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1.
Proc Natl Acad Sci U S A ; 120(31): e2222095120, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37487094

RESUMEN

The locus coeruleus (LC) is a small nucleus in the pons from which ascending and descending projections innervate major parts of the central nervous system. Its major transmitter is norepinephrine (NE). This system is evolutionarily conserved, including in humans, and its functions are associated with wakefulness and related to disorders, such as depression. Here, we performed single-cell ribonucleic acid-sequencing (RNA-seq) to subdivide neurons in the LC (24 clusters in total) into 3 NE, 17 glutamate, and 5 γ-aminobutyric acid (GABA) subtypes, and to chart their neuropeptide, cotransmitter, and receptor profiles. We found that NE neurons expressed at least 19 neuropeptide transcripts, notably galanin (Gal) but not Npy, and >30 neuropeptide receptors. Among the galanin receptors, Galr1 was expressed in ~19% of NE neurons, as was also confirmed by in situ hybridization. Unexpectedly, Galr1 was highly expressed in GABA neurons surrounding the NE ensemble. Patch-clamp electrophysiology and cell-type-specific Ca2+-imaging using GCaMP6s revealed that a GalR1 agonist inhibits up to ~35% of NE neurons. This effect is direct and does not rely on feed-forward GABA inhibition. Our results define a role for the galanin system in NE functions, and a conceptual framework for the action of many other peptides and their receptors.


Asunto(s)
Galanina , Hormonas Peptídicas , Humanos , Animales , Ratones , Locus Coeruleus , Neuronas , Ácido Glutámico , Norepinefrina
2.
Theranostics ; 13(3): 955-972, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36793870

RESUMEN

Background: Stress is an important risk factor to induce psychiatric disorders such as depression. Phloretin (PHL), a natural dihydrochalcone compound, has been shown to exhibit anti-inflammatory and anti-oxidative effects. However, the impact of PHL on the depression and the underlying mechanism remain unclear. Methods: The animal behavior tests were used to determine the protective of PHL on the chronic mild stress (CMS)-induced depression-like behaviors. The Magnetic Resonance Imaging (MRI), electron microscopy analysis, fiber photometry, electrophysiology, and Structure Illumination Microscopy (SIM) were used to investigate the protective of PHL on the structural and functional impairments induced by CMS exposure in the mPFC. The RNA sequencing, western blot, reporter gene assay, and chromatin immunoprecipitation were adopted to investigate the mechanisms. Results: We showed that PHL efficiently prevented the CMS-induced depressive-like behaviors. Moreover, PHL not only attenuated the decrease of synapse losses but also improved the dendritic spine density and neuronal activity in the mPFC after CMS exposure. Furthermore, PHL remarkably inhibited the CMS-induced microglial activation and phagocytic activity in the mPFC. In addition, we demonstrated that PHL decreased the CMS-induced synapse losses by inhibiting the deposition of complement C3 deposition onto synapses and subsequent microglia-mediated synaptic engulfment. Finally, we revealed that PHL inhibited the NF-κB-C3 axis to display neuroprotective effects. Conclusions: Our results indicate that PHL represses the NF-κB-C3 axis and subsequent microglia-mediated synaptic engulfment to protect against CMS-induced depression in the mPFC.


Asunto(s)
Depresión , Microglía , Animales , Depresión/tratamiento farmacológico , Depresión/prevención & control , Depresión/etiología , FN-kappa B , Floretina/farmacología , Neuronas/patología
3.
Neuropsychopharmacology ; 48(3): 508-517, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36076020

RESUMEN

Serum amyloid P component (SAP) is a universal constituent of human amyloid deposits including those in Alzheimer's disease. SAP has been observed to be elevated in patients with depression, and higher SAP levels are associated with better response to the antidepressant escitalopram. The mechanisms underlying these clinical observations remain unclear. We examined the effect of SAP on serotonin transporter (SERT) expression and localization using Western blot, confocal microscopy, and positron emission tomography with the radioligand [11C]DASB. We also investigated the effect of SAP on treatment response to escitalopram in mice with the forced swim test (FST), a classical behaviour paradigm to assess antidepressant effects. SAP reduced [11C]DASB binding as an index of SERT levels, consistent with Western blots showing decreased total SAP protein because of increased protein degradation. In conjunction with the global decrease in SERT levels, SAP also promotes VAMP-2 mediated SERT membrane insertion. SAP levels are correlated with behavioural despair and SSRI treatment response in mice with FST. In MDD patients, the SAP and membrane SERT levels are correlated with response to SSRI treatment. SAP has complex effects on SERT levels and localization, thereby modulating the effect of SSRIs, which could partially explain clinical variability in antidepressant treatment response. These results add to our understanding of the mechanism for antidepressant drug action, and with further work could be of clinical utility.


