Michelle Mazei-Robison, Ph.D.
Biomedical Physical Sciences Building
567 Wilson Rd Rm 3182
Department of Physiology
Michigan State University
East Lansing, MI 48824
Phone: (517) 884-5004
Psychiatric disorders now comprise a significant health and financial burden in the US, costing billions in lost production and wages. Two of the more prevalent psychiatric disorders, depression and addiction, affect millions of adults, and current therapeutic options offer limited relief. Despite the prevalence of these disorders, little is known about their underlying mechanisms. Part of the difficulty in studying the etiology of psychiatric diseases is the dearth of animal models for human disorders such as depression. Recent work has utilized a chronic social defeat model in mice that induces symptoms relevant to depression and posttraumatic stress disorder. Using this model, the importance of the mesocorticolimbic dopamine (DA) system has been revealed. This pathway consists of DA neurons in ventral tegmental area (VTA) that project to the nucleus accumbens and prefrontal cortex.
The Mazei-Robison lab is interested in understanding the molecular mechanisms that underlie changes in VTA DA neuron signaling, morphology, and activity induced in neuropsychiatric disorders such as depression and addiction. Despite evidence that dysregulation of the mesocorticolimbic DA system contributes to a number of psychiatric disorders, a detailed understanding of the main projection neurons in this pathway, the DA neurons of the VTA, is lacking. This includes the structural and functional neuroadaptations, the molecular mechanisms responsible for these adaptations, and the specific neurons and outputs affected. In particular, we are interested in the following questions:
1. Which signaling pathways in the VTA are altered by stress and drugs to mediate changes in behavior?
2. Are there morphological changes in VTA DA neurons that mediate long-term changes in behavior?
3. Are all DA neurons in the VTA similarly affected or are changes specific for subtypes of neurons in the VTA or specific output pathways?
To address these aims, we employ a wide array of cutting-edge techniques including: a battery of behavioral assays including social interaction, elevated plus maze, and conditioned place preference; neuron- and projection-specific viral-mediated gene transfer and inducible- and brain region-specific transgenic mice; optogenetic control of neuronal activity during behavioral assays; retrograde labeling, cell-filling and 3D neuronal reconstruction; immunohistochemistry, and biochemical assays such as western blotting and quantitative real-time PCR.
Overall, these studies seek to identify and characterize the molecular underpinnings of stress- and drug-induced neuroadaptations in the mesocorticolimbic circuit with the goal of illuminating novel therapeutic targets.
Vialou V., Bagot R., Cahill M., Ferguson D., Robison A.J., Ku S., Dietz D., Fallon B., Mazei-Robison M.S., Harrigan E., Winstanley C., Joshi T., Feng J., Berton O., and Nestler E.J. Prefrontal cortical circuit for depression- and anxiety-related behaviors mediated by cholecystokinin: Role of deltaFosB. In Press, Journal of Neuroscience, 2014
Der-Avakian A., Mazei-Robison M.S., Kesby J.P., Nestler E.J. and Markou A. Enduring deficits in brain reward function after chronic social defeat in rats: susceptibility, resilience, and antidepressant response. In Press, Biological Psychiatry, 2014
Walsh J.J., Friedman A.K., Sun J., Heller E.A., Ku S.M., Juarez B., Burnham V.L., Mazei-Robison M.S., Ferguson D., Golden S.A., Koo J.W., Chaudhury D., Christoffel D.J., Pomeranz L., Friedman J.M., Russo S.J., Nester E.J and Han M.H. Stress gates neural activation of BDNF in the mesolimbic reward pathway. 2014. Nature Neurosci 17: 27-9.
Robison A.J., Vialou V., Sun. H., Mazei-Robison M.S., Golden S., Dias C., Turecki G., Tamminga C., Russo S.J., and Nestler E.J. Fluoxetine epigenetically alters the CaMKII promoter in the nucleus accumbens to regulate delta FosB binding and antidepressant effects. 2013. Neuropsychopharmacology Nov. 15.
