RESUMEN
Thyroid hormones (TH) play crucial roles in brain maturation and are important for neuronal migration and neocortical lamination. Subcortical band heterotopia (SBH) represent a class of neuronal migration errors in humans that are often associated with childhood epilepsy. We have previously reported the presence of SBH in a rodent model of low level hypothyroidism induced by maternal exposure to the goitrogen, propylthiouracil (PTU). In the present study, we report the dose-response characteristics of this developmental malformation and the connectivity of heterotopic neurones with other brain regions, as well as their functionality. Pregnant rats were exposed to varying concentrations of PTU through the drinking water (0-10 p.p.m.) beginning on gestational day 6 to produce graded levels of TH insufficiency. Dose-dependent increases in the volume of the SBH present in the corpus callosum were documented in the adult offspring, with a clear presence at concentrations of PTU that resulted in minor (< 15%) reductions in maternal serum thyroxine as measured when pups were weaned. SBH contain neurones, oligodendrocytes, astrocytes and microglia. Monoaminergic and cholinergic processes were prevalent and many of the axons were myelinated. Anatomical connectivity of SBH neurones to cortical neurones and the synaptic functionality of these anatomical connections was verified by ex vivo field potential recordings. SBH persisted in adult offspring despite a return to euthyroid status on termination of exposure and these offspring displayed an increased sensitivity to seizures. Features of this model are attractive with respect to the investigation of the molecular mechanisms of cortical development, the effectiveness of therapeutic intervention in hypothyroxinaemia during pregnancy and the impact of the very modest TH imbalance that accompanies exposure to environmental contaminants.
Asunto(s)
Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/patología , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/fisiopatología , Hipotiroidismo/complicaciones , Efectos Tardíos de la Exposición Prenatal/patología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Tiroxina/sangre , Animales , Encéfalo/patología , Encéfalo/fisiopatología , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/complicaciones , Relación Dosis-Respuesta a Droga , Femenino , Hipotiroidismo/sangre , Hipotiroidismo/inducido químicamente , Exposición Materna/efectos adversos , Potenciales de la Membrana , Técnicas de Trazados de Vías Neuroanatómicas , Neuroglía/patología , Neuronas/patología , Pentilenotetrazol/farmacología , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Propiltiouracilo/farmacología , Ratas , Convulsiones/inducido químicamente , Convulsiones/complicaciones , Tirotropina/sangre , Triyodotironina/sangreRESUMEN
Vascular endothelial growth factor (VEGF) is a protein factor which has been found to play a significant role in both normal and pathological states. Its role as an angiogenic factor is well-established. More recently, VEGF has been shown to protect neurons from cell death both in vivo and in vitro. While VEGF's potential as a protective factor has been demonstrated in hypoxia-ischemia, in vitro excitotoxicity, and motor neuron degeneration, its role in seizure-induced cell loss has received little attention. A potential role in seizures is suggested by Newton et al.'s [Newton SS, Collier EF, Hunsberger J, Adams D, Terwilliger R, Selvanayagam E, Duman RS (2003) Gene profile of electroconvulsive seizures: Induction of neurotrophic and angiogenic factors. J Neurosci 23:10841-10851] finding that VEGF mRNA increases in areas of the brain that are susceptible to cell loss after electroconvulsive-shock induced seizures. Because a linear relationship does not always exist between expression of mRNA and protein, we investigated whether VEGF protein expression increased after pilocarpine-induced status epilepticus. In addition, we administered exogenous VEGF in one experiment and blocked endogenous VEGF in another to determine whether VEGF exerts a neuroprotective effect against status epilepticus-induced cell loss in one vulnerable brain region, the rat hippocampus. Our data revealed that VEGF is dramatically up-regulated in neurons and glia in hippocampus, thalamus, amygdala, and neocortex 24 h after status epilepticus. VEGF induced significant preservation of hippocampal neurons, suggesting that VEGF may play a neuroprotective role following status epilepticus.
