RESUMO
Influenza A virus (IAV) is a major zoonotic pathogen that threatens global public health. Novel strains of influenza A viruses pose a significant risk to public health due to their pandemic potential, and transmission of influenza A viruses from animals to humans is an important mechanism in the generation and introduction of IAVs that threaten human health. The purpose of this descriptive correlational study was to develop real-life training scenarios to better inform swine exhibitors of the risks they may encounter when influenza A viruses are present in swine. Educational activities were implemented in five Ohio counties where exhibition swine had historically been shedding influenza A viruses during the county fair. A total of 146 youth swine exhibitors participated in the educational programme, and an increase in the knowledge base of these youth was documented. It is expected that educating youth exhibitors about exposure to influenza A virus infections in the swine they are exhibiting will result in altered behaviours and animal husbandry practices that will improve both human and animal health.
Assuntos
Educação em Saúde , Vírus da Influenza A , Influenza Humana/prevenção & controle , Influenza Humana/virologia , Infecções por Orthomyxoviridae/virologia , Doenças dos Suínos/virologia , Adolescente , Agricultura , Criação de Animais Domésticos , Animais , Humanos , Ohio , Infecções por Orthomyxoviridae/transmissão , Suínos , Doenças dos Suínos/transmissão , ZoonosesRESUMO
The motor symptoms of both Parkinson's disease and focal dystonia arise from dysfunction of the basal ganglia, and are improved by pallidotomy or deep brain stimulation of the Globus Pallidus interna (GPi). However, Parkinson's disease is associated with a greater degree of basal ganglia-dependent learning impairment than dystonia. We attempt to understand this observation in terms of a comparison of the electrophysiology of the output of the basal ganglia between the two conditions. We use the natural experiment offered by Deep Brain Stimulation to compare GPi local field potential responses in subjects with Parkinson's disease compared to subjects with dystonia performing a forced-choice decision-making task with sensory feedback. In dystonic subjects, we found that auditory feedback was associated with the presence of high gamma oscillations nestled on a negative deflection, morphologically similar to sharp wave ripple complexes described in human rhinal cortex. These were not present in Parkinson's disease subjects. The temporal properties of the high gamma burst were modified by incorrect trial performance compared to correct trial performance. Both groups exhibited a robust low frequency response to 'incorrect' trial performance in dominant GPi but not non-dominant GPi at theta frequency. Our results suggest that cellular processes associated with striatum-dependent memory function may be selectively impaired in Parkinson's disease even if dopaminergic drugs are administered, but that error detection mechanisms are preserved.
Assuntos
Cognição/fisiologia , Estimulação Encefálica Profunda/métodos , Distúrbios Distônicos/terapia , Globo Pálido/fisiologia , Doença de Parkinson/terapia , Adulto , Idoso , Distúrbios Distônicos/diagnóstico por imagem , Potenciais Evocados/fisiologia , Feminino , Globo Pálido/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/diagnóstico por imagem , Estimulação Física , Tempo de Reação/fisiologia , Tomógrafos Computadorizados , Adulto JovemRESUMO
Marine ecosystems are subject to anthropogenic change at global, regional and local scales. Global drivers interact with regional- and local-scale impacts of both a chronic and acute nature. Natural fluctuations and those driven by climate change need to be understood to diagnose local- and regional-scale impacts, and to inform assessments of recovery. Three case studies are used to illustrate the need for long-term studies: (i) separation of the influence of fishing pressure from climate change on bottom fish in the English Channel; (ii) recovery of rocky shore assemblages from the Torrey Canyon oil spill in the southwest of England; (iii) interaction of climate change and chronic Tributyltin pollution affecting recovery of rocky shore populations following the Torrey Canyon oil spill. We emphasize that "baselines" or "reference states" are better viewed as envelopes that are dependent on the time window of observation. Recommendations are made for adaptive management in a rapidly changing world.
