The dorsal raphe nucleus in the control of energy balance

Bhave, Varun; Nectow, Alexander R.

doi:10.1016/j.tins.2021.09.004

Cited by 20 publications

(15 citation statements)

References 151 publications

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“…In those studies, we found that a GABAergic subpopulation is activated by fasting and increases food intake, while a glutamatergic (Vglut3) subpopulation is activated by refeeding and reduces food intake (DRN Vglut3 ) 6 . The DRN, located in the brainstem just below the cerebral aqueduct, is a key hub in the central nervous system that is responsible for coordinating numerous physiologic and behavioral functions 8 . These functions include, but are not limited to, regulation of emotional state, mediating social interactions and conveying pain 9 – 11 .…”

Section: Mainmentioning

confidence: 99%

Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction

et al. 2022

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Food intake and body weight are tightly regulated by neurons within specific brain regions, including the brainstem, where acute activation of dorsal raphe nucleus (DRN) glutamatergic neurons expressing the glutamate transporter Vglut3 (DRNVglut3) drive a robust suppression of food intake and enhance locomotion. Activating Vglut3 neurons in DRN suppresses food intake and increases locomotion, suggesting that modulating the activity of these neurons might alter body weight. Here, we show that DRNVglut3 neurons project to the lateral hypothalamus (LHA), a canonical feeding center that also reduces food intake. Moreover, chronic DRNVglut3 activation reduces weight in both leptin-deficient (ob/ob) and leptin-resistant diet-induced obese (DIO) male mice. Molecular profiling revealed that the orexin 1 receptor (Hcrtr1) is highly enriched in DRN Vglut3 neurons, with limited expression elsewhere in the brain. Finally, an orally bioavailable, highly selective Hcrtr1 antagonist (CVN45502) significantly reduces feeding and body weight in DIO. Hcrtr1 is also co-expressed with Vglut3 in the human DRN, suggesting that there might be a similar effect in human. These results identify a potential therapy for obesity by targeting DRNVglut3 neurons while also establishing a general strategy for developing drugs for central nervous system disorders.

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Section: Mainmentioning

confidence: 99%

Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction

et al. 2022

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“…In support of this, stimulation of hindbrain leptin receptors decreases food intake and body weight in rats (54), and a more recent study also in rats showed that decreasing the leptin receptor-expressing neurons in the hindbrain attenuates the response to leptin ( 55 Although a few studies suggest the regulation of food intake by leptin action in raphe neurons, the mechanisms underlying this phenomena remain unclear (57). Therefore, we focused our attention on the DRN, an area of the brainstem that was previously explored but with disparate results.…”

Section: Discussionmentioning

confidence: 94%

Leptin activation of dorsal raphe neurons inhibits feeding behavior

Maxwell

Smiley

Sadek

et al. 2023

Preprint

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Leptin is a homeostatic regulatory element that signals the presence of energy stores -in the form of adipocytes- which ultimately reduces food intake and increases energy expenditure. Similarly, serotonin (5-HT), a signaling molecule found in both the central and peripheral nervous systems, also regulates food intake. Here we use a combination of pharmacological manipulations, optogenetics, retrograde tracing, and in situ hybridization, combined with behavioral endpoints to physiologically and anatomically identify a novel leptin-mediated pathway between 5-HT neurons in the dorsal raphe nucleus (DRN) and hypothalamic arcuate nucleus (ARC) that controls food intake. In this study, we show that microinjecting leptin directly into the DRN reduces food intake in male Sprague-Dawley rats. This effect is mediated by leptin-receptor expressing neurons in the DRN as selective optogenetic activation of these neurons at either their ARC terminals or DRN cell bodies also reduces food intake. Anatomically, we identified a unique population of serotonergic raphe neurons expressing leptin receptors that send projections to the ARC. Finally, by utilizing in vivo microdialysis and high-performance liquid chromatography, we show that leptin administration to the DRN increases 5-HT efflux into the ARC. Overall, this study identifies a novel circuit for leptin-mediated control of food intake through a DRN-ARC pathway, utilizing 5-HT as a mechanism to control feeding behavior. Characterization of this new pathway creates opportunities for understanding how the brain controls eating behavior, as well as opens alternative routes for the treatment of eating disorders.

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“…6h ), contains gene Ucn, Slc5a7, Chodl, etc (Supplementary Fig. 9d ), significantly enriches in the sub-region of dorsal raphe nucleus (DRN) 70 . Accordingly, the identified MEGLU14 neurons (marked genes: Cartpt, Ucn, and Chodl) specifically populate in this region (Fig.…”

Section: Resultsmentioning

confidence: 99%

Spatial-ID: a cell typing method for spatially resolved transcriptomics via transfer learning and spatial embedding

Shen

Liu

et al. 2022

Nat Commun

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Spatially resolved transcriptomics provides the opportunity to investigate the gene expression profiles and the spatial context of cells in naive state, but at low transcript detection sensitivity or with limited gene throughput. Comprehensive annotating of cell types in spatially resolved transcriptomics to understand biological processes at the single cell level remains challenging. Here we propose Spatial-ID, a supervision-based cell typing method, that combines the existing knowledge of reference single-cell RNA-seq data and the spatial information of spatially resolved transcriptomics data. We present a series of benchmarking analyses on publicly available spatially resolved transcriptomics datasets, that demonstrate the superiority of Spatial-ID compared with state-of-the-art methods. Besides, we apply Spatial-ID on a self-collected mouse brain hemisphere dataset measured by Stereo-seq, that shows the scalability of Spatial-ID to three-dimensional large field tissues with subcellular spatial resolution.

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The dorsal raphe nucleus in the control of energy balance

Cited by 20 publications

References 151 publications

Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction

Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction

Leptin activation of dorsal raphe neurons inhibits feeding behavior

Spatial-ID: a cell typing method for spatially resolved transcriptomics via transfer learning and spatial embedding

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