Mechanisms of Cocaine Induced Metaplasticity In Nucleus Accumbens Neurons

Cahill, Michael

Dendritic spines are the sites of most excitatory synapses in the central nervous system, and chronic administration of drugs of abuse, such as cocaine, alters the density and morphology of such spines on medium spiny neurons (MSNs) of the nucleus accumbens (NAc), a primary reward region. In the past decade it has become clear that dendritic spine morphology dictates synaptic function. Acute and protracted withdrawal from cocaine produces opposing alterations in the synaptic structure and function of NAc MSNs such that early withdrawal (e.g., 1-day) is characterized by synaptic weakening as evidenced by de novo thin spine formation, while late withdrawal (e.g., 1-month) is characterized by the increased formation of mushroom spines and hence synaptic strengthening. Despite the seemingly disparate forms of plasticity occurring during early and late withdrawal, the synaptic reconfiguration during the withdrawal process is best conceptualized as a form of “metaplasticity” in which the initial formation of new thin spines provides a locus at which subsequent spine maturation can occur. The simplest and most elegant means through which this metaplasticity could occur would be if the same biochemical pathway undergoes biphasic alterations in NAc MSNs during early and late withdrawal. Consistent with the latter possibility, we found that the expression of the Rap1 small GTPase is upregulated during early cocaine withdrawal and, using viral-mediated gene transfer, we found that Rap1 overexpression increases thin spine formation in NAc MSNs. Conversely, Rap1 is downregulated during late cocaine withdrawal which causes mushroom spine formation. We found that Rap1 regulates spine morphogenesis by stimulating the activity of an AKT/mammalian target of rapamycin (mTOR) local translation pathway in NAc MSN synapses, which augments the synthesis of specific proteins whose mRNAs are present in spines. Further, we found that the increased (early withdrawal) and decreased (late withdrawal) expression of this pathway in NAc MSNs produces opposing effects on cocaine-mediated behavioral reward. Finally, using optogenetic methods we dissected the excitatory inputs to the NAc that regulate Rap1-AKT-mTOR signaling in NAc spines. Collectively, these findings provide the first precise mechanism by which cocaine induces metaplasticity in NAc MSNs, and we reveal the specific effects of this plasticity on reward behavior in a brain circuit-specific manner.