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1.
Cancer Sci ; 111(3): 840-848, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31925975

RESUMEN

Ionizing radiation can damage DNA and, therefore, is a risk factor for cancer. Eker rats, which carry a heterozygous germline mutation in the tumor-suppressor gene tuberous sclerosis complex 2 (Tsc2), are susceptible to radiation-induced renal carcinogenesis. However, the molecular mechanisms involved in Tsc2 inactivation are unclear. We subjected Fischer 344 × Eker (Long Evans Tsc2+/- ) F1 hybrid rats to gamma-irradiation (2 Gy) at gestational day 19 (GD19) or postnatal day 5 (PND5) and investigated the patterns of genomic alterations in the Tsc2 allele of renal tumors that developed at 1 year after irradiation (N = 24 tumors for GD19, N = 10 for PND5), in comparison with spontaneously developed tumors (N = 8 tumors). Gamma-irradiation significantly increased the multiplicity of renal tumors. The frequency of LOH at the chromosome 10q12 region, including the Tsc2 locus, was 38%, 29% and 60% in renal carcinomas developed from the nonirradiated, GD19 and PND5 groups, respectively. Array comparative genomic hybridization analysis revealed that the LOH patterns on chromosome 10 in renal carcinomas were classified into chromosomal missegregation, mitotic recombination and chromosomal deletion types. LOH of the interstitial chromosomal deletion type was observed only in radiation-associated carcinomas. Sequence analysis for the wild-type Tsc2 allele in the LOH-negative carcinomas identified deletions (nonirradiated: 26%; GD19: 21%) and base-substitution mutations (GD19: 4%). Reduced expression of Tsc2 was also observed in the majority of the LOH-negative carcinomas. Our results suggest that interstitial chromosomal deletion is a characteristic mutagenic event caused by ionizing radiation, and it may contribute to the assessment of radiation-induced cancer risk.


Asunto(s)
Neoplasias Renales/genética , Proteína 2 del Complejo de la Esclerosis Tuberosa/genética , Esclerosis Tuberosa/genética , Alelos , Animales , Deleción Cromosómica , Cromosomas Humanos Par 10/genética , Hibridación Genómica Comparativa/métodos , Rayos gamma/efectos adversos , Heterocigoto , Humanos , Masculino , Mutación/genética , Ratas , Ratas Endogámicas F344 , Ratas Long-Evans , Riesgo , Proteínas Supresoras de Tumor/genética
2.
Invest Ophthalmol Vis Sci ; 60(14): 4924-4930, 2019 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-31770432

RESUMEN

Purpose: In the dark, photoreceptor outer segments contain high levels of cyclic guanosine 3'-5' monophosphate (cGMP), which binds to ion channels, holding them open and allowing an influx of cations. Ion pumping activity, which balances cation influx, uses considerable amounts of adenosine triphosphate (ATP) and oxygen. Light reduces cation influx and thereby lowers metabolic demand. Blood vessels are compromised in the diabetic retina and may not be able to meet the higher metabolic demand in darkness. Emixustat is a visual cycle modulator (VCM) that reduces chromophore levels and, therefore, may mimic light conditions. We evaluated the effect of emixustat on oxygen consumption and cation influx in dark conditions. Methods: Cation influx was measured in rats using Mn2+-magnetic resonance imaging (MEMRI). Retinal oxygen profiles were recorded to evaluate oxygen consumption. In the MEMRI protocol, animals were treated with either emixustat or vehicle. In the oxygen protocol, animals were untreated or treated with emixustat. Results: In vehicle-treated animals, cation channel activity increased in the dark. Emixustat treatment reduced cation channel activity; activity was comparable to vehicle-treated controls in light conditions. In vehicle-treated animals, minimum retinal oxygen tension decreased as the retina recovered from a photobleach, indicating that more oxygen was being consumed. Emixustat treatment prevented the decrease in oxygen pressure after photobleach. Conclusions: Emixustat reduced the cation influx and retinal oxygen consumption associated with dark conditions. VCMs are a promising potential treatment for ischemic retinal neovascularization, such as that in diabetic retinopathy.


