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PURPOSE: This study aimed to investigate the value of magnetic resonance (MR) characteristics in differentiating the subtypes of growth hormone pituitary adenomas. MATERIALS AND METHODS: The clinical and MR imaging data of 70 patients with growth hormone pituitary adenoma confirmed by surgery and pathology were retrospectively analyzed. The tumors were divided into dense granular (DG; 36 cases) and sparse granular subtypes (SG; 34 cases). The tumors' MR features were analyzed, including the mean and maximum diameters, T2 signal intensity, T2 relative signal intensity (rSI), homogeneity, enhancement degree, and invasiveness (Knosp grade). Mann-Whitney U test and χ2 test were used to analyze MR characteristics between the 2 groups. The independent predictors and predictive probabilities of tumor subtypes were obtained via a logistic regression model, and the efficacy was compared by receiver operating characteristic curve. RESULTS: The mean and maximum diameters of growth hormone adenoma in DG and SG were 1.77 versus 2.45 and 1.95 versus 3.00 cm (median, P < 0.05), respectively. There was a significant difference between the 2 groups in T2 signal intensity and rSI (P values were 0.02 and 0.001, respectively). Most DG adenomas (86.1%) appeared as hypointense on T2 images, and 38.2% of SG adenomas were hyperintense. There was no significant difference in tumor homogeneity (P = 0.622). A significant difference was found in the Knosp grade between the 2 subtypes (P = 0.004). In addition, the enhancement degree of SG adenomas was significantly higher than that of DG adenomas (P = 0.001). Logistic regression analysis showed that high T2 rSI value and marked contrast enhancement were independent predictors of the 2 subtypes, and the odds ratios were 4.811 and 4.649, respectively. The multivariate logistic model obtained relatively high predicting efficacy, and the area under the curve, sensitivity, and specificity were 0.765, 0.882, and 0.500, respectively. CONCLUSIONS: There are significant differences in tumor size, T2 signal intensity, T2 rSI, enhancement degree, and invasiveness between DG and SG adenomas. The logistic model based on the marked contrast enhancement and high T2 rSI value has an important value in predicting the subtype of growth hormone adenoma.
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Adenoma/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Neoplasias Hipofisarias/diagnóstico por imagen , Adenoma/clasificación , Adenoma/patología , Adulto , Femenino , Hormona del Crecimiento/sangre , Humanos , Interpretación de Imagen Asistida por Computador , Masculino , Persona de Mediana Edad , Análisis Multivariante , Hipófisis/diagnóstico por imagen , Neoplasias Hipofisarias/clasificación , Neoplasias Hipofisarias/patología , Estudios RetrospectivosRESUMEN
Relapse to cocaine use after prolonged abstinence is an important clinical problem. This relapse is often induced by exposure to cues associated with cocaine use. To account for the persistent propensity for relapse, it has been suggested that cue-induced cocaine craving increases over the first several weeks of abstinence and remains high for extended periods. We and others identified an analogous phenomenon in rats that was termed 'incubation of cocaine craving': time-dependent increases in cue-induced cocaine-seeking over the first months after withdrawal from self-administered cocaine. Cocaine-seeking requires the activation of glutamate projections that excite receptors for alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) in the nucleus accumbens. Here we show that the number of synaptic AMPA receptors in the accumbens is increased after prolonged withdrawal from cocaine self-administration by the addition of new AMPA receptors lacking glutamate receptor 2 (GluR2). Furthermore, we show that these new receptors mediate the incubation of cocaine craving. Our results indicate that GluR2-lacking AMPA receptors could be a new target for drug development for the treatment of cocaine addiction. We propose that after prolonged withdrawal from cocaine, increased numbers of synaptic AMPA receptors combined with the higher conductance of GluR2-lacking AMPA receptors causes increased reactivity of accumbens neurons to cocaine-related cues, leading to an intensification of drug craving and relapse.
