Environmental Enrichment and Brain Neuroplasticity in the Kainate Rat Model of Temporal Lobe Epilepsy

Abstract

Background and purpose: Environmental enrichment (EE) improves brain function and ameliorates cognitive impairments; however, whether EE can reverse the learning and memory deficits seen following seizures remains unknown.

Methods: We tested the hypothesis that EE augments neurogenesis and attenuates the learning and memory deficits in rats subjected to kainate-induced seizures in hippocampus, amygdala and motor cortex. EE consisted of daily exposures immediately after KA lesioning (early EE) and after a 60-day period (late EE). Morphometric counting of neuron numbers (NN), dendritic branch-points and intersections (DDBPI) were performed. Spatial learning in a T-maze test was described as percent correct responses and memory in a passive-avoidance test was calculated as time spent in the small compartment where they were previously exposed to an aversive stimulus.

Results: EE increased NN and DDBPI in the normal control and in the KA-lesioned rats in all brain areas studied, after both early and late exposure to EE. Late EE resulted in significantly fewer surviving neurons than early EE in all brain areas (p < 0.0001). EE increased the percent correct responses and decreased time spent in the small compartment, after both early and late EE. The timing of EE (early vs. late) had no effect on the behavioral measurements.

Conclusions: These findings demonstrate that, after temporal lobe and motor cortex epileptic seizures in rats, EE improves neural plasticity in areas of the brain involved with emotional regulation and motor coordination, even if the EE treatment is delayed for 60 days. Future studies should determine whether EE is a useful therapeutic strategy for patients affected by seizures.

Keywords: Amygdala; Enriched environment; Epilepsy; Learning; Memory; Neurogenesis.

Figure 1

Rats in the enriched environment. Two rats are shown in a wooden cage, larger than the steel home cage, with objects for exploration (changed daily) such as tubes, running wheel, ladder, cubes, etc. Rats were allowed to explore the enriched environment for 3 hours every d for 30 days, beginning immediately following either grouping (normal control group, sham operation [sham-operated control group] or kainate lesioning [kainate experimental group]) in the immediate exposure experiment and for 3 hours every d for 30 days beginning 60 days following the grouping into the sham operation or kainate lesioning in the delayed exposure experiment.

Figure 2

Effects of 30 days environmental enrichment on neurons and morphometric cell counts in the area CA3 of hippocampus. (A) Photomicrographs showing the surviving neurons by Nissl staining in groups of 4 month-old male Wistar rats exposed to the following conditions: normal control (NC), normal control followed by environmental enrichment (NC + EE), sham-operated control followed by environmental enrichment (SC + EE), kainic acid-induced lesioning and seizures (LO) followed by immediate, 1-d post-lesion exposure to environmental enrichment (L + EE) treatments. Magnification ×40. (B) Morphometric cell counts of the surviving neurons in the same groups of 4 month-old male Wistar rats exposed to the same conditions as described for the left panel. Intergroup differences significant at *p < 0.05. ^†p < 0.01.

Figure 3

Effects of 30 days environmental enrichment on dendritic branch points, intersections and morphometric counts of dendritic branch points in the CA3 area of the hippocampus. (A) Photomicrographs showing the dendritic branch points and intersections of the surviving neurons by Golgi-Cox staining in groups of 4 month-old male Wistar rats exposed to the following conditions: normal control (NC), normal control followed by environmental enrichment (NC + EE), sham-operated control followed by environmental enrichment (SC + EE), kainic acid-induced lesioning and seizures (LO) followed by immediate, 1-day post-lesion exposure to environmental enrichment (L + EE) treatments. Magnification ×40. (B, C) Morphometric cell counts of dendritic branch points of the surviving neurons in the same groups of 4 month-old male Wistar rats exposed to the same conditions as described for the upper panel. (B) Effects of immediate (1-day post grouping for controls, 1 day postictal for lesioned rats) exposure to the environmental enrichment. (C) Effects of delayed (60 days post grouping for controls, 60 days postictal for lesioned rats) exposure to the environmental enrichment. Intergroup differences significant at *p < 0.05. ^†p < 0.01.

Figure 4

Effects of 30 days environmental enrichment on learning T-maze task. White bars compare means ± standard deviations showing percent bias, percentage of correct responses and number of alternations in groups of 4 month-old male Wistar rats exposed to the following conditions: normal control (NC), normal control plus environmental enrichment (NC + EE) and sham-operated control plus environmental enrichment (SC + EE) treatments. Black bars compare means ± standard deviations of percent bias, percentage of correct responses and number of alternations in groups of 4 month-old rats subjected to kainate-lesioning and seizures (LO) followed by treatment with environmental enrichment (L + EE). (A–C) Percent bias, percentage of correct responses and number of alternations following immediate (1 day post grouping for controls, 1 day postictal for lesioned rats). (D–F) Percent bias, percentage of correct responses and number of alternations following delayed (60 days post-grouping for controls, 60 days postictal for kainate-lesioned rats) exposure to the environmental enrichment, respectively. *Different than NC at p < 0.05. ^†Different than LO at p < 0.001.

Figure 5

Effects of 30 days environmental enrichment on exploration phase of passive-avoidance test. White bars compare means ± standard deviations of time spent in the small compartment, expressed in seconds/trial) and total number of crossings in groups of 4 month-old male Wistar rats exposed to the following conditions: normal control (NC), normal control plus environmental enrichment (NC+EE) and sham-operated control plus environmental enrichment (SC+EE) treatments. Black bars compare means ± standard deviations of time spent in the small compartment and total number of crossings in groups of 4 month-old rats subjected to kainate-lesioning and seizures (LO) followed by treatment with environmental enrichment (L+EE). (A, B) Time spent in the small compartment and total number of crossings following immediate (1 day post grouping for controls, 1 day postictal for lesioned rats). (C, D) Time spent in the small compartment and total number of crossings following delayed (60 days post grouping for controls, 60 days postictal for lesioned rats) exposure to the environmental enrichment, respectively. Intergroup differences were not significant, p > 0.1. *Different than NC at p < 0.05. ^†Different than LO at p < 0.001.

Figure 6

Effects of 30 days environmental enrichment on memory in passive-avoidance test. White bars compare means ± standard deviations of time spent in the small compartment with previous exposure to an aversive stimulus and total number of crossings in groups of 4 month-old male Wistar rats exposed to the following conditions: normal control (NC), normal control plus environmental enrichment (NC+EE) and sham-operated control plus environmental enrichment (SC+EE) treatments. Black bars compare means ± standard deviations of time spent in the small compartment and total number of crossings in groups of 4 month-old rats subjected to kainate-lesioning and seizures (LO) followed by treatment with environmental enrichment (L+EE). (A, B) Time spent in the small compartment and total number of crossings following immediate (1 day post grouping for controls, 1 day postictal for lesioned rats). (C, D) Time spent in the small compartment and total number of crossings following delayed (60 days post grouping for controls, 60 days postictal for lesioned rats) exposure to the environmental enrichment, respectively. *Different than NC at p < 0.05. ^†Different than LO at p < 0.001.