A disynaptic circuit in the globus pallidus controls locomotion inhibition

Abstract

Basal ganglia (BG) inhibit movement through two independent pathways, the indirect- and the hyperdirect-pathways. The globus pallidus (GP) has always been viewed as a simple relay within these two pathways, but its importance has changed drastically with the discovery of two functionally-distinct cell types, namely the prototypic and the arkypallidal neurons. Classic BG models suggest that all GP neurons receive GABAergic inputs from striato-pallidal indirect spiny projection neurons and glutamatergic inputs from subthalamic neurons. However, whether this synaptic connectivity scheme applies to both GP cell-types is currently unknown. Here, we optogenetically dissect the input organization of prototypic and arkypallidal neurons and further define the circuit mechanism underlying action inhibition in BG. Our results highlight that an increased activity of arkypallidal neurons is required to inhibit locomotion. Finally, this work supports the view that arkypallidal neurons are part of a novel disynaptic feedback loop that broadcast inhibitory control on movement execution.

Dissociable Roles of Pallidal Neuron Subtypes in Regulating Motor Patterns

“…Only a subset of recorded PV + neurons (8 out of 18, 44.4%) showed detectable Foxp2 + input, and the strength of this connection was the weakest among all connection types examined (Foxp2 + to PV + vs. PV + to PV − , P = 0.00023; Foxp2 + to PV + vs. Npas1 + to Npas1 − , P = 0.0053; Foxp2 + to PV + vs. Npas1 + to PV + , P = 0.0047) ( Table 6 ). The observation of this weak and likely biologically negligible connection is highly consistent with recent studies (Aristieta et al, 2020; Ketzef and Silberberg, 2020). As it was clear that the Npas1 + input targets PV + neurons, these results collectively imply that PV + neurons receive Npas1 + input largely from the Nkx2.1 + (aka Npr3 + ) subpopulation, which do not express Foxp2 ( Figure 1c ), see also (Abecassis et al, 2020).…”

“…The cellular mechanisms that mediate motor-suppression have yet to be identified. While Foxp2 + neurons have been proposed to send “stop” signals to the striatum (Mallet et al, 2016; Aristieta et al, 2020; Goenner et al, 2020), it is likely that multiple circuit elements are involved in producing complete behavioral arrest (Schmidt et al, 2013; Jahanshahi et al, 2015; Wessel and Aron, 2017). On the other hand, it is clear that the inhibitory projection to the STN (and substantial pars reticulata) mediates the motor-promoting effects, and it is consistent with the established relationship between STN activity and movement suppression (Hamani et al, 2004; Aron and Poldrack, 2006; Aron et al, 2007; Eagle et al, 2008; Schmidt et al, 2013; Schweizer et al, 2014; Fife et al, 2017; Wessel and Aron, 2017).…”

“…Although the importance of the GPe has long been recognized, our understanding of its cell types, their organization, and their functional properties is limited. While prior studies argue GPe neurons are involved in movement control (Dodson et al, 2015; Zimnik et al, 2015; Glajch et al, 2016; Mastro et al, 2017; Aristieta et al, 2020; Gu et al, 2020; Pamukcu et al, 2020), precisely how they are involved in motor function and dysfunction remains poorly defined. A major hurdle has been imposed by the complexity of the cellular makeup of the GPe.…”

Differential Synaptic Input to External Globus Pallidus Neuronal Subpopulations In Vivo

“…This could be a result of the cautious approach to minimize the expression of the ChR2 virus outside of the GPe. However, ex vivo validation of our in vivo observations supports low local arkypallidal-mediated inhibition, as suggested recently (Aristieta et al, 2020). The afferent pathways to the GPe have been described previously (Albin et al, 1989;Cazorla et al, 2014;DeLong, 1990;Kawaguchi et al, 1990;Kita et al, 1983;Robledo and Fé ger, 1990;Wu et al, 2000); however, their effect on the different GPe subpopulations was unknown.…”

Striatal Direct Pathway Targets Npas1+Pallidal Neurons

“…Our finding that iSPN-PV + input is stronger than iSPN-Npas1 + input is consistent with earlier anatomical studies showing that iSPNs form more synaptic contacts with PV + neurons compared to PV − neurons (Yuan et al, 2017). In addition, it is in line with recent electrophysiological studies that iSPNs strongly target Nkx2.1 + neurons (which are dominated by PV + neurons) while providing minimal input to Foxp2 + neurons (which are a subset of Npas1 + neurons) (Yuan et al, 2017; Aristieta et al, 2020; Ketzef and Silberberg, 2020). Furthermore, we showed that the selective targeting of iSPN input to PV + neurons was topographically conserved between spatial subdomains within the dStr—the DMS and the DLS.…”