Hcn1-dependent engram neurons in the PVN encode gastric inflammatory sensitization.

Abstract

The brain encodes peripheral inflammatory signals, but the regulatory mechanism by which the brain controls gastric inflammation remains unclear. This study reveals a circuit through which Fos-positive neurons in the paraventricular nucleus of the hypothalamus (PVN) regulate gastritis via a PVN-dorsal motor nucleus of the vagus-stomach neural circuit and the hypothalamic-pituitary-adrenal (HPA) axis. Using activity-dependent genetic labeling, chemogenetics, and optogenetics, we demonstrate that Fos^PVN neurons are essential for gastritis progression and can be activated by stress to drive chronic inflammation. Single-nucleus RNA sequencing (snRNA-seq) revealed up-regulation of hyperpolarization-activated cyclic nucleotide-gated channel 1 (<i>Hcn1</i>) in Fos^PVN neurons during gastritis. Inhibiting Hcn1 reduced neuronal excitability and ameliorated gastric pathology. Crucially, repeated activation of Fos^PVN neurons forms a specific "inflammatory sensitization," leading to the persistence of disease, whereas stress can exacerbate gastric inflammation through these Fos^PVN neurons. Our findings elucidate the central neural mechanisms encoding gastric inflammation and identify Hcn1 as a potential therapeutic target for neuromodulatory treatment of chronic inflammatory diseases.