Asunto(s)
Adaptación a la Oscuridad/fisiología , Manganeso/metabolismo , Consumo de Oxígeno/fisiología , Éteres Fenílicos/farmacología , Propanolaminas/farmacología , Retina/efectos de los fármacos , Animales , Imagen por Resonancia Magnética , Masculino , Ratas , Ratas Endogámicas BN , Ratas Long-Evans , Retina/metabolismo , cis-trans-Isomerasas/antagonistas & inhibidores
4.
Behav Processes ; 169: 103978, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31580905

RESUMEN

Temporal control of behavior might be impaired by reinforcement devaluation and other motivational operations such as delaying reinforcement of the instrumental response. Here, we report an experiment that assessed the effect of delayed reinforcement on a timing peak procedure. Using a within-subject design with a multiple two-component schedule of reinforcement, we found evidence of flat temporal generalization gradients, along with degraded response-reinforcer contingency, lower response rates and changes in the responding patterns due to delayed reinforcement. This result is consistent with the Learning to Time (LeT) and some versions of Scalar Expectancy Theory (SET).


Asunto(s)
Condicionamiento Operante/fisiología , /fisiología , Animales , Masculino , Motivación/fisiología , Ratas , Ratas Long-Evans , Esquema de Refuerzo
5.
Acta Neurobiol Exp (Wars) ; 79(3): 290-301, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31587021

RESUMEN

Post-stroke neurological deficits, such as sensorimotor impairments, are often permanent and a leading cause of disability. Stroke is also associated with changes in neuronal synchrony among different brain areas. Multiple studies demonstrated that non-invasive brain stimulation, such as transcranial direct current stimulation (tDCS), enhances the efficacy of existing rehabilitative therapies. We hypothesized that the therapeutic effects of tDCS could be due to its influence on neuronal synchrony. To study this, we recorded local field potentials in rats treated with anodal tDCS (a-tDCS) after unilateral ischemic motor cortex lesion. To enhance the effect of a-tDCS on neuronal synchrony, we added monopolar pulses (a-tDCSmp) during a treatment. We found that ischemic lesions reduced interhemispheric coherence in the low gamma frequency range. By contrast, a-tDCSmp treatment increased interhemispheric coherence along with motor improvement in a skilled reaching task. These observations indicate that increased neuronal coherence is a likely mechanism by which tDCS improves stroke recovery. Moreover, this work adds to previous evidence that measures of brain coherence could be used as a biomarker of stroke recovery, which may help in the design of more effective tDCS protocols for stroke rehabilitation.


Asunto(s)
Isquemia/terapia , Rehabilitación de Accidente Cerebrovascular , Accidente Cerebrovascular/terapia , Estimulación Transcraneal de Corriente Directa , Animales , Modelos Animales de Enfermedad , Extremidades/fisiopatología , Isquemia/fisiopatología , Masculino , Corteza Motora/fisiopatología , Ratas Long-Evans , Estimulación Transcraneal de Corriente Directa/métodos
6.
Acta Neurobiol Exp (Wars) ; 79(3): 309-317, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31587023

RESUMEN

We determined CA1 hippocampal field to be involved in self-exposure, a type of novelty­seeking behaviour that has also been associated with short 22 kHz and flat 50 kHz ultrasonic vocalizations (USV) in adult male Long-Evans rats. Rats were habituated for three days to a self-exposure cage with two nose-poke holes. On day four, the animals from the experimental group were allowed to turn the cage light off for 5 s with a nose­poke (test/self­exposure session), while rats from control-yoked group had changing light conditions coupled and identical to the experimental animals. The experimental rats performed more nose-pokes during self-exposure session than animals from the control group. This effect was accompanied by a higher density of c-Fos-positive nuclei in the hippocampal CA1. There were no significant group differences in c-Fos expression in other brain regions analysed. However, possible involvement of several other structures in self-exposure (i.e., CA3, the dentate gyrus, amygdala, prefrontal cortex, and nucleus accumbens) is also discussed, as their correlational activity, reflected by c-Fos immunoactivity, was observed in the experimental rats. During test sessions, there were more nose-pokes accompanied by short 22 kHz calls and 50 kHz calls performed by the rats of the experimental group than of the control group. The CA1 region has previously been associated with novelty; short 22 kHz USV and flat 50 kHz USV could be associated with self-exposure, also they appear to be emitted correlatively.


Asunto(s)
Conducta Exploratoria/fisiología , Hipocampo/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Vocalización Animal/fisiología , Amígdala del Cerebelo/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Masculino , Núcleo Accumbens/metabolismo , Ratas Long-Evans
7.
BMC Complement Altern Med ; 19(1): 278, 2019 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-31640743