Robison A.J., Vialou V., Mazei-Robison M.S., Feng J., Kourrich S., Collins M., Wee S.M., Koob G., Turecki G., Neve R., Thomas M., Nestler E. Behavioral and structural responses to chronic cocaine require a feedforward loop involving ΔFosB and calcium/calmodulin-dependent kinase II in the nucleus accumbens shell. 2013. J Neurosci 33: 4295-4307.
Koo JW, Mazei-Robison MS, Lobo MK. Chaudhury D, Dietz DM, LaPlant Q, Juarez B, Ferguson D, Sun H, Scobie K, Feng J, Damez-Werno D, Ohnishi YN, Ohnishi YH, Mouzon E, Han MH, Neve RL, Russo SJ, and Nestler EJ (2012) Role of VTA BDNF in regulating molecular and behavioral responses to morphine. Science 338: online 10/5/12
Mazei-Robison MS and Nestler EJ (2012) Opiate-Induced Molecular and Cellular Plasticity of Ventral Tegmental Area and Locus Coeruleus Catecholamine Neurons. Cold Spring Harb Perspect Med. Jul 2(7):a012070
Sakrikar DJ, Mazei-Robison MS, Mergy MA, Richtand NW, Han Q, Hamilton PJ, Bowton E, Galli A, Veenstra-VanderWeele J, Gill M, Blakely RD (2012) ADHD-derived coding variation in the dopamine transporter disrupts microdomain targeting and trafficking regulation. J Neurosci 32: 5385-5397.
Mazei-Robison MS, Koo JW, Friedman A, Lansink C, Robison AJ, Vinish M, Krishnan V, Kim S, Siuta M, Galli A, Niswender K, Appasani R, Horvath M, Neve RL, Worley P, Snyder S, Hurd Y, Cheer J, Han MH, Russo SJ, and Nestler EJ (2011) Role for mTOR signaling and neuronal activity in morphine-induced adaptations in ventral tegmental area dopamine neurons. Neuron 72: 977-990.
Wilkinson M, Dias C, Magida J, Mazei-Robison MS, Lobo MK, Kennedy P, Dietz D, Covington H, Russo SJ, Neve RL, Ghose S, Tamminga C, and Nestler EJ (2011) A novel role for the protein disheveled in the mouse nucleus accumbens in a social defeat model of depression. J Neurosci 31: 9084-9092.
Russo SJ, Mazei-Robison MS, Ables JL, and Nestler EJ (2008) Neurotrophic factors and structural plasticity in addiction. Neuropharmacology 56 Suppl 1: 73-82.
Krishnan V, Han MH, Mazei-Robison MS, Iniguez SD, Ables JA, Vialou V, Berton O, Ghose S, Covington HE, Wiley MD, Henderson RP, Neve RL, Eisch AJ, Tamminga CA, Russo SJ, Bolanos CA and Nestler EJ (2008) AKT signaling within the ventral tegmental area regulates cellular and behavioral responses to stressful stimuli. Biol Psychiatry 64: 691-700.
Mazei-Robison MS, Bowton E, Holy M, Schmudermaier M, Freissmuth M, Sitte HH, Galli A, and Blakely RD (2008) Anomalous dopamine release in attention-deficit hyperactivity disorder. J Neurosci 28: 7040-6. Editor’s Choice: E.M. Adler, Heading in the wrong direction? Science Signaling 1: ec254.
Mazei-Robison MS and Blakely RD (2005) Expression studies of naturally occurring human dopamine transporter variants identifies a novel state of transporter inactivation associated with Val382Ala. Neuropharmacology 49: 737-49.
Mazei-Robison MS, Couch RS, Shelton RC, Stein MA, and Blakely RD (2005) Sequence variation in the human dopamine transporter gene in children with attention deficit hyperactivity disorder. Neuropharmacology 49: 724-36.
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