Hypothesis

We propose that the dorsal motor nucleus of the vagus (DMV) defines a spatial topology that mirrors a peripheral connectome, guiding the sequential deposition of pathological tau along vagal efferent fibers into distinct regions of the enteric nervous system (ENS). Moreover, enterochromaffin (EC) cell‑derived serotonin modulates vagal efferent firing rate, thereby biasing the probability of tau trans‑synaptic transfer. Disrupting this EC‑vagal coupling should attenuate gut‑directed tau spread and preserve colonic barrier integrity, independent of central amyloid‑β load.

Mechanistic Rationale

Recent work shows that tau propagates from hippocampus to DMV and then to colonic enteric neurons via vagal motor fibers, a route blocked by vagotomy[1]. Colon‑on‑a‑chip reproduces this trans‑synaptic transfer, confirming that vagal efferents act as a conduit for pathology[1]. Yet the ENS is not a uniform tube; it comprises spatially segregated ganglia (myenteric and submucosal plexuses) that receive differential vagal innervation[2]. We hypothesize that the pattern of vagal branching creates a weighted graph analogous to the brain connectome, where edge weights reflect axonal density and synaptic compatibility. Network‑based epidemic models that successfully forecast cortical tau spread[4] can be transplanted onto this vagal‑ENS graph to predict regional tau accumulation.

Enterochromaffin cells, which reside within the intestinal epithelium, release serotonin in response to luminal cues and directly influence vagal afferent tone. Importantly, serotoninergic signaling also alters vagal efferent excitability via 5‑HT₃ receptors on DMV neurons[3]. Thus, EC activity can gate the permissiveness of the vagal conduit for tau transfer. When EC‑derived serotonin is elevated, vagal firing increases, raising the trans‑synaptic transfer probability; conversely, reducing EC serotonin dampens vagal output and limits tau seeding in the gut.

Predictions & Experimental Design

1. Mapping the vagal‑ENS connectome – Perform viral tracing (AAV‑retrograde) from distinct colonic segments (proximal, mid, distal) to label DMV neurons. Quantify axon density and construct a weighted adjacency matrix.
2. Computational forecast – Seed the matrix with tau aggregates in the hippocampus (as in[1]) and run a Susceptible‑Infected‑Recovered (SIR) diffusion model. Predict tau burden scores for myenteric and submucosal plexuses.
3. Experimental manipulation – In APP/PS1×tau transgenic mice:
   a. Chemogenetically inhibit DMV hM4Di receptors (CNO) to lower vagal efferent firing.
   b. Selectively ablate EC cells using TPH1‑Cre;DTA or pharmacologically inhibit TPH1 with pchlorophenylalanine (pCPA) to reduce serotonin.
   c. Measure colonic tau immunohistochemistry, barrier permeability (FITC‑dextran assay), and cytokine profile.
4. Control – Sham‑treated littermates and vagotomized animals.

Potential Outcomes & Implications

If the hypothesis holds, DMV inhibition or EC silencing will produce a spatially patterned reduction of colonic tau that matches the computational low‑risk nodes predicted by the vagal‑ENS model, while barrier function improves. Conversely, vagotomy should abolish the gradient altogether, confirming the neural route. A mismatch between predicted and observed tau distribution would falsify the assumption that vagal topology alone dictates spread, pointing to additional factors (e.g., local microglial‑like enteric immune cells). Successful validation would reposition the ENS as a measurable peripheral node in neurodegeneration networks, opening therapeutic avenues that target gut‑derived serotonergic signaling or vagal tone to halt brain‑to‑gut pathology propagation.