Assuntos
Mudança Climática , Pesqueiros , Poluição por Petróleo , Poluição da Água , Animais , Ecossistema , Ecotoxicologia/métodos , Inglaterra , Meio Ambiente , Peixes , Biologia Marinha/métodos , Compostos de Trialquitina/toxicidade , Poluentes Químicos da Água/toxicidadeRESUMO
Human alteration of marine ecosystems is substantial and growing. Yet, no adequate methodology exists that provides reliable predictions of how environmental degradation will affect these ecosystems at a relevant level of biological organization. The primary objective of this study was to develop a methodology to evaluate a fish's capacity to face a well-established environmental challenge, an exposure to chemically dispersed oil, and characterize the long-term consequences. Therefore, we applied high-throughput, non-lethal challenge tests to assess hypoxia tolerance, temperature susceptibility and maximal swimming speed as proxies for a fish's functional integrity. These whole animal challenge tests were implemented before (1 month) and after (1 month) juvenile European sea bass (Dicentrarchus labrax) had been acutely exposed (48h) to a mixture containing 0.08gL(-1) of weathered Arabian light crude oil plus 4% dispersant (Corexit© EC9500A), a realistic exposure concentration during an oil spill. In addition, experimental populations were then transferred into semi-natural tidal mesocosm ponds and correlates of Darwinian fitness (growth and survival) were monitored over a period of 4 months. Our results revealed that fish acutely exposed to chemically dispersed oil remained impaired in terms of their hypoxia tolerance and swimming performance, but not in temperature susceptibility for 1 month post-exposure. Nevertheless, these functional impairments had no subsequent ecological consequences under mildly selective environmental conditions since growth and survival were not impacted during the mesocosm pond study. Furthermore, the earlier effects on fish performance were presumably temporary because re-testing the fish 10 months post-exposure revealed no significant residual effects on hypoxia tolerance, temperature susceptibility and maximal swimming speed. We propose that the functional proxies and correlates of Darwinian fitness used here provide a useful assessment tool for fish health in the marine environment.
Assuntos
Bass/fisiologia , Comportamento Animal/efeitos dos fármacos , Petróleo/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Bass/crescimento & desenvolvimento , Ecossistema , Hipóxia , Natação/fisiologia , TemperaturaRESUMO
Slow spike and wave discharges (0.5-4 Hz) are a feature of many epilepsies. They are linked to pathology of the thalamocortical axis and a thalamic mechanism has been elegantly described. Here we present evidence for a separate generator in local circuits of associational areas of neocortex manifest from a background, sleep-associated delta rhythm in rat. Loss of tonic neuromodulatory excitation, mediated by nicotinic acetylcholine or serotonin (5HT3A) receptors, of 5HT3-immunopositive interneurons caused an increase in amplitude and slowing of the delta rhythm until each period became the "wave" component of the spike and wave discharge. As with the normal delta rhythm, the wave of a spike and wave discharge originated in cortical layer 5. In contrast, the "spike" component of the spike and wave discharge originated from a relative failure of fast inhibition in layers 2/3-switching pyramidal cell action potential outputs from single, sparse spiking during delta rhythms to brief, intense burst spiking, phase-locked to the field spike. The mechanisms underlying this loss of superficial layer fast inhibition, and a concomitant increase in slow inhibition, appeared to be precipitated by a loss of neuropeptide Y (NPY)-mediated local circuit inhibition and a subsequent increase in vasoactive intestinal peptide (VIP)-mediated disinhibition. Blockade of NPY Y1 receptors was sufficient to generate spike and wave discharges, whereas blockade of VIP receptors almost completely abolished this form of epileptiform activity. These data suggest that aberrant, activity-dependent neuropeptide corelease can have catastrophic effects on neocortical dynamics.
Assuntos
Modelos Neurológicos , Neocórtex/fisiopatologia , Neuropeptídeos/metabolismo , Convulsões/fisiopatologia , Animais , Modelos Animais de Doenças , Eletrofisiologia , Imuno-Histoquímica , Masculino , Neocórtex/metabolismo , Ratos , Ratos Wistar , Convulsões/metabolismoRESUMO
Cell assemblies have long been thought to be associated with brain rhythms, notably the gamma rhythm. Here, we use a computational model to show that the beta1 frequency band, as found in rat association cortex, has properties complementary to the gamma band for the creation and manipulation of cell assemblies. We focus on the ability of the beta1 rhythm to respond differently to familiar and novel stimuli, and to provide a framework for combining the two. Simulations predict that assemblies of superficial layer pyramidal cells can be maintained in the absence of continuing input or synaptic plasticity. Instead, the formation of these assemblies relies on the nesting of activity within a beta1 rhythm. In addition, cells receiving further input after assembly formation produce coexistent spiking activity, unlike the competitive spiking activity characteristic of assembly formation with gamma rhythms.