Asunto(s)
Proteínas de Transporte de Serotonina en la Membrana Plasmática , Componente Amiloide P Sérico , Humanos , Ratones , Animales , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Componente Amiloide P Sérico/metabolismo , Escitalopram , Antidepresivos/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología
4.
Cell Rep ; 40(7): 111199, 2022 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-35977516

RESUMEN

The norepinephrine neurons in locus coeruleus (LC-NE neurons) are essential for sleep arousal, pain sensation, and cocaine addiction. According to previous studies, cocaine increases NE overflow (the profile of extracellular NE level in response to stimulation) by blocking the NE reuptake. NE overflow is determined by NE release via exocytosis and reuptake through NE transporter (NET). However, whether cocaine directly affects vesicular NE release has not been directly tested. By recording quantal NE release from LC-NE neurons, we report that cocaine directly increases the frequency of quantal NE release through regulation of NET and downstream protein kinase C (PKC) signaling, and this facilitation of NE release modulates the activity of LC-NE neurons and cocaine-induced stimulant behavior. Thus, these findings expand the repertoire of mechanisms underlying the effects of cocaine on NE (pro-release and anti-reuptake), demonstrate NET as a release enhancer in LC-NE neurons, and provide potential sites for treatment of cocaine addiction.


Asunto(s)
Trastornos Relacionados con Cocaína , Cocaína , Cocaína/farmacología , Trastornos Relacionados con Cocaína/metabolismo , Humanos , Locus Coeruleus/metabolismo , Neuronas/metabolismo , Norepinefrina/metabolismo , Norepinefrina/farmacología
5.
Mol Psychiatry ; 27(1): 534-558, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-33589739

RESUMEN

Traditional antidepressants largely interfere with monoaminergic transport or degradation systems, taking several weeks to have their therapeutic actions. Moreover, a large proportion of depressed patients are resistant to these therapies. Several atypical antidepressants have been developed which interact with G protein coupled receptors (GPCRs) instead, as direct targeting of receptors may achieve more efficacious and faster antidepressant actions. The focus of this review is to provide an update on how distinct GPCRs mediate antidepressant actions and discuss recent insights into how GPCRs regulate the pathophysiology of Major Depressive Disorder (MDD). We also discuss the therapeutic potential of novel GPCR targets, which are appealing due to their ligand selectivity, expression pattern, or pharmacological profiles. Finally, we highlight recent advances in understanding GPCR pharmacology and structure, and how they may provide new avenues for drug development.


Asunto(s)
Trastorno Depresivo Mayor , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Humanos , Ligandos , Receptores Acoplados a Proteínas G/metabolismo
6.
Proc Natl Acad Sci U S A ; 118(24)2021 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-34108238

RESUMEN

Galanin receptor1 (GalR1) transcript levels are elevated in the rat ventral periaqueductal gray (vPAG) after chronic mild stress (CMS) and are related to depression-like behavior. To explore the mechanisms underlying the elevated GalR1 expression, we carried out molecular biological experiments in vitro and in animal behavioral experiments in vivo. It was found that a restricted upstream region of the GalR1 gene, from -250 to -220, harbors an E-box and plays a negative role in the GalR1 promoter activity. The transcription factor Scratch2 bound to the E-box to down-regulate GalR1 promoter activity and lower expression levels of the GalR1 gene. The expression of Scratch2 was significantly decreased in the vPAG of CMS rats. Importantly, local knockdown of Scratch2 in the vPAG caused elevated expression of GalR1 in the same region, as well as depression-like behaviors. RNAscope analysis revealed that GalR1 mRNA is expressed together with Scratch2 in both GABA and glutamate neurons. Taking these data together, our study further supports the involvement of GalR1 in mood control and suggests a role for Scratch2 as a regulator of depression-like behavior by repressing the GalR1 gene in the vPAG.


