. 2025 Aug 6;113(15):2416-2437.e6.

doi: 10.1016/j.neuron.2025.05.014. Epub 2025 Jun 6.

Distinct molecular patterns in R6/2 HD mouse brain: Insights from spatiotemporal transcriptomics

Affiliations

¹ Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92617, USA.
² Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92617, USA.
³ Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92617, USA.
⁴ Department of Pathology & Laboratory Medicine, University of California, Irvine, Irvine, CA 92617, USA.
⁵ Department of Psychiatry & Human Behavior, University of California, Irvine, Irvine, CA 92617, USA.
⁶ Department of Pathology & Laboratory Medicine, University of California, Irvine, Irvine, CA 92617, USA; Department of Biomedical Sciences, University of California, San Diego, San Diego, CA 92093, USA.
⁷ Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92617, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92617, USA.
⁸ Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92617, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92617, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92617, USA; Department of Pathology & Laboratory Medicine, University of California, Irvine, Irvine, CA 92617, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92617, USA; Center for Neurotherapeutics, University of California, Irvine, Irvine, CA 92617, USA; Department of Neurology, University of California, Irvine, Irvine, CA 92617, USA.
⁹ Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92617, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92617, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92617, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92617, USA; Center for Neurotherapeutics, University of California, Irvine, Irvine, CA 92617, USA; Department of Neurology, University of California, Irvine, Irvine, CA 92617, USA; Department of Psychiatry & Human Behavior, University of California, Irvine, Irvine, CA 92617, USA. Electronic address: lmthomps@uci.edu.

PMID: 40482637
PMCID: PMC12279385 (available on 2026-06-06)
DOI: 10.1016/j.neuron.2025.05.014

Distinct molecular patterns in R6/2 HD mouse brain: Insights from spatiotemporal transcriptomics

Mara S Burns et al. Neuron. 2025.

. 2025 Aug 6;113(15):2416-2437.e6.

doi: 10.1016/j.neuron.2025.05.014. Epub 2025 Jun 6.

Authors

Affiliations

¹ Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92617, USA.
² Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92617, USA.
³ Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92617, USA.
⁴ Department of Pathology & Laboratory Medicine, University of California, Irvine, Irvine, CA 92617, USA.
⁵ Department of Psychiatry & Human Behavior, University of California, Irvine, Irvine, CA 92617, USA.
⁶ Department of Pathology & Laboratory Medicine, University of California, Irvine, Irvine, CA 92617, USA; Department of Biomedical Sciences, University of California, San Diego, San Diego, CA 92093, USA.
⁷ Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92617, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92617, USA.
⁸ Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92617, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92617, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92617, USA; Department of Pathology & Laboratory Medicine, University of California, Irvine, Irvine, CA 92617, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92617, USA; Center for Neurotherapeutics, University of California, Irvine, Irvine, CA 92617, USA; Department of Neurology, University of California, Irvine, Irvine, CA 92617, USA.
⁹ Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92617, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92617, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92617, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92617, USA; Center for Neurotherapeutics, University of California, Irvine, Irvine, CA 92617, USA; Department of Neurology, University of California, Irvine, Irvine, CA 92617, USA; Department of Psychiatry & Human Behavior, University of California, Irvine, Irvine, CA 92617, USA. Electronic address: lmthomps@uci.edu.

PMID: 40482637
PMCID: PMC12279385 (available on 2026-06-06)
DOI: 10.1016/j.neuron.2025.05.014

Abstract

Huntington's disease (HD) is marked by widespread cellular dysregulation. To understand disease mechanisms, we and others have utilized bulk and single-cell transcriptomics, which provide cell-type information but limited spatial information. We used 10× Genomics Visium spatial transcriptomics integrated with matched single-nuclei RNA sequencing (snRNA-seq) in the rapidly progressing HD R6/2 mouse brain (post-natal day 0 [P0], 4 weeks, and 12 weeks). Our data suggest regional, temporal, and cell-type-specific regulatory pathways that establish distinct gene expression changes. Synaptic dysfunction is observed broadly throughout the brain, whereas we observed early dysregulation of the transcription factor 4 (Tcf4) that may drive cortical changes. Mitochondrial deficits are the earliest changes, beginning at P0 in the striatum. Striatal identity genes show early increased expression that becomes progressively downregulated. Finally, we identified a time-dependent dysregulation of neuropeptide Y signaling and potential interaction with the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway, which may be involved in the imbalance between Drd1 and Drd2 neuron vulnerability.

Keywords: Huntington’s disease; R62 transgenic; cell-cell signaling; metabolism; neuropeptide Y; protein kinase A; snRNA-seq; spatial transcriptomics; transcription factor 4; transcriptional dysregulation.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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Navarro Quiroz R, Villarreal Camacho J, Zarate Peñata E, Bello Lemus Y, López-Fernández C, Gomez Escorcia L, Fernández-Ponce C, Rebolledo Cobos M, Fandiño Moreno J, Fiorillo-Moreno O, Navarro Quiroz E. Navarro Quiroz R, et al. Front Immunol. 2025 Jul 21;16:1563992. doi: 10.3389/fimmu.2025.1563992. eCollection 2025. Front Immunol. 2025. PMID: 40761781 Free PMC article. Review.

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Distinct molecular patterns in R6/2 HD mouse brain: Insights from spatiotemporal transcriptomics

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Distinct molecular patterns in R6/2 HD mouse brain: Insights from spatiotemporal transcriptomics

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