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Nicholas Graziane

TitleAssistant Professor
InstitutionCollege of Medicine
DepartmentAnesthesiology and Perioperative Medicine
Address500 University Drive Hershey, PA 17033
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    Collapse Overview 
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    Education
    B.S., SUNY Buffalo, 2004
    Ph.D., SUNY Buffalo, 2010
    Postdoctoral Training, Brown University, 2010-2012
    Postdoctoral Training, University of Pittsburgh, 2012-2017

    Awards
    NIH/NIDA Addiction Training Grant, 2010 and 2013-2015
    Graduate Student Travel Award, Buffalo Chapter, SfN, 2007
    Dean's Commendation for Academic Excellence in the Pharmaceutical Sciences Program, 2003
    Siena College Franciscan Scholarship, 2000

    Narrative
    Our research looks to identify the molecular and cellular substrates that mediate a number of devastating brain diseases, including drug addiction and chronic pain. With our established animal models for these diseases, we examine changes in synaptic transmission and in intrinsic membrane excitability of neurons and circuits that are thought to control motivation, reward, and affective states using electrophysiology and optogenetic approaches.

    Our main project investigates the neurocircuits that control the long-term maintenance of opioid-context associations. Opioid-context associations occur during repeated opioid administration within a specific context (e.g., environmental surroundings), which leads to the transfer of the motivational and rewarding sensations of the drug to the environment in which they were taken. This in turn leads to drug-craving and contextual-drug relapse in drug-free states, which is a problem for abstinent opioid abusers. By identifying the neurocircuits that control and maintain opioid-context associations, we can potentially reorient the neurocircuit connections using electrical brain stimulation protocols, thus permanently eliminating the associations. In order to get to this clinically relevant endpoint, we use rodent models of addiction. Using conditioned place preference, which isolates context associations from other forms of associations like cue associations or operant associations, mice are conditioned to express opioid-context associations. Once the behavior is established, we use optogenetic techniques to isolate specific neurocircuit pathways in order to uncover changes in glutamatergic transmission in the nucleus accumbens shell, a brain that regulates and controls opioid-induced context associations. This work includes a combination of innovative techniques, including behavior, in vivo and ex vivo optogenetic techniques, and ex vivo electrophysiological approaches in transgenic animals (NIH award pending).

    Our second research interest focuses on opioid-induced hyperalgesia (OIH), which is triggered by opioid use in perioperative settings (e.g., fentanyl) or in pain and substitution therapies (e.g., morphine, methadone). Central to OIH is the periaqueductal gray (PAG), a brain region that has high levels of opioid receptor expression and is critically involved in pain modulation. The PAG modulates pain by sending excitatory glutamatergic projections to OFF-cells in the rostral ventromedial medulla (RVM), which are anti-nociceptive when activated, or by sending inhibitory GABAergic projections to ON-cells in the RVM, which are pronociceptive when activated. Despite this clear distinction for how the PAG modulates pain, it is unknown what effect OIH has on this circuit. By filling this knowledge gap, we can gain a neurobiological understanding of how opioids facilitate cross sensitization from analgesia to pronociception in supraspinal regions. This knowledge has the potential to lead to therapeutic approaches that target supraspinal OIH processing centers, thereby intervening before downstream circuits are recruited. For this project, our overall objective is to determine how, in OIH, the neuronal output of glutamate projecting neurons in the PAG is modulated. To do this, we are testing the hypothesis that, in OIH, the neuronal output from PAG-to-RVM glutamatergic-projecting neurons is decreased, leading to lower pain tolerance. The rationale for the proposed research is that once it is known how OIH alters neurocircuits in supraspinal regions, targeted clinically approved procedures such as deep brain stimulation can be used to reverse opioid-induced neuronal adaptations (NIH award pending).


