Evolution of aberrant brain-wide spatiotemporal dynamics of resting-state networks in a Huntington's disease mouse model.

Publisher: Wiley Country of Publication: United States NLM ID: 101597971 Publication Model: Print Cited Medium: Internet ISSN: 2001-1326 (Electronic) Linking ISSN: 20011326 NLM ISO Abbreviation: Clin Transl Med Subsets: MEDLINE

Publication: 2020- : [Hoboken, NJ] : Wiley
Original Publication: Heidelberg : Springer-Verlag

Huntington Disease*/physiopathology ; Huntington Disease*/genetics ; Huntington Disease*/metabolism ; Huntington Disease*/pathology ; Disease Models, Animal* ; Brain*/physiopathology ; Brain*/diagnostic imaging ; Brain*/metabolism; Animals ; Mice ; Magnetic Resonance Imaging/methods ; Male ; Disease Progression

Background: Huntington's disease (HD) is marked by irreversible loss of neuronal function for which currently no availability for disease-modifying treatment exists. Advances in the understanding of disease progression can aid biomarker development, which in turn can accelerate therapeutic discovery.
Methods: We characterised the progression of altered dynamics of whole-brain network states in the zQ175DN mouse model of HD using a dynamic functional connectivity (FC) approach to resting-state fMRI and identified quasi-periodic patterns (QPPs) of brain activity constituting the most prominent resting-state networks.
Results: The occurrence of the normative QPPs, as observed in healthy controls, was reduced in the HD model as the phenotype progressed. This uncovered progressive cessation of synchronous brain activity with phenotypic progression, which is not observed with the conventional static FC approaches. To better understand the potential underlying cause of the observed changes in these brain states, we further assessed how mutant huntingtin (mHTT) protein deposition affects astrocytes and pericytes - one of the most important effectors of neurovascular coupling, along phenotypic progression. Increased cell-type dependent mHTT deposition was observed at the age of onset of motor anomalies, in the caudate putamen, somatosensory and motor cortex, regions that are prominently involved in HD pathology as seen in humans.
Conclusion: Our findings provide meaningful insights into the development and progression of altered functional brain dynamics in this HD model and open new avenues in assessing the dynamics of whole brain states, through QPPs, in clinical HD research.
Highlights: Hyperactivity in the LCN-linked regions within short QPPs observed before motor impairment onset. DMLN QPP presents a progressive decrease in DMLN activity and occurrence along HD-like phenotype development. Breakdown of the LCN DMLN state flux at motor onset leads to a subsequent absence of the LCN DMLN QPP at an advanced HD-like stage.
(© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Neuroimage. 2021 May 1;231:117827. (PMID: 33549755)