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Trastornos Relacionados con Cocaína/fisiopatología , Cocaína , Núcleo Accumbens/metabolismo , Receptores AMPA/metabolismo , Animales , Trastornos Relacionados con Cocaína/genética , Trastornos Relacionados con Cocaína/metabolismo , Señales (Psicología) , Regulación de la Expresión Génica , Masculino , Núcleo Accumbens/fisiopatología , Ratas , Ratas Long-Evans , Ratas Sprague-Dawley , Receptores AMPA/deficiencia , Receptores AMPA/genética , Autoadministración , Factores de TiempoRESUMEN
OBJECTIVE: To explore the usefulness of texture signatures based on multiparametric magnetic resonance imaging (MRI) in predicting the subtypes of growth hormone (GH) pituitary adenoma (PA). METHODS: Forty-nine patients with GH-secreting PA confirmed by the pathological analysis were included in this retrospective study. Texture parameters based on T1-, T2-, and contrast-enhanced T1-weighted images (T1C) were extracted and compared for differences between densely granulated (DG) and sparsely granulated (SG) somatotroph adenoma by using two segmentation methods [region of interest 1 (ROI1), excluding the cystic/necrotic portion, and ROI2, containing the whole tumor]. Receiver operating characteristic (ROC) curve analysis was performed to determine the differentiating efficacy. RESULTS: Among 49 included patients, 24 were DG and 25 were SG adenomas. Nine optimal texture features with significant differences between two groups were obtained from ROI1. Based on the ROC analyses, T1WI signatures from ROI1 achieved the highest diagnostic efficacy with an AUC of 0.918, the accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 85.7, 72.0, 100.0, 100.0, and 77.4%, respectively, for differentiating DG from SG. Comparing with the T1WI signature, the T1C signature obtained relatively high efficacy with an AUC of 0.893. When combining the texture features of T1WI and T1C, the radiomics signature also had a good performance in differentiating the two groups with an AUC of 0.908. In addition, the performance got in all the signatures from ROI2 was lower than those in the corresponding signature from ROI1. CONCLUSION: Texture signatures based on MR images may be useful biomarkers to differentiate subtypes of GH-secreting PA patients.
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It is well known that the nucleus accumbens plays an important role in drug reinforcing effect and relapse. However, the cellular neuroadaptations that take place in accumbens neurons after repeated drug exposure are still not well understood, especially for opioids. Here, we examined how nucleus accumbens neuronal excitability becomes affected in rats exposed to morphine using whole-cell patch-clamp recordings. Medium spiny neurons recorded from brain slices of repeated morphine treated rats exhibited a significant decrease in the intrinsic excitability after 3-4 days withdrawal, compared to that of neurons from saline treated animals, which was indicated by the increase of current to evoke the first spike and the decrease of spike number induced by depolarizing current steps in the morphine group. Moreover, the excitability decrease was accompanied by related membrane property changes, such as resting membrane potential hyperpolarization, input resistance, and membrane time constant decrease, inward rectification increase, and action potential duration decrease. Taken together, repeated morphine exposure and short-term withdrawal may reduce nucleus accumbens activity and output by modulating intrinsic membrane properties of its output neurons, which could be an important neuroadaptation process that mediates morphine addictive effect.
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Potenciales de Acción/efectos de los fármacos , Morfina/administración & dosificación , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Síndrome de Abstinencia a Sustancias/metabolismo , Potenciales de Acción/fisiología , Animales , Masculino , Dependencia de Morfina/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
BACKGROUND: The coexistence of a gangliocytoma and a pituitary adenoma is a rare event that has been reported in only case reports. The knowledge of its diagnosis and treatment is extremely limited. CASE DESCRIPTION: We present a rare case of intrasellar-suprasellar gangliocytoma and nonfunctioning pituitary adenoma. The lesion was diagnosed preoperatively as a pituitary adenoma, and it was resected using the extended endoscopic endonasal approach. We could clearly observe 2 different textures inside the tumor. The main body of the tumor tissue was tough and fibrous with distinct lobular nodules distributed within it. To our knowledge, this is the first report of distinct compartments with heterogeneous consistencies in a mixed sellar gangliocytoma-adenoma. CONCLUSIONS: Our finding of the heterogeneous texture in the lesion of gangliocytoma associated with pituitary adenoma may help to uncover the pathogenesis of this rare disorder. This finding also supports the examination of intraoperative frozen sections to aid in diagnosis. We recommend maximized safe resection as a surgical strategy for the coexistent lesion of gangliocytoma and pituitary adenoma.