Asunto(s)
Conducta Animal , Depresión/patología , Sustancia Gris Periacueductal/patología , Receptor de Galanina Tipo 1/metabolismo , Factores de Transcripción/metabolismo , Animales , Elementos E-Box/genética , Neuronas GABAérgicas/metabolismo , Regulación de la Expresión Génica , Ácido Glutámico/metabolismo , Células PC12 , Regiones Promotoras Genéticas/genética , Unión Proteica , Ratas , Receptor de Galanina Tipo 1/genética , Estrés Psicológico/complicaciones , Factores de Transcripción/genética , Sitio de Iniciación de la Transcripción
7.
Gen Thorac Cardiovasc Surg ; 68(8): 746-753, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32390086

RESUMEN

OBJECTIVE: Palmar hyperhidrosis affects 0.6-10% of the general population, having an important impact in patients' quality of life. The definitive treatment for palmar hyperhidrosis is thoracic sympathectomy. The purpose of this study is to evaluate the quality of life after thoracic sympathectomy for palmar hyperhidrosis. METHODS: The interest studies were searched in six comprehensive databases. The quality of the studies was assessed using the risk of bias tool recommended by the Cochrane system evaluation manual. Meta-analysis was performed with RevMan version 5.3. The outcome of interest was quality of life. The subgroup analysis and sensitive analysis were performed. RESULTS: Nine trials, including 895 patients, with accessible data comparing preoperative quality of life score with postoperative quality-of-life score were used for data analysis. Compared with preoperative quality-of-life score, application of thoracic sympathectomy improved the postoperative quality of life of palmar hyperhidrosis patients (MD = 57.81, 95% CI 53.33-62.30). Subgroup analysis of the different thoracic sympathectomy segment showed that there was no significant difference in the results obtained when operated with single segment or multiple segments (single segment: MD = 61.16, 95% CI [56.10, 66.22], multiple segments: MD = 52.14, 95% CI [48.39, 55.88]). CONCLUSION: The meta-analysis provided evidence of the improved quality of life after thoracic sympathectomy for palmar hyperhidrosis.


Asunto(s)
Hiperhidrosis/cirugía , Calidad de Vida , Humanos , Hiperhidrosis/psicología , Periodo Posoperatorio , Simpatectomía , Procedimientos Quirúrgicos Torácicos
9.
Neuropeptides ; 79: 102000, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31864679

RESUMEN

The neuropeptide galanin functions via three G-protein coupled receptors, Gal1-3-R. Both Gal1-R and 2-R are involved in pain signaling at the spinal level. Here a Gal2-R-EGFP transgenic (TG) mouse was generated and studied in pain tests and by characterizing Gal2-R expression in both sensory ganglia and spinal cord. After peripheral spared nerve injury, mechanical allodynia developed and was ipsilaterally similar between wild type (WT) and TG mice. A Gal2-R-EGFP-positive signal was primarily observed in small and medium-sized dorsal root ganglion (DRG) neurons and in spinal interneurons and processes. No significant difference in size distribution of DRG neuronal profiles was found between TG and WT mice. Both percentage and fluorescence intensity of Gal2-R-EGFP-positive neuronal profiles were overall significantly upregulated in ipsilateral DRGs as compared to contralateral DRGs. There was an ipsilateral reduction in substance P-positive and calcitonin gene-related peptide (CGRP)-positive neuronal profiles, and this reduction was more pronounced in TG as compared to WT mice. Moreover, Gal2-R-EGFP partly co-localized with three pain-related neuropeptides, CGRP, neuropeptide Y and galanin, both in intact and injured DRGs, and with galanin also in local neurons in the superficial dorsal horn. Taken together, the present results provide novel information on the localization and phenotype of DRG and spinal neurons expressing the second galanin receptor, Gal2-R, and on phenotypic changes following peripheral nerve injury. Gal2-R may also be involved in autoreceptor signaling.