RESUMEN

BACKGROUND: Recent epidemiological and experimental studies suggest that cadmium and diabetes-related hyperglycemia may act synergistically to worsen metabolic regulation. The present study aims to evaluate the potential effects of Enhydra fluctuans extract in diabetes and dyslipidemia in cadmium (CdCl2) induced- normal and type 2 diabetic model rats. METHOD: Forty-eight Long-Evans rats were divided equally into the following six groups: Normal Control (N-C), Normal treated with CdCl2 (N-Cd), Normal treated with plant extract (N-P), Normal treated with both plant extract and CdCl2 (N-PCd), Diabetic treated with plant extract (DM-P) and Diabetic treated with both plant extract and CdCl2 (DM-PCd). Blood glucose and other biochemical parameters were estimated by the enzymatic colorimetric method. Histological analysis of liver and heart was done by the hematoxylin-eosin (H & E) method. RESULTS: Twenty-one days treatment of E. fluctuans extracts at a dose of 200 mg/kg significantly reduced blood glucose level in N-PCd and DM-PCd (p < 0.05), and DM-P (p < 0.01) group. The plant extract had no direct effects on total blood lipids but, it had beneficial effects on TG/HDL-C ratio in N-P and DM-PCd groups (p < 0.05). Cd induction significantly reduced body weight [(N-Cd, N-PCd, DM-PCd) (p < 0.01)], and induced liver [N-Cd (p < 0.05), N-PCd, p < 0.001] and renal impairment [N-Cd (p < 0.05)]. In bi-variate association, a significant positive correlation between serum glucose and SGPT (p < 0.05) as well as SGPT and TG/HDL ratio (p = 0.019) was found in DM-P and in the merged group. The histology of liver and heart showed severe damages including inflammation, nuclear pyknosis, loss of myocardial fibers, necrosis and fibrosis in the Cd treated groups compared to plant treated groups. CONCLUSION: E. fluctuans seems to have potent antihyperglycemic effects in diabetes and Cd toxicity along with partial antidyslipidemic properties in euglycemic and diabetic rats. Our study suggests a novel oral antihyperglycemic agent in the present environmental context.


Asunto(s)
Asteraceae/química , Cadmio/toxicidad , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hiperglucemia/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Hipolipemiantes/administración & dosificación , Extractos Vegetales/administración & dosificación , Animales , Glucemia/metabolismo , Cadmio/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Hiperglucemia/etiología , Hiperglucemia/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Lípidos/sangre , Masculino , Ratas , Ratas Long-Evans
8.
PLoS Comput Biol ; 15(10): e1007408, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31622332

RESUMEN

Surfactant Replacement Therapy (SRT), which involves instillation of a liquid-surfactant mixture directly into the lung airway tree, is a major therapeutic treatment in neonatal patients with respiratory distress syndrome (RDS). This procedure has proved to be remarkably effective in premature newborns, inducing a five-fold decrease of mortality in the past 35 years. Disappointingly, its use in adults for treating acute respiratory distress syndrome (ARDS) experienced initial success followed by failures. Our recently developed numerical model has demonstrated that transition from success to failure of SRT in adults could, in fact, have a fluid mechanical origin that is potentially reversible. Here, we present the first numerical simulations of surfactant delivery into a realistic asymmetric conducting airway tree of the rat lung and compare them with experimental results. The roles of dose volume (VD), flow rate, and multiple aliquot delivery are investigated. We find that our simulations of surfactant delivery in rat lungs are in good agreement with our experimental data. In particular, we show that the monopodial architecture of the rat airway tree plays a major role in surfactant delivery, contributing to the poor homogeneity of the end distribution of surfactant. In addition, we observe that increasing VD increases the amount of surfactant delivered to the acini after losing a portion to coating the involved airways, the coating cost volume, VCC. Finally, we quantitatively assess the improvement resulting from a multiple aliquot delivery, a method sometimes employed clinically, and find that a much larger fraction of surfactant reaches the alveolar regions in this case. This is the first direct qualitative and quantitative comparison of our numerical model with experimental studies, which enhances our previous predictions in adults and neonates while providing a tool for predicting, engineering, and optimizing patient-specific surfactant delivery in complex situations.


Asunto(s)
Surfactantes Pulmonares/administración & dosificación , Surfactantes Pulmonares/uso terapéutico , Animales , Simulación por Computador , Hidrodinámica , Pulmón/fisiología , Flujo Espiratorio Máximo/fisiología , Modelos Anatómicos , Modelos Estadísticos , Ratas , Ratas Long-Evans , Ratas Sprague-Dawley , Ratas Wistar , Tensoactivos
9.
Br J Anaesth ; 123(6): 827-838, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31623841

