Early hippocampal high-amplitude rhythmic spikes predict post-traumatic epilepsy in mice.

Oscillations, a highly conserved brain function across mammalian species, are pivotal in brain physiology and pathology. Traumatic brain injury (TBI) often leads to subacute and chronic brain oscillatory alterations associated with complications like post-traumatic epilepsy (PTE) in patients and animal models. Our recent work longitudinally recorded local field potential from the contralateral hippocampus of 12 strains of recombinant inbred Collaborative Cross (CC) mice alongside classical laboratory inbred C57BL/6J mice after lateral fluid percussion injury. In this study, we profiled the acute (<12 hr post-injury) and subacute (12-48 hr post-injury) hippocampal oscillatory responses to TBI and evaluated their predictive value for PTE. We found dynamic high-amplitude rhythmic spikes with elevated power density and reduced entropy that prevailed during the acute phase in CC031 mice who later developed PTE. This characteristic early brain oscillatory alteration is absent in CC031 sham controls or other CC and reference C57BL/6J strains that did not develop PTE after TBI. Our work provides quantitative measures linking early brain oscillation to PTE at a population level in mice under controlled experimental conditions. These findings will offer insights into circuit mechanisms and potential targets for neuromodulatory intervention.

Genetic diversity drives extreme responses to traumatic brain injury and post-traumatic epilepsy.

Traumatic brain injury (TBI) is a complex and heterogeneous condition that can cause wide-spectral neurological sequelae such as behavioral deficits, sleep abnormalities, and post-traumatic epilepsy (PTE). However, understanding the interaction of TBI phenome is challenging because few animal models can recapitulate the heterogeneity of TBI outcomes. We leveraged the genetically diverse recombinant inbred Collaborative Cross (CC) mice panel and systematically characterized TBI-related outcomes in males from 12 strains of CC and the reference C57BL/6J mice. We identified unprecedented extreme responses in multiple clinically relevant traits across CC strains, including weight change, mortality, locomotor activity, cognition, and sleep. Notably, we identified CC031 mouse strain as the first rodent model of PTE that exhibit frequent and progressive post-traumatic seizures after moderate TBI induced by lateral fluid percussion. Multivariate analysis pinpointed novel biological interactions and three principal components across TBI-related modalities. Estimate of the proportion of TBI phenotypic variability attributable to strain revealed large range of heritability, including >70% heritability of open arm entry time of elevated plus maze. Our work provides novel resources and models that can facilitate genetic mapping and the understanding of the pathobiology of TBI and PTE.

Ictal neural oscillatory alterations precede sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy is the most catastrophic outcome of epilepsy. Each year there are as many as 1.65 cases of such death for every 1000 individuals with epilepsy. Currently, there are no methods to predict or prevent this tragic event, due in part to a poor understanding of the pathologic cascade that leads to death following seizures. We recently identified enhanced seizure-induced mortality in four inbred strains from the genetically diverse Collaborative Cross mouse population. These mouse models of sudden unexpected death in epilepsy provide a unique tool to systematically examine the physiological alterations during fatal seizures, which can be studied in a controlled environment and with consideration of genetic complexity. Here, we monitored the brain oscillations and heart functions before, during, and after non-fatal and fatal seizures using a flurothyl-induced seizure model in freely moving mice. Compared with mice that survived seizures, non-survivors exhibited significant suppression of brainstem neural oscillations that coincided with cortical epileptic activities and tachycardia during the ictal phase of a fatal seizure. Non-survivors also exhibited suppressed delta (0.5-4 Hz)/gamma (30-200 Hz) phase-amplitude coupling in cortex but not in brainstem. A connectivity analysis revealed elevated synchronization of cortex and brainstem oscillations in the delta band during fatal seizures compared with non-fatal seizures. The dynamic ictal oscillatory and connectivity features of fatal seizures provide insights into sudden unexpected death in epilepsy and may suggest biomarkers and eventual therapeutic targets.

Does breeding population trajectory and age of nesting females influence disparate nestling sex ratios in two populations of Cooper's hawks?

Offspring sex ratios at the termination of parental care should theoretically be skewed toward the less expensive sex, which in most avian species would be females, the smaller gender. Among birds, however, raptors offer an unusual dynamic because they exhibit reversed size dimorphism with females being larger than males. And thus theory would predict a preponderance of male offspring. Results for raptors and birds in general have been varied although population-level estimates of sex ratios in avian offspring are generally at unity. Adaptive adjustment of sex ratios in avian offspring is difficult to predict perhaps in part due to a lack of life-history details and short-term investigations that cannot account for precision or repeatability of sex ratios across time. We conducted a novel comparative study of sex ratios in nestling Cooper's hawks (Accipiter cooperii) in two study populations across breeding generations during 11 years in Wisconsin, 2001-2011. One breeding population recently colonized metropolitan Milwaukee and exhibited rapidly increasing population growth, while the ex-Milwaukee breeding population was stable. Following life-history trade-off theory and our prediction regarding this socially monogamous species in which reversed sexual size dimorphism is extreme, first-time breeding one-year-old, second-year females in both study populations produced a preponderance of the smaller and cheaper sex, males, whereas ASY (after-second-year), ≥2-year-old females in Milwaukee produced a nestling sex ratio near unity and predictably therefore a greater proportion of females compared to ASY females in ex-Milwaukee who produced a preponderance of males. Adjustment of sex ratios in both study populations occurred at conception. Life histories and selective pressures related to breeding population trajectory in two age cohorts of nesting female Cooper's hawk likely vary, and it is possible that these differences influenced the sex ratios we documented for two age cohorts of female Cooper's hawks in Wisconsin.