Assuntos
Ritmo beta/fisiologia , Memória de Curto Prazo/fisiologia , Neurônios/fisiologia , Animais , Modelos Neurológicos , Estimulação Física , RatosRESUMO
OBJECTIVES: Defects of the mitochondrial genome (mtDNA) cause a series of rare, mainly neurological disorders. In addition, they have been implicated in more common forms of movement disorders, dementia and the ageing process. In order to try to model neuronal dysfunction associated with mitochondrial disease, we have attempted to establish a series of transmitochondrial mouse embryonic stem cells harbouring pathogenic mtDNA mutations. MATERIALS AND METHODS: Transmitochondrial embryonic stem cell cybrids were generated by fusion of cytoplasts carrying a variety of mtDNA mutations, into embryonic stem cells that had been pretreated with rhodamine 6G, to prevent transmission of endogenous mtDNA. Cybrids were differentiated into neurons and assessed for efficiency of differentiation and electrophysiological function. RESULTS: Neuronal differentiation could occur, as indicated by expression of neuronal markers. Differentiation was impaired in embryonic stem cells carrying mtDNA mutations that caused severe biochemical deficiency. Electrophysiological tests showed evidence of synaptic activity in differentiated neurons carrying non-pathogenic mtDNA mutations or in those that caused a mild defect of respiratory activity. Again, however, neurons carrying mtDNA mutations that resulted in severe biochemical deficiency had marked reduction in post-synaptic events. CONCLUSIONS: Differentiated neurons carrying severely pathogenic mtDNA defects can provide a useful model for understanding how such mutations can cause neuronal dysfunction.
Assuntos
Diferenciação Celular , DNA Mitocondrial/genética , Células-Tronco Embrionárias/patologia , Mitocôndrias/patologia , Doenças Mitocondriais/genética , Neurônios/patologia , Animais , Modelos Animais de Doenças , Transporte de Elétrons , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Células Híbridas , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/genética , Doenças Mitocondriais/metabolismo , Mutação , Neurogênese , Neurônios/citologia , Neurônios/metabolismo , Transmissão SinápticaRESUMO
Many types of electrographic seizures are readily identifiable by direct visual examination of electroencephalographic or electrocorticographic recordings. This process can, however, be painstakingly slow, and much effort has been expended to automate the process using various dynamic properties of epileptiform waveforms. As methods have become more subtle and powerful they have been used for seizure subclassification, seizure prediction, and seizure onset identification and localization. Here we concentrate on the last, with reference to seizures of neocortical origin. We briefly review some of the methods used and introduce preliminary results from a very simple dynamic model based on key electrophysiological properties found in some seizure types: occurrence of very fast oscillations (sometimes called ripples), excess gamma frequency oscillations, electroencephalographic/electrocorticographic flattening, and changes in global synchrony. We show how this multiscale analysis may reveal features unique to seizure onset and speculate on the underlying cellular and network phenomena responsible.
