Early-life seizures produce lasting alterations in the structure and function of the prefrontal cortex

Abstract

Early-life seizures (ELS) are associated with long-term behavioral disorders including autism and ADHD, suggesting that frontal lobe structures may be permanently affected. We tested whether ELS produce structural alterations in the prefrontal cortex (PFC) and impair PFC-mediated function using an operant task of behavioral flexibility in rats. Adult rats that had been exposed to 75 flurothyl seizures during postnatal days 1-10 showed decreased behavioral flexibility in the task compared to controls over multiple behavioral sessions, measured as a lever preference asymmetry (p<0.001) and a decreased efficiency of attaining food rewards (p<0.05). ELS rats also showed an increased thickness of the PFC (p<0.01), primarily attributed to layer V (p<0.01) with no differences in cell density. These structural changes correlated with lever preference behavioral impairments (p<0.05). This study demonstrates that the consequences of ELS extend to the PFC, which may help explain the high prevalence of comorbid behavioral disorders following ELS.

Figure 1

Behavioral flexibility task. In this progressive-ratio switching task, the rat was required to press a lever (yellow) for food an increasing number of times after each reward, creating a larger work requirement (red) as long as the rat persisted on the same lever. Upon switching to the other lever the work requirement was reset, then again increased after each reward until the rat switched again. This sequence was repeated until the 45 minute session was completed.

Figure 2

Total lever presses and rewards. Data indicate group means ± SEM for the total number of (A) lever presses and (B) rewards in a given session. Control (blue) and ELS (red) rats showed comparable numbers of lever presses and rewards during all of the sessions.

Figure 3

Measures of behavioral flexibility. (A) Group means ± SEM for the total number of times the rats switched back and forth between the left and right levers. A higher value indicates more flexibility to switch between the levers. ELS rats (red) showed fewer total switches between levers during the sessions compared to controls (blue). (B) Group means ± SEM for the difference in lever presses between levers divided by total presses. A higher value indicates less flexibility to work among both levers equally. ELS rats showed much higher lever preferences than control rats in the task over all sessions. (C) Inefficiency in gaining rewards, shown as group means ± SEM for the total number of lever presses divided by total rewards. ELS rats were less efficient in gaining rewards (i.e. more lever presses per reward) than control rats over all session days. As with switches, practice effects can be seen among all animals over the consecutive sessions. Asterisks indicate statistically significant differences.

Figure 4

PFC histology. Shown are group means ± SEM. (A). Compared to control rats (blue), ELS rats (red) showed thicker total PFC width (p<0.01), which was particularly prominent in the deeper layer V (p<0.01), along with a potential trend in layer VI (p=0.10). (B). No differences were seen in cell density among any of the layers.

Figure 5

Relation of behavior and histology. PFC thicknesses were positively correlated with combined lever preference scores (A), and trended toward a negative correlation with combined switches (B), implicating an enlarged PFC as a cortical substrate of increased perseverance in this study.