Effects of mutant huntingtin in oxytocin neurons on non‐motor features of Huntington's disease
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Published:2023-03-05
Issue:2
Volume:49
Page:
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ISSN:0305-1846
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Container-title:Neuropathology and Applied Neurobiology
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language:en
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Short-container-title:Neuropathology Appl Neurobio
Author:
Bergh Sofia1,
Gabery Sanaz1,
Tonetto Simone1,
Kirik Deniz2,
Petersén Åsa1ORCID,
Cheong Rachel Y.1ORCID
Affiliation:
1. Translational Neuroendocrine Research Unit, Department of Experimental Medical Science Lund University Lund Sweden
2. Brain Repair and Imaging in Neural Systems (BRAINS) Unit, Department of Experimental Medical Science Lund University Lund Sweden
Abstract
AbstractBackgroundEarly non‐motor features including anxiety, depression and altered social cognition are present in Huntington's disease (HD). The underlying neurobiological mechanisms are not known. Oxytocin (OXT) is involved in the regulation of emotion, social cognition and metabolism, and our previous work showed that the OXT system is affected early in HD. The aim of the study was to investigate the potential causal relationship between the selective expression of mutant huntingtin (mHTT) in OXT neurons and the development of non‐motor features and neuropathology.MethodsTo express mHTT only in OXT neurons, we used a novel flex‐switch adeno‐associated viral vector design to selectively express either mHTT or wild‐type HTT in the paraventricular nucleus of the hypothalamus using OXT‐Cre‐recombinase mice. We also performed a mirror experiment to selectively delete mHTT in OXT neurons using the BACHD mouse model. Mice underwent a battery of behavioural tests to assess psychiatric and social behaviours 3 months post‐injection or at 2 months of age, respectively. Post‐mortem analyses were performed to assess the effects on the OXT system.ResultsOur results show that selective expression of mHTT in OXT neurons was associated with the formation of mHTT inclusions and a 26% reduction of OXT‐immunopositive neurons as well as increased anxiety‐like behaviours compared with uninjected mice. However, selective deletion of mHTT from OXT neurons alone was not sufficient to alter the metabolic and psychiatric phenotype of the BACHD mice at this early time point.ConclusionsOur results indicate that mHTT expression can exert cell‐autonomous toxic effects on OXT neurons without affecting the non‐motor phenotype at early time points in mice.
Funder
Åhlén-stiftelsen
Fredrik och Ingrid Thurings Stiftelse
Hjärnfonden
Kungliga Fysiografiska Sällskapet i Lund
Svenska Sällskapet för Medicinsk Forskning
Vetenskapsrådet
Subject
Physiology (medical),Neurology (clinical),Neurology,Histology,Pathology and Forensic Medicine
Cited by
1 articles.
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1. Corrigendum;Neuropathology and Applied Neurobiology;2023-05-06