Trigeminal nerve direct current stimulation modulates raphe-hippocampal network synchrony in rats

Trigeminal nerve stimulation is a promising noninvasive method to modulate subcortical circuits involved in cognition. This study investigated the influence of trigeminal nerve direct current stimulation (TN-DCS) on neuronal activity and coherence between the raphe nuclei and hippocampus.

Fourteen adult male Sprague-Dawley rats (n = 10 control; n = 4 xylocaine/agonist) were implanted with silicon probes for simultaneous recordings from the hippocampus and either the dorsal (DRN) or median raphe nucleus (MnRN). Direct currents (from ±0.25 to ±3 mA) were applied to the trigeminal nerve during 3-min sessions (1 min pre-, 1 min during, 1 min post-stimulation).

Acute TN-DCS rapidly and reversibly modulated firing in the DRN, MnRN, and hippocampus in a cell-type-specific, amplitude-dependent manner. Putative non-serotonergic (p-non-SERT) raphe neurons exhibited strong increases in spike rate, whereas putative serotonergic (p-SERT) neurons did not show consistent rate changes or stimulation-induced bursts. In the hippocampus, pyramidal cells exhibited polarity-dependent, amplitude-scaled increases in spike rate, whereas interneurons displayed smaller effects that were independent of polarity. TN-DCS enhanced theta-band coupling between p-non-SERT raphe spikes and hippocampal local field potentials, increasing spike-field coherence and spike-triggered averages in both DRN and MnRN. These effects, along with spike-rate increases in MnRN and hippocampus caused by TN-DCS, were blocked or significantly reduced by local trigeminal block (xylocaine) or intra-MnRN 5-HT_1A/7 agonist (8-OH-DPAT).

TN-DCS dynamically modulates raphe-hippocampal firing and theta synchrony via predominantly amplitude-dependent mechanisms that require intact trigeminal input and serotonergic signaling, supporting its potential as a targeted neuromodulation approach for subcortical circuits involved in cognition and mood.