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Obesity is a growing global health epidemic with limited effective therapeutics. Serotonin (5-HT) is one major neurotransmitter which remains an excellent target for new weight-loss therapies, but there remains a gap in knowledge on the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using a closed-loop optogenetic feeding paradigm, we showed that the 5-HT→arcuate nucleus (ARH) circuit plays an important role in regulating meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HT neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response to GABAergic inputs can be enhanced by hunger. Additionally, deletion of the GABA receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the instrumental role of dopaminergic inputs via dopamine receptor D2 in 5-HT neurons in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HT neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, which allows for the initiation of a meal.
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http://dx.doi.org/10.1101/2024.04.26.591360 | DOI Listing |
J Cereb Blood Flow Metab
September 2025
Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
Functional PET (fPET) identifies stimulation-specific changes of physiological processes, individual molecular connectivity and group-level molecular covariance. Since there is currently no consistent analysis approach available for these techniques, we present a toolbox for unified fPET assessment. The toolbox supports analysis of data obtained with a variety of radiotracers, scanners, experimental protocols, cognitive tasks and species.
View Article and Find Full Text PDFAging Cell
September 2025
Division of Biomedical and Life Sciences, Lancaster University, Lancaster, UK.
Almost half of pregnant women globally are currently estimated to be overweight or obese. Rates of childhood obesity are also on the rise, in part because of increased consumption of dietary saturated fats. However, the long-term effect of peri- and postnatal high fat (HF) feeding on cognitive function and neuronal expression has not yet been investigated.
View Article and Find Full Text PDFMol Psychiatry
September 2025
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Waehringer Strasse 13A, 1090, Vienna, Austria.
The human monoamine transporters (MATs) for serotonin (SERT), dopamine (DAT), and norepinephrine (NET) play a key role in neurotransmission by transporting neurotransmitters from the synaptic cleft back into the neuron. MATs are embedded in the cell membrane's lipid bilayer, encompassing cholesterol, phospholipids, and sphingolipids as main components. Membrane cholesterol association has been shown for all MATs impacting transporter conformation, substrate affinity, transport velocity, and turnover rates.
View Article and Find Full Text PDFbioRxiv
August 2025
Department of Neuroscience and Department of Cell Biology, Yale University School of Medicine; New Haven, CT 06536, USA.
Understanding the organization and regulation of neurotransmission at the level of individual neurons and synapses requires tools that can track and manipulate transmitter-specific vesicles . Here, we present a suite of genetic tools in to fluorescently label and conditionally ablate the vesicular transporters for glutamate, GABA, acetylcholine, and monoamines. Using a structure-guided approach informed by protein topology and evolutionary conservation, we engineered endogenously tagged versions for each transporter that maintain their physiological function while allowing for cell-specific, bright, and stable visualization.
View Article and Find Full Text PDFbioRxiv
August 2025
Department of Biology, West Virginia University, Morgantown, United States of America.
Inhibitory local interneurons (LNs) play an essential role in sensory processing by refining stimulus representations via a diverse collection of mechanisms. The morphological and physiological traits of individual LN types, as well as their connectivity within sensory networks, enable each LN type to support different computations such as lateral inhibition or gain control and are therefore ideal targets for modulatory neurons to have widespread impacts on network activity. In this study, we combined detailed connectivity analyses, serotonin receptor expression, neurophysiology, and computational modeling to demonstrate the functional impact of serotonin on a constrained LN network in the olfactory system of .
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