RESUMEN
How do animals adopt a given behavioral strategy to solve a recurrent problem when several effective strategies are available to reach the goal? Here we provide evidence that striatal cholinergic interneurons (SCINs) modulate their activity when mice must select between different strategies with similar goal-reaching effectiveness. Using a cell type-specific transgenic murine system, we show that adult SCIN ablation impairs strategy selection in navigational tasks where a goal can be independently achieved by adopting an allocentric or egocentric strategy. SCIN-depleted mice learn to achieve the goal in these tasks, regardless of their appetitive or aversive nature, in a similar way as controls. However, they cannot shift away from their initially adopted strategies, as control mice do, as training progresses. Our results indicate that SCINs are required for shaping the probability function used for strategy selection as experience accumulates throughout training. Thus, SCINs may be critical for the resolution of cognitive conflicts emerging when several strategies compete for behavioral control while adapting to environmental demands. Our findings may increase our understanding about the emergence of perseverative/compulsive traits in neuropsychiatric disorders with a reported SCIN reduction, such as Tourette and Williams syndromes.SIGNIFICANCE STATEMENT Selecting the best suited strategy to solve a problem is vital. Accordingly, available strategies must be compared across multiple dimensions, such as goal attainment effectiveness, cost-benefit trade-off, and cognitive load. The striatum is involved in strategy selection when strategies clearly diverge in their goal attainment capacity; however, its role whenever several strategies can be used for goal reaching-therefore making selection dependent on additional strategy dimensions-remains poorly understood. Here, we show that striatal cholinergic interneurons can signal strategy competition. Furthermore, they are required to adopt a given strategy whenever strategies with similar goal attainment capacity compete for behavioral control. Our study suggests that striatal cholinergic dysfunction may result in anomalous resolution of problems whenever complex cognitive valuations are required.
Asunto(s)
Neuronas Colinérgicas/fisiología , Cuerpo Estriado/fisiología , Interneuronas/fisiología , Solución de Problemas/fisiología , Navegación Espacial/fisiología , Animales , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
The mechanisms underlying social dysfunction in neuropsychiatric conditions such as obsessive-compulsive disorder and Tourette syndrome remain uncertain. However, it is known that dysfunctions in basal ganglia, including a reduced number of striatal cholinergic interneurons (SCIN), are involved in their pathophysiology. To explore the role of SCIN in relation to perseverative behaviors, we characterized a new transgenic mouse model in which inducible ablation of SCIN is achieved with high efficiency in a cell-type- and region-specific manner. Mice were subjected to extensive behavioral testing, including assessment of social behaviors, and corticostriatal functional connectivity was evaluated in vivo Selective SCIN ablation leads to altered social interactions together with exacerbated spontaneously emitted repetitive behaviors. Lesioned mice showed normal motor coordination, balance, and general locomotion. Interestingly, only environmentally driven, but not self-directed, repetitive behaviors were exacerbated in lesioned mice. Remarkably, in mice with SCIN ablation, the normal pattern of social exploration was replayed continuously. The emerging pattern of social interactions is highly predictable and invariant across time. In vivo electrophysiological recordings indicate that SCIN ablation results in an increase of the functional connectivity between different cortical areas and the motor, but not associative, region of the striatum. Our results identify a role of SCIN in suppressing perseverative behaviors, including socially related ones. In sum, SCIN ablation in mice leads to exacerbated ritualistic-like behaviors that affect social performance, providing a link between SCIN dysfunction and the social impairments present in psychiatric disorders.SIGNIFICANCE STATEMENT We sought to uncover the impact of striatal cholinergic interneuron (SCIN) degeneration on perseverative behaviors related to obsessive-compulsive disorder (OCD) and Tourette syndrome (TS). We found that extensive SCIN ablation results in exacerbated social interactions, in which normal social contacts were replayed continuously in a highly stereotyped, ritualistic pattern. SCIN ablation also leads to an increase in other spontaneously emitted repetitive behaviors without alteration of motor coordination, balance, or locomotion. Moreover, we identify an increase of functional connectivity between frontal cortical areas and the motor region of the striatum as a putative substrate for the observed behavioral alterations. Therefore, perseveration induced by SCIN ablation extends to social performance as occurs in neuropsychiatric conditions such as OCD and TS.