Asunto(s)
Hipocampo/metabolismo , Hipocampo/patología , Neuronas/metabolismo , Neuronas/patología , Convulsiones/metabolismo , Convulsiones/patología , Estado Epiléptico/metabolismo , Estado Epiléptico/patología , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Factor A de Crecimiento Endotelial Vascular/fisiología , Animales , Vasos Sanguíneos/efectos de los fármacos , Vasos Sanguíneos/ultraestructura , Muerte Celular/fisiología , Convulsivantes , Ensayo de Inmunoadsorción Enzimática , Hipocampo/citología , Inmunohistoquímica , Técnicas In Vitro , Bombas de Infusión Implantables , Masculino , Fármacos Neuroprotectores , Pilocarpina , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Convulsiones/inducido químicamente , Estado Epiléptico/inducido químicamente , Regulación hacia Arriba/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/farmacologíaRESUMEN
Characterizing the responses of different mouse strains to experimentally-induced seizures can provide clues to the genes that are responsible for seizure susceptibility, and factors that contribute to epilepsy. This approach is optimal when sequenced mouse strains are available. Therefore, we compared two sequenced strains, DBA/2J (DBA) and A/J. These strains were compared using the chemoconvulsant pilocarpine, because pilocarpine induces status epilepticus, a state of severe, prolonged seizures. In addition, pilocarpine-induced status is followed by changes in the brain that are associated with the pathophysiology of temporal lobe epilepsy (TLE). Therefore, pilocarpine can be used to address susceptibility to severe seizures, as well as genes that could be relevant to TLE. A/J mice had a higher incidence of status, but a longer latency to status than DBA mice. DBA mice exhibited more hippocampal pyramidal cell damage. DBA mice developed more ectopic granule cells in the hilus, a result of aberrant migration of granule cells born after status. DBA mice experienced sudden death in the weeks following status, while A/J mice exhibited the most sudden death in the initial hour after pilocarpine administration. The results support previous studies of strain differences based on responses to convulsants. They suggest caution in studies of seizure susceptibility that are based only on incidence or latency. In addition, the results provide new insight into the strain-specific characteristics of DBA and A/J mice. A/J mice provide a potential resource to examine the progression to status. The DBA mouse may be valuable to clarify genes regulating other seizure-associated phenomena, such as seizure-induced neurogenesis and sudden death.
Asunto(s)
Convulsivantes/farmacología , Pilocarpina/farmacología , Estado Epiléptico/patología , Animales , Química Encefálica/efectos de los fármacos , Proteínas de Unión al ADN , Electrodos Implantados , Electroencefalografía/efectos de los fármacos , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos A , Ratones Endogámicos DBA , Fibras Musgosas del Hipocampo/patología , Proteínas del Tejido Nervioso/metabolismo , Neuronas/patología , Neuropéptido Y/metabolismo , Proteínas Nucleares/metabolismo , Especificidad de la Especie , Estado Epiléptico/inducido químicamente , Estado Epiléptico/mortalidad , Factores de TiempoRESUMEN
Corticosterone (CORT), the predominant glucocorticoid in rodents, is known to damage hippocampal area CA3. Here we investigate how that damage is represented at the cellular and ultrastructural level of analyses. Rats were injected with CORT (26.8 mg/kg, s.c.) or vehicle for 56 days. Cell counts were estimated with the physical disector method. Glial and mitochondrial volume fractions were obtained from electron micrographs. The effectiveness of the CORT dose used was demonstrated in two ways. First, CORT significantly inhibited body weight gain relative to vehicles. Second, CORT significantly reduced adrenal gland, heart and gastrocnemius muscle weight. Both the adrenal and gastrocnemius muscle weight to body weight ratios were also significantly reduced. Although absolute brain weight was reduced, the brain to body weight ratio was higher in the CORT group relative to vehicles, suggesting that the brain is more resistant to the effects of CORT than many peripheral organs and muscles. Consistent with that interpretation, CORT did not alter CA3 cell density, cell layer volume, or apical dendritic neuropil volume. Likewise, CORT did not significantly alter glial volume fraction, but did reduce mitochondrial volume fraction. These findings highlight the need for ultrastructural analyses in addition to cellular level analyses before conclusions can be drawn about the damaging effects of prolonged CORT elevations. The relative reduction in mitochondria may indicate a reduction in bioenergetic capacity that, in turn, could render CA3 vulnerable to metabolic challenges.
