The Whisker Nuisance Task Identifies a Late-Onset, Persistent Sensory Sensitivity in Diffuse Brain-Injured Rats

Abstract

Post-traumatic morbidity reduces the quality of life for traumatic brain injury (TBI) survivors by altering neuropsychological function. After midline fluid percussion injury (FPI), diffuse pathology in the ventral posterior thalamus suggests that somatosensory whisker function may be impaired post-injury. The goals of the present study were to design and validate a task to detect injury-induced somatosensory morbidity (Experiment 1), and to evaluate preliminary applications of the task (Experiment 2). In Experiment 1, male Sprague-Dawley rats were subjected to moderate FPI (*1.9 atm) or sham injury. Over an 8-week time course, the whiskers on both mystacial pads were stimulated manually with an applicator stick in an open field for three 5-min periods. Behavioral responses in this whisker nuisance task were recorded using objective criteria (max score ¼ 16). Sham animals were ambivalent or soothed by whisker stimulation (4.0 AE 0.8), whereas brain-injured rats showed aggravated responses at 1 week (6.7 AE 0.9), which became significant at 4 weeks (9.5 AE 0.5) and 8 weeks (8.4 AE 1.1) compared to sham injury, indicating chronic injury-induced sensory sensitivity. Total free serum corticosterone levels indicated a significant stress response in brain-injured (125.0 AE 17.7 ng=mL), but not uninjured animals (74.2 AE 12.2 ng=mL) in response to whisker stimulation. In Experiment 2, to evaluate applications of the whisker nuisance task, four additional uninjured and brain-injured groups were subjected to mild brain injury only, shaved whiskers after moderate brain injury, repeated whisker nuisance task stimulation after moderate brain injury, or regular opportunities for tactile exploration of an enriched environment after moderate brain injury over 4 weeks post-injury. The whisker nuisance task has the sensitivity to detect mild brain injury (7.7 AE 1.0), but morbidity was not mitigated by any of the neurorehabilitative interventions. Following diffuse brain injury, the whisker nuisance task is a promising tool to detect post-traumatic morbidity and the efficacy of therapeutic interventions that may restore discrete circuit function in brain-injured patients.

Hypersensitive Glutamate Signaling Correlates with the Development of Late-Onset Behavioral Morbidity in Diffuse Brain-Injured Circuitry

“…To demonstrate the progressive development of sensory sensitivity after diffuse brain injury, we tested uninjured and brain-injured rats in the WNT at 1 week and 1 month postinjury (McNamara et al, 2010). In their home cages, braininjured animals showed no changes in grooming, motor, or exploratory behavior compared to uninjured animals.…”

“…The VPM neurons project topographically to barrel fields in layer IV of primary somatosensory cortex (S1BF; Woolsey and Van der Loos, 1970). This whisker-barrel circuit encompasses large anatomical volumes that facilitate recordings, suffer diffuse axonal injury after mFPI (Hall and Lifshitz, 2010;Kelley et al, 2006;Lifshitz et al, 2007), and underlie the behavioral responses to whisker stimulation ( McNamara et al, 2010). Since synapses throughout the afferent circuit are primarily glutamatergic (Kidd and Isaac, 1999), we propose that alterations in glutamate regulation contribute to late-onset post-traumatic behavioral morbidity.…”

“…Brain-injured rats show early neurological impairments in learning acquisition and sensorimotor processes (Hamm, 2001;Wiley et al, 1996;Yamaki et al, 1998). Over the first month after moderate mFPI, rodents develop sensory sensitivity to constant manual whisker stimulation, as observed by robust avoidance and apprehensive behaviors, in contrast to ambivalent or curious behavior by uninjured animals ( McNamara et al, 2010). Whisker deflection drives mechanoreceptors on sensory axons that synapse in the ''barrelettes'' of the principal sensory trigeminal nucleus (Pr5) that innervate neuronal clusters in the ventral posterior medial (VPM) thalamus, called ''barreloids'' (Land et al, 1995).…”

“…( McNamara et al, 2010). After a 5-min acclimation period to the test cage, the whiskers on both mystacial pads were stimulated with a wooden applicator stick for three consecutive 5-min periods (15 min total).The predominant behavioral responses were recorded on 0-2-point non-parametric scales (0, absent, 1, present, 2, profound).…”

Progesterone sharpens temporal response profiles of sensory cortical neurons in animals exposed to traumatic brain injury.

“…We have previously argued that, in TBI, the supragranular layer-specific long-term hyperactivity indicates a TBIinduced dysfunction of the local inhibitory/excitatory balance. 26,27 This may be further confounded by the longterm establishment of inappropriate synaptic connections 15 and supragranular loss of dendrite-targeting calretninexpressing inhibitory interneurons. 16 These physiological changes could account for a response broadening in upper cortical layers but not the changes seen throughout the cortical column.…”