Assuntos
Eletroencefalografia , Convulsões/fisiopatologia , Animais , Criança , Pré-Escolar , Interpretação Estatística de Dados , Epilepsias Parciais/fisiopatologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , CamundongosRESUMO
BACKGROUND AND PURPOSE: M1 muscarinic ACh receptors (mAChRs) represent an attractive drug target for the treatment of cognitive deficits associated with diseases such as Alzheimer's disease and schizophrenia. However, the discovery of subtype-selective mAChR agonists has been hampered by the high degree of conservation of the orthosteric ACh-binding site among mAChR subtypes. The advent of functional screening assays has enabled the identification of agonists such as AC-42 (4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine), which bind to an allosteric site and selectively activate the M(1) mAChR subtype. However, studies with this compound have been limited to recombinantly expressed mAChRs. EXPERIMENTAL APPROACH: In this study, we have compared the pharmacological profile of AC-42 and a close structural analogue, 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone) at human recombinant, and rat native, mAChRs by calcium mobilization, inositol phosphate accumulation and both in vitro and in vivo electrophysiology. KEY RESULTS: Calcium mobilization and inositol phosphate accumulation assays revealed that both AC-42 and 77-LH-28-1 display high selectivity to activate the M1 mAChR over other mAChR subtypes. Furthermore, 77-LH-28-1, but not AC-42, acted as an agonist at rat hippocampal M1 receptors, as demonstrated by its ability to increase cell firing and initiate gamma frequency network oscillations. Finally, 77-LH-28-1 stimulated cell firing in the rat hippocampus in vivo following subcutaneous administration. CONCLUSIONS AND IMPLICATIONS: These data suggest that 77-LH-28-1 is a potent, selective, bioavailable and brain-penetrant agonist at the M1 mAChR and therefore that it represents a better tool than AC-42, with which to study the pharmacology of the M1 mAChR.
Assuntos
Hipocampo/efeitos dos fármacos , Agonistas Muscarínicos/farmacologia , Piperidinas/farmacologia , Quinolonas/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Potenciais de Ação , Animais , Células CHO , Sinalização do Cálcio/efeitos dos fármacos , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Hipocampo/metabolismo , Humanos , Injeções Intraperitoneais , Injeções Subcutâneas , Fosfatos de Inositol/metabolismo , Agonistas Muscarínicos/administração & dosagem , Agonistas Muscarínicos/farmacocinética , Técnicas de Patch-Clamp , Permeabilidade , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Quinolonas/administração & dosagem , Quinolonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptor Muscarínico M1 , Receptores Muscarínicos/genética , Receptores Muscarínicos/metabolismo , Proteínas Recombinantes/agonistas , Fatores de Tempo , TransfecçãoRESUMO
The level of arousal in mammals is correlated with metabolic state and specific patterns of cortical neuronal responsivity. In particular, rhythmic transitions between periods of high activity (up phases) and low activity (down phases) vary between wakefulness and deep sleep/anesthesia. Current opinion about changes in cortical response state between sleep and wakefulness is split between neuronal network-mediated mechanisms and neuronal metabolism-related mechanisms. Here, we demonstrate that slow oscillations in network state are a consequence of interactions between both mechanisms. Specifically, recurrent networks of excitatory neurons, whose membrane potential is partly governed by ATP-modulated potassium (K(ATP)) channels, mediate response-state oscillations via the interaction between excitatory network activity involving slow, kainate receptor-mediated events and the resulting activation of ATP-dependent homeostatic mechanisms. These findings suggest that K(ATP) channels function as an interface between neuronal metabolic state and network responsivity in mammalian cortex.
Assuntos
Córtex Cerebral/fisiologia , Rede Nervosa , Neurônios/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Canais de Potássio/metabolismo , RatosRESUMO
Though all in vitro models of gamma frequency network oscillations are critically dependent on GABAA receptor-mediated synaptic transmission little is known about the specific role played by different subtypes of GABAA receptor. Strong expression of the alpha5 subunit of the GABAA receptor is restricted to few brain regions, amongst them the hippocampal dendritic layers. Receptors containing this subunit may be expressed on the extrasynaptic membrane of principal cells and can mediate a tonic GABAA conductance. Using hippocampal slices of wild-type (WT) and alpha5-/- mice we investigated the role of alpha5 subunits in the generation of kainate-induced gamma frequency oscillations (20-80 Hz). The change in power of the oscillations evoked in CA3 by increasing network drive (kainate, 50-400 nm) was significantly greater in alpha5-/- than in WT slices. However, the change in frequency of gamma oscillations with increasing network drive seen in WT slices was absent in alpha5-/- slices. Raising the concentration of extracellular GABA by bathing slices in the GABA transaminase inhibitor vigabatrin and blocking uptake with tiagabine reduced the power of gamma oscillations more in WT slices than alpha5-/- slices (43%versus 15%). The data suggest that loss of this GABAA receptor subunit alters the dynamic profile of gamma oscillations to changes in network drive, possibly via actions of GABA at extrasynaptic receptors.
