RESUMO
Recent in vivo electrophysiological studies suggest that chronic dopamine depletion alters profoundly the firing pattern of basal ganglia neurons. These changes may disrupt the processing of cortical information flow from the striatum to the output nuclei, and presumably underlie the clinical manifestations of Parkinson's disease. We have recently reported that chronic nigrostriatal lesions induce changes in the functional state of striatal medium-spiny neurons (MSNs) that could facilitate spreading of cortical synchronous activity (approximately 1 Hz) to striatal target nuclei. Here we show that systemic administration of D1 dopamine agonists was sufficient to restore the changes induced by chronic nigrostriatal lesions on striatal neuronal activity into the normal state. Following systemic administration of SKF38393 or SKF81279 the membrane potential of striatal MSNs was upheld into a more hyperpolarized value and action potential firing probability decreased. D1 agonists also increased the latency to the cortically driven plateau depolarization and reduced the peak potential of the short latency depolarizing postsynaptic response to a more hyperpolarized value. The present study provides in vivo evidence indicating that pharmacological stimulation of D1-class dopamine receptors can modulate the flow of cortical information through the striatum in the parkinsonian state.
Assuntos
Córtex Cerebral/fisiologia , Corpo Estriado/fisiologia , Agonistas de Dopamina/farmacologia , Neurônios/metabolismo , Transtornos Parkinsonianos/fisiopatologia , Receptores de Dopamina D1/fisiologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Córtex Cerebral/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Eletrofisiologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Imuno-Histoquímica , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Neurônios/efeitos dos fármacos , Ratos , Receptores de Dopamina D1/efeitos dos fármacosRESUMO
1. The striatum is part of a multisynaptic loop involved in translating higher order cognitive activity into action. The main striatal computational unit is the medium spiny neuron, which integrates inputs arriving from widely distributed cortical neurons and provides the sole striatal output. 2. The membrane potential of medium spiny neurons' displays shifts between a very negative resting state (down state) and depolarizing plateaus (up states) which are driven by the excitatory cortical inputs. 3. Because striatal spiny neurons fire action potentials only during the up state, these plateau depolarizations are perceived as enabling events that allow information processing through cerebral cortex-basal ganglia circuits. In vivo intracellular recording techniques allow to investigate simultaneously the subthreshold behavior of the medium spiny neuron membrane potential (which is a "reading" of distributed patterns of cortical activity) and medium spiny neuron firing (which is an index of striatal output). 4. Recent studies combining intracellular recordings of striatal neurons with field potential recordings of the cerebral cortex illustrate how the analysis of the input-output transformations performed by medium spiny neurons may help to unveil some aspects of information processing in cerebral cortex-basal ganglia circuits, and to understand the origin of the clinical manifestations of Parkinson's disease and other neurologic and neuropsychiatric disorders that result from alterations in dopamine-dependent information processing in the cerebral cortex-basal ganglia circuits.
Assuntos
Relógios Biológicos/fisiologia , Dopamina/metabolismo , Neostriado/metabolismo , Vias Neurais/metabolismo , Neurônios/metabolismo , Potenciais de Ação/fisiologia , Animais , Dendritos/metabolismo , Humanos , Neostriado/citologia , Vias Neurais/citologia , Neurônios/citologia , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Transmissão Sináptica/fisiologiaRESUMO
Single unit recordings performed in animal models of Parkinson's disease revealed that output nuclei neurons display modifications in firing pattern and firing rate, which are supposed to give rise to the clinical manifestations of the illness. We examined the activity pattern of single units from the substantia nigra pars reticulata, the main output nuclei of the rodent basal ganglia, in urethane-anesthetized control and 6-hydroxydopamine-lesioned rats (a widespread model of Parkinson's disease). We further studied the effect of a subthalamic nucleus lesion in both experimental groups. Subthalamic nucleus lesion produces behavioral improvement in animal models of Parkinson's disease, and was expected to reverse the changes induced by 6-hydroxydopamine lesions. A meticulous statistical investigation, which included a non-biased classification of the recorded units by means of cluster analysis, allowed us to identify a low frequency oscillation of firing rate ( approximately 0.9 Hz) occurring in approximately 35% of the units recorded from 6-hydroxydopamine-lesioned rats, as the main feature differentiating 6-hydroxydopamine-lesioned and control rats. Subthalamic nucleus lesions significantly reduced the proportion of oscillatory units in 6-hydroxydopamine-lesioned rats. However, the population of nigral units recorded from rats bearing both lesions still differed significantly from control units. These results suggest that oscillatory activity in the basal ganglia output nuclei may be related to some clinical features of parkinsonism, and suggest a putative mechanism through which therapeutic interventions aimed at modifying subthalamic nucleus function produce clinical benefit in Parkinson's disease.
