PVNOXT oxytocin neurons regulate pancreatic inflammation and enzyme secretion via DMVACh in HTGP mice
Background
The central nervous system plays a critical role in regulating visceral organ functions, including glandular secretions. However, the precise anatomical and functional connections between the brain and digestive enzyme-producing pancreatic acinar cells remain largely undefined. Hypertriglyceridemia-associated acute pancreatitis (HTGP) is a severe inflammatory condition of the pancreas, and understanding the neural pathways that influence its progression could unlock novel therapeutic strategies. Current treatments often focus on symptomatic relief, leaving a gap in addressing the underlying neuro-immune mechanisms that drive pancreatic inflammation.
Study Design
Researchers utilized a hypertriglyceridemia-associated acute pancreatitis (HTGP) mouse model to investigate brain-pancreas connections. They identified a transneuronal circuit originating from a subpopulation of oxytocin neurons in the paraventricular hypothalamic nucleus (PVNOXT). This circuit projects to the exocrine pancreas via acetylcholinergic neurons in the dorsal motor nucleus of the vagus (DMVACh), directly innervating acinar cells. The study involved both silencing and stimulating these PVNOXT neurons to observe their impact on digestive enzyme secretion and the inflammatory response in the HTGP model. Further, single-cell RNA sequencing was employed to identify key genes involved in this neuro-pancreatic axis.
Results
Modulating the activity of PVNOXT neurons significantly impacted pancreatic function and inflammation in HTGP mice. Silencing PVNOXT neurons led to a suppression of digestive enzyme secretion and a notable inhibition of the inflammatory response in the HTGP model. Conversely, stimulation of these PVNOXT neurons induced inflammation by dysregulating secretory pathways within the acinar cells. This indicates a direct, functional link where hypothalamic oxytocin neurons can drive pancreatic inflammation. Single-cell RNA sequencing further revealed that WD repeat and FYVE domain-containing 1 (Wdfy1), a gene specifically expressed in the OXT neuron subpopulation, plays a critical role in mediating the acinar cell-mediated inflammatory response. > The function of Wdfy1 was found to be essential for the integrity and activity of the entire PVNOXT-DMVACh axis, highlighting a specific molecular target within this newly identified neuro-pancreatic circuit.
Key Findings
- A functional transneuronal circuit connects
PVNOXToxytocin neurons in the hypothalamus to pancreatic acinar cells viaDMVAChneurons. - Silencing
PVNOXTneurons suppresses digestive enzyme secretion and inhibits the inflammatory response inHTGPmice. - Stimulation of
PVNOXTneurons induces inflammation by dysregulating acinar cell secretory pathways. Wdfy1, a gene expressed inOXTneurons, is critical for the acinar cell-mediated inflammatory response.Wdfy1function is essential for the integrity and activity of thePVNOXT-DMVAChaxis.
Why It Matters
This research uncovers a previously undefined neuro-pancreatic axis, providing crucial insights into how the brain directly modulates pancreatic inflammation and digestive enzyme secretion. For clinicians and researchers, this identifies PVNOXT neurons and the Wdfy1 gene as potential novel therapeutic targets for conditions like hypertriglyceridemia-associated acute pancreatitis. Understanding this brain-gut connection could lead to strategies that go beyond symptomatic treatment, potentially allowing for neural modulation to prevent or mitigate pancreatic damage. While still in preclinical stages, this work suggests that future interventions might involve targeting specific hypothalamic circuits or their downstream molecular effectors to manage pancreatic inflammatory diseases, opening avenues for neuro-modulatory approaches in gastroenterology.
pvnoxt
oxytocin
pancreatitis
inflammation
hypothalamus
vagus-nerve