Clin Transl Med. 2024 Oct;14(10):e70055. (PMID: 39422700)
PLoS One. 2012;7(12):e50717. (PMID: 23284644)
Cereb Cortex Commun. 2020;1(1):tgaa044. (PMID: 32984817)
Ann Neurol. 2015 Aug;78(2):178-92. (PMID: 25914140)
Alzheimers Res Ther. 2018 Jan 09;10(1):1. (PMID: 29370870)
Ann N Y Acad Sci. 2023 Apr;1522(1):42-59. (PMID: 36864567)
Eur J Neurosci. 2014 Jul;40(2):2417-26. (PMID: 24698429)
Mov Disord. 2022 Feb;37(2):343-353. (PMID: 34752656)
Hum Brain Mapp. 2020 Jan;41(1):256-269. (PMID: 31532053)
Hum Mol Genet. 2024 Feb 18;33(5):387-399. (PMID: 37947186)
PLoS One. 2012;7(12):e49838. (PMID: 23284626)
Hum Brain Mapp. 2005 Sep;26(1):15-29. (PMID: 15852468)
Alzheimers Res Ther. 2022 Oct 10;14(1):148. (PMID: 36217211)
Neurobiol Dis. 2009 Sep;35(3):319-36. (PMID: 19464370)
Cytometry A. 2010 Jan;77(1):64-75. (PMID: 19821512)
Physiol Rev. 2009 Apr;89(2):607-48. (PMID: 19342615)
Neuroimage. 2019 May 1;191:193-204. (PMID: 30753928)
Neuron. 2014 Oct 22;84(2):262-74. (PMID: 25374354)
J Psychiatry Neurosci. 2014 Mar;39(2):87-96. (PMID: 24083458)
Ann Neurol. 2015 Aug;78(2):160-77. (PMID: 25866151)
Int J Dev Biol. 2011;55(3):261-8. (PMID: 21710434)
Radiology. 2010 Aug;256(2):598-606. (PMID: 20656843)
Sci Rep. 2018 Jul 3;8(1):10024. (PMID: 29968786)
Neurobiol Dis. 2024 Apr;193:106438. (PMID: 38365045)
Neuroimage Clin. 2013 Mar 14;2:377-84. (PMID: 24179791)
Trends Neurosci. 2000 Dec;23(12):599-605. (PMID: 11137149)
Mol Ther. 2013 Oct;21(10):1862-75. (PMID: 23799534)
J Neurosci. 2011 Aug 10;31(32):11597-616. (PMID: 21832190)
Glia. 2017 Jan;65(1):50-61. (PMID: 27615381)
Neurology. 2019 Sep 3;93(10):e1021-e1030. (PMID: 31371571)
Methods. 2015 Feb;73:18-26. (PMID: 25620005)
Neuroimage. 2021 Jan 15;225:117528. (PMID: 33157264)
Nat Methods. 2012 Jun 28;9(7):676-82. (PMID: 22743772)
PLoS One. 2020 Dec 28;15(12):e0243052. (PMID: 33370315)
Neuroimage. 2011 Jan 15;54(2):1140-50. (PMID: 20728554)
PLoS One. 2015 Apr 10;10(4):e0123527. (PMID: 25859666)
Nature. 2014 Apr 3;508(7494):55-60. (PMID: 24670647)
Brain Res. 2000 Nov 10;883(1):87-97. (PMID: 11063991)
Neuroimage. 2018 Oct 15;180(Pt B):463-484. (PMID: 29454935)
Science. 2022 Sep 23;377(6613):eabq5011. (PMID: 36137051)
Neuroimage Clin. 2019;21:101653. (PMID: 30690417)
eNeuro. 2023 Jan 9;10(1):. (PMID: 36596592)
J Huntingtons Dis. 2020;9(3):217-229. (PMID: 32925079)
J Clin Invest. 2004 Jan;113(1):14-8. (PMID: 14702101)
Neurology. 2020 May 5;94(18):e1908-e1915. (PMID: 32265233)
Proc Natl Acad Sci U S A. 2016 Nov 1;113(44):12574-12579. (PMID: 27791099)
Neurobiol Dis. 2023 Jun 1;181:106095. (PMID: 36963694)
Cereb Cortex. 2020 Apr 14;30(4):2372-2388. (PMID: 31761935)
Nat Neurosci. 2014 May;17(5):694-703. (PMID: 24686787)
J Biomed Sci. 2024 Apr 16;31(1):37. (PMID: 38627751)
Sci Rep. 2023 Jun 23;13(1):10194. (PMID: 37353500)
Neurobiol Aging. 2010 Dec;31(12):2185-91. (PMID: 19185395)
