Synaptic Changes in Pallidostriatal Circuits Observed in the Parkinsonian Model Triggers Abnormal Beta Synchrony with Accurate Spatio-temporal Properties across the Basal Ganglia.

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.

Preferential Modulatory Action of 5-HT2A Receptors on the Dynamic Regulation of Basal Ganglia Circuits.

In rodents, cortical information is transferred to the substantia nigra pars reticulata (SNr) through motor and medial prefrontal (mPF) basal ganglia (BG) circuits implicated in motor and cognitive/motivational behaviors, respectively. The serotonergic 5-HT2A receptors are located in both of these neuronal networks, displaying topographical differences with a high expression in the associative/limbic territories, and a very low expression in the subthalamic nucleus. This study investigated whether the stimulation of 5-HT2A receptors could have a specific signature on the dynamic regulation of BG circuits, preferentially modulating the mPF information processing through trans-striatal pathways. We performed in vivo single-unit extracellular recordings to assess the effect of the 5-HT2A agonist TCB-2 on the spontaneous and cortically evoked activity of lateral and medial SNr neurons in male rats (involved in motor and mPF circuits, respectively). TCB-2 (50-200 µg/kg, i.v.) increased the basal firing rate and enhanced the cortically evoked inhibitory response of medial SNr neurons (transmission through the direct striato-nigral pathway). A prior administration of the preferential 5-HT2A receptor antagonist MDL11939 (200 µg/kg, i.v.) did not modify any electrophysiological parameter, but occluded TCB-2-induced effects. In animals treated with the 5-HT synthesis inhibitor pCPA (4-chloro-dl-phenylalanine methyl ester hydrochloride), TCB-2 failed to induce the above-mentioned effects, thus suggesting the contribution of endogenous 5-HT. However, the mobilization of 5-HT induced by the acute administration of fluoxetine (10 mg/kg, i.p.) did not mimic the effects triggered by TCB-2. Overall, these data suggest that 5-HT2A receptors have a preferential modulatory action on the dynamic regulation of BG circuitry.SIGNIFICANCE STATEMENT Motor and medial prefrontal (mPF) basal ganglia (BG) circuits play an important role in integrative brain functions like movement control or cognitive/motivational behavior, respectively. Although these neuronal networks express 5-HT2A receptors, the expression is higher in associative/limbic structures than in the motor ones. We show a topographical-dependent dissociation in the effects triggered by the 5HT2A agonist TCB-2, which specifically increases the medial substantia nigra pars reticulata neuron activity and has a preferential action on mPF information processing through the striato-nigral direct pathway. These are very likely to be 5-HT2A receptor-mediated effects that require mobilization of the endogenous 5-HT system. These findings provide evidence about the specific signature of 5-HT2A receptors on the dynamic regulation of BG circuits.

Impact of dietary vitamin A on striatal function in adult rats.

The striatum is a brain structure involved in the control of voluntary movement. Striatum contains high amounts of retinoic acid, the active metabolite of vitamin A, as well as retinoid receptors, RARß and RXRγ. Previous studies revealed that disruption of retinoid signaling initiated during development is deleterious for striatal physiology and related motor functions. However, the alteration of retinoid signaling, and the importance of vitamin A supply during adulthood on striatal physiology and function has never been established. In the present study, we investigated the impact of vitamin A supply on striatal function. Adult Sprague-Dawley rats were fed with three specific diets, either sub-deficient, sufficient, or enriched in vitamin A (0.4, 5, and 20 international units [IU] of retinol per g of diet, respectively) for 6 months. We first validated that vitamin A sub-deficient diet in adult rats constitutes a physiological model of retinoid signaling reduction in the striatum. We then revealed subtle alterations of fine motor skills in sub-deficient rats using a new behavioral apparatus specifically designed to test forepaw reach-and-grasp skills relying on striatal function. Finally, we showed using qPCR analysis and immunofluorescence that the striatal dopaminergic system per se was not affected by vitamin A sub-deficiency at adult age. Rather, cholinergic synthesis in the striatum and µ-opioid receptor expression in striosomes sub-territories were the most affected by vitamin A sub-deficiency starting at adulthood. Taken together these results revealed that retinoid signaling alteration at adulthood is associated with motor learning deficits together with discrete neurobiological alterations in the striatum.

Arkypallidal neurons in basal ganglia circuits: Unveiling novel pallidostriatal loops?

Just over a decade ago, a novel GABAergic input originating from a subpopulation of external globus pallidus neurons known as Arkypallidal and projecting exclusively to the striatum was unveiled. At the single-cell level, these pallidostriatal Arkypallidal projections represent one of the largest extrinsic sources of GABA known to innervate the dorsal striatum. This discovery has sparked new questions regarding their role in striatal information processing, the circuit that recruit these neurons, and their influence on behaviour, especially in the context of action selection vs. inhibition. In this review, we will present the different anatomo-functional organization of Arkypallidal neurons as compared to classic Prototypic neurons, including their unique molecular properties and what is known about their specific input/output synaptic organization. We will further describe recent findings that demonstrate one mode of action of Arkypallidal neurons, which is to convey feedback inhibition to the striatum, and how this mechanism is differentially modulated by both striatal projection pathways. Lastly, we will delve into speculations on their mechanistic contribution to striatal action execution or inhibition.

Targeting parvalbumin-expressing neurons in the substantia nigra pars reticulata restores motor function in parkinsonian mice.

The activity of substantia nigra pars reticulata (SNr) neurons, the main output structure of basal ganglia, is altered in Parkinson's disease (PD). However, neither the underlying mechanisms nor the type of neurons responsible for PD-related motor dysfunctions have been elucidated yet. Here, we show that parvalbumin-expressing SNr neurons (SNr-PV+) occupy dorsolateral parts and possess specific electrophysiological properties compared with other SNr cells. We also report that only SNr-PV+ neurons' intrinsic excitability is reduced by downregulation of sodium leak channels in a PD mouse model. Interestingly, in anesthetized parkinsonian mice in vivo, SNr-PV+ neurons display a bursty pattern of activity dependent on glutamatergic tone. Finally, we demonstrate that chemogenetic inhibition of SNr-PV+ neurons is sufficient to alleviate motor impairments in parkinsonian mice. Overall, our findings establish cell-type-specific dysfunction in experimental parkinsonism in the SNr and provide a potential cellular therapeutic target to alleviate motor symptoms in PD.

A Disynaptic Circuit in the Globus Pallidus Controls Locomotion Inhibition.

The basal ganglia (BG) inhibit movements through two independent circuits: the striatal neuron-indirect and the subthalamic nucleus-hyperdirect pathways. These pathways exert opposite effects onto external globus pallidus (GPe) neurons, whose functional importance as a relay has changed drastically with the discovery of two distinct cell types, namely the prototypic and the arkypallidal neurons. However, little is known about the synaptic connectivity scheme of different GPe neurons toward both motor-suppressing pathways, as well as how opposite changes in GPe neuronal activity relate to locomotion inhibition. Here, we optogenetically dissect the input organizations of prototypic and arkypallidal neurons and further define the circuit mechanism and behavioral outcome associated with activation of the indirect or hyperdirect pathways. This work reveals that arkypallidal neurons are part of a novel disynaptic feedback loop differentially recruited by the indirect or hyperdirect pathways and that broadcasts inhibitory control onto locomotion only when arkypallidal neurons increase their activity.

Publisher Correction: The globus pallidus orchestrates abnormal network dynamics in a model of Parkinsonism.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The globus pallidus orchestrates abnormal network dynamics in a model of Parkinsonism.

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.