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1.
Dig Dis Sci ; 2024 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-39438414

RESUMEN

BACKGROUND/OBJECTIVES: The clinical utility of body composition in the development of complications of acute pancreatitis (AP) remains unclear. We aimed to describe the associations between body composition and the recurrence of AP. METHODS: We performed a retrospective study of patients hospitalized with AP at three tertiary care centers. Patients with computer tomography (CT) imaging of the abdomen at admission were included. A previously validated and fully automated abdominal segmentation algorithm was used for body composition analysis. Hospitalization for a recurrent episode of AP was the primary endpoint. Secondary endpoints included the development of chronic pancreatitis (CP) or diabetes mellitus (DM) in patients who were evaluated. Cox Proportional Hazards regression was used. RESULTS: From a total of 347 patients, 89 (25.6%) were hospitalized for recurrent AP (median time: 219 days). Thirty-four of 112 patients (30.4%) developed CP (median time: 311 days) and 22 of 88 (25.0%) developed DM (median time: 1104 days). After adjusting for age, male sex, first episode of AP, BUN, and severity of AP, we found that obesity, body mass index, alcohol pancreatitis, and gallstone pancreatitis were significantly associated with a recurrent episode of AP. Body composition was not associated with recurrent AP. In unadjusted analysis, subcutaneous adipose tissue (SAT) (HR 0.87 per 10 cm2, p = 0.002) was associated with CP. Skeletal muscle (SM) mass approached significance for CP (p = 0.0546). Intermuscular adipose tissue (IMAT) (HR 1.45 per 5 cm2, p = 0.0264) was associated with DM. CONCLUSION: Body composition was not associated with having a recurrent AP. At follow-up, 30% and 25% of evaluated patients developed CP and DM, respectively. A higher SAT and IMAT were associated with a lower incidence of CP and higher incidence of DM, respectively.

2.
bioRxiv ; 2023 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-37873164

RESUMEN

The striatal direct and indirect pathways constitute the core for basal ganglia function in action control. Although both striatal D1- and D2-spiny projection neurons (SPNs) receive excitatory inputs from the cerebral cortex, whether or not they share inputs from the same cortical neurons, and how pathway-specific corticostriatal projections control behavior remain largely unknown. Here using a new G-deleted rabies system in mice, we found that more than two-thirds of excitatory inputs to D2-SPNs also target D1-SPNs, while only one-third do so vice versa. Optogenetic stimulation of striatal D1- vs. D2-SPN-projecting cortical neurons differently regulate locomotion, reinforcement learning and sequence behavior, implying the functional dichotomy of pathway-specific corticostriatal subcircuits. These results reveal the partially segregated yet asymmetrically overlapping cortical projections on striatal D1- vs. D2-SPNs, and that the pathway-specific corticostriatal subcircuits distinctly control behavior. It has important implications in a wide range of neurological and psychiatric diseases affecting cortico-basal ganglia circuitry.

