RESUMO
Excessive oscillatory activity across basal ganglia (BG) nuclei in the ß frequencies (12-30 Hz) is a hallmark of Parkinson's disease (PD). While the link between oscillations and symptoms remains debated, exaggerated ß oscillations constitute an important biomarker for therapeutic effectiveness in PD. The neuronal mechanisms of ß-oscillation generation however remain unknown. Many existing models rely on a central role of the subthalamic nucleus (STN) or cortical inputs to BG. Contrarily, neural recordings and optogenetic manipulations in normal and parkinsonian rats recently highlighted the central role of the external pallidum (GPe) in abnormal ß oscillations, while showing that the integrity of STN or motor cortex is not required. Here, we evaluate the mechanisms for the generation of abnormal ß oscillations in a BG network model where neuronal and synaptic time constants, connectivity, and firing rate distributions are strongly constrained by experimental data. Guided by a mean-field approach, we show in a spiking neural network that several BG sub-circuits can drive oscillations. Strong recurrent STN-GPe connections or collateral intra-GPe connections drive γ oscillations (>40 Hz), whereas strong pallidostriatal loops drive low-ß (10-15 Hz) oscillations. We show that pathophysiological strengthening of striatal and pallidal synapses following dopamine depletion leads to the emergence of synchronized oscillatory activity in the mid-ß range with spike-phase relationships between BG neuronal populations in-line with experiments. Furthermore, inhibition of GPe, contrary to STN, abolishes oscillations. Our modeling study uncovers the neural mechanisms underlying PD ß oscillations and may thereby guide the future development of therapeutic strategies.
Assuntos
Doença de Parkinson , Núcleo Subtalâmico , Ratos , Animais , Gânglios da Base/fisiologia , Globo Pálido/fisiologia , Neurônios/fisiologia , Ritmo beta/fisiologiaRESUMO
UNLABELLED: Absence seizures are characterized by brief interruptions of conscious experience accompanied by oscillations of activity synchronized across many brain areas. Although the dynamics of the thalamocortical circuits are traditionally thought to underlie absence seizures, converging experimental evidence supports the key involvement of the basal ganglia (BG). In this theoretical work, we argue that the BG are essential for the maintenance of absence seizures. To this end, we combine analytical calculations with numerical simulations to investigate a computational model of the BG-thalamo-cortical network. We demonstrate that abnormally strong striatal feedforward inhibition can promote synchronous oscillatory activity that persists in the network over several tens of seconds as observed during seizures. We show that these maintained oscillations result from an interplay between the negative feedback through the cortico-subthalamo-nigral pathway and the striatal feedforward inhibition. The negative feedback promotes epileptic oscillations whereas the striatal feedforward inhibition suppresses the positive feedback provided by the cortico-striato-nigral pathway. Our theory is consistent with experimental evidence regarding the influence of BG on seizures (e.g., with the fact that a pharmacological blockade of the subthalamo-nigral pathway suppresses seizures). It also accounts for the observed strong suppression of the striatal output during seizures. Our theory predicts that well-timed transient excitatory inputs to the cortex advance the termination of absence seizures. In contrast with the thalamocortical theory, it also predicts that reducing the synaptic transmission along the cortico-subthalamo-nigral pathway while keeping constant the average firing rate of substantia nigra pars reticulata reduces the incidence of seizures. SIGNIFICANCE STATEMENT: Absence seizures are characterized by brief interruptions of consciousness accompanied by abnormal brain oscillations persisting tens of seconds. Thalamocortical circuits are traditionally thought to underlie absence seizures. However, recent experiments have highlighted the key role of the basal ganglia (BG). This work argues for a novel theory according to which the BG drive the oscillatory patterns of activity occurring during the seizures. It demonstrates that abnormally strong striatal feedforward inhibition promotes synchronous oscillatory activity in the BG-thalamo-cortical network and relate this property to the observed strong suppression of the striatal output during seizures. The theory is compatible with virtually all known experimental results, and it predicts that well-timed transient excitatory inputs to the cortex advance the termination of absence seizures.
