Dissociable Roles of Pallidal Neuron Subtypes in Regulating Motor Patterns

Abstract

Author contributions SC and BLB performed histological analysis. SC, QC, IYMC, HSX, YZ, HM, ZAA, and XD surveyed the intrinsic properties. QC, HMH, XD, YZ, and CJW examined the local connectivity. AP, QC, SR, and NJJ conducted the behavioral studies. IYMC developed the machine learning analysis pipeline. YC and SMB provided expertise for neuron classification. CSC wrote the manuscript with input from all co-authors. All authors reviewed and edited the manuscript. CSC designed, directed, and supervised the project.

Distinct mechanisms of CB1 and GABABreceptor presynaptic modulation of striatal indirect pathway projections to mouse Globus Pallidus

“…Optogenetic dissection of the indirect pathway has revealed that the activation of striatal iSPNs has a locomotor-suppressing effect, an effect replicated in several studies where the optogenetic manipulation was performed in the dorsomedial striatum (Cui et al, 2021;Kravitz et al, 2010;Isett et al, 2022). Conversely, the inhibition of iSPNs in the dorsolateral striatum had movement promoting effects (Cui et al, 2021), although the underlying circuitry remains unclear. Optogenetic somatic manipulations of iSPN activity will influence local iSPN collaterals in addition to downstream projections.…”

“…Further, the indirect pathway has been proposed to be involved in negative reinforcement (Kravitz et al, 2012). Optogenetic dissection of the indirect pathway has revealed that the activation of striatal iSPNs has a locomotor-suppressing effect, an effect replicated in several studies where the optogenetic manipulation was performed in the dorsomedial striatum (Cui et al, 2021;Kravitz et al, 2010;Isett et al, 2022). Conversely, the inhibition of iSPNs in the dorsolateral striatum had movement promoting effects (Cui et al, 2021), although the underlying circuitry remains unclear.…”

“…Here, we used a synapse-specific approach to focus on the iSPN-GPe projection. A detailed analysis of the striato-pallidal and pallido-pallidal circuitry has proposed that iSPN-GPe projections are the densest in the GPe and primarily target PV-expressing neurons over Npas1-expressing GPe neurons (Cui et al, 2021) and similar results in vivo have shown a preferential innervation of prototypic GPe neurons by iSPNs (Ketzef et al, 2021). In turn, PV+ neurons represent the primary source of collateral inhibition in the GPe (Cui et al, 2021;Higgs et al, 2021).…”

“…A detailed analysis of the striato-pallidal and pallido-pallidal circuitry has proposed that iSPN-GPe projections are the densest in the GPe and primarily target PV-expressing neurons over Npas1-expressing GPe neurons (Cui et al, 2021) and similar results in vivo have shown a preferential innervation of prototypic GPe neurons by iSPNs (Ketzef et al, 2021). In turn, PV+ neurons represent the primary source of collateral inhibition in the GPe (Cui et al, 2021;Higgs et al, 2021). Presynaptic inhibition of iSPN-GPe projections might therefore produce primarily a disinhibition of the output of GPe prototypic neurons to the SNr, STN and PF thalamus (Lilasharoen et al, 2020; Pamukcu et al, 2020) in addition to disinhibiting local collaterals.…”

“…Functionally, presynaptic modulation of iSPN-GPe projections has implications for motor control and action selection. The indirect pathway has been implicated in motor suppression by classic models of basal ganglia circuit function (Grillner et al, 2016;Albin et al, 1989;Kravitz et al, 2010;Cui et al, 2021;Isett et al, 2022). Further, the indirect pathway has been proposed to be involved in negative reinforcement (Kravitz et al, 2012).…”