Mice with selective elimination of striatal acetylcholine release are lean, show altered energy homeostasis and changed sleep/wake cycle

Authors

  • Monica S. Guzman,

    1. Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada
    2. Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada
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  • Xavier De Jaeger,

    1. Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada
    2. Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada
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  • Maria Drangova,

    1. Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada
    2. Department of Medical Biophysics, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada
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  • Marco A. M. Prado,

    Corresponding author
    1. Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada
    2. Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada
    • Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada
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  • Robert Gros,

    Corresponding author
    1. Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada
    2. Department of Medicine, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada
    • Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada
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  • Vania F. Prado

    Corresponding author
    1. Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada
    2. Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada
    • Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada
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Address correspondence and reprint requests to Vania F. Prado and Robert Gros, Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON N6A5K8, Canada. E-mails: vprado@robarts.ca; rgros@robarts.ca

Abstract

Cholinergic neurons are known to regulate striatal circuits; however, striatal-dependent physiological outcomes influenced by acetylcholine (ACh) are still poorly under;?>stood. Here, we used vesicular acetylcholine transporter (VAChT)D2-Cre-flox/flox mice, in which we selectively ablated the vesicular acetylcholine transporter in the striatum to dissect the specific roles of striatal ACh in metabolic homeostasis. We report that VAChTD2-Cre-flox/flox mice are lean at a young age and maintain this lean phenotype with time. The reduced body weight observed in these mutant mice is not attributable to reduced food intake or to a decrease in growth rate. In addition, changed activity could not completely explain the lean phenotype, as only young VAChTD2-Cre-flox/flox mice showed increased physical activity. Interestingly, VAChTD2-Cre-flox/flox mice show several metabolic changes, including increased plasma levels of insulin and leptin. They also show increased periods of wakefulness when compared with littermate controls. Taken together, our data suggest that striatal ACh has an important role in the modulation of metabolism and highlight the importance of striatum cholinergic tone in the regulation of energy expenditure. These new insights on how cholinergic neurons influence homeostasis open new avenues for the search of drug targets to treat obesity.

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