Assuntos
Corpo Estriado/fisiologia , Epilepsia Tipo Ausência/patologia , Modelos Neurológicos , Vias Neurais/fisiologia , Córtex Somatossensorial/fisiologia , Potenciais de Ação/fisiologia , Animais , Gânglios da Base/fisiologia , Simulação por Computador , Estimulação Elétrica , Epilepsia Tipo Ausência/fisiopatologia , Humanos , Transmissão SinápticaRESUMO
When a perturbation is applied in a sensorimotor transformation task, subjects can adapt and maintain performance by either relying on sensory feedback, or, in the absence of such feedback, on information provided by rewards. For example, in a classical rotation task where movement endpoints must be rotated to reach a fixed target, human subjects can successfully adapt their reaching movements solely on the basis of binary rewards, although this proves much more difficult than with visual feedback. Here, we investigate such a reward-driven sensorimotor adaptation process in a minimal computational model of the task. The key assumption of the model is that synaptic plasticity is gated by the reward. We study how the learning dynamics depend on the target size, the movement variability, the rotation angle and the number of targets. We show that when the movement is perturbed for multiple targets, the adaptation process for the different targets can interfere destructively or constructively depending on the similarities between the sensory stimuli (the targets) and the overlap in their neuronal representations. Destructive interferences can result in a drastic slowdown of the adaptation. As a result of interference, the time to adapt varies non-linearly with the number of targets. Our analysis shows that these interferences are weaker if the reward varies smoothly with the subject's performance instead of being binary. We demonstrate how shaping the reward or shaping the task can accelerate the adaptation dramatically by reducing the destructive interferences. We argue that experimentally investigating the dynamics of reward-driven sensorimotor adaptation for more than one sensory stimulus can shed light on the underlying learning rules.
Assuntos
Adaptação Fisiológica/fisiologia , Retroalimentação Sensorial , Desempenho Psicomotor/fisiologia , Recompensa , Algoritmos , Fenômenos Biomecânicos , Encéfalo/fisiologia , Biologia Computacional , Simulação por Computador , Humanos , Aprendizagem , Modelos Neurológicos , Movimento , Plasticidade Neuronal , Neurônios/fisiologia , Reprodutibilidade dos Testes , Rotação , Sinapses/fisiologiaRESUMO
The activity of midbrain dopaminergic neurons and their projection to the basal ganglia (BG) are thought to play a critical role in the acquisition of motor skills through reinforcement learning, as well as in the expression of learned motor behaviors. The precise role of BG dopamine (DA) in mediating and modulating motor performance and learning, however, remains unclear. In songbirds, a specialized portion of the BG is responsible for song learning and plasticity. Previously we found that DA acts on D1 receptors in Area X to modulate the BG output signal and thereby trigger changes in song variability. Here, we investigate the effect of D1 receptor blockade in the BG on song behavior in the zebra finch. We report that this manipulation abolishes social context-dependent changes in variability not only in harmonic stacks, but also in other types of syllables. However, song timing seems not to be modulated by this BG DA signal. Indeed, injections of a D1 antagonist in the BG altered neither song duration nor the change of song duration with social context. Finally, D1 receptor activation in the BG was not necessary for the modulation of other features of song, such as the number of introductory notes or motif repetitions. Together, our results suggest that activation of D1 receptors in the BG is necessary for the modulation of fine acoustic features of song with social context, while it is not involved in the regulation of song timing and structure at a larger time scale.
Assuntos
Corpo Estriado/fisiologia , Dopamina/fisiologia , Tentilhões/fisiologia , Receptores de Dopamina D1/fisiologia , Vocalização Animal/fisiologia , Animais , Benzazepinas/farmacologia , Condicionamento Psicológico/fisiologia , Corpo Estriado/citologia , Corte , Neurônios Dopaminérgicos/fisiologia , Masculino , Receptores de Dopamina D1/antagonistas & inibidores , Espectrografia do Som/métodos , Percepção do Tempo/efeitos dos fármacos , Percepção do Tempo/fisiologia , Vocalização Animal/efeitos dos fármacosRESUMO
The plasticity of nervous systems allows animals to quickly adapt to a changing environment. In particular, the structural plasticity of brain networks is often critical to the development of the central nervous system and the acquisition of complex behaviors. As an example, structural plasticity is central to the development of song-related brain circuits and may be critical for song acquisition in juvenile songbirds. Here, we review current evidences for structural plasticity and their significance from a computational point of view. We start by reviewing evidence for structural plasticity across species and categorizing them along the spatial axes as well as the along the time course during development. We introduce the vocal learning circuitry in zebra finches, as a useful example of structural plasticity, and use this specific case to explore the possible contributions of structural plasticity to computational models. Finally, we discuss current modeling studies incorporating structural plasticity and unexplored questions which are raised by such models.
