-ErbB4 pathway in the ITC did not affect excitatory input to ITC neurons from BLA neurons but increased feed-forward inhibition of (the central medial nucleus of the amygdala) CeM neurons through increased GABAergic neurotransmission of ITC neurons. We also found that the NRG1-ErbB4 signaling pathway in ITC might regulate fear extinction through P/Q-type voltage-activated Ca2+ channels (VACCs) but not through L- or N-type VACCs. Overall, our results suggest that the NRG1-ErbB4 signaling pathway in the ITC might represent a potential target for the treatment of anxiety disorders.


Asunto(s)
Amígdala del Cerebelo/fisiología , Extinción Psicológica/fisiología , Miedo/psicología , Neurregulina-1/fisiología , Amígdala del Cerebelo/metabolismo , Animales , Trastornos de Ansiedad/tratamiento farmacológico , Trastornos de Ansiedad/etiología , Canales de Calcio Tipo N/fisiología , Masculino , Ratones Endogámicos C57BL , Terapia Molecular Dirigida , Neurregulina-1/metabolismo , Receptor ErbB-4/metabolismo , Transducción de Señal/fisiología
9.
Guang Pu Xue Yu Guang Pu Fen Xi ; 29(5): 1427-30, 2009 May.
Artículo en Zh | MEDLINE | ID: mdl-19650506

RESUMEN

An analysis method was developed to determine the chemical speciation of Cu, Zn, Fe and Mn in radix scutellariae decoction using atomic absorption spectroscopy(AAS). The decoction can be divided into suspension and soluble species by 0.45 microm filter membrane and the soluble species can be separated into organism and inorganic species by LSA-10 macroporous resin. These elements in water-soluble test samples can be divided into alcohol-soluble and water-soluble by adopting n-octyl alcohol-water allocation system in man-made gastric acidity. Then, the concentration of these elements was determined by AAS, which provided more chemical speciation information about these elements instead of the total amount of them only in radix scutellariae. Deteotion limit of Cu, Zn and Mn by using the method was all 0.01 microg x mL(-1) and was 0.02 microg x mL(-1) for Fe. The RSD was in the range of 1.5%-3.6% (n=11) and the recovery rate of soluble species and inorganic species were in range of 96.7%-105.0%. The method has been successfully applied to determine the chemical speciation of Cu, Zn, Fe and Mn in radix scutellariae, which was very important for overall study of radix scutellariae.


Asunto(s)
Metales Pesados/análisis , Metales Pesados/química , Scutellaria baicalensis/química , Espectrofotometría Atómica/métodos , Cobre/análisis , Cobre/química , Hierro/análisis , Hierro/química , Cinética , Límite de Detección , Manganeso/análisis , Manganeso/química , Solventes/química , Zinc/análisis , Zinc/química
10.
Mol Neurobiol ; 56(7): 4855-4865, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30406427

RESUMEN

The dysregulation of fear learning and abnormal activities of cerebral networks may contribute to the etiologies of anxiety disorders. Although it has been proposed that decreased activity in the paraventricular nucleus of the thalamus (PVT) to the lateral central nucleus of amygdala (CeL) pathway could induce an attenuation of learned fear, no study has shown the effect of the direct optogenetic activation of PVT projecting CeL neurons in vivo on unconditioned fear-related behaviors or learned fear expression. The mechanisms that control the neuronal activity of the PVT-CeL pathway involved in anxiety are rare. Here, we found that CeL neurons have varied responses to optogenetic excitation of PVT terminals in the CeL: neurons with relative high excitability(~ 30%), neurons with relative low excitability(~ 60%), and neurons with no excitability (~ 10%). We next explored the role of the PVT-CeL pathway in unconditioned and conditioned fear-related behaviors by using optogenetics and anxiety assays in freely moving mice. We observed that temporally precise optogenetic activation of the CeL-projecting PVT neurons had no effect on unconditioned fear-related behaviors on the elevated plus maze test and the open field test. But optogenetic activation of the CeL-projecting PVT neurons increased conditioned fear expression. We then found that optogenetic long-term depression (LTD) induction in the CeL receiving PVT afferents effectively exerted a persistent attenuation of learned fear. The percentage of neurons with relative high excitability was decreased by the LTD induction, and the percentage of neurons with relative low excitability was increased by the LTD induction. Taking these results together, we identify that increased activity of the PVT-CeL pathway could lead to as excessive learned fear. The CeL neurons with relative high responses to the photo-stimulation of PVT afferents in the CeL may be the key neurons that regulate the output of learned fear expression. Our optogenetic LTD protocol may inspire the development of novel treatments for anxiety disorders involving deep brain stimulation to induce plasticity at relevant brain areas.


