Project 8E: Neuroimmune mediators of cognitive impairment in methamphetamine abuse (RENEWED)
Methamphetamine (MA) dependence causes serious psychiatric and cognitive impairments that persist following remission. Recent research suggests that the mechanisms of MA-induced neurotoxicity involve, in part, activation of microglia and alterations in neuroimmune function. However, MA modulation of pro- and anti-inflammatory cytokine expression has not yet been investigated.
The proposed pilot research project uses both rodent and human data to guide our investigation of neuroinflammation and white matter injury in MA-induced cognitive and psychiatric impairment.
The central hypothesis of the proposed translational research project is that chronic MA abuse causes prolonged immune dysregulation that damages white matter tracts, leading to cognitive and psychiatric impairment. To test this hypothesis, our proposed translational pilot project will: (1) investigate the influence of MA on cytokine expression and cognitive function in mice and (2) determine whether specific markers of immune dysregulation, namely peripheral cytokine levels and reduced white matter integrity in the corpus callosum are associated with psychiatric and cognitive impairment in MA-dependent humans. >
In Study One (Rodent Component), we will assess cognitive performance in mice using a novel-object recognition task and will correlate peripheral and central markers of inflammation following administration and withdrawal of MA. This design will allow us to directly compare the immuno-regulatory effects of MA in the periphery with those in specific brain regions, thus providing a delineation of cytokine changes that test the role of MA within our model of MA-induced neuroinflammation.
In Study Two (Human Component), we will measure peripheral cytokine levels, cognitive and psychiatric symptom severity, and white matter integrity using diffusion tensor imaging (DTI) in a sample of adults with and without MA dependence.
Ultimately, the proposed research program hopes to identify mechanisms leading to MA-induced psychiatric and cognitive impairment and to develop interventions that could prevent or ameliorate MA-induced impairments and improve recovery outcomes.