Asunto(s)
Péptido Relacionado con Gen de Calcitonina/metabolismo , Ganglios Espinales/metabolismo , Neuronas/metabolismo , Médula Espinal/metabolismo , Animales , Ratones Transgénicos , Neuronas Aferentes/metabolismo , Neuropéptido Y/metabolismo , Neuropéptidos/metabolismo , Sustancia P/metabolismo
10.
Mol Brain ; 12(1): 92, 2019 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-31707987

RESUMEN

We report the identification of a de novo GABRA1 (R214C) variant in a child with epileptic encephalopathy (EE), describe its functional characterization and pathophysiology, and evaluate its potential therapeutic options. The GABRA1 (R214C) variant was identified using whole exome sequencing, and the pathogenic effect of this mutation was investigated by comparing wild-type (WT) α1 and R214C α1 GABAA receptor-expressing HEK cells. GABA-evoked currents in these cells were recorded using whole-cell, outside-out macro-patch and cell-attached single-channel patch-clamp recordings. Changes to surface and total protein expression levels of WT α1 and R214C α1 were quantified using surface biotinylation assay and western blotting, respectively. Finally, potential therapeutic options were explored by determining the effects of modulators, including diazepam, insulin, and verapamil, on channel gating and receptor trafficking of WT and R214C GABAA receptors. We found that the GABRA1 (R214C) variant decreased whole-cell GABA-evoked currents by reducing single channel open time and both surface and total GABAA receptor expression levels. The GABA-evoked currents in R214C GABAA receptors could only be partially restored with benzodiazepine (diazepam) and insulin. However, verapamil treatment for 24 h fully restored the function of R214C mutant receptors, primarily by increasing channel open time. We conclude that the GABRA1 (R214C) variant reduces channel activity and surface expression of mutant receptors, thereby contributing to the pathogenesis of genetic EE. The functional restoration by verapamil suggests that it is a potentially new therapeutic option for patients with the R214C variant and highlights the value of precision medicine in the treatment of genetic EEs.


Asunto(s)
Epilepsia/genética , Epilepsia/fisiopatología , Mutación/genética , Receptores de GABA-A/genética , Secuencia de Aminoácidos , Niño , Canales de Cloruro/metabolismo , Diazepam/farmacología , Electroencefalografía , Epilepsia/diagnóstico por imagen , Femenino , Genotipo , Células HEK293 , Humanos , Insulina/farmacología , Activación del Canal Iónico/efectos de los fármacos , Cinética , Imagen por Resonancia Magnética , Fenotipo , Subunidades de Proteína/genética , Receptores de GABA-A/química , Verapamilo/farmacología
11.
Mediators Inflamm ; 2019: 7898095, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31736656

RESUMEN

Accumulated evidences show that neuroinflammation play a pivotal role in the pathogenesis of depression. Neuropeptide Y (NPY) and its receptors have been demonstrated to have anti-inflammative as well as antidepressant effects. In the present study, the ability of NPY to modulate depressive-like behaviors induced by lipopolysaccharides (LPS) in rats and the receptors and signaling mechanisms involved were investigated. Continuous injection LPS (i.p) for 4 days led to development of depressive-like behaviors in rats, accompanied with M1-type microglia activation and increased levels of IL-1ß as well as decreased levels of NPY and Y2R expression in the mPFC selectively. Local injection of NPY into the medial prefrontal cortex (mPFC) ameliorated the depression-like behaviors and suppressed the NLRP3 inflammasome signaling pathway. Y2R agonist PYY (3-36) mimicked and Y2R antagonist BIIE0246 abolished the NPY effects in the mPFC. All these results suggest that NPY and Y2R in the mPFC are involved in the pathophysiology of depression and NPY plays an antidepressant role in the mPFC mainly via Y2R, which suppresses the NLRP3 signaling pathway, in LPS-induced depression model rats.


Asunto(s)
Lipopolisacáridos/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Receptores de Neuropéptido Y/metabolismo , Animales , Western Blotting , Depresión/metabolismo , Interleucina-1beta/metabolismo , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal/efectos de los fármacos
12.
Neurosci Bull ; 35(6): 1035-1044, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31327148

