Dissociable Roles of Pallidal Neuron Subtypes in Regulating Motor Patterns

Abstract

We have previously established that PV+ neurons and Npas1+ neurons are distinct neuron classes in the GPe: they have different topographical, electrophysiological, circuit, and functional properties. Aside from Foxp2+ neurons, which are a unique subclass within the Npas1+ class, we lack driver lines that effectively capture other GPe neuron subclasses. In this study, we examined the utility of Kcng4-Cre, Npr3-Cre, and Npy2r-Cre mouse lines (both males and females) for the delineation of GPe neuron subtypes. By using these novel driver lines, we have provided the most exhaustive investigation of electrophysiological studies of GPe neuron subtypes to date. Corroborating our prior studies, GPe neurons can be divided into two statistically distinct clusters that map onto PV+ and Npas1+ classes. By combining optogenetics,, and machine learning-based tracking, we showed that optogenetic perturbation of GPe neuron subtypes generated unique behavioral structures. Our findings further highlighted the dissociable roles of GPe neurons in regulating movement and anxiety. We concluded that Npr3+ neurons and Kcng4+ neurons are distinct subclasses of Npas1+ neurons and PV+ neurons, respectively. Finally, by examining local collateral connectivity, we inferred the circuit mechanisms involved in the motor patterns observed with optogenetic perturbations. In summary, by identifying mouse lines that allow for manipulations of GPe neuron subtypes, we created new opportunities for interrogations of cellular and circuit substrates that can be important for motor function and dysfunction.

Striatal Direct Pathway Targets Npas1+Pallidal Neurons

“…At a circuit level, stimulation of iSPNs strongly suppresses firing of PV + neurons, thus disinhibiting the targets of PV + neurons, i.e., the STN and substantia nigra (Mastro et al, 2014; Hernandez et al, 2015; Saunders et al, 2016; Oh et al, 2017; Abecassis et al, 2020). As activity of PV + neurons promotes movement (Cherian et al, 2020; Pamukcu et al, 2020), the selective targeting of PV + neurons by iSPNs is in agreement with the movement suppressing role of DMS iSPNs (Kravitz et al, 2010; Durieux et al, 2012). Conversely, we found stimulation of DLS iSPNs promoted movement; this cannot be explained simply by the targeting properties of DLS iSPNs.…”

“…To survey the full range of motor behaviors, a machine learning approach was used to track body kinematics and movement dynamics (Cherian et al, 2020). These data are summarized in a heatmap format ( Figure 2a ).…”

“…Segregation of neurotransmitter release has also been found in other systems (Zhang et al, 2015; Lee et al, 2016; Granger et al, 2020). Given that Npas1 + neurons and PV + neurons have opposite effects on motor control (Cherian et al, 2020; Pamukcu et al, 2020), the inhibition of Npas1 + neurons by GABA and excitation of PV + neurons by substance P should work in concert to reinforce the same behavioral outcomes.…”

“…The neurons of interest are Foxp2 + (pink), Kcng4 + (purple), Npas1 + (green), PV + (orange). The plot was reproduced from Cherian et al (Cherian et al, 2020). The recordings were obtained from an Npas1 + and a PV + neuron, respectively.…”

“…However, we only have limited information about the properties of this pathway. As the GPe contains a heterogenous population of neurons (Hernandez et al, 2015; Hegeman et al, 2016; Saunders et al, 2018; Abecassis et al, 2020; Cherian et al, 2020), the identity of neurons that receive dSPN input remains elusive. Here, we hypothesized that dSPNs regulate motor output by targeting a select subset of these neurons.…”