Abstract
Epilepsy is a common chronic neurological disease that is characterized by spontaneous seizures. It is commonly comorbid with behavioral and mood disorders. No studies have yet examined the behavioral or structural brain changes associated with coriaria lactone (CL)-induced and pentylenetetrazol (PTZ)-induced kindlings. This study examined whether the increased seizure susceptibility induced by CL/PTZ is accompanied by behavioral impairments and aimed to identify associated structural brain changes. Kindling models were induced using CL and PTZ, with 10 rats in each group. After successful kindling, rats were subjected to brain structural imaging using T2-weighted imaging and underwent behavioral tests, namely, the open field test, water maze tasks, and contextual fear conditioning. Voxel-based morphometry was then used to identify possible brain structural changes associated with kindling and/or behaviors. Support-vector machine learning was also applied for the integrative analysis of behavioral changes and structural brain imaging. In the open field test, both the CL (P = 0.04) and PTZ groups (P = 0.002) spent more time in the central area than the control group. Only the PTZ group (50.29 ± 29.56 s) showed a freezing time that was significantly less than that of the control group (94.8 ± 41.04 s; P = 0.024, Tukey's HSD-corrected) in contextual fear conditioning, which is suggestive of impaired fear-associated learning ability. Furthermore, brain imaging analysis revealed that the gray matter volume (GMV) of the hippocampus changed in both the CL and PTZ groups when compared to control. The support-vector machine learning model indicated that the retrosplenial dysgranular and primary somatosensory cortices were associated with both of the mentioned kindling models. Furthermore, the support-vector regression model results indicated that kindling-associated GMV changes can be used to predict general exploratory activity in the open field test. In conclusion, this is the first study to report greater general exploratory activity in a CL-induced kindling model. Moreover, the general exploratory activity in the open field test can be predicted by the GMV of brain regions associated with kindling.
Highlights
Epilepsy is a common chronic neurological disease that is characterized by spontaneous seizures
The goal of the study was to examine whether increased seizure susceptibility induced by coriaria lactone (CL) or PTZ is accompanied by behavioral symptoms and to identify the associated structural brain changes
The main findings of this study were as follows: (1) the CLand PTZ-induced kindling models demonstrated greater general exploratory activity, as in contextual fear conditioning, only the PTZ-induced kindling model showed impaired performance, suggesting impaired contextual associative learning; (2) machine learning models revealed that the retrosplenial dysgranular cortex and primary somatosensory cortex were associated with the two kindling models; (3) the support-vector regression model results suggested that brain regions associated with kindling can be used to predict general exploratory activity
Summary
Epilepsy is a common chronic neurological disease that is characterized by spontaneous seizures It is commonly comorbid with behavioral and mood disorders (Keezer et al, 2016; Scott et al, 2017; Hingray et al, 2019). In recent years, increasing evidence has indicated that epilepsy and behavioral and mood disorders share common underlying pathophysiological mechanisms (Chang et al, 2011; Helmstaedter and Witt, 2017; Hingray et al, 2019). When the kindling is successful, animals develop seizures even with a sub-threshold stimulus (Dhir, 2012). Both electrical and chemical methods can be used for kindling (Kandratavicius et al, 2014). Multiple chemical agents, including pentylenetetrazol (PTZ), cocaine (Miller et al, 2000), and lidocaine (Simon et al, 1982), can accomplish chemical kindling and subsequently induce behavioral seizures
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