Evidence for a task-dependent switch in subthalamo-nigral basal ganglia signaling.
ABSTRACT: Basal ganglia (BG) can either facilitate or inhibit movement through excitatory and inhibitory pathways; however whether these opposing signals are dynamically regulated during healthy behavior is not known. Here, we present compelling neurophysiological evidence from three complimentary experiments in non-human primates, indicating task-specific changes in tonic BG pathway weightings during saccade behavior with different cognitive demands. First, simultaneous local field potential recording in the subthalamic nucleus (STN; BG input) and substantia nigra pars reticulata (SNr; BG output) reveals task-dependent shifts in subthalamo-nigral signals. Second, unilateral electrical stimulation of the STN, SNr, and caudate nucleus results in strikingly different saccade directionality and latency biases across the BG. Third, a simple artificial neural network representing canonical BG signaling pathways suggests that pathway weightings can be altered by cortico-BG input activation. Overall, inhibitory pathways (striato-pallidal-subthalamo-nigral) dominate during goal-driven behavior with instructed rewards, while facilitatory pathways (striato-nigral and subthalamo-pallidal-nigral) dominate during unconstrained (free reward) conditions.
Project description:BACKGROUND:The substantia nigra pars reticulata (SNr) is a major output nucleus of the basal ganglia, delivering inhibitory efferents to the relay nuclei of the thalamus. Pathological hyperactivity of SNr neurons is known to be responsible for some motor disorders e.g. in Parkinson's disease. One way to restore this pathological activity is to electrically stimulate one of the SNr input, the excitatory subthalamic nucleus (STN), which has emerged as an effective treatment for parkinsonian patients. The neuronal network and signal processing of the basal ganglia are well known but, paradoxically, the role of astrocytes in the regulation of SNr activity has never been studied. PRINCIPAL FINDINGS:In this work, we developed a rat brain slice model to study the influence of spontaneous and induced excitability of afferent nuclei on SNr astrocytes calcium activity. Astrocytes represent the main cellular population in the SNr and display spontaneous calcium activities in basal conditions. Half of this activity is autonomous (i.e. independent of synaptic activity) while the other half is dependent on spontaneous glutamate and GABA release, probably controlled by the pace-maker activity of the pallido-nigral and subthalamo-nigral loops. Modification of the activity of the loops by STN electrical stimulation disrupted this astrocytic calcium excitability through an increase of glutamate and GABA releases. Astrocytic AMPA, mGlu and GABA(A) receptors were involved in this effect. SIGNIFICANCE:Astrocytes are now viewed as active components of neural networks but their role depends on the brain structure concerned. In the SNr, evoked activity prevails and autonomous calcium activity is lower than in the cortex or hippocampus. Our data therefore reflect a specific role of SNr astrocytes in sensing the STN-GPe-SNr loops activity and suggest that SNr astrocytes could potentially feedback on SNr neuronal activity. These findings have major implications given the position of SNr in the basal ganglia network.
Project description:Dual probe microdialysis was used to investigate whether GluN2A and GluN2B NMDA receptor subunits regulate striatal output pathways under dyskinetic conditions. The preferential GluN2A antagonist NVP-AAM077 perfused in the dopamine-depleted striatum of 6-hydroxydopamine hemilesioned dyskinetic rats reduced GABA and glutamate levels in globus pallidus whereas the selective GluN2B antagonist Ro 25-6981 elevated glutamate without affecting pallidal GABA. Moreover, intrastriatal NVP-AAM077 did not affect GABA but elevated glutamate levels in substantia nigra reticulata whereas Ro 25-6981 elevated GABA and reduced nigral glutamate. To investigate whether GluN2A and GluN2B NMDA receptor subunits are involved in motor pathways underlying dyskinesia expression, systemic NVP-AAM077 and Ro 25-6981 were tested for their ability to attenuate levodopa-induced abnormal involuntary movements. NVP-AAM077 failed to prevent dyskinesia while Ro 25-6981 mildly attenuated it. We conclude that in the dyskinetic striatum, striatal GluN2A subunits tonically stimulate the striato-pallidal pathway whereas striatal GluN2B subunits tonically inhibit striato-nigral projections. Moreover, GluN2A subunits are not involved in dyskinesia expression whereas GluN2B subunits minimally contribute to it.