RESUMEN

BACKGROUND: Spinal cord injury induces inflammatory responses that include the release of cytokines and the recruitment and activation of macrophages and microglia. Neuroinflammation at the lesion site contributes to secondary tissue injury and permanent locomotor dysfunction. Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist, is anti-inflammatory and neuroprotective in both preclinical and clinical trials. We investigated the effect of DEX on the microglial response, and histological and neurological outcomes in a rat model of cervical spinal cord injury. METHODS: Anaesthetised rats underwent unilateral (right) C5 spinal cord contusion (75 kdyne) using an impactor device. The locomotor function, injury size, and inflammatory responses were assessed. The effect of DEX was also studied in a microglial cell culture model. RESULTS: DEX significantly improved the ipsilateral upper-limb motor dysfunction (grooming and paw placement; P<0.0001 and P=0.0012), decreased the injury size (P<0.05), spared white matter (P<0.05), and reduced the number of activated macrophages (P<0.05) at the injury site 4 weeks post-SCI. In DEX-treated rats after injury, tissue RNA expression indicated a significant downregulation of pro-inflammatory markers (e.g. interleukin [IL]-1ß, tumour necrosis factor-α, interleukin (IL)-6, and CD11b) and an upregulation of anti-inflammatory and pro-resolving M2 responses (e.g. IL-4, arginase-1, and CD206) (P<0.05). In lipopolysaccharide-stimulated cultured microglia, DEX produced a similar inflammation-modulatory effect as was seen in spinal cord injury. The benefits of DEX on these outcomes were mostly reversed by an α2-adrenergic receptor antagonist. CONCLUSIONS: DEX significantly improves neurological outcomes and decreases tissue damage after spinal cord injury, which is associated with modulation of neuroinflammation and is partially mediated via α2-adrenergic receptor signaling.


Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Dexmedetomidina/farmacología , Inflamación/tratamiento farmacológico , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/fisiopatología , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Microglía/efectos de los fármacos , Ratas , Ratas Long-Evans , Transducción de Señal/efectos de los fármacos , Médula Espinal/efectos de los fármacos , Médula Espinal/fisiopatología
10.
Nat Commun ; 10(1): 4704, 2019 10 17.
Artículo en Inglés | MEDLINE | ID: mdl-31624264

RESUMEN

The subjective sense of certainty, or confidence, in ambiguous sensory cues can alter the interpretation of reward feedback and facilitate learning. We trained rats to report the orientation of ambiguous visual stimuli according to a spatial stimulus-response rule that must be learned. Following choice, rats could wait a self-timed delay for reward or initiate a new trial. Waiting times increase with discrimination accuracy, demonstrating that this measure can be used as a proxy for confidence. Chemogenetic silencing of BLA shortens waiting times overall whereas ACC inhibition renders waiting times insensitive to confidence-modulating attributes of visual stimuli, suggesting contribution of ACC but not BLA to confidence computations. Subsequent reversal learning is enhanced by confidence. Both ACC and BLA inhibition block this enhancement but via differential adjustments in learning strategies and consistent use of learned rules. Altogether, we demonstrate dissociable roles for ACC and BLA in transmitting confidence and learning under uncertainty.


Asunto(s)
Complejo Nuclear Basolateral/fisiología , Conducta de Elección/fisiología , Giro del Cíngulo/fisiología , Aprendizaje Inverso/fisiología , Incertidumbre , Animales , Condicionamiento Operante/fisiología , Masculino , Estimulación Luminosa , Ratas Long-Evans , Tiempo de Reacción/fisiología , Recompensa
11.
Nat Commun ; 10(1): 4074, 2019 09 09.
Artículo en Inglés | MEDLINE | ID: mdl-31501436

RESUMEN

Previous studies indicate that the dorsolateral striatum (DLS) integrates sensorimotor information from cortical and thalamic regions to learn and execute motor habits. However, the exact contribution of sensory representations to this process is still unknown. Here we explore the role of the forelimb somatosensory flow in the DLS during the learning and execution of motor habits. First, we compare rhythmic somesthetic representations in the DLS and primary somatosensory cortex in anesthetized rats, and find that sequential and temporal stimuli contents are more strongly represented in the DLS. Then, using a behavioral protocol in which rats developed a stereotyped motor sequence, functional disconnection experiments, and pharmacologic and optogenetic manipulations in apprentice and expert animals, we reveal that somatosensory thalamic- and cortical-striatal pathways are indispensable for the temporal component of execution. Our results indicate that the somatosensory flow in the DLS provides the temporal reference for the development and execution of motor habits.