Asunto(s)
Encéfalo/efectos de los fármacos , Corticosterona/farmacología , Hipocampo/citología , Mitocondrias/efectos de los fármacos , Neuroglía/efectos de los fármacos , Animales , Antiinflamatorios/farmacología , Peso Corporal/efectos de los fármacos , Encéfalo/fisiología , Recuento de Células/métodos , Masculino , Microscopía Electrónica/métodos , Mitocondrias/ultraestructura , Neuroglía/ultraestructura , Neurópilo/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Fracciones Subcelulares/efectos de los fármacos , Factores de TiempoRESUMEN
Corticosterone (CORT), the predominant glucocorticoid in rodents, elevated for 21 days damages hippocampal subregion CA3. We tested the hypothesis that CORT would impair spatial memory, a hippocampal function. In each of the three experiments, rats received daily, subcutaneous injections of either CORT (26.8 mg/kg body weight in sesame oil) or sesame oil vehicle alone (VEH). CORT given for 21 or 56 days effectively attenuated body weight gain and reduced selective organ and muscle weights. All behavioral testing was done on tasks that are minimally stressful and avoid deprivation. For each experiment, testing commenced 24h after the last injection. CORT given for 21 days did not impair spatial working memory in the Y-maze (Experiments 1 and 2). After 56-day administration of CORT, spatial working memory was impaired in the Y-maze (Experiment 2). CORT given for 21 days also failed to impair spatial working memory in the Barnes maze (Experiment 3). However, in trials that depended solely on reference memory, the VEH group improved in performance, whereas the CORT group did not. In conclusion, CORT elevated over a period of 21 days did not impair spatial working memory, but impaired the formation of a longer-term form of memory, most likely reference memory. Impairments in spatial working memory are seen only after longer durations of CORT administration.
Asunto(s)
Corticosterona/toxicidad , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Percepción Espacial/efectos de los fármacos , Animales , Corticosterona/administración & dosificación , Relación Dosis-Respuesta a Droga , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Inyecciones Subcutáneas , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Acute bouts of exercise have been shown to produce transient increases in regional cerebral glucose utilization, oxygen uptake, and cerebral blood flow in motor cortex, striatum, and hippocampus. The purpose of this study was to determine whether or not chronic exercise will cause long-term metabolic plasticity in brain structures activated during physical activity. The activity of cytochrome oxidase (COX), is coupled to the production of ATP, and reflects long-term plasticity in metabolic capacity. The present study examined whether or not 6 months of voluntary exercise would increase COX activity in the striatum, sensorimotor cortex, and three hippocampal subfields. Five-month-old, female Long-Evans hooded rats were randomly assigned to a control or exercise condition. Exercising rats had running wheels attached to their home cages. After the training period, fresh brains were rapidly frozen and sectioned with a cryostat. COX activity was measured using COX histochemical methods and optical densitometry. Rats in the exercise condition had significantly higher optical density in the hindlimb and forelimb motor cortices (18%, P<0.01) and dorsolateral caudate putamen (17%, P<0.01), but not in the ventrolateral caudate putamen or any subfield of the hippocampus. Although exercise is believed to increase neuronal activity in the hippocampus, motor cortex and striatum, only limb representations in the motor cortex and striatum increase bioenergetic capacity after regular exercise.
Asunto(s)
Circulación Cerebrovascular/fisiología , Complejo IV de Transporte de Electrones/metabolismo , Hipocampo/metabolismo , Corteza Motora/metabolismo , Neostriado/metabolismo , Plasticidad Neuronal/fisiología , Condicionamiento Físico Animal/fisiología , Animales , Densitometría , Complejo IV de Transporte de Electrones/análisis , Procesamiento Automatizado de Datos , Femenino , Ratas , Ratas Long-EvansRESUMEN
Previous studies indicate that the hippocampus is active during exercise, and that neurotrophin expression, receptor density, and survival of dentate gyrus granule cells in the hippocampus can be modified by moderate voluntary exercise. The present study was designed to test the consequences of voluntary exercise on a hippocampal-related behavior. Exercising and control rats were tested on the standard and delayed nonmatch-to-position (DNMTP) version of the eight-arm radial maze, both of which are sensitive to hippocampal damage. Voluntarily exercising rats ran in running wheels attached to their home cage for 7 weeks prior to and throughout testing, and took 30% fewer trials to acquire criterion performance than sedentary controls. Both groups spent the same average time per arm. Once the eight-arm maze had been learned to criterion, group differences were not apparent. Exercise can facilitate acquisition of a hippocampal-related spatial learning task, but does not affect performance following acquisition. Further work will be necessary to link these effects to hippocampal-related variables shown to be influenced by exercise.