Traumatic brain injuries (TBI) frequently result in persisting post-traumatic neurological consequences, including hypersensitivity to light, with limited effective treatments. Vision is a primary sensory modality in humans, similar to whisker sensation in rodents. Primary sensory modalities incorporate a large portion of the brain for processing, making them susceptible to diffuse TBI. The goal of this proposal is to employ an experimental rodent model of diffuse TBI that highlights sensory deficits to evaluate delayed alterations in glutamate signaling as a universal consequence of TBI and its potential for modulation. Using this model in preliminary results the PI has demonstrated that TBI induces late-onset sensory hypersensitivity to whisker stimulation by post-injury day (PID) 28 that persists to PID 56. This injury-induced sensory hypersensitivity is measured using the established Whisker Nuisance Task (WNT), where whisker stimulation results in active evasion and aberrant responses in injured rats compared to ambivalence or curiosity in uninjured rats. Since the whisker circuit is glutamatergic, this research team implemented electrochemical microelectrode array technology, capable of real-time measurements of glutamate neurotransmission in vivo, for recordings within the relays of the whisker circuit in anesthetized rats. The PI reported that WNT scores positively correlate to the magnitude of potassium (KCl)-evoked glutamate release in the somatosensory thalamus and cortex. Evoked-glutamate release was sensitive to ?-conotoxin, indicating hypersensitive presynaptic glutamate release as a potential mechanism for whisker hypersensitivity. Also, 3D reconstruction of neuron morphology shows increased numbers of terminating dendrites within the thalamus at PID 28, providing a potential source for increased glutamate release. KCl-evoked glutamate responses are required in anesthetized studies since whisker stimulation-evoked glutamate responses are suppressed by anesthesia. Thus, real-time recordings of glutamate neurotransmission in the awake, freely-moving rat permits the evaluation of whisker stimulation- evoked glutamate responses during the WNT. This has led to the central hypotheses that TBI-induced sensory hypersensitivity arises from altered glutamate signaling in sensory circuits and that early rehabilitation will restore circuit function and alleviate behavioral symptoms. To test these hypotheses adult male and female rats will be subjected to diffuse TBI by midline fluid percussion and evaluated for: 1) the influence of sex on late-onset sensory hypersensitivity to whisker stimulation and glutamate neurotransmission; 2) whisker stimulated-evoked glutamate release in awake, freely-moving rats, with respect to time post-diffuse TBI, and 3) evidence that circuit-directed rehabilitation, focused on the whiskers, can mitigate hypersensitive glutamate release and concurrent behavioral sensory hypersensitivity. Impact: Coupling this model of circuit disruption with electrochemical recordings in awake, freely-moving rats allows for evaluation of glutamate signaling as a biomarker for injury-induced persisting neurological deficits for evaluation of therapeutic approaches.
The proposed project is relevant to public health because analogous to photophobia or phonophobia caused by traumatic brain injury in humans the whisker circuit in rats serves as a unique in vivo model of primary sensory circuit disruption. Coupling this in vivo model of circuit disruption with state-of-the art in vivo electrochemical recordings in awake, behaving rats provides a powerful approach to evaluate delayed alterations in glutamate signaling that contribute to injury-induced hypersensitivity. Modulation of glutamate signals with circuit-directed rehabilitation has the potential to return glutamate signaling to normal and ameliorate behavioral symptoms, with rapid translation to patient care.