Asunto(s)
Potenciales de Acción , Neuronas Colinérgicas , Conducta Compulsiva/fisiopatología , Cuerpo Estriado/fisiopatología , Interneuronas , Trastorno de la Conducta Social/fisiopatología , Animales , Conducta Compulsiva/complicaciones , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Red Nerviosa/fisiopatología , Conducta Social , Trastorno de la Conducta Social/complicacionesRESUMEN
Findings showing that neonatal lesions of the forebrain dopaminergic system in rodents lead to juvenile locomotor hyperactivity and learning deficits have been taken as evidence of face validity for the attention deficit hyperactivity disorder. However, the core cognitive and physiological intermediate phenotypes underlying this rodent syndrome remain unknown. Here we show that early postnatal dopaminergic lesions cause long-lasting deficits in exploitation of shelter, social and nutritional resources, and an imbalanced exploratory behavior, where nondirected local exploration is exacerbated, whereas sophisticated search behaviors involving sequences of goal directed actions are degraded. Importantly, some behavioral deficits do not diminish after adolescence but instead worsen or mutate, particularly those related to the exploration of wide and spatially complex environments. The in vivo electrophysiological recordings and morphological reconstructions of striatal medium spiny neurons reveal corticostriatal alterations associated to the behavioral phenotype. More specifically, an attenuation of corticostriatal functional connectivity, affecting medial prefrontal inputs more markedly than cingulate and motor inputs, is accompanied by a contraction of the dendritic arbor of striatal projection neurons in this animal model. Thus, dopaminergic neurons are essential during postnatal development for the functional and structural maturation of corticostriatal connections. From a bottom-up viewpoint, our findings suggest that neuropsychiatric conditions presumably linked to developmental alterations of the dopaminergic system should be evaluated for deficits in foraging decision making, alterations in the recruitment of corticostriatal circuits during foraging tasks, and structural disorganization of the frontostriatal connections.
Asunto(s)
Corteza Cerebral/fisiopatología , Cuerpo Estriado/crecimiento & desarrollo , Cuerpo Estriado/fisiopatología , Dopamina/metabolismo , Conducta Exploratoria/fisiología , Animales , Animales Recién Nacidos , Corteza Cerebral/crecimiento & desarrollo , Corteza Cerebral/patología , Cuerpo Estriado/patología , Dendritas/patología , Dendritas/fisiología , Modelos Animales de Enfermedad , Electrodos Implantados , Inmunohistoquímica , Ratones , Actividad Motora/fisiología , Vías Nerviosas/crecimiento & desarrollo , Vías Nerviosas/patología , Vías Nerviosas/fisiopatología , Oxidopamina , Fenotipo , Conducta Social , Conducta Espacial/fisiologíaRESUMEN
Anomalous patterns of synchronization between basal ganglia and cortex underlie the symptoms of Parkinson's disease. Computational modeling studies suggest that changes in cortical feedback loops involving trans-striatal and trans-subthalamic circuits bring up this anomalous synchronization. We asked whether striatal outflow synchronizes globus pallidus neurons with cortical activity in a rat model of Parkinson's disease. We found that striatal firing is highly increased in rats with chronic nigrostriatal lesion and that this hyperactivity can be reduced by locally infusing a competitive NMDA receptor antagonist. Moreover, NMDA receptor-dependent striatal output had frequency dependent effects on distinct pathological patterns of cortico-pallidal coupling. Blockade of striatal NMDA receptors almost completely abolished an anomalous ~1Hz cortico-pallidal anti-phase synchronization induced by nigrostriatal degeneration. Moreover, under striatal NMDA receptor blockade, synchronization with 2.5-5Hz cortical oscillations falls to negligible levels and oscillations at 10-20Hz are markedly attenuated, whereas beta synchronization (with a peak at ~26Hz) is marginally reduced. Thus, tonic activation of striatal NMDA receptors allows different forms of anomalous oscillations along the cortico-striato-pallidal axis. Moreover, the frequency dependent effects of NMDA receptors suggest that low and high frequency parkinsonian oscillations stem from partially different mechanisms. Finally, our results may help to reconcile views about the contributions of changes in firing rate and oscillatory synchronization to Parkinson's disease symptoms by showing that they are related to each other.