Assuntos
Tentilhões , Aves Canoras , Adaptação Fisiológica , Animais , Encéfalo/fisiologia , Tentilhões/fisiologia , Plasticidade Neuronal/fisiologia , Aves Canoras/fisiologia , Vocalização Animal/fisiologiaRESUMO
Cortico-basal ganglia (BG) circuits are thought to promote the acquisition of motor skills through reinforcement learning. In songbirds, a specialized portion of the BG is responsible for song learning and plasticity. This circuit generates song variability that underlies vocal experimentation in young birds and modulates song variability depending on the social context in adult birds. When male birds sing in the presence of a female, a social context associated with decreased BG-induced song variability, the extracellular dopamine (DA) level is increased in the avian BG nucleus Area X. These results suggest that DA could trigger song variability changes through its action in Area X. Consistent with this hypothesis, we report that DA delivered to Area X weakens the output signal of the avian cortico-BG circuit. Acting through D(1) receptors, DA reduced responses in Area X to song playback and to electrical stimulation of its afferent cortical nucleus HVC (used as a proper name). Specifically, DA reduced the response to direct excitatory input and decreased firing variability in Area X pallidal neurons, which provide the output to the thalamus. As a consequence, DA delivery in Area X also decreased responses to song playback in the cortical output nucleus of the BG loop, the lateral magnocellular nucleus of the anterior nidopallium. Further, interfering with D(1) receptor transmission in Area X abolished social context-related changes in song variability. In conclusion, we propose that DA acts on D(1) receptors in Area X to modulate the BG output signal and trigger changes in song variability.
Assuntos
Gânglios da Base/fisiologia , Comportamento Animal/fisiologia , Corpo Estriado/fisiologia , Receptores de Dopamina D1/fisiologia , Meio Social , Vocalização Animal/fisiologia , Estimulação Acústica/métodos , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Gânglios da Base/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Dopamina/farmacologia , Estimulação Elétrica/métodos , Tentilhões , Masculino , Receptores de Dopamina D1/agonistas , Vocalização Animal/efeitos dos fármacosRESUMO
Avian song learning shares striking similarities with human speech acquisition and requires a basal ganglia (BG)-thalamo-cortical circuit. Information processing and transmission speed in the BG is thought to be limited by synaptic architecture of two serial inhibitory connections. Propagation speed may be critical in the avian BG circuit given the temporally precise control of musculature during vocalization. We used electrical stimulation of the cortical inputs to the BG to study, with fine time resolution, the functional connectivity within this network. We found that neurons in thalamic and cortical nuclei that are not directly connected with the stimulated area can respond to the stimulation with extremely short latencies. Through pharmacological manipulations, we trace this property back to the BG and show that the cortical stimulation triggers fast disinhibition of the thalamic neurons. Surprisingly, feedforward inhibition mediated by striatal inhibitory neurons onto BG output neurons sometimes precedes the monosynaptic excitatory drive from cortical afferents. The fast feedforward inhibition lengthens a single interspike interval in BG output neurons by just a few milliseconds. This short delay is sufficient to drive a strong, brief increase in firing probability in the target thalamic neurons, evoking short-latency responses. By blocking glutamate receptors in vivo, we show that thalamic responses do not appear to rely on excitatory drive, and we show in a theoretical model that they could be mediated by postinhibitory rebound properties. Such fast signaling through disinhibition and rebound may be a crucial specialization for learning of rapid and temporally precise motor acts such as vocal communication.
