Myosin II motor activity in the lateral amygdala is required for fear memory consolidation

Abstract

Learning induces dynamic changes to the actin cytoskeleton that are required to support memory formation. However, the molecular mechanisms that mediate filamentous actin (F-actin) dynamics during learning and memory are poorly understood. Myosin II motors are highly expressed in actin-rich growth structures including dendritic spines, and we have recently shown that these molecular machines mobilize F-actin in response to synaptic stimulation and learning in the hippocampus. In this study, we report that Myosin II motors in the rat lateral amygdala (LA) are essential for fear memory formation. Pretraining infusions of the Myosin II inhibitor, blebbistatin (blebb), disrupted long term memory, while short term memory was unaffected. Interestingly, both post-training and pretesting infusions had no effect on memory formation, indicating that Myosin II motors operate during or shortly after learning to promote memory consolidation. These data support the idea that Myosin II motor-force generation is a general mechanism that supports memory consolidation in the mammalian CNS.

Selective, Retrieval-Independent Disruption of Methamphetamine-Associated Memory by Actin Depolymerization

“…We and others have previously demonstrated that learning triggers a brief window of F-actin dynamics, such that depolymerization at the time of training prevents the consolidation of hippocampus- and amygdala-dependent fear memories (30, 34-37). However, this window of actin cycling closes quickly (30, 37), stabilizing the long-term memory. As a result, intra-BLC blockade of F-actin cycling prior to testing fails to disrupt the expression of an auditory fear memory or a food reward place preference (Fig.…”

“…Unlike the impact of actin depolymerization on a METH-associated contextual memory, another BLC-dependent memory, auditory fear (35, 61), is known to become insensitive to blockade of polymerization within minutes of learning (30, 37), such that pre-test BLC blockade has no effect on the memory (34, 37). To further investigate the specificity of this effect on METH-associated memory, we explored the possibility that appetitive memories, in general, are susceptible to actin depolymerization days after training (Fig.…”

“…Importantly, memory formation fails when learning-induced F-actin dynamics are disrupted. Further, current studies report that depolymerizing agents are only effective around time of training, as F-actin rapidly stabilizes after learning (30, 34-37). …”

“…Fear conditioning was performed in rats as previously described (37). See Supplementary Information for additional details.…”

Small-Molecule Inhibitors of Myosin Proteins

“…Initial studies using blebbistatin demonstrated that the position of the cytokinetic cleavage furrow is maintained by signals from microtubules controlling nonmuscle myosin II localization [26]. Targeted inhibition of myosin II with blebbistatin has also revealed that nonmuscle myosin II plays a role in fear memory consolidation in the lateral amygdala [62], that nonmuscle myosin IIA and IIB regulate the migration of rat hepatic stellate cells [63] and that nonmuscle myosin II is required for the ligand-induced internalization of the EGFR [64]. In addition, depletion of myosin ATPase activity in plant cells using BDM demonstrates that chloroplast actin filaments reorganize in a manner independent of chloroplast movement [65] and that the actomyosin complex mediates early transduction events during the gravitropic response of snapdragon spikes [66].…”