Marisa Roberto, PhD
Scripps Research Joint Appointments
Research Focus
Neuronal Functions and Synaptic Communication: Neuropeptides and Drugs of Abuse
Alcoholism is a chronic relapsing illness that accounts for major disability worldwide and available treatments are insufficient. Current and future studies in my laboratory aim to understand the specific neuronal mechanisms that underlie synaptic and/or molecular changes to influence the development of dependence to alcohol and other drugs of abuse (nicotine, cocaine etc.). Tolerance occurs through adaptations at the cellular level, as the brain attempts to overcome the acute effects of drugs of abuse. With prolonged drug use, these adaptations often lead to significant changes in the structure and function of neurons. The synapse is the primary point for information transfer between neurons, and a central hypothesis is that synapses are the most sensitive sites of action for drugs of abuse. We primarily study the synapses of the central nucleus of the amygdala (CeA), a brain region that plays a central role in the behavioral effects of acute and chronic drug consumption, and in the physiological responses to fearful stimuli and stressful stimuli.
The aim of my group is to understand the effects of drugs of abuse on neuronal function and synaptic transmission using electrophysiological, pharmacological, and molecular methods. We have characterized several neuroadaptative changes that provide seminal insights into synaptic transmission and that will be useful towards developing new therapeutic agents to alleviate drug dependence, and particularly alcohol dependence. In parallel, our studies identified key functional roles for neuropeptide neurotransmitters in the neurocircuits that mediate motivated behavior.
Our early studies significantly advanced the field of alcohol research by elucidating critical synaptic and molecular mechanisms regarding the unique sensitivity of the γ-aminobutyric acid (GABA) and glutamatergic systems in CeA to acute and chronic ethanol. We found that an anti-epileptic drug gabapentin (a structural analogue of GABA) reverses several behavioral aspects of ethanol dependence. These behavioral and cellular findings with gabapentin suggest the potential for use as a possible medication for the treatment of alcoholism. A fundamental dichotomy exists between systems that mediate positively reinforced alcohol consumption (“reward drinking”) versus negatively reinforced intake (“relief drinking”). Over time, chronic elevated alcohol consumption results in neuroadaptations that involve the recruitment and pathological activity of extrahypothalamic stress systems, providing an incentive for negatively reinforced alcohol intake. The neuropeptide corticotropin-releasing factor (CRF) in the CeA has been hypothesized to have an important role in brain emotional function. We have characterized synaptic action of CRF in CeA and the involvement of this system and other stress-related neurotransmitters/neuroregulators (e.g.; nociceptin and neuropeptide Y) in alcohol dependence. We are also examining the actions of other neuromessenger systems, such as those for PACAP, endocannabinoids and opioids, on CeA synaptic transmission, and how these systems are affected by alcohol dependence and stress. The characterization of the amygdala neurocircuitry and connections with other brain regions (e.g. ventral tegmental area, prefrontal cortex, the bed nucleus of stria terminalis) as well as neuroinflammation are new areas of interest of my lab.
Our findings provide a framework for further molecular and cellular research that will facilitate medication development and may help tailor personalized therapies for alcoholism and other addictive disorders.
Education
Ph.D. (Biology), University of Pisa, 2001B.A. (Biology), University of Pisa, 1996
Professional Experience
2015-2017 Professor, Committee on the Neurobiology of Addictive Disorders (CNAD), Scripps Research2011-2015 Associate Professor, Committee on the Neurobiology of Addictive Disorders (CNAD), Scripps Research
Awards & Professional Activities
Presidential Award2009-Presidential Early Career Award for Scientists and Engineers (PECASE), given by the National Science and Technology Council. The PECASE award is the highest honor bestowed by the U.S. government on outstanding scientists and engineers beginning their independent careers. The PECASE award is intended to recognize scientists and engineers who show exceptional potential for leadership and service at the frontiers of scientific knowledge. The awards are conferred annually at the White House by the President. In 2009, 12 persons were selected for the PECASE award from the NIH.