RESUMEN

ETS-1 is a transcription factor that is a member of the E26 transformation-specific (ETS) family. Galanin receptor 2 (GalR2), a subtype of receptors of the neuropeptide galanin, has been shown to have an antidepressant-like effect after activation in rodents. Our previous study has shown that overexpression of ETS-1 increases the expression of GalR2 in PC12 phaeochromocytoma cells. However, whether ETS-1 has an antidepressant-like effect is still unclear. In this study, we found that chronic mild stress (CMS) decreased the expression of both ETS-1 and GalR2 in the ventral hippocampus of rats. Meanwhile, we demonstrated that overexpression of ETS-1 increased the expression of GalR2 in primary hippocampal neurons. Importantly, we showed that overexpression of ETS-1 in the ventral hippocampus counteracted the depression-like behaviors of CMS rats. Furthermore, we found that overexpression of ETS-1 increased the level of downstream phosphorylated extracellular signal-regulated protein kinases 1 and 2 (p-ERK1/2) of GalR2 in the ventral hippocampus of CMS rats. Taken together, our findings suggest that ETS-1 has an antidepressant-like effect in rats, which might be mediated by increasing the level of GalR2 and its downstream p-ERK1/2 in the ventral hippocampus.


Asunto(s)
Depresión/metabolismo , Hipocampo/metabolismo , Proteína Proto-Oncogénica c-ets-1/metabolismo , Anhedonia , Animales , Sistema de Señalización de MAP Quinasas , Masculino , Ratas , Ratas Sprague-Dawley , Receptor de Galanina Tipo 2/metabolismo , Sacarosa , Natación
13.
Mediators Inflamm ; 2019: 2716028, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31249471

RESUMEN

The neuropeptide galanin and its receptors have been found to have protective effects on neurons. However, the role of galanin on astrocytes is still unclear. The present study is aimed at investigating the effects of galanin on the viability of cultured rat cortical astrocytes after oxidative stress induced by H2O2 and possible receptor and signaling mechanisms involved. Treatment of galanin had significant protective effects against H2O2-induced toxicity in the cultured cortical astrocytes. H2O2 induced an upregulation of phosphorylated extracellular signal-related kinase1/2 (pERK1/2) in astrocytes, which was suppressed by coapplication of galanin, suggesting an involvement of the pERK1/2 signal pathway in the protective effects of galanin. GalR2 has higher expression levels than GalR1 and GalR3 in the cultured cortical astrocytes, and GalR2 agonist AR-M1896 mimicked galanin effects on the astrocytes, implying that galanin protective effects mainly mediated by GalR2. Meanwhile, galanin had no effect on the A1-type transformation of rat cortical astrocytes. All those results suggest that galanin protects rat cortical astrocytes from oxidative stress by suppressing H2O2-induced upregulation of pERK1/2, mainly through GalR2.


Asunto(s)
Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Galanina/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Animales , Western Blotting , Células Cultivadas , Peróxido de Hidrógeno/farmacología , Inmunohistoquímica , Sistema de Señalización de MAP Quinasas/genética , Estrés Oxidativo/efectos de los fármacos , Reacción en Cadena de la Polimerasa , Ratas , Ratas Sprague-Dawley , Receptor de Galanina Tipo 2/genética , Receptor de Galanina Tipo 2/metabolismo , Transducción de Señal/efectos de los fármacos
14.
Front Psychiatry ; 9: 588, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30487761

RESUMEN

Estrogen (E2) withdrawal is a core pathology mechanism for postpartum depression (PPD). Galanin (GAL), an estrogen-inducible neuropeptide has also been reported to be associated with depression. However, it still remains unclear which GAL receptors (GALRs) are involved in PPD pathologic process. In the present study, we discovered that the expression of GALR1, rather than GALR2/3, was upregulated with a region-specific pattern in the prefrontal cortex (PFC) of E2 withdrawal induced PPD model rats. Meanwhile, c-fos was also upregulated only in PFC in the same animal model. Injection of GALR1-siRNA into the bilateral PFC ameliorated depressive-like behavior of PPD rats, suggesting that the upregulation of GALR1 in PFC is involved in PPD. Moreover, Western Blot and HPLC assays demonstrated that the downregulation of CREB-BDNF signaling and 5-HT levels in the PFC of PPD rats were reversed after GALR1-siRNA injection. These comprehensive results suggest that the knock down of GALR1 in PFC alleviates depressive-like behaviors and reverse downregulation of CREB-BDNF and 5-HT levels in PPD rat model. HIGHLIGHTS  Expression level of GALR1 mRNA was significantly increased in PFC of estrogen withdraw-induced PPD rats. Injecting GALR1-siRNA into PFC alleviated depressive-like behavior and reversed the decrease of 5-HT level and CREB/BDNF signaling in PFC of PPD rats.