Project description:The motor symptoms of Parkinson's disease (PD) are linked to abnormally correlated and coherent activity in the cortex and subthalamic nucleus (STN). However, in parkinsonian mice we found that cortico-STN transmission strength had diminished by 50%-75% through loss of axo-dendritic and axo-spinous synapses, was incapable of long-term potentiation, and less effectively patterned STN activity. Optogenetic, chemogenetic, genetic, and pharmacological interrogation suggested that downregulation of cortico-STN transmission in PD mice was triggered by increased striato-pallidal transmission, leading to disinhibition of the STN and increased activation of STN NMDA receptors. Knockdown of STN NMDA receptors, which also suppresses proliferation of GABAergic pallido-STN inputs in PD mice, reduced loss of cortico-STN transmission and patterning and improved motor function. Together, the data suggest that loss of dopamine triggers a maladaptive shift in the balance of synaptic excitation and inhibition in the STN, which contributes to parkinsonian activity and motor dysfunction.
Project description:The dynamics of the subthalamo-pallidal complex in Parkinson's disease during deep brain stimulation (DBS) were studied using two models, a simple firing-rate model and a population-based model. We extended the simple firing-rate model of the complex formed by the subthalamic nucleus (STN) and the external segment of the Globus Pallidus (GPe) to explore its dynamical regime during DBS. More specifically, the modulation of neuronal activity (i.e., pattern and amplitude) during DBS was studied. A similar approach was used with the population-based model. Simulation results revealed a gradual decrease in bursting activity in STN cells when the DBS frequency increased. In addition, the contribution of the stimulation current type (mono- or biphasic) to the results was also examined. A comparison of the two models indicated that the population-based model was more biologically realistic and more appropriate for exploring DBS mechanisms. Understanding the underlying mechanisms of DBS is a prerequisite for developing new stimulation protocols.
Project description:BACKGROUND AND PURPOSE:In the sensorimotor (SM) and medial prefrontal (mPF) basal ganglia (BG) circuits, the cortical information is transferred to the substantia nigra pars reticulata (SNr) through the hyperdirect trans-subthalamic pathway and through the direct and indirect trans-striatal pathways. The cannabinoid CB1 receptor, which is highly expressed in both BG circuits, may participate in the regulation of motor and motivational behaviours. Here, we investigated the modulation of cortico-nigral information transmission through the BG circuits by cannabinoids. EXPERIMENTAL APPROACH:We used single-unit recordings of SNr neurons along with simultaneous electrical stimulation of motor or mPF cortex in anaesthetized rats. KEY RESULTS:Cortical stimulation elicited a triphasic response in the SNr neurons from both SM and mPF-BG circuits, which consisted of an early excitation (hyperdirect transmission pathway), an inhibition (direct transmission pathway), and a late excitation (indirect transmission pathway). In the SM circuit, after ?9 -tetrahydrocannabinol or WIN 55,212-2 administration, the inhibition and the late excitation were decreased or completely lost, whereas the early excitation response remained unaltered. However, cannabinoid administration dramatically decreased all the responses in the mPF circuit. The CB1 receptor antagonist AM251 (2 mg·kg-1 , i.v.) did not modify the triphasic response, but blocked the effects induced by cannabinoid agonists. CONCLUSIONS AND IMPLICATIONS:CB1 receptor activation modulates the SM information transmission through the trans-striatal pathways and profoundly decreases the cortico-BG transmission through the mPF circuit. These results may be relevant for elucidating the involvement of the cannabinoid system in motor performance and in decision making or goal-directed behaviour.