· Young Investigator Award from the Research Society on Alcoholism 2005: Plenary Lecture at the18th Annual,
Baltimore 2006.
· Researcher at The Pearson Center for Alcoholism and Addiction Research.
· Faculty Member, The Harold L. Dorris Neurological Research Institute (2005-2010)
· Young Investigator Symposium Award from the European Society for Biomedical Research on Alcoholism
(ESBRA) 2007.
· Organizer of the (2008, 2011, 2014 and 2017) International Meeting "Alcoholism and Stress: A Framework for Future Treatment Strategies", Volterra (Pisa), Italy.
· Knight of the “Order of Merit of the Republic of Italy” (2011)
· 6th Edition of the International Prize “Genoa: a woman standing out from the crowd” (2013)
· The Jacob P. Waletzky Award from the Society for Neuroscience (2016)
Selected References
Varodayan F., de Guglielmo G., Logrip M.L., George O., and Roberto M. Alcohol dependence disrupts amygdalar L-type voltage-gated calcium channel mechanisms. J Neurosci. 2017 Mar 31. pii: 3721-16. doi: 10.1523/JNEUROSCI.3721-16.2017. [Epub ahead of print]
Natividad L.A., Buczynski M.W., Herman M.A., Kirson D., Oleata C.S., Ciccocioppo R., Roberto M., Parsons L.H. (2017) Anxiety-like predisposition involves deficient anandamide regulation of excitatory signaling in the central amygdala. Biol Psychiatry. 2017 Jan 13. pii: S0006-3223(17)30037-9. doi: 10.1016/j.biopsych.2017.01.005. [Epub ahead of print].
Harris R.A., Bajo M., Bell R.L., Blednov Y.A., Varodayan F.P., Truitt J., de Guglielmo G., Lasek A.W., Logrip M.L., Vendruscolo L., Roberts A.J., Roberts E., George O., Mayfield J., Billiar T., Hackam D., Mayfield R.D., Koob G.F., Roberto M., Homanics G.E. (2017) Genetic and pharmacologic manipulation of TLR4 has minimal impact on ethanol consumption in rodents. J Neurosci. 2017 Feb 1;37(5):1139-1155. doi: 10.1523/JNEUROSCI.2002-16.2016.
Logrip M.L., Oleata C.S. and Roberto M. Sex differences in alcohol and corticosterone modulation of glutamatergic input from the basolateral to the central nucleus of the amygdala. Neuropharmacology 2017 Mar 1;114:123-134. doi: 10.1016/j.neuropharm.2016.11.021.
Herman M.A., Contet C. and Roberto M. (2016) A functional switch in tonic GABA currents alters the output of central amygdala CRF receptor-1 neurons following chronic ethanol exposure. J Neurosci. 2016 Oct 19;36(42):10729-10741.
Schmeichel B.E., Herman M.A., Roberto M., Koob G.F. (2016) Hypocretin in the central amygdala mediates escalated cocaine self-administration and stress-induced reinstatement in rats. In press in Biological Psychiatry. http://dx.doi.org/10.1016/j.biopsych.2016.06.010
Varodayan F., Bajo M., Soni N, George L., Madamba S., Schweitzer P. and Roberto M. (2016) Chronic ethanol exposure alters cannabinoid CB(1) receptor function at the GABAergic synapses in rat basolateral amygdala. Addict Biol. 2016 Jan 20. doi: 10.1111/adb.12369. [Epub ahead of print]
Buczynski M.W., Herman M.A., K. Hsu, Natividad L.A., Irimia C., Polis I.Y., Pugh H., Chang J.W., Niphakis M.J., Cravatt B.F., Roberto M., and Parsons L.H. (2016) Diacylglycerol lipase-alpha inhibits GABA release in the ventral tegmental area during chronic nicotine exposure to facilitate drug self-administration. Proc Natl Acad Sci USA. 2016 Jan 26;113(4):1086-91. doi: 10.1073/pnas.1522672113. Epub 2016 Jan 11.