15.
Theranostics ; 8(17): 4679-4694, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30279731

RESUMEN

Autologous neural stem cells (NSCs) may offer a promising source for deriving dopaminergic (DA) cells for treatment of Parkinson's disease (PD). Methods: By using Sendai virus, human peripheral blood mononuclear cells (PBMNCs) were reprogrammed to induced NSCs (iNSCs), which were then differentiated to dopaminergic neurons in vitro. Whole-genome deep sequencing was performed to search for mutations that had accumulated during the reprogramming and expansion processes. To find the optimal differentiation stage of cells for transplantation, DA precursors obtained at various differentiation time points were tested by engraftment into brains of naïve immunodeficient mice. At last, the safety and efficacy of iNSC-derived DA precursors were tested by transplantation into the striatum of immunodeficient PD mouse models. Results: PBMNC-derived iNSCs showed similar characteristics to fetal NSCs, and were able to specifically differentiate to DA neurons with high efficiency in vitro. The sequencing data proved that no harmful SNVs, Indels and CNVs were generated during the reprogramming and expansion processes. DA precursors obtained between differentiation day 10 to 13 in vitro were most suitable for transplantation when a balanced graft survival and maturation were taken into account. Two weeks after transplantation of DA precursors into mouse PD models, the motor functions of PD mice started to improve, and continued to improve until the end of the experiments. No graft overgrowth or tumor was observed, and a significant number of A9-specific midbrain DA neurons were surviving in the striatum. Conclusion: This study confirmed the efficacy of iNSC-derived DA precursors in a mouse PD model, and emphasized the necessity of genomic sequencing and vigorous safety assessment before any clinical translation using iNSCs.


Asunto(s)
Trasplante de Células/métodos , Neuronas Dopaminérgicas/fisiología , Células-Madre Neurales/fisiología , Enfermedad de Parkinson/terapia , Animales , Células Sanguíneas , Diferenciación Celular , Técnicas de Reprogramación Celular , Modelos Animales de Enfermedad , Humanos , Locomoción , Ratones , Enfermedad de Parkinson/patología
16.
J Neurosci Methods ; 307: 46-52, 2018 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-29960027

RESUMEN

BACKGROUND: Various neurological and psychological disorders are related to cortical volume changes in specific brain regions, which can be measured in vivo using structural magnetic resonance imaging (sMRI). There is an increasing interest in MRI studies using rat models, especially in longitudinal studies of brain disorders and pharmacologic interventions. However, morphometric changes observed in sMRI are only meaningful if the measurements are reliable. To date, a systematic evaluation of the test-retest reliability of the morphometric measures in the rat brain is still lacking. NEW METHOD: We rigorously evaluated the test-retest reliability of morphometric measures derived from the voxel-based morphometry (VBM) analysis. 37 Sprague-Dawley rats were scanned twice at an interval of six hours and the gray matter volume was estimated using the VBM-DARTEL method. The intraclass coefficient, percent volume change and Pearson correlation coefficient were used to evaluate the reliability in 96 subregions of the rat brain. RESULTS: Most subregions showed excellent test-retest reliabilities within an interval of 6 h while a few regions demonstrated lower reliability, especially in the retrosplenial granular cortex. The results were consistent between different methods of reliability assessment. COMPARISON WITH EXISTING METHOD: To the best of our knowledge, this is the first study to quantify the test-retest reliability of the VBM measurements of the rat brain. CONCLUSION: Atlas-based cortical volume of the rat brain can be reliably estimated using the VBM-DARTEL method in most subregions. However, findings in subregions with lower reliability must be interpreted with caution.