Asunto(s)
Ondas Encefálicas , Corteza Cerebral/fisiopatología , Sincronización de Fase en Electroencefalografía , Globo Pálido/fisiopatología , Neostriado/fisiopatología , Enfermedad de Parkinson/fisiopatología , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Corteza Cerebral/metabolismo , Modelos Animales de Enfermedad , Globo Pálido/metabolismo , Masculino , Enfermedad de Parkinson/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Altered corticostriatal information processing associated with early dopamine systems dysfunction may contribute to attention deficit/hyperactivity disorder (ADHD). Mice with neonatal dopamine-depleting lesions exhibit hyperactivity that wanes after puberty and is reduced by psychostimulants, reminiscent of some aspects of ADHD. To assess whether the maturation of corticostriatal functional connectivity is altered by early dopamine depletion, we examined preadolescent and postadolescent urethane-anesthetized mice with or without dopamine-depleting lesions. Specifically, we assessed (1) synchronization between striatal neuron discharges and oscillations in frontal cortex field potentials and (2) striatal neuron responses to frontal cortex stimulation. In adult control mice striatal neurons were less spontaneously active, less responsive to cortical stimulation, and more temporally tuned to cortical rhythms than in infants. Striatal neurons from hyperlocomotor mice required more current to respond to cortical input and were less phase locked to ongoing oscillations, resulting in fewer neurons responding to refined cortical commands. By adulthood some electrophysiological deficits waned together with hyperlocomotion, but striatal spontaneous activity remained substantially elevated. Moreover, dopamine-depleted animals showing normal locomotor scores exhibited normal corticostriatal synchronization, suggesting that the lesion allows, but is not sufficient, for the emergence of corticostriatal changes and hyperactivity. Although amphetamine normalized corticostriatal tuning in hyperlocomotor mice, it reduced horizontal activity in dopamine-depleted animals regardless of their locomotor phenotype, suggesting that amphetamine modified locomotion through a parallel mechanism, rather than that modified by dopamine depletion. In summary, functional maturation of striatal activity continues after infancy, and early dopamine depletion delays the maturation of core functional capacities of the corticostriatal system.
Asunto(s)
Corteza Cerebral/fisiopatología , Cuerpo Estriado/fisiopatología , Dopamina/metabolismo , Hipercinesia/metabolismo , Hipercinesia/patología , Hipercinesia/fisiopatología , Vías Nerviosas/fisiopatología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Factores de Edad , Anfetamina , Animales , Animales Recién Nacidos , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/crecimiento & desarrollo , Corteza Cerebral/patología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Dopamina/deficiencia , Estimulación Eléctrica/métodos , Hipercinesia/inducido químicamente , Locomoción/efectos de los fármacos , Locomoción/fisiología , Ratones , Vías Nerviosas/metabolismo , Vías Nerviosas/patología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Oxidopamina , Serotonina/metabolismoRESUMEN
A role of NMDA receptors in corticostriatal synaptic plasticity is widely acknowledged. However, the conditions that allow NMDA receptor activation in the striatum in vivo remain obscure. Here we show that NMDA receptors contribute to sustain the membrane potential of striatal medium spiny projection neurons close to threshold during spontaneous UP states in vivo. Moreover, we found that the blockade of striatal NMDA receptors reduces markedly the spontaneous firing of ensembles of medium spiny neurons during slow waves in urethane-anesthetized rats. We speculate that recurrent activation of NMDA receptors during UP states allows off-line information flow through the striatum and system level consolidation during habit formation.
