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Divergent pallidal pathways underlying distinct Parkinsonian behavioral deficits
Varoth Lilascharoen, Eric Hou-Jen Wang, Nam Do, Stefan Carl Pate, Amanda Ngoc Tran, Christopher Dabin Yoon, Jun-Hyeok Choi, Xiao-Yun Wang, Horia Pribiag, Young-Gyun Park, Kwanghun Chung, Byung Kook Lim
PMID: 33723433 DOI: 10.1038/s41593-021-00810-y
Abstract
The basal ganglia regulate a wide range of behaviors, including motor control and cognitive functions, and are profoundly affected in Parkinson's disease (PD). However, the functional organization of different basal ganglia nuclei has not been fully elucidated at the circuit level. In this study, we investigated the functional roles of distinct parvalbumin-expressing neuronal populations in the external globus pallidus (GPe-PV) and their contributions to different PD-related behaviors. We demonstrate that substantia nigra pars reticulata (SNr)-projecting GPe-PV neurons and parafascicular thalamus (PF)-projecting GPe-PV neurons are associated with locomotion and reversal learning, respectively. In a mouse model of PD, we found that selective manipulation of the SNr-projecting GPe-PV neurons alleviated locomotor deficit, whereas manipulation of the PF-projecting GPe-PV neurons rescued the impaired reversal learning. Our findings establish the behavioral importance of two distinct GPe-PV neuronal populations and, thereby, provide a new framework for understanding the circuit basis of different behavioral deficits in the Parkinsonian state.
GPe: External globus pallidus
GPi: Internal globus pallidus (entopeduncular nucleus in rodents)
STN: Subthalamic nucleus
SNr: Substantia nigra pars reticulata
PF: Parafascicular thalamus
Figure 1: Distinct subpopulation of GPe targets distinct brain areas (SNr and PF)
- a, b: Projection from GPe to other brain structures (GPi, STN PF, and SNr)
- c, d, e, f: Distinct synaptic projection from GPe to PF and other structures. GPe - PF connection is very specific. Since GPe - SNr projection and GPe - STN projection share common inputs, would be inactivating either of two regions induce similar behavior changes?Figure 2: Distinct inputs onto GPe-SNr projection and GPe-PV projection
- a, b, c, d: two-step retrograde tracing and results
- e, f: Cell-type-specific projection (GPe-SNr: Nkx2-1, Scn4b, Lhx6 [D2 receptor] / GPe-PF: Nkx2-01, Scn4b [D1 receptor])Figure 3: Slice electrophysiological properties
- a: Strategy for marking of the target neuron
- b: Recording of GPe-SNr and GPe-PF
- c, d: Firing rate difference and Coefficient of variation (CV)
- e-l: Current injection to either GPe-SNr neurons and GPe-PF neurons and their electrophysiological propertiesFigure 4: In-vivo calcium imaging (fiber photometry) and behavior modulation (Locomotion)
- a: Schematic of recording of both GPe-SNr terminal and GPe-PF terminal in behaving animals
- b, c, d: Both GPe-SNr and GPe-PF axons were modulated by locomotion initiation and termination
- e, f, g: Schematic of optogenetic modulation and results. Activation of GPe-SNr projection increased the speed of animals, and the effects lasted even after the light termination. No such changes were observed in GPe-PF activation.
- h, i, j: Chemogenetic inactivation. Inactivation of GPe-SNr decreased the speed.Figure 5: In-vivo calcium imaging and behavior modulation (Cognitive function: reversal learning)
- a: Schematic of the reversal task
- b: Example fluorescence trace of axon terminals
- c, d, e: GPe-SNr axons did not significantly change their response during reversal learning
- f, g, h: GPe-PF axons significantly increased response after choice & correct vs. incorrect choice
- i, j, k: Optogenetic modulation and results. Activation of GPe-PF projection decreased performance, specifically during the reversal learning
- l, m, n: Chemogenetic inhibition results. Both GPe-SNr projections and GPe-PF projections are not necessary for the association and reversal learning.Figure 6: Electrophysiological changes under the dopamine depletion
- a, b, c, d, e: Measuring dopamine depletion effects on GPe neurons. No effects were found.
- f-k: Scheme for measuring synaptic output from GPe-SNr projection and GPe-PF projection. Quantal-like inhibitory postsynaptic currents (qIPSCs) were measured. Also, paired-pulse ratio (PPR), which is the ratio of the amplitude of the second response to that of the previous response, was measured (Measuring the probability of vesicular release at the synapse)Figure 7: Dopamine depletion and behavior rescue by optogenetic and chemogenetic modulation
- a: Schematic
- b: Dopamine depletion was rescued by optogenetic activation of GPe-SNr projection
- c, d: inhibition of SNr increased movement (rescued behavior)
- e: Schematic
-f: Inhibition of GPe-PF projection increased behavior performance
Image: Infographic vector created by macrovector - www.freepik.com