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Adenoma/cirugía , Ganglioneuroma/cirugía , Neoplasias Primarias Múltiples/cirugía , Neoplasias Hipofisarias/cirugía , Adenoma/diagnóstico , Diagnóstico Diferencial , Femenino , Ganglioneuroma/diagnóstico , Ganglioneuroma/patología , Humanos , Imagen por Resonancia Magnética/métodos , Persona de Mediana Edad , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias Primarias Múltiples/patología , Neuroendoscopía , Neoplasias Hipofisarias/diagnósticoRESUMEN
BACKGROUND AND PURPOSE: The endocannabinoid (eCB) system is involved in pathways that regulate drug addiction and eCB-mediated synaptic plasticity has been linked with addictive behaviours. Here, we investigated the molecular mechanisms underlying the changes in eCB-dependent synaptic plasticity in the nucleus accumbens core (NAcc) following short-term withdrawal from repeated morphine treatment. EXPERIMENTAL APPROACH: Conditioned place preference (CPP) was used to evaluate the rewarding effects of morphine in rats. Evoked inhibitory postsynaptic currents of medium spiny neurons in NAcc were measured using whole-cell patch-clamp recordings. Changes in depolarization-induced suppression of inhibition (DSI) in the NAcc were assessed to determine the effect of short-term morphine withdrawal on the eCB system. To identify the potential modulation mechanism of short-term morphine withdrawal on the eCB system, the expression of diacylglycerol lipase α (DGL-α) and monoacylglycerol lipase was detected by Western blot analysis. KEY RESULTS: Repeated morphine administration for 7 days induced stable CPP. Compared with the saline group, the level of DSI in the NAcc was significantly increased in rats after short-term morphine withdrawal. Furthermore, this increase in DSI coincided with a significant increase in the expression of DGL-α. CONCLUSIONS AND IMPLICATIONS: Short-term morphine withdrawal potentiates eCB modulation of inhibitory synaptic transmission in the NAcc. We also found that DGL-α expression was elevated after short-term morphine withdrawal, suggesting that the eCB 2-arachidonyl-glycerol but not anandamide mediates the increase in DSI. These findings provide useful insights into the mechanisms underlying eCB-mediated plasticity in the NAcc during drug addiction. LINKED ARTICLES: This article is part of a themed section on Endocannabinoids. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.7/issuetoc.
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Endocannabinoides/metabolismo , Lipoproteína Lipasa/metabolismo , Dependencia de Morfina/fisiopatología , Morfina/efectos adversos , Núcleo Accumbens/fisiopatología , Síndrome de Abstinencia a Sustancias/fisiopatología , Transmisión Sináptica , Animales , Condicionamiento Psicológico , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiopatología , Dependencia de Morfina/metabolismo , Dependencia de Morfina/psicología , Inhibición Neural , Núcleo Accumbens/metabolismo , Ratas Sprague-Dawley , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/psicologíaRESUMEN
Diabetes mellitus is a common metabolic disease in human beings with characteristic symptoms of hyperglycemia, chronic inflammation and insulin resistance. One of the most common complications of early-onset diabetes mellitus is peripheral diabetic neuropathy, which is manifested either by loss of nociception or by allodynia and hyperalgesia. Dietary fatty acids, especially polyunsaturated fatty acids, have been shown the potential of anti-inflammation and modulating neuron excitability. The present study investigated the effects of docosahexaenoic acid (DHA) on the excitability of dorsal root ganglion (DRG) neurons in streptozotocin (STZ)-induced diabetes rats. The effects of DHA on the allodynia and hyperalgesia of diabetic rats were also evaluated. Dietary DHA supplementation effectively attenuated both allodynia and hyperalgesia induced by STZ injection. DHA supplementation decreased the excitability of DRG neurons by decreasing the sodium currents and increasing potassium currents, which may contribute to the effect of alleviating allodynia and hyperalgesia in diabetic rats. The results suggested that DHA might be useful as an adjuvant therapy for the prevention and treatment of painful diabetic neuropathy.
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Ácidos Docosahexaenoicos/farmacología , Ganglios Espinales/patología , Hiperalgesia/tratamiento farmacológico , Neuronas/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/genética , Animales , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/complicaciones , Modelos Animales de Enfermedad , Hiperalgesia/etiología , Canales Iónicos/metabolismo , Masculino , Neuronas/metabolismo , Dimensión del Dolor , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Bloqueadores de los Canales de Sodio/farmacología , Estreptozocina/toxicidad , Tetrodotoxina/farmacología , Factores de TiempoRESUMEN
BACKGROUND: Refinement of mature cognitive functions, such as working memory and decision making, typically takes place during adolescence. The acquisition of these functions is linked to the protracted development of the prefrontal cortex (PFC) and dopamine facilitation of glutamatergic transmission. However, the mechanisms that support these changes during adolescence remain elusive. METHODS: Electrophysiological recordings (in vitro and in vivo) combined with pharmacologic manipulations were employed to determine how N-methyl-D-aspartate transmission in the medial PFC changes during the adolescent transition to adulthood. The relative contribution of GluN2B transmission and its modulation by postsynaptic protein kinase A and D1 receptor signaling were determined in two distinct age groups of rats: postnatal day (P)25 to P40 and P50 to P80. RESULTS: We found that only N-methyl-D-aspartate receptor transmission onto the apical dendrite of layer V pyramidal neurons undergoes late adolescent remodeling due to a functional emergence of GluN2B function after P40. Both protein kinase A and dopamine D1 receptor signaling are required for the functional expression of GluN2B transmission and to sustain PFC plasticity in response to ventral hippocampal, but not basolateral amygdala, inputs. CONCLUSIONS: Thus, the late adolescent acquisition of GluN2B function provides a mechanism for dopamine D1-mediated regulation of PFC responses in an input-specific manner.