Assuntos
Gânglios da Base/fisiologia , Inibição Neural/fisiologia , Neurônios/fisiologia , Transmissão Sináptica/fisiologia , Potenciais de Ação , Animais , Córtex Cerebral/fisiologia , Estimulação Elétrica , Tentilhões , Masculino , Modelos Neurológicos , Vias Neurais/fisiologia , Probabilidade , Receptores de Glutamato/metabolismo , Tálamo/fisiologia , Fatores de TempoRESUMO
Dystonia is a heterogeneous syndrome of movement disorders characterized by involuntary muscle contractions leading to abnormal movements and postures. While medical treatment is often ineffective, deep brain stimulation (DBS) of the internal pallidum improves dystonia. Here, we studied the impact of DBS in the entopeduncular nucleus (EP), the rodent equivalent of the human globus pallidus internus, on basal ganglia output in the dt(sz)-hamster, a well-characterized model of dystonia by extracellular recordings. Previous work has shown that EP-DBS improves dystonic symptoms in dt(sz)-hamsters. We report that EP-DBS changes firing pattern in the EP, most neurons switching to a less regular firing pattern during DBS. In contrast, EP-DBS did not change the average firing rate of EP neurons. EP neurons display multiphasic responses to each stimulation impulse, likely underlying the disruption of their firing rhythm. Finally, neurons in the substantia nigra pars reticulata display similar responses to EP-DBS, supporting the idea that EP-DBS affects basal ganglia output activity through the activation of common afferent fibers.
Assuntos
Potenciais de Ação/fisiologia , Gânglios da Base/fisiopatologia , Distonia/fisiopatologia , Neurônios/fisiologia , Análise de Variância , Animais , Cricetinae , Estimulação Encefálica Profunda , Eletrodos Implantados , Eletrofisiologia , Núcleo Entopeduncular/fisiopatologia , Feminino , Masculino , Processamento de Sinais Assistido por Computador , Substância Negra/fisiopatologiaRESUMO
The dynamical properties of cortico-basal ganglia (CBG) circuits are dramatically altered following the loss of dopamine in Parkinson's disease (PD). The neural circuit dysfunctions associated with PD include spike-rate alteration concomitant with excessive oscillatory spike-synchronization in the beta frequency range (12-30 Hz). Which neuronal circuits orchestrate and propagate these abnormal neural dynamics in CBG remains unknown. In this work, we combine in vivo electrophysiological recordings with advanced optogenetic manipulations in normal and 6-OHDA rats to shed light on the mechanistic principle underlying circuit dysfunction in PD. Our results show that abnormal neural dynamics present in a rat model of PD do not rely on cortical or subthalamic nucleus activity but critically dependent on globus pallidus (GP) integrity. Our findings highlight the pivotal role played by the GP which operates as a hub nucleus capable of orchestrating firing rate and synchronization changes across CBG circuits both in normal and pathological conditions.
Assuntos
Globo Pálido/fisiopatologia , Rede Nervosa/fisiopatologia , Transtornos Parkinsonianos/fisiopatologia , Potenciais de Ação/fisiologia , Animais , Gânglios da Base/fisiopatologia , Ritmo beta , Modelos Animais de Doenças , Córtex Motor/fisiopatologia , Neurônios/metabolismo , Optogenética , Oxidopamina , Ratos , Núcleo Subtalâmico/fisiopatologiaRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Striatal cholinergic interneurons (CINs) are the main source of acetylcholine in the striatum and are believed to play an important role in basal ganglia physiology and pathophysiology. The role of CINs in striatal function is known mostly from extracellular recordings of tonically active striatal neurons in monkeys, which are believed to correspond to CINs. Because these neurons transiently respond to motivationally cues with brief pauses, flanked by bursts of increased activity, they are classically viewed as key players in reward-related learning. However, CIN modulatory function within the striatal network has been mainly inferred from the action of acetylcholine agonists/antagonists or through CIN activation. These manipulations are far from recapitulating CIN activity in response to behaviorally-relevant stimuli. New technical tools such as optogenetics allow researchers to specifically manipulate this sparse neuronal population and to mimic their typical pause response. For example, it is now possible to investigate how short inhibition of CIN activity shapes striatal properties. Here, we review the most recent literature and show how these new techniques have brought considerable insights into the functional role of CINs in normal and pathological states, raising several interesting and novel questions. To continue moving forward, it is crucial to determine in detail CIN activity changes during behavior, particularly in rodents. We will also discuss how computational approaches combined with optogenetics will contribute to further our understanding of the CIN role in striatal circuits.