Assuntos
Potenciais de Ação/fisiologia , Relógios Biológicos , Vias Neurais/fisiologia , Neurônios/fisiologia , Doença de Parkinson/fisiopatologia , Substância Negra/fisiologia , Núcleo Subtalâmico/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Agonistas de Aminoácidos Excitatórios/farmacologia , Ácido Caínico/farmacologia , Masculino , Degeneração Neural/induzido quimicamente , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Vias Neurais/citologia , Vias Neurais/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurotoxinas/farmacologia , Oxidopamina/farmacologia , Doença de Parkinson/patologia , Ratos , Ratos Sprague-Dawley , Substância Negra/citologia , Substância Negra/efeitos dos fármacos , Núcleo Subtalâmico/citologia , Núcleo Subtalâmico/efeitos dos fármacos , Simpatolíticos/farmacologiaRESUMO
Neurons in the basal ganglia output nuclei display rhythmic burst firing after chronic nigrostriatal lesions. The thalamocortical network is a strong endogenous generator of oscillatory activity, and the striatum receives a massive projection from the cerebral cortex. Actually, the membrane potential of striatal projection neurons displays periodic shifts between a very negative resting potential (down state) and depolarizing plateaus (up states) during which they can fire action potentials. We hypothesized that an increased excitability of striatal neurons may allow transmission of cortical slow rhythms through the striatum to the remaining basal ganglia in experimental parkinsonism. In vivo intracellular recordings revealed that striatal projection neurons from rats with chronic nigrostriatal lesions had a more depolarized membrane potential during both the down and up states and an increased firing probability during the up events. Furthermore, lesioned rats had significantly fewer silent neurons than control rats. Simultaneous recordings of the frontal electrocorticogram and membrane potential of striatal projection neurons revealed that the signals were oscillating synchronously in the frequency range 0.4-2 Hz, both in control rats and rats with chronic nigrostriatal lesions. Spreading of the slow cortical rhythm is limited by the very low firing probability of control rat neurons, but a slow oscillation is well reflected in spike trains of approximately 60% of lesioned rat neurons. These findings provide in vivo evidence for a role of dopamine in controlling the flow of cortical activity through the striatum and may be of outstanding relevance for understanding the pathophysiology of Parkinson's disease.
Assuntos
Relógios Biológicos , Córtex Cerebral/fisiopatologia , Potenciais da Membrana , Neurônios , Doença de Parkinson Secundária/fisiopatologia , Potenciais de Ação , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Corpo Estriado/fisiopatologia , Estimulação Elétrica , Lobo Frontal/fisiopatologia , Masculino , Neurônios/fisiologia , Oxidopamina , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/patologia , Periodicidade , Ratos , Ratos Sprague-Dawley , Tempo de Reação , Processamento de Sinais Assistido por Computador , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Substância Negra/fisiopatologiaRESUMO
In order to increase our understanding of Parkinson's disease pathophysiology, we studied the effects of intrastriatally administered selective dopamine receptor agonists on single units from the substantia nigra pars reticulata of 6-hydroxydopamine (6-OHDA)-lesioned rats with or without an additional subthalamic nucleus lesion. Nigral pars reticulata units of 6-OHDA-lesioned rats were classified into two types, showing regular and bursting discharge patterns, respectively ('non-burst' and 'burst' units). Non-burst and burst units showed distinct responses to intrastriatal quinpirole (the former were excited and burst units inhibited). Furthermore, subthalamic nucleus lesions significantly decreased the number of nigral units showing a spontaneous bursting pattern, and reduced the proportion of units that responded to quinpirole. In contrast, subthalamic lesions did not alter the proportion of nigral units that responded to SKF38393, although the lesions changed some response features, e.g. response type and magnitude. Burst analysis showed that quinpirole did not modify the discharge pattern of burst units, whereas SKF38393 produced a shift to regular firing in 62% of the burst units tested. In conjunction, our results support that: (i) the subthalamic nucleus has an important influence on output nuclei firing pattern; (ii) striatal D2 receptors have a strong influence on nigral firing rate, and a less relevant role in controlling firing pattern; (iii) burst and non-burst units differ in their response to selective stimulation of striatal dopamine receptors; (iv) the effects of striatal D2 receptors on nigral units are mainly, though not exclusively, mediated by the subthalamic nucleus; and (v) nigral responses to SKF38393 involve the subthalamic nucleus.
Assuntos
Corpo Estriado/fisiologia , Neurônios/fisiologia , Receptores de Dopamina D2/fisiologia , Substância Negra/fisiologia , Núcleo Subtalâmico/fisiologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Benzazepinas/farmacologia , Antagonistas de Dopamina/farmacologia , Ácido Caínico/toxicidade , Masculino , Neurônios/efeitos dos fármacos , Oxidopamina/toxicidade , Quimpirol/farmacologia , Ratos , Ratos Sprague-Dawley , Salicilamidas/farmacologia , Substância Negra/efeitos dos fármacos , Núcleo Subtalâmico/efeitos dos fármacosRESUMO
After intrastriatal administration of selective dopamine receptor agonists only a small percentage of substantia nigra pars reticulata single units showed changes in firing rate (23% after SKF38393 and 17% after quinpirole). After their intrastriatal co-administration, however, or after the application of the non-selective dopamine receptor agonist apomorphine, 72% and 69% of units responded, respectively. This result confirms the participation of the striatum in the phenomenon of D1-D2 receptor interaction, and show that co-activation of both receptor subtypes produced a maximal effect on basal ganglia output nuclei.
