Person:

Kopec, Ashley

The ability to form long-lasting memories is critical to survival and thus is highly conserved across the animal kingdom. By virtue of its complexity, this same ability is vulnerable to disruption by a wide variety of neuronal traumas and pathologies. To identify effective therapies with which to treat memory disorders, it is critical to have a clear understanding of the cellular and molecular mechanisms which subserve normal learning and memory. A significant challenge to achieving this level of understanding is posed by the wide range of distinct temporal and spatial profiles of molecular signaling induced by learning-related stimuli. In this review we propose that a useful framework within which to address this challenge is to view the molecular foundation of long-lasting plasticity as composed of unique spatial and temporal molecular networks that mediate signaling both within neurons (such as via kinase signaling) as well as between neurons (such as via growth factor signaling). We propose that evaluating how cells integrate and interpret these concurrent and interacting molecular networks has the potential to significantly advance our understanding of the mechanisms underlying learning and memory formation.

Early-life conditions can contribute to the propensity for developing neuropsychiatric disease, including substance abuse disorders. However, the long-lasting mechanisms that shape risk or resilience for drug addiction remain unclear. Previous work has shown that a neonatal handling procedure in rats (which promotes enriched maternal care) attenuates morphine conditioning, reduces morphine-induced glial activation, and increases microglial expression of the anti-inflammatory cytokine interleukin-10 (IL-10). We thus hypothesized that anti-inflammatory signaling may underlie the effects of early-life experience on later-life opioid drug-taking. Here we demonstrate that neonatal handling attenuates intravenous self-administration of the opioid remifentanil in a drug-concentration-dependent manner. Transcriptional profiling of the nucleus accumbens (NAc) from handled rats following repeated exposure to remifentanil reveals a suppression of pro-inflammatory cytokine and chemokine gene expression, consistent with an anti-inflammatory phenotype. To determine if anti-inflammatory signaling alters drug-taking behavior, we administered intracranial injections of plasmid DNA encoding IL-10 (pDNA-IL-10) into the NAc of non-handled rats. We discovered that pDNA-IL-10 treatment reduces remifentanil self-administration in a drug-concentration-dependent manner, similar to the effect of handling. In contrast, neither handling nor pDNA-IL-10 treatment alters self-administration of food or sucrose rewards. These collective observations suggest that neuroimmune signaling mechanisms in the NAc are shaped by early-life experience and may modify motivated behaviors for opioid drugs. Moreover, manipulation of the IL-10 signaling pathway represents a novel approach for influencing opioid reinforcement.