Research Focus

 Neuronal Functions and Synaptic Communication: Neuropeptides and Drugs of Abuse

The challenge of current and future studies in the Roberto laboratory is to understand which specific neuronal mechanisms underlie synaptic and/or molecular changes that influence the development of drugs addiction and alcohol dependence. Alcohol abuse causes 4% of the global disease burden, and accounts for extensive unmet medical needs. With prolonged alcohol abuse, adaptations occur at the cellular level as the brain attempts to overcome the acute effects of alcohol intake, often these adaptations lead to near-permanent adverse changes in the structure and function of neurons. The synapse is the primary point for information transfer between neurons, and a central hypothesis of alcohol research is that synapses are the most sensitive sites of ethanol action. Thus, the Roberto laboratory focuses on the synapses of the central nucleus of the amygdala (CeA), a brain region considered to be crucial in mediating the behavioral effects of acute and chronic drug consumption. The aim is to understand the effects of neuropeptides and abused drugs on neuronal function and synaptic transmission using electrophysiological, pharmacological, and molecular methods. The working hypothesis is that neuroadaptations occur in the neural circuitry in response to chronic consumption of drugs of abuse, triggering the ‘drive’ or craving to take drugs. The discovery and characterization of such neuroadaptative changes has and will continue to be useful toward developing new therapeutic agents to alleviate drug dependence, and particularly alcohol dependence.

Dr. Roberto’s 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. Dr. Roberto first identified a clear presynaptic effect of acute ethanol in enhancing vesicular GABA release and decreasing glutamatergic transmission in CeA neurons, and that these neuroadaptations play a role in the development of alcohol dependence. In particular, her findings provided a cellular mechanism for previous behavioral data suggesting that GABA in the CeA plays a major role in the transition to ethanol dependence. As a long-term, Dr. Roberto’s group seeks to build on these neurobiological mechanisms to identify novel molecules that moderate alcoholism. For example, Dr. Roberto 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”). Classical activation of brain reward systems by alcohol is likely confined to early stages of the dependence process and to individuals with a genetic susceptibility. Over time, chronic elevated alcohol exposure 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. Thus, Dr. Roberto has characterized synaptic action of CRF at CeA synapses and the involvement of this system and other stress-related neurotransmitters/neuroregulators (e.g.; nociceptin and neuropeptide Y) in alcohol dependence. Her 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.

Future Research Plans

 Future research is focused on understanding the neural mechanisms that mediate addiction to drugs of abuse and on uncovering key neuroadaptative sites associated with the transition to addiction. We will further explore the role of the CeA synapses in ethanol dependence and excessive drinking and test the interactions of ethanol and specific neuropeptides (e.g.; nociceptin, NPY etc) at these synapses. Notably, the findings of the Dr. Roberto laboratory point to a novel but recurring theme: the presynaptic effects of ethanol and neuropeptides are regulated by multiple presynaptic GPCRs and protein kinases. The ultimate goal of Dr. Roberto’s research is to fully characterize the intracellular signaling pathways which regulate vesicular GABA release. Future studies will use advanced imaging and immunohistochemical techniques to dissect the neuronal circuitry underlying alcohol and drug dependence. A long-term goal in the context of these basic neurobiological studies is the development of novel molecules that moderate alcohol dependence by acting at the cellular level in brain regions such as the amygdala that are associated with ethanol-dependence.

Education

B.A., Biology, University of Pisa, 1996
Ph.D., Biology, University of Pisa, 2001

Awards & Professional Activities

Presidential Award

2009-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 by annually at the White House by the President following recommendations from participating agencies. 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.
The Scripps Research Education Programs (2006-present).
The Scripps Education Outreach Programs (2006-present).
Young Investigator Symposium Award from the European Society for Biomedical Research on Alcoholism (ESBRA) 2007.
Member of the Fundraising Committee for RSA (2007-present).
Member of the RSA Research Priorities Committee (2008-2010).
Organizer of the First (2008) and Second (2011) International Meeting "Alcoholism and Stress: A Framework for Future Treatment Strategies", Volterra (Pisa), Italy.
Member of the Membership Committee, International Society for Biomedical Research on Alcoholism (2010-present).

Selected References

Roberto M., Cruz M.T, Bajo M., Siggins G.R. 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.

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) Amygdala GABA release and CRF: Key mediators of alcohol dependence. Biological Psychiatry 67(9):831-9. Epub 2010 Jan 8.

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., Gilpin N., O’Dell L.E., Cruz M.T., Morse A.C., Siggins G.R. and Koob G.F. (2008) Cellular and behavioral rationale for GABApentin treatment of alcohol dependence. Journal of Neuroscience 28 (22): 5762-5771.

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., Bajo M., Madamba S., Crawford E. and Siggins G.R. (2006) Chronic ethanol exposure and protracted abstinence alter NMDA receptors in central amygdala. Neuropsychopharmacology 31, 988-996.

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

http://www.volterraconference.com