Developmental dopamine loss rewires striatal circuits to promote locomotion

Jie Dong; Breanna T. Sullivan; Victor M.Martinez Smith; Lupeng Wang; Lulu Tian; Justin Kung; Bin Song; Shirong Lin; Andreanna Le; Lixin Sun; Lisa Chang; Jinhui Ding; Weidong Le; Jun Jia; Huaibin Cai

doi:10.1186/s13024-025-00920-2

Developmental dopamine loss rewires striatal circuits to promote locomotion

Jie Dong, Breanna T. Sullivan, Victor M.Martinez Smith, Lupeng Wang, Lulu Tian, Justin Kung, Bin Song, Shirong Lin, Andreanna Le, Lixin Sun, Lisa Chang, Jinhui Ding, Weidong Le, Jun Jia, Huaibin Cai

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Abstract

Background: Motor symptoms of Parkinson’s disease (PD) primarily result from the degeneration of nigrostriatal dopaminergic neurons (DANs), particularly the Aldehyde Dehydrogenase 1A1-positive (ALDH1A1⁺) subpopulation. Pitx3-deficient mice exhibit selective developmental loss of ALDH1A1⁺ DANs but paradoxically display hyperlocomotion, suggesting compensatory changes in striatal circuitry. The dorsal striatum contains four main types of spiny projection neurons (SPNs): patch (or striosome) and matrix subtypes of both direct-pathway (dSPNs) and indirect-pathway (iSPNs). Activation of patch dSPNs suppresses locomotion by inhibiting ALDH1A1⁺ DANs. Methods: We combined RNAscope in situ hybridization with SPN subtype-specific reporter mice to quantify patch and total dSPNs and iSPNs in Pitx3-deficient and control mice. Three patch SPN reporter lines (Kremen1^{2A − Cre}, Nr4a1-GFP, and Pdyn^IRES−Cre) were used to map projections. Optogenetic stimulation was performed in freely moving mice to assess the behavioral effects of activating patch dSPNs and iSPNs. Results: Pitx3-deficient mice showed no change in the overall dSPN: iSPN ratio but exhibited a marked shift in the patch dSPN: patch iSPN ratio, which decreased from 1.7 in control mice to 0.7 in the Pitx3-deficient group. Accordingly, patch dSPN projections to the substantia nigra pars reticulata (SNr) were reduced, whereas patch iSPN projections to the globus pallidus externus (GPe) were enhanced. Notably, while optogenetic stimulation of patch dSPNs and iSPNs suppressed locomotion in control mice, the same stimulation promoted locomotion in Pitx3-deficient mice. Conclusions: Our findings reveal a selective reorganization of patch SPNs in response to developmental loss of ALDH1A1⁺ DANs, characterized by reduced patch dSPN and enhanced patch iSPN influence. This shift may underlie the paradoxical hyperlocomotion observed in Pitx3-deficient mice and provides insight into circuit-level adaptations with potential therapeutic relevance for PD.

Original language	English (US)
Article number	7
Pages (from-to)	7
Journal	Molecular Neurodegeneration
Volume	21
Issue number	1
DOIs	https://doi.org/10.1186/s13024-025-00920-2
State	Published - Jan 3 2026

Keywords

ALDH1A1
Direct-pathway
Dopaminergic neurons
Indirect-pathway
Kremen1
Optogenetics, and Neuromodulation
Parkinson’s disease
Pitx3
Striatal projection neurons

ASJC Scopus subject areas

Molecular Biology
Clinical Neurology
Cellular and Molecular Neuroscience

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10.1186/s13024-025-00920-2

Cite this

@article{42f8fb2708264379ba1ace059f5bf75b,

title = "Developmental dopamine loss rewires striatal circuits to promote locomotion",

