Hcn1-dependent engram neurons in the PVN encode gastric inflammatory memory [saline]

The brain encodes peripheral inflammatory signals, yet the mechanisms underlying the storage and retrieval of stomach-specific immune information remain unclear. This study reveals a novel pathway 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 FosPVN neurons are essential for gastritis progression and can be activated by stress to drive chronic inflammation. Single-nucleus RNA sequencing (snRNA-seq) revealed significant upregulation of hyperpolarization-activated cyclic nucleotide-gated channel 1 (Hcn1) in FosPVN neurons during gastritis. Inhibiting Hcn1 reduced neuronal excitability and ameliorated gastric pathology. Crucially, repeated activation of FosPVN neurons forms a specific "inflammatory memory" leading to the persistence of disease, while stress can exacerbate gastric inflammation through these FosPVN 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. Overall design: Single-nucleus RNA-sequencing of male mice with oral gavage of saline (saline group)