J Neurosci Res. 2019 Dec;97(12):1624-1635. (PMID: 31353533)
Sci Transl Med. 2019 Oct 16;11(514):. (PMID: 31619545)
PLoS Biol. 2022 Aug 1;20(8):e3001735. (PMID: 35914002)
Proc Natl Acad Sci U S A. 2019 Mar 5;116(10):4689-4695. (PMID: 30782826)
Curr Protoc Neurosci. 2018 Apr;83(1):e47. (PMID: 30040221)
Front Integr Neurosci. 2014 May 27;8:41. (PMID: 24904325)
Fluids Barriers CNS. 2011 Jan 18;8(1):8. (PMID: 21349156)
Brain. 2021 Nov 29;144(10):3101-3113. (PMID: 34043007)
Med Image Anal. 1998 Jun;2(2):143-68. (PMID: 10646760)
Neurosci Biobehav Rev. 2013 Mar;37(3):480-90. (PMID: 23376047)
Proc Natl Acad Sci U S A. 2023 Jan 31;120(5):e2202435120. (PMID: 36693103)
Nat Neurosci. 2016 Aug;19(8):1100-14. (PMID: 27322419)
Commun Biol. 2021 Jan 19;4(1):86. (PMID: 33469150)
Front Neural Circuits. 2017 Feb 03;11:5. (PMID: 28217085)
Acta Neuropathol Commun. 2019 Jun 4;7(1):93. (PMID: 31164177)
J Magn Reson Imaging. 2009 Aug;30(2):384-93. (PMID: 19629982)
Adv Exp Med Biol. 2018;1049:1-28. (PMID: 29427096)
Neuron. 2021 Feb 3;109(3):545-559.e8. (PMID: 33290731)
Cell. 1993 Mar 26;72(6):971-83. (PMID: 8458085)
Brain Connect. 2013;3(1):31-40. (PMID: 23106103)
Handb Clin Neurol. 2017;144:247-261. (PMID: 28947121)
Hum Mol Genet. 2016 Sep 1;25(17):3654-3675. (PMID: 27378694)
Brain Commun. 2023 Jan 20;5(1):fcad010. (PMID: 36756307)
Neurobiol Aging. 2014 Feb;35(2):431-41. (PMID: 24074808)
Neuroimage. 2015 Jul 15;115:281-91. (PMID: 25913701)
J Neurophysiol. 2015 Apr 1;113(7):2953-66. (PMID: 25673747)
Proc Natl Acad Sci U S A. 2019 Oct 15;116(42):21219-21227. (PMID: 31570622)
Nat Rev Neurol. 2014 Apr;10(4):204-16. (PMID: 24614516)
J Neurophysiol. 2015 Jul;114(1):114-24. (PMID: 26041826)
Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):253-8. (PMID: 12506194)
Nat Rev Neurol. 2016 Aug;12(8):439-54. (PMID: 27364743)
iScience. 2020 Sep 07;23(9):101542. (PMID: 33083769)
Nat Rev Dis Primers. 2015 Apr 23;1:15005. (PMID: 27188817)
Cereb Cortex. 2014 Mar;24(3):663-76. (PMID: 23146964)
Biomed Pharmacother. 2018 Sep;105:1205-1222. (PMID: 30021357)
Neuroimage. 2000 Nov;12(5):582-7. (PMID: 11034865)
Front Cell Neurosci. 2019 Jun 28;13:282. (PMID: 31316352)
Trends Neurosci. 2017 Jul;40(7):422-437. (PMID: 28578789)
Nature. 2021 Oct;598(7879):188-194. (PMID: 34616074)
Neuroimage Clin. 2019;23:101913. (PMID: 31491822)
Science. 2020 Aug 14;369(6505):787-793. (PMID: 32675289)

CHDI Foundation, Inc.; Hercules Foundation; Flemish Government department EWI; OZ3544 Flemish Impulse; I000123N Research Foundation Flanders FWO; I003420N Research Foundation Flanders FWO

Keywords: Huntington's disease; VEGF; astrocytes; biomarkers; large‐scale brain networks; neurodegeneration; pericytes; quasi‐periodic patterns; resting‐state fMRI

Date Created: 20241018 Date Completed: 20241018 Latest Revision: 20241020

20250114

PMC11488302

10.1002/ctm2.70055

39422700