Asunto(s)
Cuerpo Estriado/fisiología , Activación del Canal Iónico/fisiología , Aprendizaje/fisiología , Neuronas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Masculino , Potenciales de la Membrana/fisiología , Microdiálisis , Ratas , Ratas Sprague-DawleyRESUMEN
Coordinated near-threshold depolarized states in cortical and striatal neurons may contribute to form functionally segregated channels of information processing. Recent anatomical studies have identified pathways that could support spiraling interactions across corticostriatal channels, but a functional outcome of such spiraling remains to be identified. Here, we examined whether plateau depolarizations (UP states) in striatal neurons relate better to active epochs in local field potentials recorded from closely related cortical areas than to those recorded in less-related cortical areas. Our results show that, in anesthetized rats, the coordination between cortical areas and striatal regions obeys a mediolateral gradient and keeps track of slow wave trajectory across the neocortex. Moreover, activity in one cortical area induced phase advances in UP state onset and phase delays in UP state termination in nonmatching striatal regions, reflecting the existence of functional connections that could encode large-scale interactions between corticostriatal channels as subthreshold influences on striatal projection neurons.
Asunto(s)
Canales Iónicos/fisiología , Potenciales de la Membrana/fisiología , Neostriado/fisiología , Anestesia , Animales , Electrodos , Activación del Canal Iónico/efectos de los fármacos , Masculino , Potenciales de la Membrana/efectos de los fármacos , Corteza Motora/efectos de los fármacos , Corteza Motora/fisiología , Neocórtex/efectos de los fármacos , Neocórtex/fisiología , Neostriado/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/fisiología , Ratas , Ratas Sprague-Dawley , Uretano/administración & dosificación , Uretano/farmacologíaRESUMEN
The main clinical manifestations of Parkinson's disease are caused by alterations of basal ganglia activity that are tied in with the progressive loss of mesencephalic dopaminergic neurons. Recent theoretical and modeling studies have suggested that changes in resting neuronal activity occurred later in the course of the disease than those evoked by phasic cortical input. However, there is no empirical support for this proposal. Here we report a marked increase in the responsiveness of globus pallidus neurons to electrical motor cortex stimulation, in the absence of noticeable changes in resting activity, in anesthetized rats that had consistently shown a deficit in forelimb use during behavioral testing before the experiments, and had approximately 45% dopamine neurons spared in the substantia nigra. Pallidal neurons were also over-responsive to motor cortex stimulation and lost spatial selectivity for cortical inputs in rats with extensive nigrostriatal damage. After partial lesions, over-responsiveness was mainly due to an increased proportion of neurons showing excitatory responses, while extensive lesions led to an increased likelihood of inhibitory responding neurons. Changes in resting neuronal activity, comprising pauses disrupting tonic discharge, occurred across different global brain states, including an activated condition which shares similarities with natural patterns of cortical activity seen in awake states and rapid eye-movement sleep, but only after massive nigrostriatal degeneration. These results suggest that a loss of functional segregation and an abnormal temporal encoding of phasic cortical inputs by globus pallidus neurons may contribute to inducing early motor impairment in Parkinson's disease.
Asunto(s)
Potenciales de Acción/fisiología , Lateralidad Funcional/fisiología , Globo Pálido/patología , Globo Pálido/fisiopatología , Neuronas/fisiología , Trastornos Parkinsonianos/patología , Animales , Conducta Animal , Mapeo Encefálico , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Masculino , Oxidopamina , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/complicaciones , Ratas , Ratas Sprague-Dawley , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
During movement, inhibitory neurons in the basal ganglia output nuclei show complex modulations of firing, which are presumptively driven by corticostriatal and corticosubthalamic input. Reductions in discharge should facilitate movement by disinhibiting thalamic and brain stem nuclei while increases would do the opposite. A proposal that nigrostriatal dopamine pathway degeneration disrupts trans-striatal pathways' balance resulting in sustained overactivity of basal ganglia output nuclei neurons and Parkinson's disease clinical signs is not fully supported by experimental evidence, which instead shows abnormal synchronous oscillatory activity in animal models and patients. Yet, the possibility that variation in motor cortex activity drives transient overactivity in output nuclei neurons in parkinsonism has not been explored. In Sprague-Dawley rats with 6-hydroxydopamine (6-OHDA)-induced nigrostriatal lesions, approximately 50% substantia nigra pars reticulata (SNpr) units show abnormal cortically driven slow oscillations of discharge. Moreover, these units selectively show abnormal responses to motor cortex stimulation consisting in augmented excitations of an odd latency, which overlapped that of inhibitory responses presumptively mediated by the trans-striatal direct pathway in control rats. Delivering D1 or D2 dopamine agonists into the striatum of parkinsonian rats by reverse microdialysis reduced these abnormal excitations but had no effect on pathological oscillations. The present study establishes that dopamine-deficiency related changes of striatal function contribute to producing abnormally augmented excitatory responses to motor cortex stimulation in the SNpr. If a similar transient overactivity of basal ganglia output were driven by motor cortex input during movement, it could contribute to impeding movement initiation or execution in Parkinson's disease.