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The dorsal pallium (a.k.a. cortex in mammals) makes a loop circuit with the basal ganglia and the thalamus known to control and adapt behavior but the who's who of the functional roles of these structures is still debated. Influenced by the Triune brain theory that was proposed in the early sixties, many current theories propose a hierarchical organization on the top of which stands the cortex to which the subcortical structures are subordinated. In particular, habits formation has been proposed to reflect a switch from conscious on-line control of behavior by the cortex, to a fully automated subcortical control. In this review, we propose to revalue the function of the network in light of the current experimental evidence concerning the anatomy and physiology of the basal ganglia-cortical circuits in vertebrates. We briefly review the current theories and show that they could be encompassed in a broader framework of skill learning and performance. Then, after reminding the state of the art concerning the anatomical architecture of the network and the underlying dynamic processes, we summarize the evolution of the anatomical and physiological substrate of skill learning and performance among vertebrates. We then review experimental evidence supporting for the hypothesis that the development of automatized skills relies on the BG teaching cortical circuits and is actually a late feature linked with the development of a specialized cortex or pallium that evolved in parallel in different taxa. We finally propose a minimal computational framework where this hypothesis can be explicitly implemented and tested.
Assuntos
Córtex Cerebral/fisiologia , Aprendizagem/fisiologia , Destreza Motora/fisiologia , Vias Neurais/fisiologia , Animais , HumanosRESUMO
Speech is a complex sensorimotor skill, and vocal learning involves both the basal ganglia and the cerebellum. These subcortical structures interact indirectly through their respective loops with thalamo-cortical and brainstem networks, and directly via subcortical pathways, but the role of their interaction during sensorimotor learning remains undetermined. While songbirds and their song-dedicated basal ganglia-thalamo-cortical circuitry offer a unique opportunity to study subcortical circuits involved in vocal learning, the cerebellar contribution to avian song learning remains unknown. We demonstrate that the cerebellum provides a strong input to the song-related basal ganglia nucleus in zebra finches. Cerebellar signals are transmitted to the basal ganglia via a disynaptic connection through the thalamus and then conveyed to their cortical target and to the premotor nucleus controlling song production. Finally, cerebellar lesions impair juvenile song learning, opening new opportunities to investigate how subcortical interactions between the cerebellum and basal ganglia contribute to sensorimotor learning.
Assuntos
Gânglios da Base/fisiologia , Cerebelo/fisiologia , Córtex Cerebral/fisiologia , Tentilhões/fisiologia , Aprendizagem , Vias Neurais/fisiologia , Tálamo/fisiologia , Vocalização Animal/fisiologia , Animais , Estimulação Encefálica Profunda , Vias Neurais/anatomia & histologia , Neurônios/fisiologia , Fonética , Células de Purkinje/metabolismo , Espectrografia do Som , Sinapses/fisiologia , Fatores de TempoRESUMO
Experiments performed in normal animals suggest that the basal ganglia (BG) are crucial in motor program selection. BG are also involved in movement disorders. In particular, BG neuronal activity in parkinsonian animals and patients is more oscillatory and more synchronous than in normal individuals. We propose a new model for the function and dysfunction of the motor part of BG. We hypothesize that the striatum, the subthalamic nucleus, the internal pallidum (GPi), the thalamus, and the cortex are involved in closed feedback loops. The direct (cortex-striatum-GPi-thalamus-cortex) and the hyperdirect loops (cortex-subthalamic nucleus-GPi-thalamus-cortex), which have different polarities, play a key role in the model. We show that the competition between these two loops provides the BG-cortex system with the ability to perform motor program selection. Under the assumption that dopamine potentiates corticostriatal synaptic transmission, we demonstrate that, in our model, moderate dopamine depletion leads to a complete loss of action selection ability. High depletion can lead to synchronous oscillations. These modifications of the network dynamical state stem from an imbalance between the feedback in the direct and hyperdirect loops when dopamine is depleted. Our model predicts that the loss of selection ability occurs before the appearance of oscillations, suggesting that Parkinson's disease motor impairments are not directly related to abnormal oscillatory activity. Another major prediction of our model is that synchronous oscillations driven by the hyperdirect loop appear in BG after inactivation of the striatum.
