1000 Section - Neural mechanism of trigeminal nerve stimulation recovering defensive arousal responses in traumatic brain injury

Objectives : Defensive arousal responses reflect an organism’s sensitivity to environmental threats and represent a core component of consciousness. Trigeminal nerve stimulation (TNS) has shown therapeutic potential for disorders of consciousness, yet the underlying neuronal subtypes and circuit mechanisms remain unclear. This study aimed to determine how TNS engages trigeminal ganglion (TG)–centered pathways to restore defensive arousal after traumatic brain injury (TBI).

Design:

• A TBI mouse model was generated using a weight-drop method.


• Defensive arousal was assessed through visual and auditory threat-evoked behaviors.


• Viral tracing, chemogenetic manipulation, patch-clamp electrophysiology, calcium imaging, and neurotransmitter sensors were used to identify TG neuronal subtypes involved in TNS responses and to dissect downstream pathways.


• Two circuits were examined: a Tac1⁺ TG → locus coeruleus (LC) → superior colliculus (SC) pathway supporting recovery of visual sensitivity, and a Piezo2⁺ TG → paraventricular hypothalamic nucleus (PVN) → substantia nigra pars compacta (SNc) → dorsal striatum (DS) pathway supporting motor restoration.


• Behavioral and neurophysiological outcomes were compared between TNS-treated and untreated TBI mice.

Results:

• TNS significantly enhanced defensive responses to both visual and auditory threats compared with untreated TBI mice.


• TNS selectively activated Tac1⁺ and Piezo2⁺ TG neurons.


• Activation of the Tac1⁺ TG → LC → SC circuit enhanced noradrenaline release in the SC and restored visual receptive field sensitivity in TBI mice.


• Activation of the Piezo2⁺ TG → PVN → SNc → DS circuit increased dopamine release in the DS and improved TBI-induced motor deficits.

Conclusion: This study identifies two complementary TG-centered circuits through which TNS restores defensive arousal following TBI: a noradrenergic pathway that rescues sensory responsiveness and a dopaminergic pathway that improves motor function. These findings provide mechanistic evidence supporting TNS as a promising therapeutic strategy for promoting recovery of arousal in disorders of consciousness and highlight specific neural pathways that may guide future clinical translation.