3.
Gastroenterology ; 165(6): 1533-1546.e4, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37657758

RESUMEN

BACKGROUND & AIMS: The aims of our case-control study were (1) to develop an automated 3-dimensional (3D) Convolutional Neural Network (CNN) for detection of pancreatic ductal adenocarcinoma (PDA) on diagnostic computed tomography scans (CTs), (2) evaluate its generalizability on multi-institutional public data sets, (3) its utility as a potential screening tool using a simulated cohort with high pretest probability, and (4) its ability to detect visually occult preinvasive cancer on prediagnostic CTs. METHODS: A 3D-CNN classification system was trained using algorithmically generated bounding boxes and pancreatic masks on a curated data set of 696 portal phase diagnostic CTs with PDA and 1080 control images with a nonneoplastic pancreas. The model was evaluated on (1) an intramural hold-out test subset (409 CTs with PDA, 829 controls); (2) a simulated cohort with a case-control distribution that matched the risk of PDA in glycemically defined new-onset diabetes, and Enriching New-Onset Diabetes for Pancreatic Cancer score ≥3; (3) multi-institutional public data sets (194 CTs with PDA, 80 controls), and (4) a cohort of 100 prediagnostic CTs (i.e., CTs incidentally acquired 3-36 months before clinical diagnosis of PDA) without a focal mass, and 134 controls. RESULTS: Of the CTs in the intramural test subset, 798 (64%) were from other hospitals. The model correctly classified 360 CTs (88%) with PDA and 783 control CTs (94%), with a mean accuracy 0.92 (95% CI, 0.91-0.94), area under the receiver operating characteristic (AUROC) curve of 0.97 (95% CI, 0.96-0.98), sensitivity of 0.88 (95% CI, 0.85-0.91), and specificity of 0.95 (95% CI, 0.93-0.96). Activation areas on heat maps overlapped with the tumor in 350 of 360 CTs (97%). Performance was high across tumor stages (sensitivity of 0.80, 0.87, 0.95, and 1.0 on T1 through T4 stages, respectively), comparable for hypodense vs isodense tumors (sensitivity: 0.90 vs 0.82), different age, sex, CT slice thicknesses, and vendors (all P > .05), and generalizable on both the simulated cohort (accuracy, 0.95 [95% 0.94-0.95]; AUROC curve, 0.97 [95% CI, 0.94-0.99]) and public data sets (accuracy, 0.86 [95% CI, 0.82-0.90]; AUROC curve, 0.90 [95% CI, 0.86-0.95]). Despite being exclusively trained on diagnostic CTs with larger tumors, the model could detect occult PDA on prediagnostic CTs (accuracy, 0.84 [95% CI, 0.79-0.88]; AUROC curve, 0.91 [95% CI, 0.86-0.94]; sensitivity, 0.75 [95% CI, 0.67-0.84]; and specificity, 0.90 [95% CI, 0.85-0.95]) at a median 475 days (range, 93-1082 days) before clinical diagnosis. CONCLUSIONS: This automated artificial intelligence model trained on a large and diverse data set shows high accuracy and generalizable performance for detection of PDA on diagnostic CTs as well as for visually occult PDA on prediagnostic CTs. Prospective validation with blood-based biomarkers is warranted to assess the potential for early detection of sporadic PDA in high-risk individuals.


Asunto(s)
Carcinoma Ductal Pancreático , Diabetes Mellitus , Neoplasias Pancreáticas , Humanos , Inteligencia Artificial , Estudios de Casos y Controles , Detección Precoz del Cáncer , Neoplasias Pancreáticas/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Carcinoma Ductal Pancreático/diagnóstico por imagen , Estudios Retrospectivos
4.
Mayo Clin Proc ; 98(5): 689-700, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36931980

RESUMEN

OBJECTIVE: To evaluate the performance of an internally developed and previously validated artificial intelligence (AI) algorithm for magnetic resonance (MR)-derived total kidney volume (TKV) in autosomal dominant polycystic kidney disease (ADPKD) when implemented in clinical practice. PATIENTS AND METHODS: The study included adult patients with ADPKD seen by a nephrologist at our institution between November 2019 and January 2021 and undergoing an MR imaging examination as part of standard clinical care. Thirty-three nephrologists ordered MR imaging, requesting AI-based TKV calculation for 170 cases in these 161 unique patients. We tracked implementation and performance of the algorithm over 1 year. A radiologist and a radiology technologist reviewed all cases (N=170) for quality and accuracy. Manual editing of algorithm output occurred at radiology or radiology technologist discretion. Performance was assessed by comparing AI-based and manually edited segmentations via measures of similarity and dissimilarity to ensure expected performance. We analyzed ADPKD severity class assignment of algorithm-derived vs manually edited TKV to assess impact. RESULTS: Clinical implementation was successful. Artificial intelligence algorithm-based segmentation showed high levels of agreement and was noninferior to interobserver variability and other methods for determining TKV. Of manually edited cases (n=84), the AI-algorithm TKV output showed a small mean volume difference of -3.3%. Agreement for disease class between AI-based and manually edited segmentation was high (five cases differed). CONCLUSION: Performance of an AI algorithm in real-life clinical practice can be preserved if there is careful development and validation and if the implementation environment closely matches the development conditions.