Assuntos
Relógios Biológicos/fisiologia , Hipocampo/fisiologia , Ácido Caínico/farmacologia , Subunidades Proteicas/fisiologia , Receptores de GABA-A/fisiologia , Animais , Relógios Biológicos/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
Gamma (30-80 Hz) oscillations occur in mammalian electroencephalogram in a manner that indicates cognitive relevance. In vitro models of gamma oscillations demonstrate two forms of oscillation: one occurring transiently and driven by discrete afferent input and the second occurring persistently in response to activation of excitatory metabotropic receptors. The mechanism underlying persistent gamma oscillations has been suggested to involve gap-junctional communication between axons of principal neurons, but the precise relationship between this neuronal activity and the gamma oscillation has remained elusive. Here we demonstrate that gamma oscillations coexist with high-frequency oscillations (>90 Hz). High-frequency oscillations can be generated in the axonal plexus even when it is physically isolated from pyramidal cell bodies. They were enhanced in networks by nonsomatic gamma-aminobutyric acid type A (GABA(A)) receptor activation, were modulated by perisomatic GABAA receptor-mediated synaptic input to principal cells, and provided the phasic input to interneurons required to generate persistent gamma-frequency oscillations. The data suggest that high-frequency oscillations occurred as a consequence of random activity within the axonal plexus. Interneurons provide a mechanism by which this random activity is both amplified and organized into a coherent network rhythm.
Assuntos
Neurônios/fisiologia , Ácido gama-Aminobutírico/fisiologia , Animais , Técnicas In Vitro , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/fisiologiaRESUMO
The effects of general anaesthetics and temperature on carbachol-evoked gamma oscillations in the rat hippocampal brain slice preparation were investigated. The frequency of the oscillations was found to be dependent on temperature in the range 32-25 degrees C, with a linear reduction in frequency from 40-17 Hz over this temperature range. The volatile anaesthetics isoflurane and halothane, and the intravenous anaesthetics thiopental, propofol and R(+)-etomidate caused a reduction in the frequency of the oscillations, in a concentration-dependent manner, over a range of clinically relevant concentrations. On the other hand, the intravenous agent ketamine and the "inactive" S(-)-isomer of etomidate had no significant effect on the oscillation frequency. The oscillations were markedly asymmetric over one cycle with a relatively rapid "rising" phase followed by a slower "decaying" phase. The decrease in oscillation frequency was due to an increase in the time-course of the "decaying phase" of the oscillation with little effect on the "rising" phase, consistent with the idea that carbachol-evoked gamma oscillations are trains of GABAergic inhibitory postsynaptic potentials and that the anaesthetics are acting postsynaptically at the GABA(A) receptor.
Assuntos
Anestésicos Gerais/farmacologia , Carbacol/farmacologia , Eletroencefalografia/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Parassimpatomiméticos/farmacologia , Anestésicos Inalatórios/farmacologia , Anestésicos Intravenosos/farmacologia , Animais , Relação Dose-Resposta a Droga , Eletrofisiologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Técnicas In Vitro , Rede Nervosa/efeitos dos fármacos , Técnicas de Patch-Clamp , Ratos , Soluções , Temperatura , Ácido gama-Aminobutírico/fisiologiaRESUMO
Theta frequency oscillations are a predominant feature of rhythmic activity in the hippocampus. We demonstrate that hippocampal area CA1 generates atropine-resistant theta population oscillations in response to metabotropic glutamate receptor activation under conditions of reduced AMPA receptor activation. This activity occurred in the absence of inputs from area CA3 and extra-ammonic areas. Field theta oscillations were co-expressed with pyramidal distal apical dendritic burst spiking and were temporally related to trains of IPSPs with slow kinetics. Pyramidal somatic responses showed theta oscillations consisted of compound inhibitory synaptic potentials with initial IPSPs with slow kinetics followed by trains of smaller, faster IPSPs. Pharmacological modulation of IPSPs altered the theta oscillation suggesting an inhibitory network origin. Somatic IPSPs, dendritic burst firing and stratum pyramidale interneuron activity were all temporally correlated with spiking in stratum oriens interneurons demonstrating intrinsic theta-frequency oscillations. Disruption of spiking in these interneurons was accompanied by a loss of both field theta and theta frequency IPSP trains. We suggest that population theta oscillations can be generated as a consequence of intrinsic theta frequency spiking activity in a subset of stratum oriens interneurons controlling electrogenesis in pyramidal cell apical dendrites.
