Serotonin activates paraventricular thalamic neurons through direct depolarization and indirect disinhibition from zona incerta.

Paraventricular thalamus (PVT) is a midline thalamic area that receives dense GABA projections from zona incerta (ZI) for the regulation of feeding behaviours. Activation of central serotonin (5‐HT) signalling is known to inhibit food intake. Although previous studies have reported both 5‐HT fibres and receptors in the PVT, it remains unknown how 5‐HT regulates PVT neurons and whether PVT 5‐HT signalling is involved in the control of food intake. Using slice patch‐clamp recordings in combination with optogenetics, we found that 5‐HT not only directly excited PVT neurons by activating 5‐HT7 receptors to modulate hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels but also disinhibited these neurons by acting on presynaptic 5‐HT1A receptors to reduce GABA inhibition. Specifically, 5‐HT depressed photostimulation‐evoked inhibitory postsynaptic currents (eIPSCs) in PVT neurons innervated by channelrhodopsin‐2‐positive GABA axons from ZI. Using paired‐pulse photostimulation, we found 5‐HT increased paired‐pulse ratios of eIPSCs, suggesting 5‐HT decreases ZI–PVT GABA release. Furthermore, we found that exposure to a high‐fat–high‐sucrose diet for 2 weeks impaired both 5‐HT inhibition of ZI–PVT GABA transmission and 5‐HT excitation of PVT neurons. Using retrograde tracer in combination with immunocytochemistry and slice electrophysiology, we found that PVT‐projecting dorsal raphe neurons expressed 5‐HT and were inhibited by food deprivation. Together, our study reveals the mechanism by which 5‐HT activates PVT neurons through both direct excitation and indirect disinhibition from the ZI. The downregulation in 5‐HT excitation and disinhibition of PVT neurons may contribute to the development of overeating and obesity after chronic high‐fat diet. Key points: Serotonin (5‐HT) depolarizes and excites paraventricular thalamus (PVT) neurons. 5‐HT7 receptors are responsible for 5‐HT excitation of PVT neurons and the coupling of hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels to 5‐HT receptors in part mediates the excitatory effect of 5‐HT.5‐HT depresses the frequency of spontaneous inhibitory but not excitatory postsynaptic currents in PVT neurons. 5‐HT1A receptors contribute to the depressive effect of 5‐HT on inhibitory transmissions.5‐HT inhibits GABA release from zona incerta (ZI) GABA terminals in PVT.Chronic high‐fat diet not only impairs 5‐HT inhibition of the ZI–PVT GABA transmission but also downregulates 5‐HT excitation of PVT neurons.PVT‐projecting dorsal raphe neurons express 5‐HT and are inhibited by food deprivation. [ABSTRACT FROM AUTHOR]