Assuntos
Gânglios da Base/fisiologia , Relógios Biológicos , Modelos Neurológicos , Movimento , Rede Nervosa/fisiopatologia , Vias Neurais/fisiopatologia , Doença de Parkinson/fisiopatologia , Potenciais de Ação , Animais , Encéfalo/fisiopatologia , Simulação por Computador , Dopamina/metabolismo , Retroalimentação , Humanos , Inibição Neural , NeurôniosRESUMO
The plasticity of nervous systems allows animals to quickly adapt to a changing environment. In particular, seasonal plasticity of brain structure and behavior is often critical to survival or mating in seasonal climates. Songbirds provide striking examples of seasonal changes in neural circuits and vocal behavior and have emerged as a leading model for adult brain plasticity. While seasonal plasticity and the well-characterized process of juvenile song learning may share common neural mechanisms, the extent of their similarity remains unclear. Especially, it is unknown whether the basal ganglia (BG)-forebrain loop which implements song learning in juveniles by driving vocal exploration participates in seasonal plasticity. To address this issue, we performed bilateral lesions of the output structure of the song-related BG-forebrain circuit (the magnocellular nucleus of the anterior nidopallium) in canaries during the breeding season, when song is most stereotyped, and just after resuming singing in early fall, when canaries sing their most variable songs and may produce new syllable types. Lesions drastically reduced song acoustic variability, increased song and phrase duration, and decreased syntax variability in early fall, reverting at least partially seasonal changes observed between the breeding season and early fall. On the contrary, lesions did not affect singing behavior during the breeding season. Our results therefore indicate that the BG-forebrain pathway introduces acoustic and syntactic variability in song when canaries resume singing in early fall. We propose that BG-forebrain circuits actively participate in seasonal plasticity by injecting variability in behavior during non-breeding season. SIGNIFICANCE STATEMENT: The study of seasonal plasticity in temperate songbirds has provided important insights into the mechanisms of structural and functional plasticity in the central nervous system. The precise function and mechanisms of seasonal song plasticity however remain poorly understood. We show here that a basal ganglia-forebrain circuit involved in the acquisition and maintenance of birdsong is actively inducing song variability outside the breeding season, when singing is most variable, while having little effect on the stereotyped singing during the breeding season. Our results suggest that seasonal plasticity reflects an active song-maintenance process akin to juvenile learning, and that basal ganglia-forebrain circuits can drive plasticity in a learned vocal behavior during the non-injury-induced degeneration and reconstruction of the neural circuit underlying its production.
Assuntos
Gânglios da Base/fisiologia , Plasticidade Neuronal , Prosencéfalo/fisiologia , Vocalização Animal , Animais , Canários , Masculino , Atividade Motora , Vias Neurais/fisiologia , Estações do Ano , Processamento de Sinais Assistido por Computador , Espectrografia do SomRESUMO
The ability to generate variable movements is essential for learning and adjusting complex behaviours. This variability has been linked to the temporal irregularity of neuronal activity in the central nervous system. However, how neuronal irregularity actually translates into behavioural variability is unclear. Here we combine modelling, electrophysiological and behavioural studies to address this issue. We demonstrate that a model circuit comprising topographically organized and strongly recurrent neural networks can autonomously generate irregular motor behaviours. Simultaneous recordings of neurons in singing finches reveal that neural correlations increase across the circuit driving song variability, in agreement with the model predictions. Analysing behavioural data, we find remarkable similarities in the babbling statistics of 5-6-month-old human infants and juveniles from three songbird species and show that our model naturally accounts for these 'universal' statistics.