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Envejecimiento/fisiología , Proteínas Quinasas Dependientes de AMP Cíclico/fisiología , Corteza Prefrontal/crecimiento & desarrollo , Corteza Prefrontal/fisiología , Receptores de Dopamina D1/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Animales , Estimulación Encefálica Profunda , Potenciales Postsinápticos Excitadores/fisiología , Masculino , Ratas , Transmisión Sináptica/fisiologíaRESUMEN
The function of TRPV1 (transient receptor potential vanilloid subfamily, member 1) in the central nervous system is gradually elucidated. It has been recently proved to be expressed in nucleus accumbens (NAc), a region playing an essential role in mediating opioid craving and taking behaviors. Based on the general role of TRPV1 antagonist in blocking neural over-excitability by both pre- and post-synaptic mechanisms, TRPV1 antagonist capsazepine (CPZ) was tested for its ability to prohibit persistent opioid craving in rats. In the present study, we assessed the expression of TRPV1 in nucleus accumbens and investigated the effect of CPZ in bilateral nucleus accumbens on persistent morphine conditioned place preference (mCPP) in rats. We also evaluated the side-effect of CPZ on activity by comparing cross-beam times between groups. We found that morphine conditioned place preference increased the TRPV1 expression and CPZ attenuated morphine conditioned place preference in a dose-dependent and target-specific manner after both short- and long-term spontaneous withdrawal, reflected by the reduction of the increased time in morphine-paired side. CPZ (10 nM) could induce prolonged and stable inhibition of morphine conditioned place preference expression. More importantly, CPZ did not cause dysfunction of activity in the subjects tested, which indicates the inhibitory effect was not obtained at the sacrifice of regular movement. Collectively, these results indicated that injection of TRPV1 antagonist in nucleus accumbens is capable of attenuating persistent morphine conditioned place preference without affecting normal activity. Thus, TRPV1 antagonist is one of the promising therapeutic drugs for the treatment of opioid addiction.
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Capsaicina/análogos & derivados , Ansia/efectos de los fármacos , Núcleo Accumbens/metabolismo , Conducta Espacial/efectos de los fármacos , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/metabolismo , Animales , Western Blotting , Capsaicina/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Microscopía Inmunoelectrónica , Morfina , Ratas , Ratas Sprague-DawleyRESUMEN
Relapse is a major clinical problem and remains a major challenge in the treatment of drug addiction. There is strong evidence that the endocannabinoid system of the nucleus accumben core (NAcc) is involved in drug-seeking behavior, as well as in the mechanisms that underlie relapse to drug use. To reveal the mechanism that underlies this finding, we examined the expression pattern of the cannabinoid receptor 1 (CB1-R) in the NAcc of SD rats that had been undergoing morphine withdrawal (MW) for 1 day, 3 days and 3 weeks (acute, latent and chronic phases, respectively). Morphine exposure induced conditioned place preference (CPP) in rats. Significant increase of CB1-R expression in NAcc was observed in animals in the 1 day, 3 days and 3 weeks morphine withdrawal compare to the control group. Immunofluorescence labeling showed axonal fibers or terminals by fluorescence microscope observation. Immunoelectron microscopy detection showed silver-gold particles located in the presynaptic membranes that mainly give rise to symmetrical synapses. Quantitative electron microscopy showed an increase in number of CB1-R-positive terminals in the morphine withdrawal groups and the number of immunogold particles was significantly increased at these inhibitory terminals. We also confirmed that infusions of the CB1-R antagonist rimonabant into the NAcc attenuated the CPP during morphine withdrawal. Our present data have thus indicated that increasing pattern of CB1-R expression in the NAcc during above morphine withdrawal phases, which might underlie the relapse associated drug seeking behavior after morphine withdrawal.
