Abstracts

Rationale: A major difficulty in deciphering the complex issue of cognitive outcomes following ELS in children is the gulf between the behavioral/mental spheres in which these deficits occur and the underlying physiological and developmental domains that are both the cause of these deficits and the most likely target for intervention. There remains a major gap in determining how the myriad of structural and functional changes after seizures result in cognitive impairment. The flurothyl model of recurrent early life seizures (ELS) has been linked to cognitive deficits in working memory and spatial memory that are thought to be a result of alterations to functional interactions between the hippocampus (HPC) and medial prefrontal cortex (mPFC). We have adapted a systems biology approach to quantitatively measure the interactions of single cells and network oscillations in the HPC and mPFC in relation to performance on a complex spatial task as well as sociability. We hypothesize that ELS induced cognitive impairment is the result of neural discoordination within and between the mPFC and HC networks relative to local field oscillations that are thought to underpin key aspects of memory encoding and recall. Methods: Male and Female Sprague Dawley rats were split into control (M=6; F=4) and ELS (M=8; F=6) groups. ELS animals were given 50 flurothyl induced seizures from P15 to P25 while control animals experienced no seizures but were separated from dames for a similar amount of time as ELS animals. Post ELS, the rats were assessed for sociability by measuring the amount of time the rats chose to spend with a toy, a familiar rat, or a new rat. The animals were also trained in an active avoidance task on a rotating arena over the course of two consecutive training days consisting of eight 10-minute avoidance sessions per day. Ability to meet task criterion and strategies of active avoidance for each rat were evaluated. Rats in each group were then implanted in both the mPFC, CA1, and CA3 fields of the HPC with arrays of driveable microwire tetrodes. Local field potentials in the delta, theta, slow gamma, and medium gamma bandwidths were recorded and analyzed with respect to the activity of single neurons in each region during performance of the active avoidance task, at rest in a flower pot, and during sleep. At the end of data collection, animals were sacrificed and brain tissue was prepared with a Golgi fixative kit to allow for the visualization and analysis of dendritic projections in the hippocampus and prefrontal cortex. Results: Male ELS animals exhibit a trend for being less likely to meet task criterion in the active avoidance task (3/8) in comparison to male control animals (5/6). Remarkably, all ELS females (6/6) and all control females (4/4) were able to meet task criterion. Electrophysiological and histological analysis will resolve if sex or physiological changes are more important determinants of cognitive outcome. Conclusions: Male ELS animals trend toward worse performance in the active avoidance task than male controls while the performance of female rats is unaffected by ELS. Ongoing electrophysiological and histological work will determine if sex features may be neuroprotective against recurrent seizure or if sex represents a confound for aversive learning measures. Funding: Funded by NIH Grant NS108765 to GLH and JMB