Assuntos
Canários/fisiologia , Tentilhões/fisiologia , Rede Nervosa , Neurônios/fisiologia , Pardais/fisiologia , Comportamento Verbal/fisiologia , Vocalização Animal/fisiologia , Animais , Sistema Nervoso Central , Feminino , Humanos , Lactente , Aprendizagem/fisiologia , Masculino , Modelos Neurológicos , Destreza Motora , Vias Neurais/fisiologiaRESUMO
High frequency stimulation (HFS) of the subthalamic nucleus (STN) is a well-established therapeutic approach for the treatment of late-stage Parkinson's disease. Although the underlying cause of this illness remains a mystery, changes in firing rate and synchronized activity in different basal ganglia nuclei have been related to its symptoms. Here we investigated the impact of STN-HFS on firing rate as well as correlated and oscillatory activity in the STN network in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned non-human primates by using simultaneous extracellular single-unit recordings. STN-HFS reduced (i) the firing rate of STN neurons, (ii) the oscillatory activity at an individual STN neuron level as well as (iii) the correlated and oscillatory activity between pairs of STN neurons, while contralateral rigidity was improved. A detailed analysis showed that the decrease of mean firing rate resulted from the resetting of firing probability to virtually zero by the stimulus pulse. Subsequently, STN neurons resumed their activity after a mean duration of 2.9 +/- 0.1 ms and their firing probability returned to baseline values approximately 7 ms after the onset of the stimulus pulse, the recovery of the firing probability being represented by a sigmoid function. Thus, the overall decrease of the mean firing rate resulted from the repetition of this dynamical process with a frequency of 130 Hz (interstimulus interval approximately 7.7 ms), allowing the neuron to fire with its baseline firing rate only for a very short period. Although the mechanisms underlying the desynchronization of neuronal activity in the STN network remain unclear, the resetting of STN neuron firing probability by the electrical stimulus would rather be expected to increase oscillatory activity at an individual neuron level as well as correlated and oscillatory activity between pairs of STN neurons. However, assuming the resetting of firing rate to be the consequence of a transient GABAergic inhibition through excitation of presynaptic GABAergic axon terminals, different recovery periods of STN neurons might delay the appearance of synchronized oscillations, particularly if they are not generated locally. In conclusion, our study provides new evidence that STN-HFS decreases oscillatory activity in the STN network. Although the exact relation between oscillatory activity and Parkinson's disease symptoms remains to be determined, the present results suggest that STN-HFS might at least partially exert its beneficial effects through the reduction of oscillatory activity in the STN network and consequently in the entire cortex-basal ganglia-cortex network.
Assuntos
Estimulação Elétrica/métodos , Núcleo Subtalâmico/fisiologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Potenciais de Ação/fisiologia , Animais , Feminino , Macaca mulatta , Neurônios/fisiologia , Neurotoxinas , Doença de Parkinson/fisiopatologia , Ácido gama-Aminobutírico/fisiologiaRESUMO
Dysfunction of the dopaminergic system leads to motor, cognitive, and motivational symptoms in brain disorders such as Parkinson's disease. The basal ganglia (BG) are involved in sensorimotor learning and receive a strong dopaminergic signal, shown to play an important role in social interactions. The function of the dopaminergic input to the BG in the integration of social cues during sensorimotor learning remains however largely unexplored. Songbirds use learned vocalizations to communicate during courtship and aggressive behaviors. Like language learning in humans, song learning strongly depends on social interactions. In songbirds, a specialized BG-thalamo-cortical loop devoted to song is particularly tractable for elucidating the signals carried by dopamine in the BG, and the function of dopamine signaling in mediating social cues during skill learning and execution. Here, I review experimental findings uncovering the physiological effects and function of the dopaminergic signal in the songbird BG, in light of our knowledge of the BG-dopamine interactions in mammals. Interestingly, the compact nature of the striato-pallidal circuits in birds led to new insight on the physiological effects of the dopaminergic input on the BG network as a whole. In singing birds, D1-like receptor agonist and antagonist can modulate the spectral variability of syllables bi-directionally, suggesting that social context-dependent changes in spectral variability are triggered by dopaminergic input through D1-like receptors. As variability is crucial for exploration during motor learning, but must be reduced after learning to optimize performance, I propose that, the dopaminergic input to the BG could be responsible for the social-dependent regulation of the exploration/exploitation balance in birdsong, and possibly in learned skills in other vertebrates.
Assuntos
Gânglios da Base/metabolismo , Dopamina/metabolismo , Aprendizagem/fisiologia , Comportamento Social , Vocalização Animal/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Gânglios da Base/citologia , Gânglios da Base/efeitos dos fármacos , Dopamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Aprendizagem/efeitos dos fármacos , Aves Canoras , Vocalização Animal/efeitos dos fármacosRESUMO
While high-frequency stimulation of the subthalamic nucleus (STN-HFS) is highly effective in the treatment of Parkinson's disease (PD), the mechanisms underlying its therapeutic action remain unclear. Here, we report changes of single-neuron pallidal activity during STN-HFS in a parkinsonian patient. STN-HFS increased firing rate in both segments of the pallidum. Neurons displayed time-locked responses to stimulation pulses, with an early excitation followed by inhibition and late excitation. Finally, pallidal neurons fired more regularly during STN-HFS. The time-locked responses and increased firing regularity may override abnormally patterned pallidal activity, and thereby significantly contribute to the clinical efficacy of STN-HFS in PD.