Asunto(s)
Cuerpo Estriado/fisiopatología , Corteza Motora/fisiopatología , Vías Nerviosas/fisiopatología , Trastornos Parkinsonianos/fisiopatología , Sustancia Negra/fisiopatología , Potenciales de Acción/fisiología , Animales , Relojes Biológicos/fisiología , Cuerpo Estriado/metabolismo , Dopamina/deficiencia , Agonistas de Dopamina/farmacología , Estimulación Eléctrica , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Masculino , Inhibición Neural/fisiología , Vías Nerviosas/metabolismo , Neuronas/metabolismo , Neuronas/fisiología , Oxidopamina , Trastornos Parkinsonianos/metabolismo , Ratas , Ratas Sprague-Dawley , Sustancia Negra/metabolismo , Transmisión Sináptica/fisiologíaRESUMEN
There is a debate as to what modifications of neuronal activity underlie the clinical manifestations of Parkinson's disease and the efficacy of antiparkinsonian pharmacotherapy. Previous studies suggest that release of GABAergic striatopallidal neurons from D2 receptor-mediated inhibition allows spreading of cortical rhythms to the globus pallidus (GP) in rats with 6-hydroxydopamine-induced nigrostriatal lesions. Here this abnormal spreading was thoroughly investigated. In control urethane-anaesthetized rats most GP neurons were excited during the active part of cortical slow waves ('direct-phase' neurons). Two neuronal populations having opposite phase relationships with cortical and striatal activity coexisted in the GP of 6-hydroxydopamine-lesioned rats. 'Inverse-phase' GP units exhibited reduced firing coupled to striatal activation during slow waves, suggesting that this GP oscillation was driven by striatopallidal hyperactivity. Half of the pallidonigral neurons identified by antidromic stimulation exhibited inverse-phase activity. Therefore, spreading of inverse-phase oscillations through pallidonigral axons might contribute to the abnormal direct-phase cortical entrainment of basal ganglia output described previously. Systemic administration of the D2 agonist quinpirole to 6-hydroxydopamine-lesioned rats reduced GP inverse-phase coupling with slow waves, and this effect was reversed by the D2 antagonist eticlopride. Because striatopallidal hyperactivity was only slightly reduced by quinpirole, other mechanisms might have contributed to the effect of quinpirole on GP oscillations. These results suggest that antiparkinsonian efficacy may rely on other actions of D2 agonists on basal ganglia activity. However, abnormal slow rhythms may promote enduring changes in functional connectivity along the striatopallidal axis, contributing to D2 agonist-resistant clinical signs of parkinsonism.
Asunto(s)
Ganglios Basales/fisiología , Cuerpo Estriado/patología , Dopamina/metabolismo , Receptores de Dopamina D2/metabolismo , Sustancia Negra/patología , Potenciales de Acción/fisiología , Animales , Agonistas de Dopamina/metabolismo , Electrofisiología , Masculino , Neuronas/fisiología , Quinpirol/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
In vivo, cortical neurons and striatal medium spiny neurons (MSN) display robust subthreshold depolarizations (Up states) during which they are enabled to fire action potentials. In the cortex, Up states are believed to occur simultaneously in a neuronal ensemble and to be sustained by local network interactions. It is known that MSN are impelled into the Up state by extra-striatal (primarily cortical) inputs, but the mechanisms that sustain and determine the end of striatal Up states are still debated. Furthermore, it has not been established if brisk perturbations of ongoing cortical oscillations alter rhythmic transitions between Up and Down states in striatal neurons. Here we report that MSN Up states terminate abruptly when persistent activity in cortical ensembles providing afferents to a given striatal region is turned off by local electrical stimulation or ends spontaneously. In addition, we found that phase perturbations in MSN membrane potential slow oscillations induced by cortical stimulation replicate the stimulus-induced dynamics of spiking activity in cortical ensembles. Overall, these results suggest that striatal Up states are single-cell subthreshold representations of episodes of persistent spiking in cortical ensembles. A precise spatial and temporal alignment between episodes of cortical persistent activity and striatal Up states would allow MSN to detect specific cortical inputs embedded within a more general cortical signal.