Asunto(s)
Amígdala del Cerebelo/fisiología , Miedo/fisiología , Depresión Sináptica a Largo Plazo/fisiología , Memoria/fisiología , Optogenética , Núcleo Hipotalámico Paraventricular/fisiología , Potenciales de Acción/fisiología , Animales , Enfermedad Crónica , Masculino , Ratones Endogámicos C57BL , Neuronas/fisiología , Estrés Psicológico/fisiopatología , Transmisión Sináptica/fisiología
11.
Front Pharmacol ; 9: 328, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29681855

RESUMEN

Gallic acid (GA) is a polyphenolic natural product widely distributed in food, beverage, and traditional Chinese herbs with beneficial effects on the cardiovascular system. In this research, a comparative study was conducted to investigate the possible difference of pharmacokinetic process in normal and isoproterenol-induced myocardial infarcted rats after oral administration of GA monohydrate with the dose of 50 and 100 mg/kg, respectively. Quantification of GA in rat plasma was achieved by using a simple and rapid high-performance liquid chromatographic method. The results revealed that pharmacokinetics of GA were greatly different between normal and pathological state. GA exhibited slower absorption into the bloodstream, and yielded 1.7-fold (50 mg/kg GA) and 1.3-fold (100 mg/kg GA) less values of area under concentration-time curve as well as 2.5-fold lower of maximum blood concentration (Cmax) in MI rats than those in normal rats. In addition, significant prolonged T1/2 and MRT as well as decreased CL were also registered in MI rats. Our findings suggest that myocardial infarction could alter the pharmacokinetic process of GA, and thus the potential pharmacokinetic differences of herbal preparations (or dietary nutrition) containing GA between normal and pathological conditions should be brought to the forefront seriously in clinical practice.

13.
J Pharm Biomed Anal ; 43(2): 774-8, 2007 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-17055209

RESUMEN

Ropinirole is a nonergoline dopamine D(2)-receptor agonist and has been proven to be effective in both monotherapy and combination therapy for idiopathic Parkinson's disease. The purpose of the present study was to examine the effect of Madopar on the pharmacokinetics of ropinirole in healthy Chinese volunteers by using liquid chromatography tandem mass spectrometry (HPLC/MS/MS). A single dose of 1mg ropinirole was given orally after administration of the placebo or Madopar (containing 200 mg levodopa and 50 mg benserazide) to six healthy males and six healthy females in a cross-over randomized study with a minimum washout period of 8 days. Pharmacokinetic parameters were calculated for both treatments. Coadministration of ropinirole and Madopar did not result in a notable change in rate or extent of availability of ropinirole, as shown by the ratios (90% confidence intervals) of 1.045 (0.900, 1.222) for C(max) (maximum plasma concentration) and 1.167 (1.086, 1.262) for AUC(0-inf) (the area under the concentration-time curve). Likewise, no significant difference in any of the other pharmacokinetic parameters [T(max) (the time needed to reach the C(max)), MRT (mean residence time), volume of distribution (V/F), and clearance (CL/F)] was observed between the treatment groups. No clinically relevant adverse effects were detected under either conditions and there are no pharmacokinetic grounds for adjusting the dose of ropinirole when given in combination with Madopar in Chinese patients.


Asunto(s)
Antiparkinsonianos/farmacología , Antiparkinsonianos/farmacocinética , Inhibidores de Descarboxilasas de Aminoácidos Aromáticos , Benserazida/farmacología , Inhibidores Enzimáticos/farmacología , Indoles/farmacocinética , Levodopa/farmacología , Adulto , Antiparkinsonianos/sangre , Pueblo Asiatico , Cromatografía Líquida de Alta Presión/métodos , Estudios Cruzados , Combinación de Medicamentos , Interacciones Farmacológicas , Femenino , Humanos , Indoles/sangre , Modelos Lineales , Masculino , Valores de Referencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrometría de Masas en Tándem/métodos
14.
Neuropharmacology ; 118: 242-250, 2017 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-28302570

