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

Area of Science:

• Neuroscience
• Gastroenterology
• Immunology

Background:

• The brain's role in regulating peripheral inflammation, particularly gastric inflammation, is not fully understood.
• Existing knowledge gaps hinder the development of effective treatments for chronic inflammatory conditions.

Purpose of the Study:

• To elucidate the neural mechanisms by which the brain controls gastric inflammation.
• To identify specific neuronal circuits and molecular targets involved in regulating gastritis.

Main Methods:

• Utilized activity-dependent genetic labeling, chemogenetics, and optogenetics to investigate neuronal activity.
• Employed single-nucleus RNA sequencing (snRNA-seq) to identify molecular changes in relevant neurons.
• Assessed the impact of neuronal manipulation and molecular inhibition on gastric pathology.

Main Results:

• Identified a neural circuit involving Fos-positive neurons in the paraventricular nucleus of the hypothalamus (PVN) that regulates gastritis.
• Demonstrated that stress activates Fos^PVN neurons, promoting chronic inflammation and disease persistence.
• Discovered up-regulation of hyperpolarization-activated cyclic nucleotide-gated channel 1 (Hcn1) in Fos^PVN neurons during gastritis, with Hcn1 inhibition ameliorating pathology.

Conclusions:

• Fos^PVN neurons are critical regulators of gastric inflammation, mediating disease progression and inflammatory sensitization.
• Stress exacerbates gastritis through activation of the PVN-dorsal motor nucleus of the vagus-stomach neural circuit and the hypothalamic-pituitary-adrenal (HPA) axis.
• Hcn1 represents a promising therapeutic target for neuromodulatory treatments of chronic inflammatory diseases.