Asunto(s)
Potenciales de Acción/fisiología , Relojes Biológicos/fisiología , Corteza Cerebral/fisiología , Cuerpo Estriado/fisiología , Estimulación Eléctrica/métodos , Potenciales Evocados/fisiología , Inhibición Neural/fisiología , Adaptación Fisiológica/fisiología , Animales , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Pleiotrophin (PTN), a developmentally-regulated trophic factor, is over-expressed in the striatum of parkinsonian rats. Because striatal PTN can provide trophic support to dopamine neurons, we identified the cellular types containing PTN in the striatum of adult rats. By means of fluorescent double-immunolabeling, we found PTN to co-localize with a neuronal nuclei marker but not with glial fibrillary acidic protein. The number, distribution, and morphology of the PTN-immunolabeled cells suggested that they were interneurons. Further double-immunolabeling studies ruled out PTN localization to calretinin- and parvalbumin-containing interneurons. Instead, approximately 40% of the PTN-immunolabeled neurons contained nitric oxide synthase or somatostatin and approximately 60% expressed the vesicular acetylcholine transporter, supporting that they were GABAergic nitric oxide synthase/somatostatin-containing and cholinergic interneurons. Further work is necessary to determine if PTN from striatal interneurons can provide trophic support to dopamine neurons.
Asunto(s)
Proteínas Portadoras/metabolismo , Citocinas/metabolismo , Interneuronas/metabolismo , Neostriado/metabolismo , Animales , Western Blotting , Calbindina 2 , Femenino , Técnica del Anticuerpo Fluorescente , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Inmunoquímica , Inmunohistoquímica , Peso Molecular , Neostriado/citología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Parvalbúminas/metabolismo , Ratas , Ratas Wistar , Proteína G de Unión al Calcio S100/metabolismo , Proteínas de Transporte Vesicular de Acetilcolina/metabolismoRESUMEN
Severe chronic dopamine (DA) depletion increases the proportion of neurons in the basal ganglia that fire rhythmic bursts of action potential (LFO units) synchronously with the cortical oscillations. Here we report on how different levels of mesencephalic DA denervation affect substantia nigra pars reticulata (SNpr) neuronal activity in the rat and its relationship to akinesia (stepping test). Chronic nigrostriatal lesion induced with 0 (control group), 4, 6 or 8 microg of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle resulted in a dose-dependent decrease of tyrosine hydroxylase positive (TH+) neurons in the SN and ventral tegmental area (VTA). Although 4 microg of 6-OHDA reduced the number of TH+ neurons in the SN by approximately 60%, both stepping test performance and SNpr neuronal activity remained indistinguishable from control animals. By contrast, animals that received 6 microg of 6-OHDA showed a marked reduction of TH+ cells in the SN ( approximately 75%) and VTA ( approximately 55%), a significant stepping test deficit and an increased proportion of LFO units. These changes were not dramatically enhanced with 8 microg 6-OHDA, a dose that induced an extensive DA lesion (> 95%) in the SN and approximately 70% reduction of DA neurons in the VTA. These results suggest a threshold level of DA denervation for both the appearance of motor deficits and LFO units. Thus, the presence of LFO activity in the SNpr is not related to a complete nigrostriatal DA neuron depletion (ultimate stage parkinsonism); instead, it may reflect a functional disruption of cortico-basal ganglia dynamics associated with clinically relevant stages of the disease.