Asunto(s)
Aprendizaje , Actividad Motora/fisiología , Neostriado/fisiología , Sensación/fisiología , Animales , Miembro Anterior/fisiología , Red Nerviosa/fisiología , Optogenética , Ratas Long-Evans , Factores de Tiempo
12.
Nat Commun ; 10(1): 3934, 2019 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-31477694

RESUMEN

Drug addiction is a chronic relapsing disorder of compulsive drug use. Studies of the neurobehavioral factors that promote drug relapse have yet to produce an effective treatment. Here we take a different approach and examine the factors that suppress-rather than promote-relapse. Adapting Pavlovian procedures to suppress operant drug response, we determined the anti-relapse action of environmental cues that signal drug omission (unavailability) in rats. Under laboratory conditions linked to compulsive drug use and heightened relapse risk, drug omission cues suppressed three major modes of relapse-promotion (drug-predictive cues, stress, and drug exposure) for cocaine and alcohol. This relapse-suppression is, in part, driven by omission cue-reactive neurons, which constitute small subsets of glutamatergic and GABAergic cells, in the infralimbic cortex. Future studies of such neural activity-based cellular units (neuronal ensembles/memory engram cells) for relapse-suppression can be used to identify alternate targets for addiction medicine through functional characterization of anti-relapse mechanisms.


Asunto(s)
Cocaína/farmacología , Condicionamiento Operante/efectos de los fármacos , Señales (Psicología) , Neuronas/fisiología , Corteza Prefrontal/efectos de los fármacos , Alcoholismo/fisiopatología , Alcoholismo/prevención & control , Animales , Cocaína/administración & dosificación , Conducta Compulsiva/fisiopatología , Conducta Compulsiva/prevención & control , Condicionamiento Operante/fisiología , Inhibidores de Captación de Dopamina/farmacología , Masculino , Corteza Prefrontal/fisiopatología , Ratas Long-Evans , Ratas Sprague-Dawley , Ratas Transgénicas , Recurrencia , Trastornos Relacionados con Sustancias/fisiopatología , Trastornos Relacionados con Sustancias/prevención & control
13.
Int J Mol Sci ; 20(17)2019 08 30.
Artículo en Inglés | MEDLINE | ID: mdl-31480394

RESUMEN

Feeding rats with high-fat diet (HFD) with a single streptozotocin (STZ) injection induced obesity, slightly elevated fasting blood glucose and impaired glucose and insulin tolerance, and caused cardiac hypertrophy and mild diastolic dysfunction as published before by Koncsos et al. in 2016. Here we aimed to explore the renal consequences in the same groups of rats. Male Long-Evans rats were fed normal chow (CON; n = 9) or HFD containing 40% lard and were administered STZ at 20 mg/kg (i.p.) at week four (prediabetic rats, PRED, n = 9). At week 21 blood and urine samples were taken and kidney and liver samples were collected for histology, immunohistochemistry and for analysis of gene expression. HFD and STZ increased body weight and visceral adiposity and plasma leptin concentration. Despite hyperleptinemia, plasma C-reactive protein concentration decreased in PRED rats. Immunohistochemistry revealed elevated collagen IV protein expression in the glomeruli, and Lcn2 mRNA expression increased, while Il-1ß mRNA expression decreased in both the renal cortex and medulla in PRED vs. CON rats. Kidney histology, urinary protein excretion, plasma creatinine, glomerular Feret diameter, desmin protein expression, and cortical and medullary mRNA expression of TGF-ß1, Nrf2, and PPARγ were similar in CON and PRED rats. Reduced AMPKα phosphorylation of the autophagy regulator Akt was the first sign of liver damage, while plasma lipid and liver enzyme concentrations were similar. In conclusion, glomerular collagen deposition and increased lipocalin-2 expression were the early signs of kidney injury, while most biomarkers of inflammation, oxidative stress and fibrosis were negative in the kidneys of obese, prediabetic rats with mild heart and liver injury.


Asunto(s)
Colágeno/metabolismo , Glomérulos Renales/lesiones , Glomérulos Renales/metabolismo , Lipocalina 2/metabolismo , Obesidad/metabolismo , Estado Prediabético/metabolismo , Tejido Adiposo/metabolismo , Animales , Biomarcadores/metabolismo , Peso Corporal , Dieta Alta en Grasa , Fibrosis , Regulación de la Expresión Génica , Inflamación/genética , Inflamación/patología , Glomérulos Renales/patología , Lípidos/sangre , Hígado/enzimología , Hígado/patología , Hígado/fisiopatología , Masculino , MicroARNs/genética , MicroARNs/metabolismo , Obesidad/sangre , Estrés Oxidativo/genética , Fosforilación , Fosfoserina/metabolismo , Estado Prediabético/sangre , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Long-Evans , Estreptozocina
14.
Nat Commun ; 10(1): 3970, 2019 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-31481701