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Modelos Animales de Enfermedad , Dependencia de Morfina/metabolismo , Núcleo Accumbens/metabolismo , Receptor Cannabinoide CB1/biosíntesis , Síndrome de Abstinencia a Sustancias/metabolismo , Regulación hacia Arriba/fisiología , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Ratas WistarRESUMEN
High-voltage spindles (HVSs) have been reported to appear spontaneously and widely in the cortical-basal ganglia networks of rats. Our previous study showed that dopamine depletion can significantly increase the power and coherence of HVSs in the globus pallidus (GP) and motor cortex of freely moving rats. However, it is unclear whether dopamine regulates HVS activity by acting on dopamine D1-like receptors or D2-like receptors. We employed local-field potential and electrocorticogram methods to simultaneously record the oscillatory activities in the GP and primary motor cortex (M1) in freely moving rats following systemic administration of dopamine receptor antagonists or saline. The results showed that the dopamine D2-like receptor antagonists, raclopride and haloperidol, significantly increased the number and duration of HVSs, and the relative power associated with HVS activity in the GP and M1 cortex. Coherence values for HVS activity between the GP and M1 cortex area were also significantly increased by dopamine D2-like receptor antagonists. On the contrary, the selective dopamine D1-like receptor antagonist, SCH23390, had no significant effect on the number, duration, or relative power of HVSs, or HVS-related coherence between M1 and GP. In conclusion, dopamine D2-like receptors, but not D1-like receptors, were involved in HVS regulation. This supports the important role of dopamine D2-like receptors in the regulation of HVSs. An siRNA knock-down experiment on the striatum confirmed our conclusion.
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Ondas Encefálicas/efectos de los fármacos , Antagonistas de los Receptores de Dopamina D2 , Globo Pálido/fisiología , Corteza Motora/fisiología , Animales , Benzazepinas/farmacología , Técnicas de Silenciamiento del Gen , Globo Pálido/efectos de los fármacos , Haloperidol/farmacología , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Corteza Motora/efectos de los fármacos , Racloprida/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/antagonistas & inhibidores , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismoRESUMEN
It is known that ßig-h3 is involved in the invasive process of many types of tumors, but its mechanism in glioma cells has not been fully clarified. Using immunofluorescent double-staining and confocal imaging analysis, and co-immunoprecipitation assays, we found that ßig-h3 co-localized with integrin α5ß1 in U87 cells. We sought to elucidate the function of this interaction by performing cell invasion assays and gelatin zymography experiments. We found that siRNA knockdowns of ßig-h3 and calpain-2 impaired cell invasion and MMP secretion. Moreover, ßig-h3, integrins and calpain-2 are known to be regulated by Ca(2+), and they are also involved in tumor cell invasion. Therefore, we further investigated if calpain-2 was relevant to ßig-h3-integrin α5ß1 interaction to affect U87 cell invasion. Our data showed that ßig-h3 co-localized with integrin α5ß1 to enhance the invasion of U87 cells, and that calpain-2, is involved in this process, acting as a downstream molecule.
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Astrocitos/metabolismo , Astrocitoma/metabolismo , Calpaína/metabolismo , Movimiento Celular/fisiología , Proteínas de la Matriz Extracelular/metabolismo , Integrina alfa5beta1/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Calpaína/genética , Adhesión Celular/fisiología , Línea Celular Tumoral , Proteínas de la Matriz Extracelular/genética , Humanos , Integrina alfa5beta1/genética , ARN Interferente Pequeño , Factor de Crecimiento Transformador beta/genéticaRESUMEN
Previous research has demonstrated that diabetes induced learning and memory deficits. However, the mechanism of memory impairment induced by diabetes is poorly understood. Sprague-Dawley rats were used in the present study to investigate the effect of streptozotocin (STZ)-induced diabetes on spatial learning and memory with the Morris water maze. The excitability of CA1 pyramidal neurons in hippocampus was also examined. Diabetes impaired spatial learning and memory of rats. Diabetes decreased the membrane excitability of CA1 pyramidal neurons, effects which may contribute to the behavioral deficits. To investigate the further ionic mechanisms, the sodium currents and the potassium currents were detected. Diabetes decreased both transient and persistent sodium currents, and increased both transient and sustained potassium currents, which leads to the reduction of neuron excitability and to the increase of firing accommodation. The results of the present study suggested that sodium and potassium currents contributed to the inhibitory effect of diabetes on neuron excitability, further influencing learning and memory processing. Modulating the ion channels and increasing the membrane excitability are possible candidates for preventing the impairments of diabetes on hippocampal function.