Asunto(s)
Ganglios Basales/fisiología , Dopamina/fisiología , Discinesias/fisiopatología , Animales , Ganglios Basales/citología , Recuento de Células , Desnervación , Electrofisiología , Espacio Extracelular/enzimología , Hidroxidopaminas , Inmunohistoquímica , Masculino , Mesencéfalo/fisiología , Neuronas/fisiología , Ratas , Ratas Sprague-Dawley , Sustancia Negra/patología , Sustancia Negra/fisiología , Simpatectomía Química , Tirosina 3-Monooxigenasa/metabolismo , Área Tegmental Ventral/metabolismo , Área Tegmental Ventral/patologíaRESUMEN
Levodopa, the major treatment for patients with Parkinson's disease, has been shown to induce a variety of compensatory effects, including facilitation of sprouting by dopaminergic neurons, in experimental animals with lesions leading to denervation of the striatum. To better understand the cellular and molecular environment where most of these compensatory changes take place, in particular elements that might contribute to the recovery of dopaminergic innervation, we have constructed a differential expression library enriched in transcripts from the striata of rats with lesions of the medial forebrain bundle treated with levodopa for 6 months. We have used this library to screen an expression array of rat genes representing the major cell functions, and have identified several that are involved in neurotrophic mechanisms and plasticity. We have confirmed the differential expression of selected transcripts by non-radioactive in situ hybridization, and report that the growth factor pleiotrophin, myelin basic protein and calmodulin are overexpressed in the denervated striatum of levodopa-treated rats.
Asunto(s)
Antiparkinsonianos/farmacología , Encefalopatías/metabolismo , Cuerpo Estriado/metabolismo , Expresión Génica/efectos de los fármacos , Levodopa/farmacología , Sustancia Negra/metabolismo , Animales , Conducta Animal , Encefalopatías/inducido químicamente , Calmodulina/genética , Calmodulina/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Recuento de Células/métodos , Cuerpo Estriado/lesiones , Citocinas/genética , Citocinas/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Femenino , Lateralidad Funcional/fisiología , Biblioteca de Genes , Inmunohistoquímica/métodos , Hibridación in Situ/métodos , Glicoproteínas de Membrana/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Proteína Básica de Mielina/genética , Proteína Básica de Mielina/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Oxidopamina , Radioinmunoensayo/métodos , Ratas , Ratas WistarRESUMEN
Although the issue of in vivo levodopa toxicity appears to be settled by now in the light of recent findings, a crucial aspect was not accounted for the experiments designed to tackle that question. Levodopa could in fact be non-toxic on surviving dopamine neurons, but that could not be the case when the drug is administered at the same time those neurons are undergoing degeneration, which is what happens in the clinical setting. Dopaminergic neurons could in that situation be more vulnerable to levodopa's potential toxic action. Our aim was to determine if oral administration of levodopa is toxic for mesencephalic dopaminergic neurons that are actively involved in a degenerative process. We induced delayed retrograde degeneration of the nigrostriatal system in rats by injecting 6-hydroxydopamine (6-OHDA) intrastriatally. Treatment was started the day after the injection. Dopaminergic markers were histologically studied at the striatal and nigral levels, to determine degree of damage of the nigrostriatal dopaminergic system in levodopa- and vehicle-treated rats. No significant differences between levodopa or vehicle-treated rats were found in: (i) striatal immunoautoradiographic labeling for tyrosine hydroxylase (TH) and the membrane dopamine transporter (DAT); (ii) cell counts of TH-immunoreactive (TH-ir) neurons remaining in the substantia nigra and ventral tegmental area (VTA); (iii) surface area of remaining TH-immunoreactive neurons in the substantia nigra. The present experiments demonstrate that levodopa does not enhance delayed retrograde degeneration of dopaminergic neurons induced by intrastriatal administration of 6-OHDA.