Asunto(s)
Mapeo Encefálico , Corteza Cerebral/diagnóstico por imagen , Animales , Sustancia Gris/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Reproducibilidad de los Resultados , Sustancia Blanca/diagnóstico por imagen
17.
Biochem Biophys Res Commun ; 503(1): 79-85, 2018 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-29852172

RESUMEN

The noradrenergic neurons of the locus coeruleus (LC) are associated with various brain functions and psychiatric disorders, such as addiction and depression. It has been shown that neuropeptide galanin (GAL) inhibits neuronal excitability in LC, but the mechanisms remain unclear. In the present study, we investigated the ionic and signal transduction mechanisms underlying inhibitory effect of GAL on LC neurons using whole-cell patch clamp recording in rat brain slices. Bath application of GAL decreased the spontaneous firings and induced a dose-dependent hyperpolarization of LC neurons and this effect was attenuated by knockdown of Galr1, but not Galr2, confirming that mainly GALR1 mediates the inhibition effect of GAL. The inhibitory effect of GAL was also blocked by treatments of pertussis toxin (PTX), GTP-γ-s or GDP-ß-s, respectively, indicating that the functions of PTX sensitive Gi/o protein are required for GAL-induced hyperpolarization. Moreover, the blockers of GIRK (tertiapin-Q or SCH2 3390 hydrochloride) attenuated the GAL response while blocker of BK/SK/KATP channels or TASK-1/3 channels did not affect it significantly, suggesting that GIRK channels play an important role in GAL-induced hyperpolarization in LC neurons. Taken together, the inhibitory effect of GAL on LC neurons is mediated by GALR1 via PTX-sensitive Gi/o proteins, which activate GIRK channels.


Asunto(s)
Canales de Potasio Rectificados Internamente Asociados a la Proteína G/metabolismo , Locus Coeruleus/metabolismo , Receptor de Galanina Tipo 1/metabolismo , Neuronas Adrenérgicas/efectos de los fármacos , Neuronas Adrenérgicas/metabolismo , Animales , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/antagonistas & inhibidores , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Galanina/metabolismo , Técnicas de Silenciamiento del Gen , Locus Coeruleus/citología , Locus Coeruleus/efectos de los fármacos , Masculino , Técnicas de Placa-Clamp , Toxina del Pertussis/farmacología , Bloqueadores de los Canales de Potasio/farmacología , Precursores de Proteínas/metabolismo , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/genética , Ratas , Ratas Sprague-Dawley , Receptor de Galanina Tipo 1/antagonistas & inhibidores , Receptor de Galanina Tipo 1/genética , Receptor de Galanina Tipo 2/antagonistas & inhibidores , Receptor de Galanina Tipo 2/genética , Receptor de Galanina Tipo 2/metabolismo , Transducción de Señal
18.
Int J Mol Med ; 41(4): 2225-2232, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29393394

RESUMEN

Previous studies demonstrated that Nav1.5 splice variants, including Nav1.5a and Nav1.5c, were expressed in dorsal root ganglia (DRG) neurons. However, since nine Nav1.5 isoforms have been identified, whether other Nav1.5 splice variants, especially the neonatal Nav1.5 splice variant, express in the DRG neurons is still unknown. In this study, we systematically investigated the expression of adult and neonatal Nav1.5 isoforms in the DRG neurons and axon of peripheral sensory neurons of rats with spared nerve injury (SNI) by RT-PCR, DNA sequencing, restriction enzyme digestion, immunohistochemistry and immunofluorescence methods. The results demonstrated that both adult and neonatal Nav1.5 isoforms were expressed in the DRG neurons, but their expression ratio was ~2.5:1. In SNI rat models, the expression of both adult and neonatal Nav1.5 decreased by approximately a half in both mRNA and protein levels. In contrast, the expression of protein kinase C (PKC)-γ, one of the negative modulators for sodium currents, increased by ~1-fold. Taken together, this study first confirmed the expression of both adult and neonatal Nav1.5 isoforms in the DRG neurons and axon of peripheral sensory neurons of rat, but their expression level decreased in pain models. The upregulation of PKC-γ may directly or indirectly downregulate the expression of Nav1.5 isoforms in SNI rat models, which may further involve in the pathological process of neuropathic pain.