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Membrana Celular/fisiología , Diabetes Mellitus Experimental/fisiopatología , Diabetes Mellitus Experimental/psicología , Hipocampo/fisiopatología , Aprendizaje por Laberinto/fisiología , Células Piramidales/fisiología , Animales , Glucemia/fisiología , Peso Corporal/fisiología , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/fisiopatología , Interpretación Estadística de Datos , Fenómenos Electrofisiológicos , Masculino , Memoria/fisiología , Neuronas/fisiología , Técnicas de Placa-Clamp , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio con Entrada de Voltaje/efectos de los fármacos , Canales de Potasio con Entrada de Voltaje/fisiología , Ratas , Ratas Sprague-Dawley , Canales de Sodio/fisiología , Tetrodotoxina/farmacologíaRESUMEN
Further understanding of how prefrontal cortex (PFC) circuit change during postnatal development is of great interest due to its role in working memory and decision-making, two cognitive abilities that are refined late in adolescence and become altered in schizophrenia. While it is evident that dopamine facilitation of glutamate responses occurs during adolescence in the PFC, little is known about the cellular mechanisms that support these changes. Among them, a developmental facilitation of postsynaptic Ca(2+) function is of particular interest given its role in coordinating neuronal ensembles, a process thought to contribute to maturation of PFC function. Here we conducted whole-cell patch clamp recordings of deep-layer pyramidal neurons in PFC brain slices and determined how somatic-evoked Ca(2+)-mediated plateau depolarizations change throughout postnatal day (PD) 25 (juvenile) to adulthood (PD 80). Postsynaptic Ca(2+) potentials in the PFC increase in duration throughout postnatal development. A remarkable shift from short to prolonged depolarizations was observed after PD 40. This change is reflected by an enhancement of L-type Ca(2+) channel function and postsynaptic PKA signaling. We speculate that such a protracted developmental facilitation of Ca(2+) response in the PFC may contribute to improvement of working memory performance through adolescence.
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Canales de Calcio Tipo L/fisiología , Calcio/fisiología , Proteínas Quinasas Dependientes de AMP Cíclico/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Corteza Prefrontal/fisiología , Receptores de Dopamina D1/fisiología , Transducción de Señal/fisiología , Animales , Técnicas In Vitro , Masculino , Técnicas de Placa-Clamp , Corteza Prefrontal/crecimiento & desarrollo , Corteza Prefrontal/metabolismo , Células Piramidales/citología , Células Piramidales/crecimiento & desarrollo , Células Piramidales/fisiología , Ratas , Regulación hacia ArribaRESUMEN
Cue-induced cocaine seeking intensifies or incubates after withdrawal from extended access cocaine self-administration, a phenomenon termed incubation of cocaine craving. The expression of incubated craving is mediated by Ca²âº-permeable AMPA receptors (CP-AMPARs) in the nucleus accumbens (NAc). Thus, CP-AMPARs are a potential target for therapeutic intervention, making it important to understand mechanisms that govern their accumulation. Here we used subcellular fractionation and biotinylation of NAc tissue to examine the abundance and distribution of AMPAR subunits, and GluA1 phosphorylation, in the incubation model. We also studied two transmembrane AMPA receptor regulatory proteins (TARPs), γ-2 and γ-4. Our results, together with earlier findings, suggest that some of the new CP-AMPARs are synaptic. These are probably associated with γ-2, but they are loosely tethered to the PSD. Levels of GluA1 phosphorylated at serine 845 (pS845 GluA1) were significantly increased in biotinylated tissue and in an extrasynaptic membrane-enriched fraction. These results suggest that increased synaptic levels of CP-AMPARs may result in part from an increase in pS845 GluA1 in extrasynaptic membranes, given that S845 phosphorylation primes GluA1-containing AMPARs for synaptic insertion and extrasynaptic AMPARs supply the synapse. Some of the new extrasynaptic CP-AMPARs are likely associated with γ-4, rather than γ-2. The maintenance of CP-AMPARs in NAc synapses during withdrawal is accompanied by activation of CaMKII and ERK2 but not CaMKI. Overall, AMPAR plasticity in the incubation model shares some features with better described forms of synaptic plasticity, although the timing of the phenomenon and the persistence of related neuroadaptations are significantly different.