abstract = "Background: Motor symptoms of Parkinson{\textquoteright}s disease (PD) primarily result from the degeneration of nigrostriatal dopaminergic neurons (DANs), particularly the Aldehyde Dehydrogenase 1A1-positive (ALDH1A1⁺) subpopulation. Pitx3-deficient mice exhibit selective developmental loss of ALDH1A1⁺ DANs but paradoxically display hyperlocomotion, suggesting compensatory changes in striatal circuitry. The dorsal striatum contains four main types of spiny projection neurons (SPNs): patch (or striosome) and matrix subtypes of both direct-pathway (dSPNs) and indirect-pathway (iSPNs). Activation of patch dSPNs suppresses locomotion by inhibiting ALDH1A1⁺ DANs. Methods: We combined RNAscope in situ hybridization with SPN subtype-specific reporter mice to quantify patch and total dSPNs and iSPNs in Pitx3-deficient and control mice. Three patch SPN reporter lines (Kremen12A − Cre, Nr4a1-GFP, and PdynIRES−Cre) were used to map projections. Optogenetic stimulation was performed in freely moving mice to assess the behavioral effects of activating patch dSPNs and iSPNs. Results: Pitx3-deficient mice showed no change in the overall dSPN: iSPN ratio but exhibited a marked shift in the patch dSPN: patch iSPN ratio, which decreased from 1.7 in control mice to 0.7 in the Pitx3-deficient group. Accordingly, patch dSPN projections to the substantia nigra pars reticulata (SNr) were reduced, whereas patch iSPN projections to the globus pallidus externus (GPe) were enhanced. Notably, while optogenetic stimulation of patch dSPNs and iSPNs suppressed locomotion in control mice, the same stimulation promoted locomotion in Pitx3-deficient mice. Conclusions: Our findings reveal a selective reorganization of patch SPNs in response to developmental loss of ALDH1A1⁺ DANs, characterized by reduced patch dSPN and enhanced patch iSPN influence. This shift may underlie the paradoxical hyperlocomotion observed in Pitx3-deficient mice and provides insight into circuit-level adaptations with potential therapeutic relevance for PD.",

keywords = "ALDH1A1, Direct-pathway, Dopaminergic neurons, Indirect-pathway, Kremen1, Optogenetics, and Neuromodulation, Parkinson{\textquoteright}s disease, Pitx3, Striatal projection neurons",

author = "Jie Dong and Sullivan, \{Breanna T.\} and Smith, \{Victor M.Martinez\} and Lupeng Wang and Lulu Tian and Justin Kung and Bin Song and Shirong Lin and Andreanna Le and Lixin Sun and Lisa Chang and Jinhui Ding and Weidong Le and Jun Jia and Huaibin Cai",

note = "Publisher Copyright: {\textcopyright} This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2025.",

year = "2026",

month = jan,

day = "3",

doi = "10.1186/s13024-025-00920-2",

language = "English (US)",

volume = "21",

pages = "7",

journal = "Molecular Neurodegeneration",

issn = "1750-1326",

publisher = "BioMed Central",

number = "1",

}

TY - JOUR

T1 - Developmental dopamine loss rewires striatal circuits to promote locomotion

AU - Dong, Jie

AU - Sullivan, Breanna T.

AU - Smith, Victor M.Martinez

AU - Wang, Lupeng

AU - Tian, Lulu

AU - Kung, Justin

AU - Song, Bin

AU - Lin, Shirong

AU - Le, Andreanna

AU - Sun, Lixin

AU - Chang, Lisa

AU - Ding, Jinhui

AU - Le, Weidong

AU - Jia, Jun

AU - Cai, Huaibin

N1 - Publisher Copyright: © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2025.

