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BackgroundCognitive changes in type 1 myotonic dystrophy (DM1) have a pronounced negative effect on quality of life measures. Despite this, the neural basis of these changes is poorly understood. DM1 patients demonstrate deficits in motivation and cognitive flexibility, reflective of apathy and obsessive-compulsive / autistic-like traits.ObjectiveThese traits can be readily assessed using reversal learning and appetitive extinction tasks. Reversal learning assesses the ability to learn following a change in a rule and can evaluate cognitive flexibility and habitual responding, while appetitive extinction assesses the ability to suppress a stimulus-action response following the change in the stimulus-reward relationship from rewarded to non-rewarded.MethodsIn this study we evaluated the performance of a mouse model of DM1, the DMSXL mouse in reversal learning and appetitive extinction tasks.ResultsSimilar to C57/BL6 wild type (WT) mice, DMSXL mice were able to learn stimulus reward relationships, however, in the late phase of reversal learning experiment DMSXL mice demonstrated increased habit-like behavior (increased number of correct responses). Following rule switching, DMSXL mice produced an increased number of errors compared to WT and showed increased latency to deliver correct responses. In the extinction task, DMSXL mice showed the ability to more rapidly extinguish a previously rewarded response than WT mice.ConclusionsThese findings constitute differences in cognitive flexibility, rule learning and motivation between DMSXL and WT mice which may inform our understanding of cognitive changes in DM1.
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http://dx.doi.org/10.1177/22143602251339350 | DOI Listing |
J Neuromuscul Dis
July 2025
Department of Cognitive Neuroscience, Donders Institute for Brain Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
BackgroundCognitive changes in type 1 myotonic dystrophy (DM1) have a pronounced negative effect on quality of life measures. Despite this, the neural basis of these changes is poorly understood. DM1 patients demonstrate deficits in motivation and cognitive flexibility, reflective of apathy and obsessive-compulsive / autistic-like traits.
View Article and Find Full Text PDFComput Struct Biotechnol J
February 2025
Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, QC J1E 4K8, Canada.
Myotonic Dystrophy type 1 (DM1) is caused by a CTG repeat expansion in the 3' untranslated region of the DMPK gene. This expansion leads to the production of toxic RNA transcripts, which accumulate in the nucleus and interfere with normal RNA processing. DM1 affects a broad range of tissues and systems such as the skeletal muscle, the central nervous system, cardiac, visual, reproductive, and gastrointestinal (GI) system.
View Article and Find Full Text PDFClin Transl Med
February 2025
Institute of Biochemistry and Cell Biology, CNR, Rome, Italy.
Background: Myotonic dystrophy type 1 (DM1) is a genetic multisystemic disease, characterised by pleiotropic symptoms that exhibit notable variability in severity, nature and age of onset. The genetic cause of DM1 is the expansion of unstable CTG-repeats in the 3' untranslated region (UTR) of the DMPK gene, resulting in the accumulation of toxic CUG-transcripts that sequester RNA-binding proteins and form nuclear foci in DM1 affected tissues and, consequently, alter various cellular processes. Therapeutic gene editing for treatment of monogenic diseases is a powerful technology that could in principle remove definitively the disease-causing genetic defect.
View Article and Find Full Text PDFCommun Med (Lond)
January 2025
Dyne Therapeutics Inc, Waltham, MA, USA.
Background: We developed the FORCE platform to overcome limitations of oligonucleotide delivery to muscle and enable their applicability to neuromuscular disorders. The platform consists of an antigen-binding fragment, highly specific for the human transferrin receptor 1 (TfR1), conjugated to an oligonucleotide via a cleavable valine-citrulline linker. Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by expanded CUG triplets in the DMPK RNA, which sequester splicing proteins in the nucleus, lead to spliceopathy, and drive disease progression.
View Article and Find Full Text PDFBiomed Pharmacother
November 2024
Cardiovascular Research Program, VA New York Harbor Healthcare System, New York, NY, USA; Department of Medicine, Cell Biology and Pharmacology, State University of New York Downstate Health Sciences University, New York, NY, USA; Department of Medicine, NYU Langone School of Medicine, New Yor
Background: Myotonic dystrophy type 1 (DM1) is a multiorgan disorder with significant cardiac involvement. ECG abnormalities, including arrhythmias, occur in 80 % of DM1 patients and are the second-most common cause of death after respiratory complications; however, the mechanisms underlying the arrhythmogenesis remain unclear. The objective of this study was to investigate the basis of the electrophysiological abnormalities in DM1 using the DMSXL mouse model.
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