Neuroplasticity in specific limbic system circuits may mediate specific kindling induced changes in animal affect—implications for understanding anxiety associated with epilepsy

Abstract

In two complementary experiments, we studied the effects of low frequency stimulation (LFS) of the amygdala on behavioral effects of kindling in rats and cats. These studies tested the hypothesis that kindling induced long term potentiation (KLTP) in amygdala circuits underlies interictal behavioral change. Since LFS can depotentiate LTP, it was predicted that LFS should both depotentiate KLTP and reverse behavioral effects of kindling. In cats, the effects of LFS on KLTP of amygdala efferents was studied, and related to behavioral effects. Partial ventral hippocampal kindling in cats and right amygdala kindling in rodents lastingly increased defensive response to rats in cats, and anxiety-like behavior (ALB) in the elevated plus-maze in rats. In addition, partial kindling reduced predatory attack behavior in cats independent of its effects on defensive response. Partial kindling also induced KLTP of amygdala efferent transmission to ventromedial hypothalamus (VMH) and periaqueductal gray (PAG) in left and right hemispheres. Depotentiation of amygdala efferent KLTP by bilateral amygdala LFS selectively reduced KLTP in right amygdala efferents. At the same time, defensive behavior, but not attack behavior, was returned to levels seen prior to partial kindling. Defensiveness returned to post kindling levels between 44 and 76 days after LFS. At the same time, LTP was restored in the right Amygdalo-PAG pathway only. These findings suggest that lasting change in affect produced by kindling depends on LTP of right amygdala efferent transmission to PAG, replicating studies of the effects of FG-7142 on brain and behavior in the cat. The findings suggest further that the spectrum of behavioral changes produced by partial kindling are dependent on changes in a variety of neural circuits, and that amygdala efferent transmission changes are responsible for changes in defensive behavior, but not attack behavior. Effects of LFS were not due to damage, as thresholds to evoke amygdala efferent response were unchanged. Other data suggest KLTP and depotentiation in right Amygdalo-PAG may reflect changes in glutamate receptor density/synapse number. Kindling effects on rat ALB persisted for at least 1 month. Bilateral but not unilateral amygdala LFS reversed the effects of kindling on risk assessment in the plus maze for at least 3 weeks. Bilateral LFS also reversed the effects of kindling on open arm exploration, but effects were shorter lived, appearing at 1 day but not 3 weeks after kindling and LFS. These findings are consistent with other studies which suggest that amygdala neuroplasticity in separable amygdala circuits mediates lasting changes in open arm avoidance and risk assessment. Taken together, the findings of both studies support the hypothesis that a form of LTP of specific amygdala circuits underlies lasting changes in affect produced by limbic kindling. Clinical implications of these findings are discussed.