A fundamental question in neuroscience is how the structure and function of the brain is modified by experience. One compelling model of experience-dependent plasticity is behavioral sensitization-a long-lasting increase in the locomotor stimulatory effects of drugs of abuse following repeated exposure. Behavioral sensitization is also a prominent model for the intensification of drug craving that occurs in human addicts. My laboratory seeks to identify the cellular and molecular mechanisms that underlie this form of plasticity, as well as the genetic factors that may predispose an individual to sensitization. We are currently studying two cellular correlates of drug-induced plasticity, long-term depression at glutamatergic synapses in the nucleus accumbens-a key site of action of drugs of abuse in the brain-and the increases in the length of dendrites and the density of dendritic spines that also occur in accumbens neurons. We are using several complementary approaches to determine the relationship that each of these correlates has with behavioral sensitization and with each other: behavioral studies to determine the consequences of drug exposure, the use of transgenic and knockout mice, analysis of dendritic morphology via several staining methods and whole-cell recordings in brain slices to investigate synaptic function. These studies will provide insight into the cellular and molecular mechanisms of an important form of experience-dependent plasticity that may hold some of the clues to drug addiction.
(For a comprehensive list of recent publications, refer to PubMed, a service provided by the National Library of Medicine.)
Hearing MC, Jedynak J, Ebner SR, Ingebretson A, Asp AJ, Fischer RA, Schmidt C, Larson EB, Thomas MJ. Reversal of morphine-induced cell-type-specific synaptic plasticity in the nucleus accumbens shell blocks reinstatement. Proc Natl Acad Sci U S A. 2016 Jan 19;113(3):757-62.
Jedynak J, Hearing M, Ingebretson A, Ebner SR, Kelly M, Fischer RA, Kourrich SJ, and Thomas MJ. Cocaine and amphetamine induce overlapping but distinct patterns of AMPAR plasticity in nucleus accumbens medium spiny neurons. Neuropsychopharmacology 2015 Jun 12.
Wydeven N, Marron Fernandez de Velasco E, Du Y, Benneyworth MA, Hearing MC, Fischer RA, Thomas MJ, Weaver CD, Wickman K. Mechanisms underlying the activation of G-protein-gated inwardly rectifying K+ (GIRK) channels by the novel anxiolytic drug, ML297. Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10755-60.
Smith LN, Jedynak JP, Fontenot MR, Hale CF, Dietz KC, Taniguchi M, Thomas FS, Zirlin BC, Birnbaum SG, Huber KM, Thomas MJ, Cowan CW. Fragile X mental retardation protein regulates synaptic and behavioral plasticity to repeated cocaine administration. Neuron. 2014 May 7;82(3):645-58.
Rothwell PE, Thomas MJ, Gewirtz JC. Protracted manifestations of acute dependence after a single morphine exposure. Psychopharmacology (Berl). 2011 Aug 11.
Penrod RD, Kourrich S, Kearney E, Thomas MJ, Lanier LM. An embryonic culture system for the investigation of striatal medium spiny neuron dendritic spine development and plasticity. J Neurosci Methods. 2011 Aug 30;200(1):1-13. Epub 2011 Jun 13.
Rothwell PE, Kourrich S, Thomas MJ. Synaptic adaptations in the nucleus accumbens caused by experiences linked to relapse. Biol Psychiatry. 2011 Jun 1;69(11):1124-6. Epub 2011 Feb 16.
Rothwell PE, Kourrich S, Thomas MJ. Environmental novelty causes stress-like adaptations at nucleus accumbens synapses: implications for studying addiction-related plasticity. Neuropharmacology. 2011 Dec;61(7):1152-9. Epub 2011 Feb 16.
Rothwell PE, Gewirtz JC, Thomas MJ. Episodic withdrawal promotes psychomotor sensitization to morphine. Neuropsychopharmacology. 2010 Dec;35(13):2579-89. Epub 2010 Sep 1.
Kourrich S, Thomas MJ. Similar neurons, opposite adaptations: psychostimulant experience differentially alters firing properties in accumbens core versus shell. J Neurosci. 2009 Sep 30;29(39):12275-83.
Rothwell PE, Thomas MJ, Gewirtz JC. Distinct profiles of anxiety and dysphoria during spontaneous withdrawal from acute morphine exposure. Neuropsychopharmacology. 2009 Sep;34(10):2285-95. Epub 2009 Jun 3.
Thomas MJ, Kalivas PW, Shaham Y. Neuroplasticity in the mesolimbic dopamine system and cocaine addiction. Br J Pharmacol. 2008 May;154(2):327-42. Epub 2008 Mar 17. Review.
Groth RD, Weick JP, Bradley KC, Luoma JI, Aravamudan B, Klug JR, Thomas MJ, Mermelstein PG. D1 dopamine receptor activation of NFAT-mediated striatal gene expression.
Eur J Neurosci. 2008 Jan;27(1):31-42.
Former Graduate Students:
Rachel Penrod (Neuroscience, University of Minnesota).
Patrick Rothwell (Ph.D. 2010, Neuroscience, University of Minnesota).