Asunto(s)
Riñón Poliquístico Autosómico Dominante , Adulto , Humanos , Riñón Poliquístico Autosómico Dominante/diagnóstico por imagen , Inteligencia Artificial , Riñón/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Algoritmos , Espectroscopía de Resonancia Magnética
5.
Elife ; 72018 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-29714166

RESUMEN

Striatal cholinergic (ChAT) and parvalbumin (PV) interneurons exert powerful influences on striatal function in health and disease, yet little is known about the organization of their inputs. Here using rabies tracing, electrophysiology and genetic tools, we compare the whole-brain inputs to these two types of striatal interneurons and dissect their functional connectivity in mice. ChAT interneurons receive a substantial cortical input from associative regions of cortex, such as the orbitofrontal cortex. Amongst subcortical inputs, a previously unknown inhibitory thalamic reticular nucleus input to striatal PV interneurons is identified. Additionally, the external segment of the globus pallidus targets striatal ChAT interneurons, which is sufficient to inhibit tonic ChAT interneuron firing. Finally, we describe a novel excitatory pathway from the pedunculopontine nucleus that innervates ChAT interneurons. These results establish the brain-wide direct inputs of two major types of striatal interneurons and allude to distinct roles in regulating striatal activity and controlling behavior.


Asunto(s)
Acetilcolina/metabolismo , Encéfalo/fisiología , Cuerpo Estriado/fisiología , Interneuronas/fisiología , Parvalbúminas/metabolismo , Potenciales de Acción , Animales , Encéfalo/citología , Células Cultivadas , Cuerpo Estriado/citología , Femenino , Interneuronas/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Tálamo/citología , Tálamo/fisiología
6.
Cell Stem Cell ; 22(5): 684-697.e9, 2018 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-29727680

RESUMEN

Despite widespread interest in using human induced pluripotent stem cells (hiPSCs) in neurological disease modeling, a suitable model system to study human neuronal connectivity is lacking. Here, we report a comprehensive and efficient differentiation paradigm for hiPSCs that generate multiple CA3 pyramidal neuron subtypes as detected by single-cell RNA sequencing (RNA-seq). This differentiation paradigm exhibits characteristics of neuronal network maturation, and rabies virus tracing revealed synaptic connections between stem cell-derived dentate gyrus (DG) and CA3 neurons in vitro recapitulating the neuronal connectivity within the hippocampus. Because hippocampal dysfunction has been implicated in schizophrenia, we applied DG and CA3 differentiation paradigms to schizophrenia-patient-derived hiPSCs. We detected reduced activity in DG-CA3 co-culture and deficits in spontaneous and evoked activity in CA3 neurons from schizophrenia-patient-derived hiPSCs. Our approach offers critical insights into the network activity aspects of schizophrenia and may serve as a promising tool for modeling diseases with hippocampal vulnerability. VIDEO ABSTRACT.


Asunto(s)
Hipocampo/patología , Células Madre Pluripotentes Inducidas/patología , Neuronas/patología , Adulto , Animales , Diferenciación Celular , Giro Dentado/metabolismo , Giro Dentado/patología , Femenino , Hipocampo/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Neuronas/metabolismo , Esquizofrenia/metabolismo , Esquizofrenia/patología , Adulto Joven
7.
Neuron ; 91(5): 1069-1084, 2016 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-27568516

RESUMEN

The striatum contains neurochemically defined compartments termed patches and matrix. Previous studies suggest patches preferentially receive limbic inputs and project to dopamine neurons in substantia nigra pars compacta (SNc), whereas matrix neurons receive sensorimotor inputs and do not innervate SNc. Using BAC-Cre transgenic mice with viral tracing techniques, we mapped brain-wide differences in the input-output organization of the patch/matrix. Findings reveal a displaced population of striatal patch neurons termed "exo-patch," which reside in matrix zones but have neurochemistry, connectivity, and electrophysiological characteristics resembling patch neurons. Contrary to previous studies, results show patch/exo-patch and matrix neurons receive both limbic and sensorimotor information. A novel inhibitory projection from bed nucleus of the stria terminalis to patch/exo-patch neurons was revealed. Projections to SNc were found to originate from patch/exo-patch and matrix neurons. These findings redefine patch/matrix beyond traditional neurochemical topography and reveal new principles about their input-output connectivity, providing a foundation for future functional studies.


