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

The arousal state is defined as the degree to which an individual is aware of themselves and their surroundings, and is a crucial component of consciousness. Trigeminal nerve stimulation (TNS), a non-invasive clinical neuromodulation technique, has shown potential in aiding the functional recovery of patients with impaired consciousness. Understanding the specific neuronal subpopulations and circuits through which TNS improves arousal states is essential for advancing its clinical application. Methods: A mouse model of traumatic brain injury (TBI) was established using a weight-drop technique to induce neurological dysfunction, and the arousal state was assessed through visual and auditory defensive responses. Techniques such as viral tracing, chemogenetics, patch-clamp recordings, calcium signaling, and neurotransmitter probes were employed to investigate the relevant subpopulations of trigeminal ganglion (TG) neurons and the underlying mechanisms in the central nervous system. Results: Neuronal subgroups involved in TNS therapy at the key peripheral nucleus, the TG, were identified. Two distinct types of neurons were found to contribute differently: The Tac1+TG-locus coeruleus (LC)-superior colliculus (SC) pathway elevated noradrenaline levels in the SC, enhancing receptive field sensitivity recovery in TBI mice; the Piezo2+TG-paraventricular hypothalamic nucleus (PVN)-substantia nigra pars compacta (SNc)-dorsal striatum (DS) pathway initiated dopamine (DA) release in the DS, ameliorating motor disorders in TBI mice. Conclusion: These pathways contribute to the improvement of defensive arousal responses from different perspectives. The findings from this study imply that TNS effectively restores defensive arousal responses to visual and auditory threats in mice suffering from TBI, offering insights that may facilitate the implementation of TNS therapy in clinical settings.