Distinct globus pallidus circuits regulate motor and cognitive functions

Abstract

A recent article by Lilascharoen et al. identified two distinct pathways in the globus pallidus (GPe) that are associated with discrete behaviors. Dysfunctions in these pathways were shown to underlie Parkinsonian motor and cognitive deficits in mice, and selective manipulation of these circuits rescued locomotor deficits and improved behavioral flexibility.

Keywords: Parkinson's disease; cognitive function; external segment of the globus pallidus (GPe); locomotion; parvalbumin; reversal learning.

Figure 1.. Schematic representation illustrating distinct GPe pathways associated with motor and cognitive functions.

(Upper panel) Viral strategy used by Lilascharoen et al. [8] to map the input and output organization of GPe neurons projecting to the SNr (PV^GPe-SNr) in PV–cre mice. PV^GPe-SNr neurons receive more inputs from striatal D2-SPNs and fewer inputs from striatal D1-SPNs (left). Optogenetic activation of PV^GPe-SNr axon terminals with optical fibers implanted in the SNr increases locomotor activity and was sufficient to restore locomotion in dopamine-depleted mice, with locomotion persisting beyond the photostimulation period. (Lower panel) Viral strategy to map the input and output organization of GPe neurons projecting to the PF (PV^GPe-PF) in PV-cre mice. PV^GPe-PF neurons preferentially receive projections from striatal D1-SPNs and have fewer projections from striatal D2-SPNs (left). Dopamine depletion (6-OHDA lesion) impairs cognitive flexibility in a context-based food-foraging task. Chemogenetic inhibition of PV^GPe-PF neurons significantly improves the reversal-learning performance in the dopamine-depleted mice. Mouse icons adapted from 'Icon Pack: Mice', by BioRender.com (2021); retrieved from https://app.biorender.com/biorender-templates. Abbreviations: AAV, adeno-associated virus; CNO, clozapine-N-oxide; D1/D2, dopamine D1/D2 receptor-expressing neurons; EIAV, equine infectious anemia lenti virus; EnvA, avian tumor virus envelope A protein; fDIO, Flp-dependent, double-floxed, inverted open reading frame; GPe, globus pallidus; hM4DI, human muscarinic M4 receptor exclusively activated by a designer drug (CNO); oChlEF, channelrhodopsin variant; 6-OHDA, 6-hydroxydopamine; oPBG, optimized Pasteur rabies strain G and B19G chimeric protein; PF, parafascicular nucleus; PV, parvalbumin; RG, rabies glycoprotein; RVΔG, glycoprotein (G)-deleted rabies virus; SNr, substantia nigra pars reticulata; SPN, spiny projection neurons; STR, striatum; TVA, avian tumor vims receptor A.