Asunto(s)
Antiparkinsonianos/farmacología , Levodopa/farmacología , Degeneración Nerviosa/tratamiento farmacológico , Neuronas/efectos de los fármacos , Administración Oral , Animales , Antiparkinsonianos/administración & dosificación , Modelos Animales de Enfermedad , Dopamina/metabolismo , Femenino , Inmunohistoquímica , Inyecciones Intraventriculares , Levodopa/administración & dosificación , Mesencéfalo/efectos de los fármacos , Mesencéfalo/patología , Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/patología , Neuronas/patología , Oxidopamina/administración & dosificación , Oxidopamina/toxicidad , Trastornos Parkinsonianos/tratamiento farmacológico , Ratas , Ratas Wistar , Factores de Tiempo , Tirosina 3-Monooxigenasa/efectos de los fármacos , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
A high proportion of neurons in the basal ganglia display rhythmic burst firing after chronic nigrostriatal lesions. For instance, the periodic bursts exhibited by certain striatal and subthalamic nucleus neurons in 6-hydroxydopamine-lesioned rats seem to be driven by the approximately 1 Hz high-amplitude rhythm that is prevalent in the cerebral cortex of anaesthetized animals. Because the striatum and subthalamic nucleus are the main afferent structures of the substantia nigra pars reticulata, we examined the possibility that the low-frequency modulations (periodic bursts) that are evident in approximately 50% nigral pars reticulata neurons in the parkinsonian condition were also coupled to this slow cortical rhythm. By recording the frontal cortex field potential simultaneously with single-unit activity in the substantia nigra pars reticulata of anaesthetized rats, we proved the following. (i) The firing of nigral pars reticulata units from sham-lesioned rats is not coupled to the approximately 1 Hz frontal cortex slow oscillation. (ii) Approximately 50% nigral pars reticulata units from 6-hydroxydopamine-lesioned rats oscillate synchronously with the approximately 1 Hz cortical rhythm, with the cortex leading the substantia nigra by approximately 55 ms; the remaining approximately 50% nigral pars reticulata units behave as the units recorded from sham-lesioned rats. (iii) Periodic bursting in nigral pars reticulata units from 6-hydroxydopamine-lesioned rats is disrupted by episodes of desynchronization of cortical field potential activity. Our results strongly support that nigrostriatal lesions promote the spreading of low-frequency cortical rhythms to the substantia nigra pars reticulata and may be of outstanding relevance for understanding the pathophysiology of Parkinson's disease.
Asunto(s)
Sincronización Cortical , Vías Nerviosas/fisiología , Neuronas/fisiología , Sustancia Negra/fisiología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Adrenérgicos/farmacología , Animales , Ganglios Basales/fisiología , Modelos Animales de Enfermedad , Estimulación Eléctrica , Masculino , Vías Nerviosas/efectos de los fármacos , Neuronas/efectos de los fármacos , Oxidopamina/farmacología , Trastornos Parkinsonianos/fisiopatología , Ratas , Ratas Sprague-Dawley , Sustancia Negra/efectos de los fármacosRESUMEN
In anaesthetised animals, the very negative resting membrane potential of striatal spiny neurones (down state) is interrupted periodically by depolarising plateaux (up states) which are probably driven by excitatory input. In the absence of active synaptic input, as occurs in vitro, potassium currents hold the membrane potential of striatal spiny neurones in the down state. Because striatal spiny neurones fire action potentials only during the up state, these plateau depolarisations have been perceived as enabling events that allow information processing through cerebral cortex-basal ganglia circuits. Recent studies have demonstrated that the robust membrane potential fluctuation of spiny neurones is strongly correlated to the slow electroencephalographic rhythms that are typical of slow wave sleep and anaesthesia. To further understand the impact of cortical activity states on striatal function, we studied the membrane potential of striatal neurones during cortical desynchronised states. Simultaneous in vivo recordings of striatal neurones and the electrocorticogram in urethane-anaesthetised rats revealed that rhythmic alternation between up and down states was disrupted during episodes of spontaneous or induced cortical desynchronisation. Instead of showing robust two-state fluctuations, the membrane potential of striatal neurones displayed a persisting depolarised state with fast, low-amplitude modulations. Spiny neurones remained in this persistent up state until the cortex resumed ~1 Hz synchronous activity. Most of the recorded neurones exhibited a low firing probability, irrespective of the cortical activity state. Time series analysis failed to reveal significant correlations between the membrane potential of striatal neurones and the desynchronised electrocorticogram. Our results suggest that during cortical desynchronisation continuous uncorrelated excitatory input sustains the membrane potential of striatal neurones in a persisting depolarised state, but that substantial additional input is necessary to impel the neurones to threshold. Our data support that the prevailing cortical activity state determines the duration of the enabling depolarising events that take place in striatal spiny neurones.