RESUMEN

Anxiety disorders contribute to the pathophysiology of psychiatric diseases, including major depression, substance abuse, and schizophrenia. The hippocampus is important for anxiety modulation. However, the mechanisms that control the neuronal activity of the hippocampus in anxiety are still not clear. We found that Endothelin-1 (ET1) mRNA in the hippocampus was down-regulated in high-anxiety mice. Neutralizing endogenous ET1 in the hippocampal CA1 enhanced anxiety-like behaviors. We next revealed that most expression of ET1 and its receptors in the CA1 takes place in pyramidal neurons, and the ET1 signaling pathway directly regulated the excitability of CA1 pyramidal neurons and glutamatergic synaptic neurotransmission. Finally, we proved that neutralizing endogenous CA1 ET1 produces anxiogenic effects on low-anxiety mice, whereas infusing exogenous ET1 into the CA1 alleviates the anxiety susceptibility of high-anxiety mice. Together, these results indicate that ET1 signaling is critical in maintaining the excitability of glutamatergic neurons in the hippocampus and, thus, in modulating anxiety-like behaviors. Because ET1 is a risk factor for ischemic stroke, our findings might also help to explain the potential mechanism of emotional abnormality in stroke.


Asunto(s)
Ansiedad/patología , Endotelina-1/metabolismo , Hipocampo/metabolismo , Hipocampo/patología , Células Piramidales/metabolismo , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/genética , Animales , Biofisica , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Modelos Animales de Enfermedad , Estimulación Eléctrica , Endotelina-1/genética , Endotelina-1/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/genética , Conducta Exploratoria/efectos de los fármacos , Privación de Alimentos , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Técnicas de Placa-Clamp , Células Piramidales/efectos de los fármacos , Receptores de Endotelina/genética , Receptores de Endotelina/metabolismo
15.
Sci Rep ; 7(1): 2316, 2017 05 24.
Artículo en Inglés | MEDLINE | ID: mdl-28539637

RESUMEN

An abnormal neuronal activity in the amygdala is involved in the pathogenesis of anxiety disorders. However, little is known about the mechanisms. High-anxiety mice and low-anxiety mice, representing the innate extremes of anxiety-related behaviors, were first grouped according to their anxiety levels in the elevated plus maze test. We found that the mRNA for endothelin-1 (ET1) and ET1 B-type receptors (ETBRs) in the amygdala was down-regulated in high-anxiety mice compared with low-anxiety mice. Knocking down basolateral amygdala (BLA) ET1 expression enhanced anxiety-like behaviors, whereas over-expressing ETBRs, but not A-type receptors (ETARs), had an anxiolytic effect. The combined down-regulation of ETBR and ET1 had no additional anxiogenic effect compared to knocking down the ETBR gene alone, suggesting that BLA ET1 acts through ETBRs to regulate anxiety-like behaviors. To explore the mechanism underlying this phenomenon further, we verified that most of the ET1 and the ET1 receptors in the BLA were expressed in pyramidal neurons. The ET1-ETBR signaling pathway decreased the firing frequencies and threshold currents for the action potentials of BLA pyramidal neurons but did not alter BLA synaptic neurotransmission. Together, these results indicate that amygdalar ET1-ETBR signaling could attenuate anxiety-like behaviors by directly decreasing the excitability of glutamatergic neurons.


Asunto(s)
Trastornos de Ansiedad/genética , Endotelina-1/genética , Receptor de Endotelina B/genética , Transmisión Sináptica/genética , Potenciales de Acción , Animales , Trastornos de Ansiedad/metabolismo , Trastornos de Ansiedad/fisiopatología , Complejo Nuclear Basolateral/metabolismo , Complejo Nuclear Basolateral/patología , Conducta Animal/fisiología , Regulación de la Expresión Génica/genética , Técnicas de Silenciamiento del Gen , Humanos , Aprendizaje por Laberinto , Ratones , Células Piramidales/metabolismo , Células Piramidales/patología , Transducción de Señal
16.
Neuroscience ; 329: 182-92, 2016 08 04.
Artículo en Inglés | MEDLINE | ID: mdl-27189883

RESUMEN

The bed nucleus of the stria terminalis (BNST), a nucleus defined as part of the extended amygdala, is involved in the expression of anxiety disorders. However, the regulatory mechanisms of BNST inhibitory activity that is involved in anxiety are unknown. Here, we showed that blocking neuregulin 1 (NRG1)-ErbB4 signaling in the BNST of mice, by either neutralizing endogenous NRG1 with ecto-Erbb4 or antagonizing the ErbB4 receptor with its specific inhibitor, produced anxiogenic responses. Interestingly, application of exogenous NRG1 into the BNST induced no anxiolytic effects, suggesting saturating activity of endogenous NRG1. While infusion of the GABAA receptor antagonist bicuculline into the BNST also led to anxiety-related behaviors, it did not worsen the anxiogenic effects produced by blocking NRG1-ErbB4 signaling, suggesting possible involvement of GABAergic neurotransmission. Further, in vitro electrophysiological recordings showed that BNST NRG1-ErbB4 signaling regulated the presynaptic GABA release. Together, these results suggest that NRG1-ErbB4 signaling in the BNST may play an important role in regulating anxiety-like behaviors.