Herman M.A., Sidhu H., Stouffer D.G., Kreifeldt M., Le D., Cates-Gatto C., Munoz M.B., Roberts A.J., Parsons L.H., Roberto M., Wickmand K., Slesinger P.E. and Contet C. (2015) GIRK3 gates activation of the mesolimbic dopaminergic pathway by ethanol. Proc Natl Acad Sci U S A. 2015 Jun 2;112(22):7091-6. doi: 10.1073/pnas.1416146112. Epub 2015 May 11.
Bajo M., Herman M.A., Varodayan F.P., Oleata C.S., Madamba S.G., Harris R.A., Blednov Y. A., and Roberto M. (2015) Role of the IL-1 receptor antagonist in ethanol-induced regulation of GABAergic transmission in the central amygdala. Brain Behav Immun. 2015 Mar;45:189-97. doi: 10.1016/j.bbi.2014.11.011. Epub 2014 Dec 3.
Grieder T.E., Herman M., Contet C., Tan L.A., Vargas-Perez H., Cohen A, Chwalek M, Maal-Bared G, Freiling J., Schlosburg J.E., Clark L., Crawford E., Koebel P., Repunte-Canonigo V., Sanna P., Tapper A.R., Roberto M., Kieffer B.L., Sawchenko P.E., Koob G.F., van der Kooy D., George O. (2014) VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation. Nat Neurosci. 2014 Dec;17(12):1751-8. doi: 10.1038/nn.3872. Epub 2014 Nov 17.
Herman M.A and Roberto M. (2014) Cell-type-specific tonic GABA signaling in the rat central amygdala is selectively altered by acute and chronic ethanol. Addiction Biology, Aug 29. doi: 10.1111/adb.12181. [Epub ahead of print]
Repunte-Canonigo V., Herman M.A, Kawamuraa T., Kranzler H.R., Sherva R., Gelernter J., Farrer L.A., Roberto M. and Sanna P.P. (2014) The neurofibromatosis type 1 (Nf1) gene regulates alcohol intake, GABA release in the central amygdala, and is associated with alcohol dependence in humans. Biol Psychiatry. 2014 Aug 19. pii: S0006-3223(14)00606-4. doi: 10.1016/ j.biopsych.2014.07.031. [Epub ahead of print]
Ciccocioppo R., de Guglielmo G., Hansson A.C., Ubaldi M., Kallupi M., Cruz M.T., Oleata C.S., Heilig M. and Roberto M. (2014) Restraint Stress alters Nociceptin/Orphanin FQ and CRF systems in the rat central amygdala: Significance for anxiety-like behaviors. The Journal of Neuroscience, Jan8; 34(2):363-72. doi: 10.1523/JNEUROSCI.2400-13.2014
Nimitvilai S., Herman H., You C., Arora D.S., McElvain M.A., Roberto M. and Brodie M.S. (2014) Dopamine D2 receptor desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release. Neuropharmacology. Mar 19;82C:28-40. doi: 10.1016/j.neuropharm.2014.03.006. [Epub ahead of print]
Herman M.A., Contet C., Justice N.J., Vale W. and Roberto M. (2013) Subunit-specific tonic GABA currents and differential effects of ethanol within the central amygdala circuitry of CRF1 reporter mice. The Journal of Neuroscience, 20;33(8):3284-98..
Kallupi M., Wee S., Edwards S., Whitfield T.W., Oleata C.S., Luu G., Schmeichel B.E., Koob G.F. and Roberto M. (2013) Kappa Opioid Receptor-Mediated Dysregulation of GABAergic Transmission in the Central Amygdala in Cocaine Addiction. Biological Psychiatry, 2013 Oct 1;74(7):520-8. doi: 10.1016/j.biopsych.2013.04.028. Epub 2013 Jun 14.
