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Mol Metab. 2017 Jun 7;6(8):909-921. doi: 10.1016/j.molmet.2017.06.002. eCollection 2017 Aug.

Serotonergic modulation of the activity of GLP-1 producing neurons in the nucleus of the solitary tract in mouse.

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Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, University College London, London, WC1E 6BT, UK.
Cardiovascular Medicine, Human Physiology and Centre for Neuroscience, Flinders University, Bedford Park, SA 5042, Australia.
Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.
Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, University College London, London, WC1E 6BT, UK. Electronic address:



Glucagon-like peptide-1 (GLP-1) and 5-HT are potent regulators of food intake within the brain. GLP-1 is expressed by preproglucagon (PPG) neurons in the nucleus tractus solitarius (NTS). We have previously shown that PPG neurons innervate 5-HT neurons in the ventral brainstem. Here, we investigate whether PPG neurons receive serotonergic input and respond to 5-HT.


We employed immunohistochemistry to reveal serotonergic innervation of PPG neurons. We investigated the responsiveness of PPG neurons to 5-HT using in vitro Ca2+ imaging in brainstem slices from transgenic mice expressing the Ca2+ indicator, GCaMP3, in PPG neurons, and cell-attached patch-clamp recordings.


Close appositions from 5-HT-immunoreactive axons occurred on many PPG neurons. Application of 20 μM 5-HT produced robust Ca2+ responses in NTS PPG dendrites but little change in somata. Dendritic Ca2+ spikes were concentration-dependent (2, 20, and 200 μM) and unaffected by blockade of glutamatergic transmission, suggesting 5-HT receptors on PPG neurons. Neither activation nor blockade of 5-HT3 receptors affected [Ca2+]i. In contrast, inhibition of 5-HT2 receptors attenuated increases in intracellular Ca2+ and 5-HT2C receptor activation produced Ca2+ spikes. Patch-clamp recordings revealed that 44% of cells decreased their firing rate under 5-HT, an effect blocked by 5-HT1A receptor antagonism.


PPG neurons respond directly to 5-HT with a 5-HT2C receptor-dependent increase in dendritic [Ca2+]i. Electrical responses to 5-HT revealed additional inhibitory effects due to somatic 5-HT1A receptors. Reciprocal innervation between 5-HT and PPG neurons suggests that the coordinated activity of these brainstem neurons may play a role in the regulation of food intake.


5-HT, 5-hydroxytryptamine; CCK-8, cholecystokinin-8; CNS, central nervous system; Dendritic calcium; GCaMP; GLP-1, glucagon-like peptide-1; HPA, hypothalamic–pituitary–adrenal; IRT, intermediate reticular nucleus; NTS; NTS, nucleus tractus solitarius; PBN, parabrachial nucleus; PPG, preproglucagon; Preproglucagon; Serotonin; YFP, yellow fluorescent protein

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