Asunto(s)
Axones/patología , Regulación hacia Abajo , Ganglios Espinales/patología , Canal de Sodio Activado por Voltaje NAV1.5/genética , Neuralgia/genética , Células Receptoras Sensoriales/patología , Animales , Axones/metabolismo , Modelos Animales de Enfermedad , Ganglios Espinales/citología , Ganglios Espinales/metabolismo , Masculino , Canal de Sodio Activado por Voltaje NAV1.5/análisis , Neuralgia/patología , ARN Mensajero/análisis , ARN Mensajero/genética , Ratas Sprague-Dawley , Células Receptoras Sensoriales/citología , Células Receptoras Sensoriales/metabolismo
19.
Med Sci Monit ; 24: 397-404, 2018 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-29352772

RESUMEN

BACKGROUND Congenital single-side deafness (SSD) affects sound localization even after cochlear implantation (CI) in some conditions. The medial nucleus of the trapezoid body (MNTB) plays an important role in binaural benefit and sound localization, but little is known about intrinsic molecular changes in MNTB with SSD. We aimed to observe changes in MNTB in early-developmental SSD rats, including the key neurotransmitters (GABA, Gly, Glu) and major receptors (GABAa-R/GABAb-R for GABA, Gly-R for Gly, and AMPA/NMDA for Glu). MATERIAL AND METHODS The model of early-developmental SSD was acquired by right cochlear ablation at P12 and confirmed by ABR. High-performance liquid chromatography fluorescence detection (HPLC-FLD) was performed to measure the levels of neurotransmitters in MNTB. The relative expression of neurotransmitter receptors was tested by quantitative real-time PCR analysis. RESULTS (1) The right MNTB of experimental rats had an increase in GABA, Gly, and Glu at 4 weeks after right cochlear ablation (P<0.05). (2) At 2 weeks, the left MNTB of experimental rats showed increases in GABAa-R, GABAb-R, Gly-R, and AMPA, while the right MNTB showed lower expression of NMDA (P<0.05). The higher receptors in left MNTB decreased to a level at which we found no difference at 1 week for GABAa-R and GABAb-R (P>0.05), and was even reversed for Gly-R and AMPA (P<0.05). (3) Gly level was significantly increased at 2 weeks bilaterally and continued to 4 weeks in the left MNTB (P<0.05). CONCLUSIONS Early-developmental SSD can lead to asymmetric distribution of neurotransmitters and receptors in MNTB, which can be the fundamental cause of defective sound localization after cochlear implantation.


Asunto(s)
Sordera/metabolismo , Neurotransmisores/fisiología , Receptores de Neurotransmisores/fisiología , Potenciales de Acción , Animales , Sordera/fisiopatología , Femenino , Masculino , Neurotransmisores/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de GABA/metabolismo , Receptores de Neurotransmisores/metabolismo , Cuerpo Trapezoide/citología , Cuerpo Trapezoide/fisiología , Ácido gamma-Aminobutírico/metabolismo
20.
Behav Brain Res ; 336: 236-243, 2018 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-28889022

RESUMEN

Oxytocin (OXT) has been considered as a neuroregulator mediating social behaviors and stress-related disorders. Recent clinical studies suggest that OXT might also act as antidepressant in postpartum depression (PPD) patients, but the mechanism is still unknown. In the present study, we explored the effect of OXT in paraventricular nucleus (PVN) and possible signaling pathway involved in a PPD rat model induced by gestation restraint stress (GRS). PPD rats exhibited depressive-like behaviors with significantly longer immobility time, shorter climbing time, and lower sucrose consumption compared to the control rats. Plasma corticosterone (CORT) level was also higher in PPD rats. While PVN and supraoptic nucleus (SON) are main OXT synthesis regions in the brain, GRS-induced decrease of mRNA and peptide level of OXT was seen only in PVN. The expression of TrkB in PVN was increased in PPD rats. Local injection of OXT (20ng) into PVN reversed GRS-induced depressive-like behaviors and high plasma CORT level in PPD rats. Moreover, injection of OXT also reversed GRS-induced increase of TrkB in PVN of PPD rats. All those data suggest that OXT plays an antidepressant role by, at least in part, modulating HPA axis via TrkB in PVN of PPD rats.


Asunto(s)
Depresión Posparto/tratamiento farmacológico , Depresión Posparto/metabolismo , Oxitocina/farmacología , Animales , Antidepresivos/metabolismo , Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Corticosterona/metabolismo , Depresión/tratamiento farmacológico , Depresión/metabolismo , Modelos Animales de Enfermedad , Femenino , Sistema Hipotálamo-Hipofisario/metabolismo , Inyecciones Intraventriculares , Masculino , Oxitocina/administración & dosificación , Núcleo Hipotalámico Paraventricular , Sistema Hipófiso-Suprarrenal/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Conducta Social , Estrés Psicológico
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