Asunto(s)
Cuerpo Estriado/fisiología , Lóbulo Límbico/fisiología , Corteza Sensoriomotora/fisiología , Núcleos Septales/fisiología , Animales , Ratones , Ratones Transgénicos , Vías Nerviosas/fisiología , Técnicas de Trazados de Vías Neuroanatómicas , Neuronas/fisiología , Sustancia Negra/fisiología
8.
Science ; 350(6267): 1525-9, 2015 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-26680198

RESUMEN

Dysfunction of microRNA (miRNA) metabolism is thought to underlie diseases affecting motoneurons. One miRNA, miR-218, is abundantly and selectively expressed by developing and mature motoneurons. Here we show that mutant mice lacking miR-218 die neonatally and exhibit neuromuscular junction defects, motoneuron hyperexcitability, and progressive motoneuron cell loss, all of which are hallmarks of motoneuron diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. Gene profiling reveals that miR-218 modestly represses a cohort of hundreds of genes that are neuronally enriched but are not specific to a single neuron subpopulation. Thus, the set of messenger RNAs targeted by miR-218, designated TARGET(218), defines a neuronal gene network that is selectively tuned down in motoneurons to prevent neuromuscular failure and neurodegeneration.


Asunto(s)
Regulación de la Expresión Génica , MicroARNs/fisiología , Enfermedad de la Neurona Motora/genética , Neuronas Motoras/fisiología , Enfermedades Neurodegenerativas/genética , Animales , Redes Reguladoras de Genes , Ratones , Ratones Noqueados , MicroARNs/genética , Enfermedad de la Neurona Motora/fisiopatología , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Enfermedades Neurodegenerativas/patología , Médula Espinal/metabolismo , Médula Espinal/fisiopatología
9.
PLoS One ; 7(9): e45323, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23028932

RESUMEN

Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is abundant in striatal medium spiny neurons (MSNs). CaMKII is dynamically regulated by changes in dopamine signaling, as occurs in Parkinson's disease as well as addiction. Although CaMKII has been extensively studied in the hippocampus where it regulates excitatory synaptic transmission, relatively little is known about how it modulates neuronal function in the striatum. Therefore, we examined the impact of selectively overexpressing an EGFP-fused CaMKII inhibitory peptide (EAC3I) in striatal medium spiny neurons (MSNs) using a novel transgenic mouse model. EAC3I-expressing cells exhibited markedly decreased excitatory transmission, indicated by a decrease in the frequency of spontaneous excitatory postsynaptic currents (sEPSCs). This decrease was not accompanied by changes in the probability of release, levels of glutamate at the synapse, or changes in dendritic spine density. CaMKII regulation of the AMPA receptor subunit GluA1 is a major means by which the kinase regulates neuronal function in the hippocampus. We found that the decrease in striatal excitatory transmission seen in the EAC3I mice is mimicked by deletion of GluA1. Further, while CaMKII inhibition decreased excitatory transmission onto MSNs, it increased their intrinsic excitability. These data suggest that CaMKII plays a critical role in setting the excitability rheostat of striatal MSNs by coordinating excitatory synaptic drive and the resulting depolarization response.


Asunto(s)
Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/antagonistas & inhibidores , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Cuerpo Estriado/metabolismo , Neuronas/metabolismo , Péptidos/metabolismo , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Potenciales Postsinápticos Excitadores/genética , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Masculino , Ratones , Ratones Transgénicos , Péptidos/genética , Receptores AMPA/genética , Receptores AMPA/metabolismo , Transmisión Sináptica/genética , Transmisión Sináptica/fisiología
10.
J Neurosci ; 32(19): 6578-86, 2012 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-22573680

RESUMEN

Changes in CaMKII-regulated synaptic excitability are a means through which experience may modify neuronal function and shape behavior. While behavior in rodent addiction models is linked with CaMKII activity in the nucleus accumbens (NAc) shell, the key cellular adaptations that forge this link are unclear. Using a mouse strain with striatal-specific expression of autonomously active CaMKII (T286D), we demonstrate that while persistent CaMKII activity induces behaviors comparable to those in mice repeatedly exposed to psychostimulants, it is insufficient to increase AMPAR-mediated synaptic strength in NAc shell. However, autonomous CaMKII upregulates A-type K(+) current (IA) and decreases firing in shell neurons. Importantly, inactivating the transgene with doxycycline eliminates both the IA-mediated firing decrease and the elevated behavioral response to cocaine. This study identifies CaMKII regulation of IA in NAc shell neurons as a novel cellular contributor to the sensitization of cocaine reward.