RESUMEN

Gamma is a ubiquitous brain rhythm hypothesized to support cognitive, perceptual, and mnemonic functions by coordinating neuronal interactions. While much correlational evidence supports this hypothesis, direct experimental tests have been lacking. Since gamma occurs as brief bursts of varying frequencies and durations, most existing approaches to manipulate gamma are either too slow, delivered irrespective of the rhythm's presence, not spectrally specific, or unsuitable for bidirectional modulation. Here, we overcome these limitations with an approach that accurately detects and modulates endogenous gamma oscillations, using closed-loop signal processing and optogenetic stimulation. We first show that the rat basolateral amygdala (BLA) exhibits prominent gamma oscillations during the consolidation of contextual memories. We then boost or diminish gamma during consolidation, in turn enhancing or impairing subsequent memory strength. Overall, our study establishes the role of gamma oscillations in memory consolidation and introduces a versatile method for studying fast network rhythms in vivo.


Asunto(s)
Complejo Nuclear Basolateral/fisiología , Ritmo Gamma/fisiología , Memoria Espacial/fisiología , Animales , Conducta Apetitiva/fisiología , Reacción de Prevención/fisiología , Masculino , Consolidación de la Memoria/fisiología , Optogenética , Ratas Long-Evans
15.
Reprod Toxicol ; 88: 85-90, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31369804

RESUMEN

Endocrine-disrupting compounds (EDCs) are found in the environment due to their use in industrial and manufacturing activities. Exposure of the population to bisphenol A (BPA) and di (2-ethylhexyl) phthalate (DEHP) is significant because they are present in many consumer products. EDCs target the reproductive tract because they express high levels of steroid hormone receptors, which act as transcriptional factors to regulate reproductive development. In the present study, timed-pregnant Long-Evans female rats (n = 8-10) were administered BPA and DEHP by oral gavage at 2.5 or 25 µg/kg body weight and 5 or 50 µg/kg body weight, respectively. Exposures to chemicals were limited to the period between gestational days 12 and 21 followed by assessment of testicular development in male offspring in the postnatal period. Leydig cells and Sertoli cells are the two major somatic cells present in the testis. The 17ß-hydroxysteroid dehydrogenase (17ß-HSD) steroidogenic enzyme is a marker for Leydig cell maturation, whereas transferrin is a marker for Sertoli cell differentiation. At day 10 post-partum, testes were obtained from cohorts of control and chemical-exposed male rats and processed to measure 17ß-HSD and transferrin expression levels in western blots. Compared to control, 17ßHSD enzyme protein was increased in BPA-treated rats but levels were decreased in animals exposed to DEHP (P < 0.05). Transferrin protein was decreased in male rats exposed to both BPA and DEHP compared to control animals (P < 0.05). To assess qualitative cellular changes within the spermatogenic epithelium, testes were obtained from separate cohorts of male rats at 35 days of age and processed for histopathological analysis. Results showed that prenatal exposures of male rats to BPA and DEHP caused disruption of the spermatogenic epithelium evident as disorganization and atrophy of seminiferous tubules as well as desquamation of germ cells into the tubular lumen. Together, results from the present study support the view that developmental exposures to environmentally relevant levels of BPA and DEHP are associated with disruptions of testicular cell development, which have implications for endocrine and exocrine functions of testis.


Asunto(s)
Compuestos de Bencidrilo/toxicidad , Dietilhexil Ftalato/toxicidad , Disruptores Endocrinos/toxicidad , Fenoles/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Túbulos Seminíferos/efectos de los fármacos , Animales , Compuestos de Bencidrilo/administración & dosificación , Dietilhexil Ftalato/administración & dosificación , Femenino , Masculino , Fenoles/administración & dosificación , Embarazo , Ratas , Ratas Long-Evans , Receptores Androgénicos/metabolismo , Túbulos Seminíferos/crecimiento & desarrollo , Túbulos Seminíferos/patología , Testículo/efectos de los fármacos , Testículo/crecimiento & desarrollo , Testículo/patología
16.
Nat Neurosci ; 22(9): 1493-1502, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31406366

RESUMEN

Although Weber's law is the most firmly established regularity in sensation, no principled way has been identified to choose between its many proposed explanations. We investigated Weber's law by training rats to discriminate the relative intensity of sounds at the two ears at various absolute levels. These experiments revealed the existence of a psychophysical regularity, which we term time-intensity equivalence in discrimination (TIED), describing how reaction times change as a function of absolute level. The TIED enables the mathematical specification of the computational basis of Weber's law, placing strict requirements on how stimulus intensity is encoded in the stochastic activity of sensory neurons and revealing that discriminative choices must be based on bounded exact accumulation of evidence. We further demonstrate that this mechanism is not only necessary for the TIED to hold but is also sufficient to provide a virtually complete quantitative description of the behavior of the rats.