Asunto(s)
Ansiedad/metabolismo , Neurregulina-1/metabolismo , Receptor ErbB-4/metabolismo , Núcleos Septales/metabolismo , Animales , Bicuculina/farmacología , Fármacos del Sistema Nervioso Central/farmacología , Antagonistas de Receptores de GABA-A/farmacología , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Ratones Endogámicos C57BL , Modelos Animales , Neurregulina-1/administración & dosificación , Neurregulina-1/antagonistas & inhibidores , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/metabolismo , Pirimidinas/farmacología , Receptor ErbB-4/antagonistas & inhibidores , Receptores de GABA-A/metabolismo , Núcleos Septales/efectos de los fármacos , Técnicas de Cultivo de Tejidos , Ácido gamma-Aminobutírico/metabolismo
17.
Mol Neurobiol ; 53(3): 2054-2064, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25899174

RESUMEN

Endothelin1 (ET1) is a potent vasoconstrictor that is also known to be a neuropeptide that is involved in neural circuits. We examined the role of ET1 that has been implicated in the anxiogenic process. We found that infusing ET1 into the IL cortex increased anxiety-like behaviors. The ET(A) receptor (ET(A)R) antagonist (BQ123) but not the ET(B) receptor (ET(B)R) antagonist (BQ788) alleviated ET1-induced anxiety. ET1 had no effect on GABAergic neurotransmission or NMDA receptor (NMDAR)-mediated neurotransmission, but increased AMPA receptor (AMPAR)-mediated excitatory synaptic transmission. The changes in AMPAR-mediated excitatory postsynaptic currents were due to presynaptic mechanisms. Finally, we found that the AMPAR antagonists (CNQX) and BQ123 reversed ET1's anxiogenic effect, with parallel and corresponding electrophysiological changes. Moreover, infusing CNQX + BQ123 into the IL had no additional anxiolytic effect compared to CNQX treatment alone. Altogether, our findings establish a previously unknown anxiogenic action of ET1 in the IL cortex. AMPAR-mediated glutamatergic neurotransmission may underlie the mechanism of ET1-ET(A)R signaling pathway in the regulation of anxiety.


Asunto(s)
Ansiedad/metabolismo , Endotelina-1/metabolismo , Sistema Límbico/metabolismo , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , 6-Ciano 7-nitroquinoxalina 2,3-diona/uso terapéutico , Animales , Ansiedad/tratamiento farmacológico , Conducta Animal , Ácido Glutámico/metabolismo , Sistema Límbico/efectos de los fármacos , Sistema Límbico/patología , Masculino , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/uso terapéutico , Receptores AMPA/metabolismo , Receptores de Endotelina/metabolismo , Transmisión Sináptica/efectos de los fármacos
18.
Neuropsychopharmacology ; 40(4): 974-86, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25308353

RESUMEN

Anxiety disorder is related to the pathophysiology of psychiatric diseases, including major depression, substance abuse, and schizophrenia. The amygdala is important for manifestation and modulation of anxiety. However, relatively little is known regarding the mechanisms that control the amygdala inhibitory activity that is involved in anxiety. We found that almost all ErbB4, which is the only autonomous receptor of neuregulin 1 (NRG1) in the basolateral amygdala (BLA), was expressed in GABAergic neurons. Endogenous NRG1-ErbB4 signaling pathway in the BLA could modulate anxiety-like behaviors and GABA release, whereas it had no effect on glutamatergic transmission. The administration of NRG1 into the BLA of high-anxiety mice alleviated their anxiety and enhanced GABAergic neurotransmission. Moreover, exogenous NRG1 also produced an anxiolytic effect in the stressed mice. Together, these observations indicated that NRG1-ErbB4 signaling is critical to maintaining GABAergic activity in the amygdala and thus to modulating anxiety-like behaviors. Because NRG1 and ErbB4 are susceptibility genes of schizophrenia, our findings might also help to explain the potential mechanism of emotional abnormality in schizophrenia.


