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Complex cognitive and motivational deficits precede motor dysfunction in the zQ175 (190 CAG repeat) Huntington's disease model

D.J. Harrison, P. Linehan, Y. Patel, Zubeyde Bayram-Weston Orcid Logo, A.E. Rosser, S.B. Dunnett, S.P. Brooks, M.J. Lelos

Experimental Neurology, Volume: 392, Issue: 115350, Start page: 115350

Swansea University Author: Zubeyde Bayram-Weston Orcid Logo

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DOI (Published version): 10.1016/j.expneurol.2025.115350

Abstract

Huntington's disease (HD) is a progressive, inherited neurodegenerative disorder characterised by motor, cognitive, and neuropsychiatric dysfunction for which several mouse models have been developed. Knock-in models, such as zQ175, retain the genetic context observed in people with HD by intro...

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Published in: Experimental Neurology
ISSN: 0014-4886
Published: Elsevier BV 2025
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URI: https://cronfa.swan.ac.uk/Record/cronfa70352
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In this study, we conducted a comprehensive, longitudinal analysis of phenotypic changes in the zQ175 mouse, with a focus on exploring the emergence of complex cognitive processes. Our findings indicate that robust cognitive and motivational deficits precede motor dysfunction in this model, with some apparent sex differences. Specifically, male zQ175 mice were slower to habituate to a novel environment and they showed impaired sensorimotor gating, in comparison to female mice. By 12 weeks old, cognitive deficits were observed in zQ175 mice of both sexes on a Pavlovian classical conditioning task. Reduced motivation to work for reward was identified as early as 27 weeks, while attentional and visuospatial deficits were also detected in the 5-choice serial reaction time task. Implicit learning deficits were identified at 30 weeks. zQ175 mice were hypoactive at &#x223C;24 weeks but became hyperactive by 60 weeks of age. Motor impairments emerged by 24 weeks for females and 48 weeks for males. Thus, we observed a wide range of cognitive deficits (attentional, visuospatial, sensorimotor, instrumental and implicit learning), as well as a gradual progression of motor changes. 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spelling 2025-10-24T11:02:30.5205791 v2 70352 2025-09-15 Complex cognitive and motivational deficits precede motor dysfunction in the zQ175 (190 CAG repeat) Huntington's disease model 93ba509b96e1eacf70cd2afd51361094 0000-0003-4560-8186 Zubeyde Bayram-Weston Zubeyde Bayram-Weston true false 2025-09-15 HSOC Huntington's disease (HD) is a progressive, inherited neurodegenerative disorder characterised by motor, cognitive, and neuropsychiatric dysfunction for which several mouse models have been developed. Knock-in models, such as zQ175, retain the genetic context observed in people with HD by introducing CAG repeats into the native huntingtin gene. In this study, we conducted a comprehensive, longitudinal analysis of phenotypic changes in the zQ175 mouse, with a focus on exploring the emergence of complex cognitive processes. Our findings indicate that robust cognitive and motivational deficits precede motor dysfunction in this model, with some apparent sex differences. Specifically, male zQ175 mice were slower to habituate to a novel environment and they showed impaired sensorimotor gating, in comparison to female mice. By 12 weeks old, cognitive deficits were observed in zQ175 mice of both sexes on a Pavlovian classical conditioning task. Reduced motivation to work for reward was identified as early as 27 weeks, while attentional and visuospatial deficits were also detected in the 5-choice serial reaction time task. Implicit learning deficits were identified at 30 weeks. zQ175 mice were hypoactive at ∼24 weeks but became hyperactive by 60 weeks of age. Motor impairments emerged by 24 weeks for females and 48 weeks for males. Thus, we observed a wide range of cognitive deficits (attentional, visuospatial, sensorimotor, instrumental and implicit learning), as well as a gradual progression of motor changes. This detailed phenotypic timeline establishes the face validity of this model insofar as these mice present with complex neuropsychiatric and cognitive impairments that are evident in people with HD. Journal Article Experimental Neurology 392 115350 115350 Elsevier BV 0014-4886 Huntington&apos;s disease; zQ175; Mouse model; Cognition; Neuropsychiatric; Motor; Behaviour 1 10 2025 2025-10-01 10.1016/j.expneurol.2025.115350 COLLEGE NANME Health and Social Care School COLLEGE CODE HSOC Swansea University Another institution paid the OA fee This project was funded by CHDI (the Cure Huntington's Disease Initiative) charity, an MRC grant (MR/T033428/1), with support from the Hodge Centre for Translational Neuroscience. 