Methamphetamine Learning Induces Persistent and Selective Nonmuscle Myosin II-Dependent Spine Motility in the Basolateral Amygdala.

Nonmuscle myosin II inhibition (NMIIi) in the basolateral amygdala (BLA), but not dorsal hippocampus (CA1), selectively disrupts memories associated with methamphetamine (METH) days after learning, without retrieval. However, the molecular mechanisms underlying this selective vulnerability remain poorly understood. A known function of NMII is to transiently activate synaptic actin dynamics with learning. Therefore, we hypothesized that METH-associated learning perpetuates NMII-driven actin dynamics in synapses, leading to an extended window of vulnerability for memory disruption. We used time-lapse two-photon imaging of dendritic spine motility in acutely prepared brain slices from female and male mice following METH-associated learning as a readout of actin-myosin dynamics. Spine motility was persistently increased in the BLA, but not in CA1. Consistent with the memory disrupting effect of intra-BLA NMII inhibition, METH-induced changes to BLA spine dynamics were reversed by a single systemic injection of an NMII inhibitor. Intra-CA1 NMII inhibition, on the other hand, did not disrupt METH-associated memory. Thus, we report identification of a previously unknown ability for spine actin dynamics to persist days after stimulation and that this is under the control of NMII. Further, these perpetual NMII-driven spine actin dynamics in BLA neurons may contribute to the unique susceptibility of METH-associated memories. There are no Food and Drug Administration-approved pharmacotherapies to prevent relapse to the use of stimulants, such as methamphetamine (METH). Environmental cues become associated with drug use, such that the memories can elicit strong motivation to seek the drug during abstinence. We previously reported that the storage of METH-associated memories is uniquely vulnerable to immediate, retrieval-independent, and lasting disruption by direct actin depolymerization or by inhibiting the actin driver nonmuscle myosin II (NMII) in the BLA or systemically. Here we report a potential structural mechanism responsible for the unique vulnerability of METH-associated memories and METH-seeking behavior to NMII inhibition within the BLA.