Asunto(s)
Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/fisiología , Cocaína/farmacología , Cuerpo Estriado/enzimología , Receptores AMPA/fisiología , Recompensa , Regulación hacia Arriba/genética , Animales , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Cuerpo Estriado/efectos de los fármacos , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/genética , Técnicas de Cultivo de Órganos , Sinapsis/efectos de los fármacos , Sinapsis/genética
11.
Proc Natl Acad Sci U S A ; 109(5): E278-87, 2012 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-22219357

RESUMEN

The bed nucleus of the stria terminalis (BNST) is a critical region for alcohol/drug-induced negative affect and stress-induced reinstatement. NMDA receptor (NMDAR)-dependent plasticity, such as long-term potentiation (LTP), has been postulated to play key roles in alcohol and drug addiction; yet, to date, little is understood regarding the mechanisms underlying LTP of the BNST, or its regulation by ethanol. Acute and chronic exposure to ethanol modulates glutamate transmission via actions on NMDARs. Despite intense investigation, tests of subunit specificity of ethanol actions on NMDARs using pharmacological approaches have produced mixed results. Thus, we use a conditional GluN2B KO mouse line to assess both basal and ethanol-dependent function of this subunit at glutamate synapses in the BNST. Deletion of GluN2B eliminated LTP, as well as actions of ethanol on NMDAR function. Further, we show that chronic ethanol exposure enhances LTP formation in the BNST. Using KO-validated pharmacological approaches with Ro25-6981 and memantine, we provide evidence suggesting that chronic ethanol exposure enhances LTP in the BNST via paradoxical extrasynaptic NMDAR involvement. These findings demonstrate that GluN2B is a key point of regulation for ethanol's actions and suggest a unique role of extrasynaptic GluN2B-containing receptors in facilitating LTP.


Asunto(s)
Etanol/farmacología , Ácido Glutámico/metabolismo , Receptores de N-Metil-D-Aspartato/fisiología , Sinapsis/fisiología , Animales , Etanol/administración & dosificación , Potenciación a Largo Plazo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de N-Metil-D-Aspartato/genética , Sinapsis/efectos de los fármacos
12.
Proc Natl Acad Sci U S A ; 107(5): 2271-6, 2010 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-20133871

RESUMEN

Long-term depression (LTD) is an important synaptic mechanism for limiting excitatory influence over circuits subserving cognitive and emotional behavior. A major means of LTD induction is through the recruitment of signaling via G(q)-linked receptors activated by norepinephrine (NE), acetylcholine, and glutamate. Receptors from these transmitter families have been proposed to converge on a common postsynaptic LTD maintenance mechanism, such that hetero- and homosynaptic induction produce similar alterations in glutamate synapse efficacy. We report that in the dorsolateral and ventrolateral bed nucleus of the stria terminalis (BNST), recruitment of G(q)-linked receptors by glutamate or NE initiates mechanistically distinct forms of postsynaptically maintained LTD and these LTDs are differentially regulated by stress exposure. In particular, we show that although both mGluR5- and alpha(1)-adrenergic receptor (AR)-dependent LTDs involve postsynaptic endocytosis, the alpha(1)-AR-initiated LTD exclusively involves modulation of signaling through calcium-permeable AMPA receptors. Further, alpha(1)-AR- but not mGluR5- dependent LTD is disrupted by restraint stress. alpha(1)-AR LTD is also impaired in mice chronically exposed to ethanol. These data thus suggest that in the BNST, NE- and glutamate-activated G(q)-linked signaling pathways differentially tune glutamate synapse efficacy in response to stress.