Assuntos
Atropina/farmacologia , Hipocampo/fisiologia , Parassimpatolíticos/farmacologia , Ritmo Teta/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Dendritos/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Interneurônios/fisiologia , Interneurônios/ultraestrutura , Masculino , Inibição Neural/fisiologia , Quinoxalinas/farmacologia , Ratos , Ratos Wistar , Receptores de AMPA/antagonistas & inibidores , Receptores de AMPA/fisiologia , Receptores de Glutamato Metabotrópico/fisiologiaRESUMO
1. The tetanus toxin seizure model, which is associated with spontaneous and intermittent generalized and non-generalized seizures, is considered to reflect human complex partial epilepsy. The purpose of the present study was to investigate and compare the anticonvulsant effects of carbamazepine with that of levetiracetam, a new anti-epileptic drug in this model. 2. One microl of tetanus toxin solution (containing 12 mLD(50) microl(-1) of tetanus toxin) was placed stereotactically into the rat left hippocampus resulting in generalized and non-generalized seizures. 3. Carbamazepine (4 mg kg(-1) h(-1)) and levetiracetam (8 and 16 mg kg(-1) h(-1)) were administered during a 7 day period via an osmotic minipump which was placed in the peritoneal cavity. Carbamazepine (4 mg kg(-1) h(-1)) exhibited no significant anticonvulsant effect, compared to control, when the entire 7 day study period was evaluated but the reduction in generalized seizures was greater (35.5%) than that for non-generalized seizures (12.6%). However, during the first 2 days of carbamazepine administration a significant reduction in both generalized seizure frequency (90%) and duration (25%) was observed. Non-generalized seizures were unaffected. This time-dependent anticonvulsant effect exactly paralleled the central (CSF) and peripheral (serum) kinetics of carbamazepine in that steady-state concentrations declined over time, with the highest concentrations achieved during the first 2 days. Also there was a significant 27.3% reduction in duration of generalized seizures during the 7 day study period (P=0.0001). 4. Levetiracetam administration (8 and 16 mg kg(-1) h(-1)) was associated with a dose-dependent reduction in the frequency of both generalized (39 v 57%) and non-generalized (36 v 41%) seizures. However, seizure suppression was more substantial for generalized seizures. Also a significant dose-dependent reduction in overall generalized seizure duration was observed. 5. These data provide experimental evidence for the clinical efficacy of levetiracetam for the management of patients with complex partial seizures. Furthermore, levetiracetam probably does not act by preventing ictogenesis per se but acts to reduce seizure severity and seizure generalization.