Asunto(s)
Amígdala del Cerebelo/metabolismo , Ansiedad/patología , Ansiedad/fisiopatología , Regulación de la Expresión Génica/fisiología , Proteínas de la Mielina/metabolismo , Receptor ErbB-4/metabolismo , Receptores de Superficie Celular/metabolismo , Amígdala del Cerebelo/citología , Amígdala del Cerebelo/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Conducta Alimentaria/efectos de los fármacos , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Proteínas Ligadas a GPI/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Glutamato Descarboxilasa/genética , Glutamato Descarboxilasa/metabolismo , Técnicas In Vitro , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas de la Mielina/genética , Proteínas de la Mielina/farmacología , Receptor Nogo 1 , Pirimidinas/farmacología , Quinazolinas/farmacología , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/genética , Receptor ErbB-4/genética , Receptor ErbB-4/farmacología , Receptores de Superficie Celular/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Tirfostinos/farmacología , Ácido gamma-Aminobutírico/metabolismo
19.
Neuron ; 84(4): 835-46, 2014 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-25451196

RESUMEN

Inhibitory neurotransmission in amygdala is important for fear learning and memory. However, mechanisms that control the inhibitory activity in amygdala are not well understood. We provide evidence that neuregulin 1 (NRG1) and its receptor ErbB4 tyrosine kinase are critical for maintaining GABAergic activity in amygdala. Neutralizing endogenous NRG1, inhibition, or genetic ablation of ErbB4, which was expressed in a majority of palvalbumin (PV)+ neurons in amygdala, reduced GABAergic transmission and inhibited tone-cued fear conditioning. Specific ablation of ErbB4 in PV+ neurons reduced eIPSC/eEPSC ratios and impaired fear conditioning. Notably, expression of ErbB4 in amygdala was sufficient to diminish synaptic dysfunction and fear conditioning deficits in PV-ErbB4-/- mice. These observations indicated that NRG1 signaling maintains high GABAergic activity in amygdala and, thus, regulates fear memory. Considering that both NRG1 and ErbB4 are susceptibility genes of schizophrenia, our study sheds light on potential pathophysiological mechanisms of this disorder.


Asunto(s)
Amígdala del Cerebelo/metabolismo , Miedo/fisiología , Memoria/fisiología , Neurregulina-1/metabolismo , Receptor ErbB-4/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Animales , Condicionamiento Clásico/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Potenciales Postsinápticos Inhibidores/fisiología , Interneuronas/fisiología , Ratones , Neuronas/metabolismo , Parvalbúminas/metabolismo , Sinapsis/fisiología
20.
Neuropharmacology ; 72: 148-56, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23643746

RESUMEN

The medial prefrontal cortex (mPFC) has been implicated in modulating anxiety. However, it is unknown whether excitatory or inhibitory neurotransmission in the infralimbic (IL) subregion of the mPFC underlies the pathology of anxiety-related behavior. To address this issue, we infused the GABAA receptor (GABAAR) antagonist bicuculline to temporarily activate the IL cortex. IL cortex activation decreased the time spent in the center area in the open field test, decreased exploration of the open-arms in the elevated plus maze test, and increased the latency to bite food in the novelty-suppressed feeding test. These findings substantiate the GABAergic system's role in anxiety-related behaviors. IL cortex inactivation with the AMPA receptor (AMPAR) antagonist CNQX produced opposite, anxiolytic effects. However, infusion of the NMDA receptor (NMDAR) antagonist AP5 into the IL cortex had no significant effect. Additionally, we did not observe motor activity deficits or appetite deficits following inhibition of GABAergic or glutamatergic neurotransmission. Interestingly, we found parallel and corresponding electrophysiological changes in anxious mice; compared to mice with relatively low anxiety, the relatively high anxiety mice exhibited smaller evoked inhibitory postsynaptic currents (eIPSCs) and larger AMPA-mediated evoked excitatory postsynaptic currents (eEPSCs) in pyramidal neurons in the IL cortex. The changes of eIPSCs and eEPSCs were due to presynaptic mechanisms. Our results suggest that imbalances of neurotransmission in the IL cortex may cause a net increase in excitatory inputs onto pyramidal neurons, which may underlie the pathogenic mechanism of anxiety disorders.


Asunto(s)
Ansiedad/patología , Potenciales Postsinápticos Excitadores/fisiología , Corteza Prefrontal/fisiopatología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , 6-Ciano 7-nitroquinoxalina 2,3-diona/uso terapéutico , Animales , Animales Recién Nacidos , Ansiedad/inducido químicamente , Ansiedad/tratamiento farmacológico , Bicuculina/toxicidad , Modelos Animales de Enfermedad , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Antagonistas de Receptores de GABA-A/toxicidad , Técnicas In Vitro , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Inyecciones Intraventriculares , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Técnicas de Placa-Clamp , Corteza Prefrontal/efectos de los fármacos
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