Spreading Depolarizations Contribute to the Acute Behavior Deficits Associated With a Mild Traumatic Brain Injury in Mice.

Concussions or mild traumatic brain injuries (mTBIs) are often described and diagnosed by the acute signs and symptoms of neurological dysfunction including weakness, dizziness, disorientation, headaches, and altered mental state. The cellular and physiological mechanisms of neurological dysfunction and acute symptoms are unclear. Spreading depolarizations (SDs) occur after severe TBIs and have recently been identified in closed-skull mouse models of mTBIs. SDs are massive waves of complete depolarization that result in suppression of cortical activity for multiple minutes. Despite the clear disruption of brain physiology after SDs, the role of SDs in the acute neurological dysfunction and acute behavioral deficits following mTBIs remains unclear. We used a closed-skull mouse model of mTBI and a series of behavioral tasks collectively scored as the neurological severity score (NSS) to assess acute behavior. Our results indicate that mTBIs are associated with significant behavioral deficits in the open field and NSS tasks relative to sham-condition animals. The behavioral deficits associated with the mTBI recovered within 3 h. We show here that the presence of mTBI-induced bilateral SDs were significantly associated with the acute behavioral deficits. To identify the role of SDs in the acute behavioral deficits, we used exogenous potassium and optogenetic approaches to induce SDs in the absence of the mTBI. Bilateral SDs alone were associated with similar behavioral deficits in the open field and NSS tasks. Collectively, these studies demonstrate that bilateral SDs are linked to the acute behavioral deficits associated with mTBIs.

Pupillary reflex and behavioral masking responses to light as functional measures of retinal degeneration in mice.

BACKGROUND: Pre-clinical testing of retinal pathology and treatment efficacy depends on reliable and valid measures of retinal function. The electroretinogram (ERG) and tests of visual acuity are the ideal standard, but can be unmeasurable while useful vision remains. Non-image-forming responses to light such as the pupillary light reflex (PLR) are attractive surrogates. However, it is not clear how accurately such responses reflect changes in visual capability in specific disease models. The purpose of this study was to test whether measures of non-visual responses to light correlate with previously determined visual function in two photoreceptor degenerations. METHODS: The sensitivity of masking behavior (light induced changes in running wheel activity) and the PLR were measured in 3-month-old wild-type mice (WT) with intact inner retinal circuitry, Pde6b-rd1/rd1 mice (rd1) with early and rapid loss of rods and cones, and Prph2-Rd2/Rd2 mice (Rd2) with a slower progressive loss of rods and cones. RESULTS: In rd1 mice, negative masking had increased sensitivity, positive masking was absent, and the sensitivity of the PLR was severely reduced. In Rd2 mice, positive masking identified useful vision at higher light levels, but there was a limited decrease in the irradiance sensitivity of negative masking and the PLR, and the amplitude of change for both underestimated the reduction in irradiance sensitivity of image-forming vision. CONCLUSIONS: Together these data show that in a given disease, two responses to light can be affected in opposite ways, and that for a given response to light, the change in the response does not accurately represent the degree of pathology. However, the extent of the deficit in the PLR means that even a limited rescue of rod/cone function might be measured by increased PLR amplitude. In addition, positive masking has the potential to measure effective treatment in both models by restoring responses or shifting thresholds to lower irradiances.