Project description:The theory of phase oscillators is an essential tool for understanding population dynamics of pacemaking neurons. GABAergic pacemakers in the substantia nigra pars reticulata (SNr), a main basal ganglia (BG) output nucleus, receive inputs from the direct and indirect pathways at distal and proximal regions of their dendritic arbors, respectively. We combine theory, optogenetic stimulation and electrophysiological experiments in acute brain slices to ask how dendritic properties impact the propensity of the various inputs, arriving at different locations along the dendrite, to recruit or entrain SNr pacemakers. By combining cable theory with sinusoidally-modulated optogenetic activation of either proximal somatodendritic regions or the entire somatodendritic arbor of SNr neurons, we construct an analytical model that accurately fits the empirically measured somatic current response to inputs arising from illuminating the soma and various portions of the dendritic field. We show that the extent of the dendritic tree that is illuminated generates measurable and systematic differences in the pacemaker's phase response curve (PRC), causing a shift in its peak. Finally, we show that the divergent PRCs correctly predict differences in two major features of the collective dynamics of SNr neurons: the fidelity of population responses to sudden step-like changes in inputs; and the phase latency at which SNr neurons are entrained by rhythmic stimulation, which can occur in the BG under both physiological and pathophysiological conditions. Our novel method generates measurable and physiologically meaningful spatial effects, and provides the first empirical demonstration of how the collective responses of SNr pacemakers are determined by the transmission properties of their dendrites. SNr dendrites may serve to delay distal striatal inputs so that they impinge on the spike initiation zone simultaneously with pallidal and subthalamic inputs in order to guarantee a fair competition between the influence of the monosynaptic direct- and polysynaptic indirect pathways.
Project description:The Basal Ganglia (BG) is a central structure involved in multiple cortical and subcortical loops. Some of these loops are believed to be responsible for saccade target selection. We study here how the very specific structural relationships of these saccadic loops can affect the ability of learning spatial and feature-based tasks. We propose a model of saccade generation with reinforcement learning capabilities based on our previous BG and superior colliculus models. It is structured around the interactions of two parallel cortico-basal loops and one tecto-basal loop. The two cortical loops separately deal with spatial and non-spatial information to select targets in a concurrent way. The subcortical loop is used to make the final target selection leading to the production of the saccade. These different loops may work in concert or disturb each other regarding reward maximization. Interactions between these loops and their learning capabilities are tested on different saccade tasks. The results show the ability of this model to correctly learn basic target selection based on different criteria (spatial or not). Moreover the model reproduces and explains training dependent express saccades toward targets based on a spatial criterion. Finally, the model predicts that in absence of prefrontal control, the spatial loop should dominate.
Project description:The basal ganglia are a subcortical assembly of nuclei involved in many aspects of behavior. Three of the nuclei have high firing rates and inhibitory influences: the substantia nigra pars reticulata (SNr), globus pallidus interna (GPi), and globus pallidus externa (GPe). The SNr contains a wide range of visual, cognitive, and motor signals that have been shown to contribute to saccadic eye movements. Our hypothesis was that GPe and GPi neurons carry similarly diverse signals during saccadic behavior. We recorded from GPe, GPi, and SNr neurons in monkeys that made memory-guided saccades and found that neurons in all three structures had increases or decreases in activity synchronized with saccade generation, visual stimulation, or reward. Comparing GPe neurons with GPi neurons, we found relatively more visual-related activity in GPe and more reward-related activity in GPi. Comparing both pallidal samples with the SNr, we found a greater resemblance between GPe and SNr neurons than that between GPi and SNr neurons. As expected from a known inhibitory projection from GPe to SNr, there was a general reversal of sign in activity modulations between the structures: bursts of activity were relatively more common in GPe and pauses more common in SNr. We analyzed the response fields of neurons in all three structures and found relatively narrow and lateralized fields early in trials (during visual and saccadic events) followed by a broadening later in trials (during reward). Our data reinforce an emerging, new consensus that the GPe and GPi, in addition to the SNr, contribute to oculomotor behavior.