Asunto(s)
Percepción Auditiva/fisiología , Encéfalo/fisiología , Modelos Neurológicos , Tiempo de Reacción/fisiología , Estimulación Acústica , Animales , Femenino , Ratas , Ratas Long-Evans
17.
Nat Neurosci ; 22(9): 1450-1459, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31427771

RESUMEN

The rodent hippocampus spontaneously generates bursts of neural activity (replay) that can depict spatial trajectories to reward locations, suggesting a role in model-based behavioral control. A largely separate literature emphasizes reward revaluation as the litmus test for such control, yet the content of hippocampal replay under revaluation conditions is unknown. We examined the content of awake replay events following motivational shifts between hunger and thirst. On a T-maze offering free choice between food and water outcomes, rats shifted their behavior toward the restricted outcome, but replay content was shifted away from the restricted outcome. This effect preceded experience on the task each day and did not reverse with experience. These results demonstrate that replay content is not limited to reflecting recent experience or trajectories toward the preferred goal and suggest a role for motivational states in determining replay content.


Asunto(s)
Conducta Animal/fisiología , Hipocampo/fisiología , Motivación/fisiología , Recompensa , Animales , Masculino , Ratas , Ratas Long-Evans
18.
J Immunol Res ; 2019: 8535273, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31467935

RESUMEN

Background: Age-related macular degeneration (AMD), the most common cause of blindness in the developed world, usually affects individuals older than 60 years of age. The majority of visual loss in this disease is attributable to the development of choroidal neovascularization (CNV). Mononuclear phagocytes, including monocytes and their tissue descendants, macrophages, have long been implicated in the pathogenesis of neovascular AMD (nvAMD). Current therapies for nvAMD are based on targeting vascular endothelial growth factor (VEGF). This study is aimed at assessing if perturbation of chemokine signaling and mononuclear cell recruitment may serve as novel complementary therapeutic targets for nvAMD. Methods: A promiscuous chemokine antagonist (BKT130), aflibercept treatment, or combined BKT130+aflibercept treatment was tested in an in vivo laser-induced model of choroidal neovascularization (LI-CNV) and in an ex vivo choroidal sprouting assay (CSA). Quantification of CD11b+ cell in the CNV area was performed, and mRNA levels of genes implicated in CNV growth were measured in the retina and RPE-choroid. Results: BKT130 reduced the CNV area and recruitment of CD11b+ cells by 30-35%. No effect of BKT130 on macrophages' proangiogenic phenotype was demonstrated ex vivo, but a lower VEGFA and CCR2 expression was found in the RPE-choroid and a lower expression of TNFα and NOS1 was found in both RPE-choroid and retinal tissues in the LI-CNV model under treatment with BKT130. Conclusions: Targeting monocyte recruitment via perturbation of chemokine signaling can reduce the size of experimental CNV and should be evaluated as a potential novel therapeutic modality for nvAMD.


Asunto(s)
Quimiocinas/antagonistas & inhibidores , Neovascularización Coroidal/tratamiento farmacológico , Monocitos/efectos de los fármacos , Anciano , Anciano de 80 o más Años , Animales , Antígeno CD11b/metabolismo , Movimiento Celular/efectos de los fármacos , Quimiocinas/metabolismo , Neovascularización Coroidal/etiología , Neovascularización Coroidal/metabolismo , Neovascularización Coroidal/patología , Femenino , Humanos , Rayos Láser , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Monocitos/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Ratas , Ratas Long-Evans , Receptores CCR2/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Retina/metabolismo , Retina/patología , Factor de Necrosis Tumoral alfa/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo
19.
Adv Exp Med Biol ; 1155: 801-819, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31468449