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    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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    1. Polter AM, Barcomb K, Chen RW, Dingess PM, Graziane NM, Brown TE, Kauer JA. Constitutive activation of kappa opioid receptors at ventral tegmental area inhibitory synapses following acute stress. Elife. 2017 04 12; 6. PMID: 28402252.
      View in: PubMed
    2. Graziane NM, Sun S, Wright WJ, Jang D, Liu Z, Huang YH, Nestler EJ, Wang YT, Schlüter OM, Dong Y. Opposing mechanisms mediate morphine- and cocaine-induced generation of silent synapses. Nat Neurosci. 2016 07; 19(7):915-25. PMID: 27239940; PMCID: PMC4925174 [Available on 11/30/16].
    3. Wei J, Graziane NM, Gu Z, Yan Z. DISC1 Protein Regulates ?-Aminobutyric Acid, Type A (GABAA) Receptor Trafficking and Inhibitory Synaptic Transmission in Cortical Neurons. J Biol Chem. 2015 Nov 13; 290(46):27680-7. PMID: 26424793; PMCID: PMC4646017 [Available on 11/13/16].
    4. Polter AM, Bishop RA, Briand LA, Graziane NM, Pierce RC, Kauer JA. Poststress block of kappa opioid receptors rescues long-term potentiation of inhibitory synapses and prevents reinstatement of cocaine seeking. Biol Psychiatry. 2014 Nov 15; 76(10):785-93. PMID: 24957331; PMCID: PMC4240751.
    5. Lee BR, Ma YY, Huang YH, Wang X, Otaka M, Ishikawa M, Neumann PA, Graziane NM, Brown TE, Suska A, Guo C, Lobo MK, Sesack SR, Wolf ME, Nestler EJ, Shaham Y, Schlüter OM, Dong Y. Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving. Nat Neurosci. 2013 Nov; 16(11):1644-51. PMID: 24077564; PMCID: PMC3815713.
    6. Wei J, Graziane NM, Wang H, Zhong P, Wang Q, Liu W, Hayashi-Takagi A, Korth C, Sawa A, Brandon NJ, Yan Z. Regulation of N-methyl-D-aspartate receptors by disrupted-in-schizophrenia-1. Biol Psychiatry. 2014 Mar 01; 75(5):414-424. PMID: 23906531; PMCID: PMC3864617.
    7. Graziane NM, Polter AM, Briand LA, Pierce RC, Kauer JA. Kappa opioid receptors regulate stress-induced cocaine seeking and synaptic plasticity. Neuron. 2013 Mar 06; 77(5):942-54. PMID: 23473323; PMCID: PMC3632376.
    8. Borschel WF, Myers JM, Kasperek EM, Smith TP, Graziane NM, Nowak LM, Popescu GK. Gating reaction mechanism of neuronal NMDA receptors. J Neurophysiol. 2012 Dec; 108(11):3105-15. PMID: 22993263; PMCID: PMC3544869.
    9. Wang Q, Charych EI, Pulito VL, Lee JB, Graziane NM, Crozier RA, Revilla-Sanchez R, Kelly MP, Dunlop AJ, Murdoch H, Taylor N, Xie Y, Pausch M, Hayashi-Takagi A, Ishizuka K, Seshadri S, Bates B, Kariya K, Sawa A, Weinberg RJ, Moss SJ, Houslay MD, Yan Z, Brandon NJ. The psychiatric disease risk factors DISC1 and TNIK interact to regulate synapse composition and function. Mol Psychiatry. 2011 Oct; 16(10):1006-23. PMID: 20838393; PMCID: PMC3176992.
    10. Hayashi-Takagi A, Takaki M, Graziane N, Seshadri S, Murdoch H, Dunlop AJ, Makino Y, Seshadri AJ, Ishizuka K, Srivastava DP, Xie Z, Baraban JM, Houslay MD, Tomoda T, Brandon NJ, Kamiya A, Yan Z, Penzes P, Sawa A. Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1. Nat Neurosci. 2010 Mar; 13(3):327-32. PMID: 20139976; PMCID: PMC2846623.
    11. Graziane NM, Yuen EY, Yan Z. Dopamine D4 Receptors Regulate GABAA Receptor Trafficking via an Actin/Cofilin/Myosin-dependent Mechanism. J Biol Chem. 2009 Mar 27; 284(13):8329-36. PMID: 19179335; PMCID: PMC2659191.
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