Assuntos
Anticonvulsivantes/uso terapêutico , Carbamazepina/uso terapêutico , Epilepsia Parcial Complexa/tratamento farmacológico , Piracetam/análogos & derivados , Piracetam/uso terapêutico , Toxina Tetânica/toxicidade , Animais , Epilepsia Parcial Complexa/induzido quimicamente , Epilepsia Parcial Complexa/fisiopatologia , Levetiracetam , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
The dentate gyrus is thought to be a key area in containing the spread of seizure discharges in temporal lobe epilepsy. We investigated whether it actively contributes to the transition to seizure in vivo using the tetanus toxin chronic experimental epilepsy. Brief epileptic discharges lasted <2 s in freely moving animals and were clearly distinguishable from spontaneous seizures that lasted tens of seconds. This suggested that the changes underpinning the transition to seizure started within the first few seconds of seizure onset. During this period, we found that the amplitude of dentate gyrus population spikes depressed initially, but from 1.1 s after seizure onset, they potentiated. The amplitude and number of CA3 population spikes paralleled the pattern found in the dentate gyrus. We used hippocampal slices to study dentate filtering in more detail. The perforant pathway was stimulated repetitively at the frequency of field postsynaptic potentials found during epileptic discharges in vivo. The amplitude of dentate gyrus population spikes decreased to a steady state in naïve hippocampal slices. In hippocampal slices prepared from rats previously injected with tetanus toxin, population spike amplitude decreased transiently and then potentiated. We found that the biphasic profile and rate of potentiation of dentate population spikes in vivo can be reproduced in naïve hippocampal slices by blocking GABA(B) receptors. We conclude that the filtering properties of the dentate gyrus are altered in the tetanus toxin model of epilepsy and propose how this contributes to the transition to seizure in our animals.
Assuntos
Giro Denteado/fisiopatologia , Epilepsia/induzido quimicamente , Epilepsia/fisiopatologia , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Toxina Tetânica , Animais , Eletroencefalografia , Potenciais Evocados/efeitos dos fármacos , Potenciais Evocados/fisiologia , Antagonistas GABAérgicos/farmacologia , Antagonistas de Receptores de GABA-A , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Gamma-frequency (30-70 Hz) oscillations in populations of interneurons may be of functional relevance in the brain by virtue of their ability to induce synchronous firing in principal neurons. Such a role would require that neurons, 1 mm or more apart, be able to synchronize their activity, despite the presence of axonal conduction delays and of the limited axonal spread of many interneurons. We showed previously that interneuron doublet firing can help to synchronize gamma oscillations, provided that sufficiently many pyramidal neurons are active; we also suggested that gap junctions, between the axons of principal neurons, could contribute to the long-range synchrony of gamma oscillations induced in the hippocampus by carbachol in vitro. Here we consider interneuron network gamma: that is, gamma oscillations in pharmacologically isolated networks of tonically excited interneurons, with frequency gated by mutual GABA(A) receptor-mediated IPSPs. We provide simulation and electrophysiological evidence that interneuronal gap junctions (presumably dendritic) can enhance the synchrony of such gamma oscillations, in spatially extended interneuron networks. There appears to be a sharp threshold conductance, below which the interneuron dendritic gap junctions do not exert a synchronizing role.
Assuntos
Relógios Biológicos/fisiologia , Dendritos/fisiologia , Junções Comunicantes/fisiologia , Interneurônios/fisiologia , Modelos Neurológicos , Rede Nervosa/fisiologia , Animais , Relógios Biológicos/efeitos dos fármacos , Carbenoxolona/farmacologia , Simulação por Computador , Estimulação Elétrica , Junções Comunicantes/efeitos dos fármacos , Ácido Glutâmico/farmacologia , Glicina/análogos & derivados , Glicina/farmacologia , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Técnicas In Vitro , Interneurônios/efeitos dos fármacos , Masculino , Rede Nervosa/efeitos dos fármacos , Redes Neurais de Computação , Potássio/farmacologia , Ratos , Ratos Wistar , Receptores de GABA-A/fisiologia , Resorcinóis/farmacologia , Limiar Sensorial/fisiologia , Estimulação QuímicaRESUMO
gamma (30-70 Hz) followed by beta (10-30 Hz) oscillations are evoked in humans by sensory stimuli and may be involved in working memory. Phenomenologically similar gamma-->beta oscillations can be evoked in hippocampal slices by strong two-site tetanic stimulation. Weaker stimulation leads only to two-site synchronized gamma. In vitro oscillations have memory-like features: (1) EPSPs increase during gamma-->beta; (2) after a strong one-site stimulus, two-site stimulation produces desynchronized gamma; and (3) a single synchronized gamma-->beta epoch allows a subsequent weak stimulus to induce synchronized gamma-->beta. Features 2 and 3 last >50 min and so are unlikely to be caused by presynaptic effects. A previous model replicated the gamma-->beta transition when it was assumed that K(+) conductance(s) increases and there is an ad hoc increase in pyramidal EPSCs. Here, we have refined the model, so that both pyramidal-->pyramidal and pyramidal-->interneuron synapses are modifiable. This model, in a self-organized way, replicates the gamma-->beta transition, along with features 1 and 2 above. Feature 3 is replicated if learning rates, or the time course of K(+) current block, are graded with stimulus intensity. Synaptic plasticity allows simulated oscillations to synchronize between sites separated by axon conduction delays over 10 msec. Our data suggest that one function of gamma oscillations is to permit synaptic plasticity, which is then expressed in the form of beta oscillations. We propose that the period of gamma oscillations, approximately 25 msec, is "designed" to match the time course of [Ca(2+)](i) fluctuations in dendrites, thus facilitating learning.
