Browsing by Author "Dietrich, Marcelo O"
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- A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineagesPublication . Pereira, Mafalda M. A.; Mahú, Inês; Seixas, Elsa; Martinéz-Sánchez, Noelia; Kubasova, Nadiya; Pirzgalska, Roksana M; Cohen, Paul; Dietrich, Marcelo O; López, Miguel; Bernardes, Gonçalo J. L.; Domingos, Ana I.Conditional expression of diphtheria toxin receptor (DTR) is widely used for tissue-specific ablation of cells. However, diphtheria toxin (DT) crosses the blood-brain barrier, which limits its utility for ablating peripheral cells using Cre drivers that are also expressed in the central nervous system (CNS). Here we report the development of a brain-sparing DT, termed BRAINSPAReDT, for tissue-specific genetic ablation of cells outside the CNS. We prevent blood-brain barrier passage of DT through PEGylation, which polarizes the molecule and increases its size. We validate BRAINSPAReDT with regional genetic sympathectomy: BRAINSPAReDT ablates peripheral but not central catecholaminergic neurons, thus avoiding the Parkinson-like phenotype associated with full dopaminergic depletion. Regional sympathectomy compromises adipose tissue thermogenesis, and renders mice susceptible to obesity. We provide a proof of principle that BRAINSPAReDT can be used for Cre/DTR tissue-specific ablation outside the brain using CNS drivers, while consolidating the link between adiposity and the sympathetic nervous system.
- Hypothalamic melanin concentrating hormone neurons communicate the nutrient value of sugarPublication . Domingos, Ana I; Sordillo, Aylesse; Dietrich, Marcelo O; Liu, Zhong-Wu; Tellez, Luis A; Vaynshteyn, Jake; Ferreira, Jozelia G; Ekstrand, Mats I; Horvath, Tamas L; de Araujo, Ivan E; Friedman, Jeffrey MSugars that contain glucose, such as sucrose, are generally preferred to artificial sweeteners owing to their post-ingestive rewarding effect, which elevates striatal dopamine (DA) release. While the post-ingestive rewarding effect, which artificial sweeteners do not have, signals the nutrient value of sugar and influences food preference, the neural circuitry that mediates the rewarding effect of glucose is unknown. In this study, we show that optogenetic activation of melanin-concentrating hormone (MCH) neurons during intake of the artificial sweetener sucralose increases striatal dopamine levels and inverts the normal preference for sucrose vs sucralose. Conversely, animals with ablation of MCH neurons no longer prefer sucrose to sucralose and show reduced striatal DA release upon sucrose ingestion. We further show that MCH neurons project to reward areas and are required for the post-ingestive rewarding effect of sucrose in sweet-blind Trpm5(-/-) mice. These studies identify an essential component of the neural pathways linking nutrient sensing and food reward. DOI: http://dx.doi.org/10.7554/eLife.01462.001.