PY - 2026/1/3

Y1 - 2026/1/3

N2 - Background: Motor symptoms of Parkinson’s disease (PD) primarily result from the degeneration of nigrostriatal dopaminergic neurons (DANs), particularly the Aldehyde Dehydrogenase 1A1-positive (ALDH1A1⁺) subpopulation. Pitx3-deficient mice exhibit selective developmental loss of ALDH1A1⁺ DANs but paradoxically display hyperlocomotion, suggesting compensatory changes in striatal circuitry. The dorsal striatum contains four main types of spiny projection neurons (SPNs): patch (or striosome) and matrix subtypes of both direct-pathway (dSPNs) and indirect-pathway (iSPNs). Activation of patch dSPNs suppresses locomotion by inhibiting ALDH1A1⁺ DANs. Methods: We combined RNAscope in situ hybridization with SPN subtype-specific reporter mice to quantify patch and total dSPNs and iSPNs in Pitx3-deficient and control mice. Three patch SPN reporter lines (Kremen12A − Cre, Nr4a1-GFP, and PdynIRES−Cre) were used to map projections. Optogenetic stimulation was performed in freely moving mice to assess the behavioral effects of activating patch dSPNs and iSPNs. Results: Pitx3-deficient mice showed no change in the overall dSPN: iSPN ratio but exhibited a marked shift in the patch dSPN: patch iSPN ratio, which decreased from 1.7 in control mice to 0.7 in the Pitx3-deficient group. Accordingly, patch dSPN projections to the substantia nigra pars reticulata (SNr) were reduced, whereas patch iSPN projections to the globus pallidus externus (GPe) were enhanced. Notably, while optogenetic stimulation of patch dSPNs and iSPNs suppressed locomotion in control mice, the same stimulation promoted locomotion in Pitx3-deficient mice. Conclusions: Our findings reveal a selective reorganization of patch SPNs in response to developmental loss of ALDH1A1⁺ DANs, characterized by reduced patch dSPN and enhanced patch iSPN influence. This shift may underlie the paradoxical hyperlocomotion observed in Pitx3-deficient mice and provides insight into circuit-level adaptations with potential therapeutic relevance for PD.

AB - Background: Motor symptoms of Parkinson’s disease (PD) primarily result from the degeneration of nigrostriatal dopaminergic neurons (DANs), particularly the Aldehyde Dehydrogenase 1A1-positive (ALDH1A1⁺) subpopulation. Pitx3-deficient mice exhibit selective developmental loss of ALDH1A1⁺ DANs but paradoxically display hyperlocomotion, suggesting compensatory changes in striatal circuitry. The dorsal striatum contains four main types of spiny projection neurons (SPNs): patch (or striosome) and matrix subtypes of both direct-pathway (dSPNs) and indirect-pathway (iSPNs). Activation of patch dSPNs suppresses locomotion by inhibiting ALDH1A1⁺ DANs. Methods: We combined RNAscope in situ hybridization with SPN subtype-specific reporter mice to quantify patch and total dSPNs and iSPNs in Pitx3-deficient and control mice. Three patch SPN reporter lines (Kremen12A − Cre, Nr4a1-GFP, and PdynIRES−Cre) were used to map projections. Optogenetic stimulation was performed in freely moving mice to assess the behavioral effects of activating patch dSPNs and iSPNs. Results: Pitx3-deficient mice showed no change in the overall dSPN: iSPN ratio but exhibited a marked shift in the patch dSPN: patch iSPN ratio, which decreased from 1.7 in control mice to 0.7 in the Pitx3-deficient group. Accordingly, patch dSPN projections to the substantia nigra pars reticulata (SNr) were reduced, whereas patch iSPN projections to the globus pallidus externus (GPe) were enhanced. Notably, while optogenetic stimulation of patch dSPNs and iSPNs suppressed locomotion in control mice, the same stimulation promoted locomotion in Pitx3-deficient mice. Conclusions: Our findings reveal a selective reorganization of patch SPNs in response to developmental loss of ALDH1A1⁺ DANs, characterized by reduced patch dSPN and enhanced patch iSPN influence. This shift may underlie the paradoxical hyperlocomotion observed in Pitx3-deficient mice and provides insight into circuit-level adaptations with potential therapeutic relevance for PD.

KW - ALDH1A1

KW - Direct-pathway

KW - Dopaminergic neurons

KW - Indirect-pathway

KW - Kremen1

KW - Optogenetics, and Neuromodulation

KW - Parkinson’s disease

KW - Pitx3

KW - Striatal projection neurons

UR - https://www.scopus.com/pages/publications/105029103430

UR - https://www.scopus.com/inward/citedby.url?scp=105029103430&partnerID=8YFLogxK

U2 - 10.1186/s13024-025-00920-2

DO - 10.1186/s13024-025-00920-2

M3 - Article

C2 - 41485044

AN - SCOPUS:105029103430

SN - 1750-1326

VL - 21

SP - 7

JO - Molecular Neurodegeneration

JF - Molecular Neurodegeneration

IS - 1

M1 - 7

ER -

Developmental dopamine loss rewires striatal circuits to promote locomotion

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