Research in the Graves lab focuses on the pathogenesis of neurodegenerative diseases and stimulant-induced neurotoxicity. Bridging the gap between neurodegenerative diseases and stimulant-induced neurotoxicity is methamphetamine, which has been reported to increase the risk for developing Parkinson’s disease. This has drawn our attention to the role of mitochondria in determining the vulnerability of monoaminergic neurons and the mechanisms by which mitochondrial viability and function is impacted by drugs that disrupt vesicular packaging of neurotransmitters.
In addition to and complementing our work on neurodegeneration, we also direct our efforts towards understanding how striatal function is altered in response to perturbations in dopamine. In Parkinson’s disease there is a progressive loss of dopamine resulting in impaired motor function whereas drugs of abuse increase dopamine and can lead to addiction. Using rodent models of Parkinson’s disease and drug addiction we are able to assess the extremes of too little dopamine versus too much dopamine, the associated functional changes in striatal neurons, and the behavioral consequences.
To accomplish our research goals we use a combination of electrophysiological, optical, immunohistochemical, and behavioral techniques.
- Graves SM, Schwarzschild SE, Tai RA, Chen Y, Surmeier DJ. Mitochondrial oxidant stress mediates methamphetamine neurotoxicity in substantia nigra dopaminergic neurons. Neurobiol Dis. 2021 May 31;156:105409.
- Zhai S, Shen W, Graves SM, Surmeier DJ. Dopaminergic modulation of striatal function and Parkinson's disease. J Neural Transm (Vienna). 2019 Apr;126(4):411-422.
- Du Y, Graves SM. Spiny projection neuron dynamics in toxin and transgenic models of Parkinson's disease. Front Neural Circuits. 2019 Mar 15;13:17.
- Ceglia I, Lee K-W, Cahill ME, Graves SM, Surmeier DJ, Nestler EJ, Nairn AC, Greengard P, Kim Y. WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine. Proc Natl Acad Sci U S A. 2017;114:1395-1400.
- Sebel LE, Graves SM, Chan CS, Surmeier DJ. Haloperidol selectively remodels striatal indirect pathway circuits. Neuropsychopharmacology. 2017;42(4):963-973.
- Graves SM, Clark MJ, Traynor JR, Hu XI, Napier TC. Nucleus accumbens shell excitability is decreased by methamphetamine self-administration and increased by 5-HT2C receptor inverse agonism and agonism. Neuropharmacology. 2015;89:113-21.
- Fieblinger T*, Graves SM*, Sebel LE, Alcacer C, Plotkin JL, Gertler TS, Chan CS, Heiman M, Greengard P, Cenci MA, Surmeier DJ. Cell type-specific plasticity of striatal projection neurons in parkinsonism and L-DOPA-induced dyskinesia. Nat Comm. 2014;5:5316.*Co-first authors