Assuntos
2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Corpo Estriado/fisiologia , Agonistas de Dopamina/farmacologia , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/administração & dosagem , Animais , Apomorfina/administração & dosagem , Apomorfina/farmacologia , Corpo Estriado/efeitos dos fármacos , Agonistas de Dopamina/administração & dosagem , Eletrofisiologia/métodos , Potenciais Evocados/efeitos dos fármacos , Masculino , Microinjeções , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Quimpirol/administração & dosagem , Quimpirol/farmacologia , Ratos , Ratos Sprague-Dawley , Substância Negra/efeitos dos fármacos , Substância Negra/fisiologiaRESUMO
The spontaneous activity and the response to intrastriatal application of apomorphine of substantia nigra pars reticulata (SNpr) single units was studied in four experimental groups of rats: (1) normal rats; (2) subthalamic nucleus (STN) lesioned rats; (3) rats bearing a 6-hydroxydopamine (60HDA) lesion; and (4) 60HDA-lesioned animals with an additional STN lesion. Thirty-eight percent of units from 60HDA-lesioned rats showed a bursting pattern of spontaneous activity, which was never found in normal rats. STN lesions had no effect on the spontaneous activity of SNpr units from normal rats, but reduced the percentage of burst units in 60HDA-lesioned animals. Intrastriatal apomorphine produced responses in 62% of SNpr units from normal rats and 85% of units from 60HDA-lesioned animals (P < 0.05). In addition, the modifications in the firing rate and in the coefficient of variation of the interspike intervals induced by intrastriatal apomorphine were significantly greater for the units isolated from 60HDA-lesioned rats. In particular, it was noted that all the burst units responded to apomorphine, showing the highest changes in firing rate and coefficient of variation. However, intrastriatal apomorphine did not always turn the activity of burst units into a more physiological pattern. STN lesions reduced the percentage of units responding to intrastriatal apomorphine in normal rats. In 60HDA-lesioned rats, STN lesions reduced the number of responsive units, and their change in mean firing rate and coefficient of variation. Our results show that the STN participates in the genesis of the bursting pattern of activity of SNpr units in 60HDA-lesioned rats, and that STN lesions can partially revert the abnormal spontaneous and apomorphine-induced responses of SNpr units in these animals.
Assuntos
Apomorfina/farmacologia , Corpo Estriado/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Neurônios/efeitos dos fármacos , Substância Negra/efeitos dos fármacos , Núcleos Talâmicos/efeitos dos fármacos , Animais , Ácido Caínico/farmacologia , Masculino , Neurotoxinas , Oxidopamina , Ratos , Ratos Sprague-Dawley , Valores de Referência , Substância Negra/citologia , Substância Negra/patologiaRESUMO
Previous studies from different laboratories have suggested that qEEG could be useful for distinguishing dementia from normality. Our aims were: (1) to study the ability of qEEG to distinguish dementia among different pathological conditions in ambulatory settings; (2) to compare the ability of classical statistical analysis and of neural networks in classifying qEEG data. We were able to obtain a multiple discriminant function using a training set of patients, which classified correctly more than 91% of the qEEGs from an independent group of patients, with less than 5% of false positives. Kohonen's neural network was trained with the same set of patients. This unsupervised learning artificial neural network performed the classification of the independent sample with an accuracy comparable to that of the multiple discriminant function. Our results suggest that the use of unsupervised learning algorithms could be an interesting alternative in the classification of data obtained from psychiatric patients where definition of their clinical profile is not always a simple task.
Assuntos
Encéfalo/fisiopatologia , Redes Neurais de Computação , Adulto , Idoso , Ansiedade/fisiopatologia , Demência/fisiopatologia , Transtorno Depressivo/fisiopatologia , Eletroencefalografia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The role of the mesopontine area and superior colliculus in turning behavior induced by systemic administration of apomorphine was studied in rats bearing a unilateral entopeduncular lesion. Bilateral electrolytic damage of the superior colliculus resulted in an enhancement of the ipsilateral circling response to apomorphine, perhaps as a consequence of an increased locomotor drive in such animals. Bilateral electrolytic lesions of the mesopontine area decreased apomorphine-induced turning in entopeduncular rats, while a bilateral kainic acid lesion of the same region was ineffective. It was concluded that the pedunculopontine nucleus and adjacent reticular formation are not an essential link for the striopallidal complex output mediating circling in this model. Fibers running through this region could be implicated in the expression of the behavior under study. Since a unilateral electrolytic lesion of the mesopontine area contralateral to the damaged entopeduncular nucleus reduced drug-induced turning, we propose that an uncrossed pathway from the intact striopallidal complex mediates circling in our rats.