Asunto(s)
Subunidades alfa de la Proteína de Unión al GTP Gq-G11/fisiología , Núcleos Septales/fisiología , Alcoholismo/fisiopatología , Animales , Etanol/toxicidad , Ácido Glutámico/farmacología , Humanos , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Depresión Sináptica a Largo Plazo/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Norepinefrina/farmacología , Receptor de Angiotensina Tipo 1/fisiología , Receptor del Glutamato Metabotropico 5 , Receptores AMPA/fisiología , Receptores de Glutamato Metabotrópico/fisiología , Núcleos Septales/efectos de los fármacos , Transducción de Señal , Estrés Fisiológico
13.
Eur J Neurosci ; 27(1): 31-42, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18184313

RESUMEN

Exposure to drugs of abuse activates gene expression and protein synthesis that result in long-lasting adaptations in striatal signaling. Therefore, identification of the transcription factors that couple drug exposure to gene expression is of particular importance. Members of the nuclear factor of activated T-cells (NFATc) family of transcription factors have recently been implicated in shaping neuronal function throughout the rodent nervous system. Here we demonstrate that regulation of NFAT-mediated gene expression may also be a factor in drug-induced changes to striatal functioning. In cultured rat striatal neurons, stimulation of D1 dopamine receptors induces NFAT-dependent transcription through activation of L-type calcium channels. Additionally, the genes encoding inositol-1,4,5-trisphosphate receptor type 1 and glutamate receptor subunit 2 are regulated by striatal NFATc4 activity. Consistent with these in-vitro data, repeated exposure to cocaine triggers striatal NFATc4 nuclear translocation and the up-regulation of inositol-1,4,5-trisphosphate receptor type 1 and glutamate receptor subunit 2 gene expression in vivo, suggesting that cocaine-induced increases in gene expression may be partially mediated through activation of NFAT-dependent transcription. Collectively, these findings reveal a novel molecular pathway that may contribute to the enduring modifications in striatal functioning that occur following the administration of drugs of abuse.


Asunto(s)
Cuerpo Estriado/metabolismo , Expresión Génica/fisiología , Factores de Transcripción NFATC/metabolismo , Receptores de Dopamina D1/fisiología , Animales , Animales Recién Nacidos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Células Cultivadas , Inmunoprecipitación de Cromatina/métodos , Cocaína/farmacología , Cuerpo Estriado/efectos de los fármacos , Inhibidores de Captación de Dopamina/farmacología , Ensayo de Cambio de Movilidad Electroforética/métodos , Agonistas de Aminoácidos Excitadores/farmacología , Expresión Génica/efectos de los fármacos , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Ratones , Ratones Endogámicos C57BL , Ratas , Receptores AMPA/metabolismo , Transfección/métodos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/farmacología
14.
J Neurosci ; 27(30): 7921-8, 2007 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-17652583

RESUMEN

Plasticity of glutamatergic synapses is a fundamental mechanism through which experience changes neural function to impact future behavior. In animal models of addiction, glutamatergic signaling in the nucleus accumbens (NAc) exerts powerful control over drug-seeking behavior. However, little is known about whether, how or when experience with drugs may trigger synaptic plasticity in this key nucleus. Using whole-cell synaptic physiology in NAc brain slices, we demonstrate that a progression of bidirectional changes in glutamatergic synaptic strength occurs after repeated in vivo exposure to cocaine. During a protracted drug-free period, NAc neurons from cocaine-experienced mice develop a robust potentiation of AMPAR-mediated synaptic transmission. However, a single re-exposure to cocaine during extended withdrawal becomes a potent stimulus for synaptic depression, abruptly reversing the initial potentiation. These enduring modifications in AMPAR-mediated responses and plasticity may provide a neural substrate for disrupted processing of drug-related stimuli in drug-experienced individuals.


Asunto(s)
Trastornos Relacionados con Cocaína , Cocaína/administración & dosificación , Plasticidad Neuronal/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Sinapsis/efectos de los fármacos , Animales , Trastornos Relacionados con Cocaína/fisiopatología , Trastornos Relacionados con Cocaína/psicología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Red Nerviosa/efectos de los fármacos , Red Nerviosa/fisiología , Plasticidad Neuronal/fisiología , Núcleo Accumbens/fisiología , Sinapsis/fisiología
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