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Exploring the link between hedonic overeating and prefrontal cortex dysfunction in the Ts65Dn trisomic mouse model

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Abstract

Individuals with Down syndrome (DS) have a higher prevalence of obesity compared to the general population. Conventionally, this has been attributed to endocrine issues and lack of exercise. However, deficits in neural reward responses and dopaminergic disturbances in DS may be contributing factors. To investigate this, we focused on a mouse model (Ts65Dn) bearing some triplicated genes homologous to trisomy 21. Through detailed meal pattern analysis in male Ts65Dn mice, we observed an increased preference for energy-dense food, pointing towards a potential “hedonic” overeating behavior. Moreover, trisomic mice exhibited higher scores in compulsivity and inflexibility tests when limited access to energy-dense food and quinine hydrochloride adulteration were introduced, compared to euploid controls. Interestingly, when we activated prelimbic-to-nucleus accumbens projections in Ts65Dn male mice using a chemogenetic approach, impulsive and compulsive behaviors significantly decreased, shedding light on a promising intervention avenue. Our findings uncover a novel mechanism behind the vulnerability to overeating and offer potential new pathways for tackling obesity through innovative interventions.

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Acknowledgements

Figure 6a–b were created with BioRender.com. We acknowledge the PRBB animal facility, and the CRG histology facility. We thank the Advanced Light Microscopy Unit (ALMU) at the CRG for their support in the confocal data acquisition process.

Funding

This work was supported by the Fondation Jérôme Lejeune #2002 (MD, MML, MF, AF), MINECO (PID2019-110755RB-I00/AEI/1013039/501100011033, RTC2019-007230-1 and RTC2019-007329-1 (MD, AF, MML, IT), Fundació La Marató De TV3 (201620-31) (EM.G, MD, MML, MF, IT) and 202212-30-31-32 (MD, MML, AFB), European Union’s Horizon 2020 research and innovation programme under grant agreement No 848077 (MD, MML, MF, AF), Brain Initiative (1R01EB 028159-01) (MD, MML) and grants from Université de Paris and CNRS (JD and NJ). ‘Plan Nacional Sobre Drogas of the Spanish Ministry of Health’ (#PNSD-2019I006) and Spanish Ministerio de Ciencia e Innovación (ERA-NET) PCI2021-122073-2A to E.M.-G. The laboratory of MD is supported by DIUE de la Generalitat de Catalunya (Grups Consolidats 2017 SGR 926). We acknowledge the support of the Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa (CEX2020-001049-S, MCIN/AEI/10.13039/501100011033), and the Generalitat de Catalunya through the CERCA programme. The CIBER of Rare Diseases is an initiative of the ISCIII. CS received the FI grant from Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) de la Generalitat de Catalunya, AFB received an FPI-SO fellowship (PRE2018-084504). J.D also acknowledges the Mass spectrometry platform of UMR 8601 laboratory.

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Author notes

  1. Marta Fructuoso and Álvaro Fernández-Blanco have contributed equally to this study.

Authors and Affiliations

  1. Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, 08003, Barcelona, Spain

    Marta Fructuoso, Álvaro Fernández-Blanco, Cèsar Sierra, María Martínez de Lagrán, Nicola Lorenzon, Ilario De Toma & Mara Dierssen

  2. Laboratory of Neuropharmacology-Neurophar, Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain

    Ana Gallego-Román, Elena Martín-García, Rafael Maldonado & Mara Dierssen

  3. Human Pharmacology and Clinical Neurosciences Research Group, Neurosciences Research Program, Hospital Del Mar Medical Research Institute (IMIM), 08003, Barcelona, Spain

    Klaus Langohr, Elena Martín-García, Rafael Maldonado & Mara Dierssen

  4. Departament de Psicobiologia i Metodologia de Les Ciències de la Salut, Universitat Autònoma de Barcelona (UAB), Cerdanyola del Vallès, Barcelona, Spain

    Elena Martín-García & Julien Dairou

  5. Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologique, UMR 8601, CNRS, Université de Paris, 75013, Paris, France

    Elena Martín-García & Julien Dairou

  6. BFA, UMR 8251, CNRS, Université de Paris, 75013, Paris, France

    Nathalie Janel

  7. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

    Mara Dierssen

  8. Department of Statistics and Operations Research, Universitat Politècnica de Catalunya/ BARCELONATECH, Barcelona, Spain

    Klaus Langohr

Authors
  1. Marta Fructuoso
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Contributions

MD, MF, ÁF, EM and RM designed the experiments and discussed the results. MF, ÁF, AG and MMdL performed the experiments and MF, ÁF and AG analyzed the behavioral studies. MF, JD, and NJ performed and analyzed the bioamine determination by HPLC. CS quantified the expression of Ddr1 and Ddr2 by q-PCR. NL contributed to the acquisition of confocal images. IdT performed the correlations and statistical analysis between the behavioral and the brain bioamine’s data. MF, and ÁF did the statistical analysis of the results. MF, ÁF and MD wrote the manuscript. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Mara Dierssen.

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The authors declare no competing financial interests.

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All experimental procedures were approved by the local ethical committee (Comité Ético de Experimentación Animal del PRBB (CEEA-PRBB); procedure number MDS-12-1464P3), and met the guidelines of the local (law 32/2007) and European regulations (EU directive n° 86/609, EU decree 2001-486) and the Standards for the use of Laboratory Animals n° A5388-01 (NIH).

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Fructuoso, M., Fernández-Blanco, Á., Gallego-Román, A. et al. Exploring the link between hedonic overeating and prefrontal cortex dysfunction in the Ts65Dn trisomic mouse model. Cell. Mol. Life Sci. 80, 370 (2023). https://doi.org/10.1007/s00018-023-05009-x

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