2025-10-24T11:02:30.5205791 2025-09-15T10:20:10.5095636 Faculty of Medicine, Health and Life Sciences School of Health and Social Care - Healthcare Science D.J. Harrison 1 P. Linehan 2 Y. Patel 3 Zubeyde Bayram-Weston 0000-0003-4560-8186 4 A.E. Rosser 5 S.B. Dunnett 6 S.P. Brooks 7 M.J. Lelos 8 70352__35468__72d83bf2951b474f8a54664c3d75c6f2.pdf 70352.VoR.pdf 2025-10-24T10:27:54.1884013 Output 5522235 application/pdf Version of Record true © 2025 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license. true eng http://creativecommons.org/licenses/by/4.0/
title Complex cognitive and motivational deficits precede motor dysfunction in the zQ175 (190 CAG repeat) Huntington's disease model
spellingShingle Complex cognitive and motivational deficits precede motor dysfunction in the zQ175 (190 CAG repeat) Huntington's disease model
Zubeyde Bayram-Weston
title_short Complex cognitive and motivational deficits precede motor dysfunction in the zQ175 (190 CAG repeat) Huntington's disease model
title_full Complex cognitive and motivational deficits precede motor dysfunction in the zQ175 (190 CAG repeat) Huntington's disease model
title_fullStr Complex cognitive and motivational deficits precede motor dysfunction in the zQ175 (190 CAG repeat) Huntington's disease model
title_full_unstemmed Complex cognitive and motivational deficits precede motor dysfunction in the zQ175 (190 CAG repeat) Huntington's disease model
title_sort Complex cognitive and motivational deficits precede motor dysfunction in the zQ175 (190 CAG repeat) Huntington's disease model
author_id_str_mv 93ba509b96e1eacf70cd2afd51361094
author_id_fullname_str_mv 93ba509b96e1eacf70cd2afd51361094_***_Zubeyde Bayram-Weston
author Zubeyde Bayram-Weston
author2 D.J. Harrison
P. Linehan
Y. Patel
Zubeyde Bayram-Weston
A.E. Rosser
S.B. Dunnett
S.P. Brooks
M.J. Lelos
format Journal article
container_title Experimental Neurology
container_volume 392
container_issue 115350
container_start_page 115350
publishDate 2025
institution Swansea University
issn 0014-4886
doi_str_mv 10.1016/j.expneurol.2025.115350
publisher Elsevier BV
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str School of Health and Social Care - Healthcare Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}School of Health and Social Care - Healthcare Science
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description Huntington's disease (HD) is a progressive, inherited neurodegenerative disorder characterised by motor, cognitive, and neuropsychiatric dysfunction for which several mouse models have been developed. Knock-in models, such as zQ175, retain the genetic context observed in people with HD by introducing CAG repeats into the native huntingtin gene. In this study, we conducted a comprehensive, longitudinal analysis of phenotypic changes in the zQ175 mouse, with a focus on exploring the emergence of complex cognitive processes. Our findings indicate that robust cognitive and motivational deficits precede motor dysfunction in this model, with some apparent sex differences. Specifically, male zQ175 mice were slower to habituate to a novel environment and they showed impaired sensorimotor gating, in comparison to female mice. By 12 weeks old, cognitive deficits were observed in zQ175 mice of both sexes on a Pavlovian classical conditioning task. Reduced motivation to work for reward was identified as early as 27 weeks, while attentional and visuospatial deficits were also detected in the 5-choice serial reaction time task. Implicit learning deficits were identified at 30 weeks. zQ175 mice were hypoactive at ∼24 weeks but became hyperactive by 60 weeks of age. Motor impairments emerged by 24 weeks for females and 48 weeks for males. Thus, we observed a wide range of cognitive deficits (attentional, visuospatial, sensorimotor, instrumental and implicit learning), as well as a gradual progression of motor changes. This detailed phenotypic timeline establishes the face validity of this model insofar as these mice present with complex neuropsychiatric and cognitive impairments that are evident in people with HD.
published_date 2025-10-01T05:32:26Z
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