Project description:The substantia nigra pars reticulata (SNr), where the basal ganglia (BG) direct and indirect pathways converge, contains among the highest expression of cannabinoid receptor type 1 (CB1r) in the brain. Hence, SNr is an ideal locus to study pathway interactions and cannabinergic modulations. The objective of this study was to characterize the effects of systemic injections of the CB1r agonist (CP55940) on the balanced activity of the direct/indirect pathways in the SNr and its associated behaviors. To this aim, we recorded somatosensory and pathway-specific representations in the spiking activity of the SNr of male rats under CP55940. CB1r activation mainly decreased the inhibitory, potentially direct pathway component while sparing the excitatory, potentially indirect pathway component of somatosensory responses. As a result, cutaneous stimulation produced unbalanced responses favoring increased SNr firing rates, suggesting a potential locus for cannabinergic motor-related effects. To test this hypothesis, we implemented an <i>ad hoc</i> behavioral protocol for rats in which systemic administration of CP55940 produced kinematic impairments that were completely reverted by nigral injections of the CB1r antagonist (AM251). Our data suggest that cannabinoid-related motor effects are associated with unbalanced direct/indirect pathway activations that may be reverted by CB1r manipulation at the SNr.<b>SIGNIFICANCE STATEMENT</b> The cannabinergic system has been the target of multiple studies to master its potential use as a therapeutic agent. However, significant advances have been precluded by the lack of mechanistic explanations for the variety of its desirable/undesirable effects. Here, we have combined electrophysiological recordings, pharmacological and optogenetic manipulations, and an <i>ad hoc</i> behavioral protocol to understand how basal ganglia (BG) is affected by cannabinoids. We found that cannabinoids principally affect inhibitory inputs, potentially from the direct pathway, resulting in unbalanced responses in the substantia nigra pars reticulata (SNr) and suggesting a mechanism for the cannabinoid-related slowness of movements. This possibility was confirmed by behavioral experiments in which cannabinoid-related slowness of purposeful movements was reverted by cannabinoid receptor type 1 (CB1r) manipulations directly into the SNr.
Project description:Severe gait disturbances in idiopathic Parkinson's disease (PD) are observed in up to 80% of all patients in advanced disease stages with important impact on quality of life. There is an unmet need for further symptomatic therapeutic strategies, particularly as gait disturbances generally respond unfavourably to dopaminergic medication and conventional deep brain stimulation of the subthalamic nucleus in advanced disease stages. Recent pathophysiological research pointed to nigro-pontine networks entrained to locomotor integration. Stimulation of the pedunculopontine nucleus is currently under investigation, however, hitherto remains controversial. The substantia nigra pars reticulata (SNr)--entrained into integrative locomotor networks--is pathologically overactive in PD. High-frequent stimulation of the substantia nigra pars reticulata preferentially modulated axial symptoms and therefore is suggested as a novel therapeutic candidate target for neuromodulation of refractory gait disturbances in PD.12 patients with idiopathic Parkinson's disease and refractory gait disturbances under best individual subthalamic nucleus stimulation and dopaminergic medication will be enroled into this double-blind 2 × 2 cross-over clinical trial. The treatment consists of two different stimulation settings using (i) conventional stimulation of the subthalamic nucleus [STNmono] and (ii) combined stimulation of distant electrode contacts located in the subthalamic nucleus and caudal border zone of STN and substantia nigra pars reticulata [STN+SNr]. The primary outcome measure is the change of the cumulative 'axial score' (UPDRS II items '13-15' and UPRDS III items '27-31') at three weeks of constant stimulation in either condition. Secondary outcome measures include specific scores on freezing of gait, balance function, quality of life, non-motor symptoms, and neuropsychiatric symptoms. The aim of the present trial is to investigate the efficacy and safety of a three week constant combined stimulation on [STN+SNr] compared to [STNmono]. The results will clarify, whether stimulation on nigral contacts additional to subthalamic stimulation will improve therapeutic response of otherwise refractory gait disturbances in PD.The trial was registered with the clinical trials register of http://www.clinicaltrials.gov (NCT01355835).