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.

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.

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.