Assuntos
Relógios Biológicos/fisiologia , Redes Neurais de Computação , Plasticidade Neuronal/fisiologia , Transmissão Sináptica/fisiologia , Analgésicos Opioides/farmacologia , Animais , Relógios Biológicos/efeitos dos fármacos , Cálcio/metabolismo , Estimulação Elétrica/métodos , Agonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Técnicas In Vitro , Interneurônios/efeitos dos fármacos , Interneurônios/fisiologia , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Morfina/farmacologia , Inibição Neural/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Potássio/metabolismo , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Ratos , Ratos Sprague-Dawley , Tempo de Reação/fisiologia , Reprodutibilidade dos Testes , Transmissão Sináptica/efeitos dos fármacos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologiaRESUMO
Neural processing occurs in parallel in distant cortical areas even for simple perceptual tasks. Associated cognitive binding is believed to occur through the interareal synchronization of rhythmic activity in the gamma (30-80 Hz) range. Such oscillations arise as an emergent property of the neuronal network and require conventional chemical neurotransmission. To test the potential role of gap junction-mediated electrical signaling in this network property, we generated mice lacking connexin 36, the major neuronal connexin. Here we show that the loss of this protein disrupts gamma frequency network oscillations in vitro but leaves high frequency (150 Hz) rhythms, which may involve gap junctions between principal cells (Schmitz et al., 2001), unaffected. Thus, specific connexins differentially deployed throughout cortical networks are likely to regulate different functional aspects of neuronal information processing in the mature brain.
Assuntos
Encéfalo/fisiologia , Conexinas/fisiologia , Hipocampo/fisiologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Envelhecimento , Animais , Encéfalo/crescimento & desenvolvimento , Carbacol/farmacologia , Córtex Cerebral/fisiologia , Conexinas/deficiência , Conexinas/genética , Eletroencefalografia , Junções Comunicantes/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Hipocampo/efeitos dos fármacos , Técnicas In Vitro , Ácido Caínico/farmacologia , Camundongos , Camundongos Knockout , Neurônios/efeitos dos fármacos , Oscilometria , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Transcrição Gênica , Proteína delta-2 de Junções ComunicantesRESUMO
Gamma oscillations synchronized between distant neuronal populations may be critical for binding together brain regions devoted to common processing tasks. Network modeling predicts that such synchrony depends in part on the fast time course of excitatory postsynaptic potentials (EPSPs) in interneurons, and that even moderate slowing of this time course will disrupt synchrony. We generated mice with slowed interneuron EPSPs by gene targeting, in which the gene encoding the 67-kDa form of glutamic acid decarboxylase (GAD67) was altered to drive expression of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor subunit GluR-B. GluR-B is a determinant of the relatively slow EPSPs in excitatory neurons and is normally expressed at low levels in gamma-aminobutyric acid (GABA)ergic interneurons, but at high levels in the GAD-GluR-B mice. In both wild-type and GAD-GluR-B mice, tetanic stimuli evoked gamma oscillations that were indistinguishable in local field potential recordings. Remarkably, however, oscillation synchrony between spatially separated sites was severely disrupted in the mutant, in association with changes in interneuron firing patterns. The congruence between mouse and model suggests that the rapid time course of AMPA receptor-mediated EPSPs in interneurons might serve to allow gamma oscillations to synchronize over distance.