RESUMEN

Lead (Pb2+) is a developmental neurotoxicant that causes alterations in the brain's excitation-to-inhibition (E/I) balance. By increasing chloride concentration through GABA-ARs, taurine serves as an effective inhibitory compound for maintaining appropriate levels of brain excitability. Considering this pharmacological mechanism of taurine facilitated inhibition through the GABA-AR, the present pilot study sought to explore the anxiolytic potential of taurine derivatives. Treatment groups consisted of the following developmental Pb2+-exposures: Control (0 ppm) and Perinatal (150 ppm or 1000 ppm lead acetate in the drinking water). Rats were scheduled for behavioral tests between postnatal days (PND) 36-45 with random assignments to either solutions of Saline, Taurine, or Taurine Derived compounds (i.e., TD-101, TD-102, or TD-103) to assess the rats' responsiveness to each drug in mitigating the developmental Pb2+-exposure through the GABAergic system. Long Evans Hooded rats were assessed using an Open Field (OF) test for preliminary locomotor assessment. Approximately 24-h after the OF, the same rats were exposed to the Elevated Plus Maze (EPM) and were given an i.p. injection of 43 mg/Kg of the Saline, Taurine, or TD drugs 15-min prior to testing. Each rat was tested using the random assignment method for each pharmacological condition, which was conducted using a triple-blind procedure. The OF data revealed that locomotor activity was unaffected by Pb2+-exposure with no gender differences observed. However, Pb2+-exposure induced an anxiogenic response in the EPM, which interestingly, was ameliorated in a gender-specific manner in response to taurine and TD drugs. Female rats exhibited more anxiogenic behavior than the male rats; and as such, exhibited a greater degree of anxiety that were recovered in response to Taurine and its derivatives as a drug therapy. The results from the present psychopharmacological pilot study suggests that Taurine and its derivatives could provide useful data for further exploring the pharmacological mechanisms and actions of Taurine and the associated GABAergic receptor properties by which these compounds alleviate anxiety as a potential behavioral pharmacotherapy for treating anxiety and other associated mood disorders.


Asunto(s)
Ansiolíticos/farmacología , Ansiedad/tratamiento farmacológico , Plomo/efectos adversos , Exposición Materna/efectos adversos , Taurina/farmacología , Animales , Femenino , Masculino , Proyectos Piloto , Embarazo , Efectos Tardíos de la Exposición Prenatal , Distribución Aleatoria , Ratas , Ratas Long-Evans
20.
Adv Exp Med Biol ; 1155: 821-846, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31468450

RESUMEN

Lead (Pb2+) is a developmental neurotoxicant that causes lifelong cognitive dysfunctions. In particular, Pb2+-induced frontoexecutive dysfunctions emerge later in life when the cortex is fully myelinated, thereby permitting the ability to assess the extent to which Pb2+ has developmentally impacted higher order cognitive and behavioral systems. The present study evaluated the effects of developmental Pb2+-exposure (150 ppm lead acetate in the drinking water) in Long Evans Hooded rats through the Attention Set-Shift Test (ASST) between postnatal days (PND) 60-90. Treatment groups were comprised of Control (0 ppm), Perinatal (150 ppm), and Perinatal+Taurine (150 ppm + 0.05% Taurine in the drinking water) rats (N = 36; n = 6 per treatment group for each sex). Frontoexecutive functions were evaluated based on trials-to-criterion (TTC) and errors-to-criterion (ETC) measures for simple and complex discriminations (SD & CD), intradimensional and extradimensional shifts (ID & ED), as well as reversals (Rev) of the CD, I-, and ED stages, respectively. Post-testing, the prelimbic (PrL), infralimbic (IL), orbital ventral frontal (OV), orbital ventro-lateral (OVL), and hippocampal (HP) brain regions were extracted and processed through Liquid Chromatography/Mass Spectrophotometry (LC/MS) for determining the GABA and Taurine ratios relative to Glutamate, Dopamine, Norepinephrine, Epinephrine, and Serotonin. The ASST data revealed that Perinatal rats are negatively impacted by developmental Pb2+-exposures evidenced by increased TTC and ETC to learn the SD, ID, and ID-Rev with unique sex-based differences in frontoexecutive dysfunctions. Moreover, Perinatal+Taurine co-treated rats exhibited a recovery of the frontoexecutive dysfunctions observed in Perinatal rats to levels equivalent to Control rats across both sexes. The LC/MS data revealed altered brain sub-region specific patterns across the PrL, IL, OV, OVL, and HP in response to developmental Pb2+-exposure that produced an altered neurochemical signaling profile in a sex-dependent manner, which may underlie the observed frontoexecutive dysfunctions, cognitive inflexibility, and associated motivation deficits. When taurine co-treatment was administered concurrently for the duration of developmental Pb2+-exposure, the observed frontoexecutive dysfunctions were significantly reduced in both ASST task performance and neurochemical ratios that were comparable to Control levels for both sexes. Altogether, the data suggest that taurine co-treatment may facilitate neuroprotection, mitigate neurotransmitter excitability balancing, and perhaps ameliorate against neurotoxicant exposures in early development as a potential psychopharmacotherapy.


Asunto(s)
Atención , Función Ejecutiva , Plomo/efectos adversos , Exposición Materna/efectos adversos , Taurina/farmacología , Animales , Femenino , Aprendizaje , Masculino , Fármacos Neuroprotectores/farmacología , Embarazo , Ratas , Ratas Long-Evans
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