PROJECT SUMMARY/ABSTRACT Methamphetamine (meth) is a powerfully addictive psychostimulant capable of causing neuronal damage. Recent studies by my mentor, Dr. Graves, found that meth increases mitochondrial stress in the axons of substantia nigra pars compacta (SNc) dopamine (DA) neurons resulting from MAO metabolism of cytosolic DA. Pilot studies showed similar effects in the axons of Locus coeruleus (LC) norepinephrine (NE) neurons. Using a 28-day meth administration paradigm, recent studies by Dr. Graves found degeneration of SNc DA neurons and that pharmacological inhibition of MAO was neuroprotective. Pilot studies similarly show chronic meth- induced LC degeneration that is attenuated by MAO inhibition. These data suggest that axonal MAO- dependent mitochondrial stress contributes to chronic meth-induced degeneration. The overarching goal of this proposal is to determine the progression and presentation of degeneration, whether neuronal (as opposed to astrocytic) MAO enzymes are necessary for degeneration, and the behavioral consequences of chronic meth-induced SNc and LC degeneration. My central hypothesis is that chronic meth induces a neuronal MAO-dependent dying-back pattern of SNc and LC degeneration resulting in cognitive impairment and will be tested in the following aims: Aim 1: Determine if chronic meth produces a dying-back pattern of SNc and LC degeneration. Meth increases axonal, but not somatic MAO-dependent mitochondrial stress, and MAO inhibition prevented chronic meth-induced SNc and LC degeneration; these data suggest that MAO-dependent axonal mitochondrial stress drives degeneration. I therefore hypothesize that chronic meth will produce a dying-back pattern of SNc and LC degeneration, where axonal loss precedes somatic loss. Aim 2: Determine if neuronal MAO is necessary for chronic meth-induced SNc and LC degeneration. Studies show systemic MAO inhibition prevented chronic meth-induced SNc and LC degeneration, but MAO enzymes are expressed in neurons and astrocytes. Given that meth increased mitochondrial stress in SNc and LC axons, I hypothesize that neuronal MAO is necessary for degeneration. Aim 3: Determine the behavioral consequences of chronic meth-induced SNc and LC degeneration. SNc degeneration and LC lesioning are associated with impairments in novel object recognition and context-associated fear conditioning assays, respectively; I therefore hypothesize that chronic meth-induced degeneration of the SNc and LC will lead to similar behavioral impairments. I will test my hypotheses by training in and using immunofluorescence, unbiased stereological assessment of neuronal and axonal degeneration, behavioral analysis, and both genetic and pharmacological inhibition of MAO enzymes. Testing my hypotheses will provide me with outstanding technical and conceptual training as a research scientist. Completion of proposed aims will improve our understanding of the neurodegenerative consequences of chronic meth, expanding k...