Kallupi M., Varodayan F., Oleata C.S., Correia D., Luu G. and Roberto M. (2013) Nociceptin/ orphanin FQ decreases glutamate transmission and blocks ethanol-induced effects in the central amygdala of naïve and ethanol-depended rats. Neuropsychopharmacology, Oct 30. doi: 10.1038/ npp.2013.308. [Epub ahead of print]
Cruz M.T., Herman M., Kallupi M. and Roberto M. (2012) Nociceptin/orphanin FQ blockade of the CRF-induced GABA Release in the Central Amygdala is enhanced after chronic ethanol treatment. Biological Psychiatry 15;71(8):666-76. Epub ahead of print on Dec 5.
Gilpin N.W., Misra K., Herman M., Cruz M.T., Koob G.F. and Roberto M. (2011) Neuropeptide Y opposes alcohol effects on GABA release in amygdala and blocks the transition to alcohol dependence. Biological Psychiatry Jun 1;69(11):1091-9. Epub ahead of print on Apr 3 2011.
Roberto M., Cruz M.T., Gilpin N.W., Sabino V., Schweitzer P., Bajo M., Cottone P., Madamba S.M, Stouffer D.G., Zorrilla E.P., Koob G.F., Siggins G.R, Parsons L.H. (2010) Corticotropin releasing factor-induced amygdala gamma-aminobutyric Acid release plays a key role in alcohol dependence Biological Psychiatry 67(9):831-9. Epub 2010 Jan 8.
Roberto M., Cruz M.T, Bajo M., Siggins G.R., Parsons L.H. and Schweitzer P. (2010) The CB1 system tonically regulates inhibitory transmission and depresses the effect of ethanol in central amygdala. Neuropsycopharmacology 35(9):1962-72
Cottone P., Sabino V., Roberto M., Bajo M, Pockros L., Steardo L.; Rice K.C., Grigoriadis D.E, Conti B., Koob G.F., Zorrilla E.P. (2009) CRF system recruitment mediates dark side of compulsive eating. Proceedings of National Academy of Sciences USA 24;106(47):20016-20.
Bajo M., Cruz M.T., Siggins G.R., Messing R. and Roberto M. (2008) Protein kinase C epsilon mediation of CRF- and ethanol-induced GABA release in central amygdala. Proceedings of National Academy of Sciences USA 105(24):8410-5.
Roberto M. and Siggins G.R. (2006) Nociceptin/Orphanin FQ inhibits the ethanol-induced enhancement of GABAergic transmission in the central amygdala. Proceedings of National Academy of Sciences USA 103: 9715-9721.
Roberto M. and Siggins G.R. (2006) Nociceptin/Orphanin FQ inhibits the ethanol-induced enhancement of GABAergic transmission in the central amygdala. Proceedings of National Academy of Sciences USA 103: 9715-9721
Roberto M., Schweitzer P., Madamba S., Stouffer D.G., Parsons L.H. and Siggins G.R. (2004) Acute and chronic ethanol alter glutamatergic synaptic transmission in rat central amygdala: an in vitro and in vivo analysis. Journal of Neuroscience 24 (7): 1594-603.
Roberto M., Madamba S.G., Stouffer D.G., Parsons L.H. and Siggins G.R. (2004) Increased GABA release in the central amygdala of ethanol-dependent rats. Journal of Neuroscience 24(45):10159-66.
Roberto M., Madamba S., Moore S.D., Tallent M.K. and Siggins G.R. (2003) Ethanol increases GABAergic transmission at both pre- and postsynaptic sites in rat central amygdala neurons. Proceedings of National Academy of Sciences USA 100:4, 2053-2058.
Links
Committee on the Neurobiology of Addictive Disorders
http://volterraconference.com/
http://www.sciencedaily.com¬/releases/2008/05/080528121256.htm
http://www.usatoday.com/news/health/2010-01-29-stress-alcoholism_N.htm?csp=usat.me
http://www.drugdiscoverynews.com/index.php?newsarticle=5725
http://alert.psychiatricnews.org/2013/06/addictions-dark-side-rises-as-important.html