Training and Education

The training program will primarily consist of direct research training in the laboratory, although there will also be formal didactic instruction, seminars, lectures, journal clubs, a program retreat and interaction with visiting scholars to enhance their training. In particular, postdoctoral fellows can take advantage of the formal courses in basic science as well as our newly developed course in drug abuse research that will provide a uniform and organized component to the training experience. We will also sponsor a lecture/visiting scholars’ series in drug abuse to provide close interaction with other established researchers in the field.

Training Areas:

Trainees will be able to apply to and choose from a specific research theme among the five research themes that are based on the expertise of the faculty:

• Signaling Mechanisms of Addiction
  Mentors: Benson, Devi, Filizola, Hurd, Iyengar, Nestler
  In this area, trainees will study receptors and signaling pathways that mediate the effects of addictive drugs, with opportunities to apply a wide range of classical biochemical, cell biological, molecular biological and computational methods. One focus of interest in this training area is the emerging importance of opiate receptor dimerization, which adds a layer of complexity to opiate effects by shaping the pharmacology of opioid receptors and routing their signal outputs. Another focus of interest is on the role of epigenetic mechanisms in drug addiction. Ongoing research also includes investigating the ability of the G-protein-coupled opiate and cannabinoid receptors to regulate voltage-gated calcium channels, which promises to shed light on the modulatory effects of addictive drugs on neurotransmitter release. Other current projects include proteins associated with NMDA receptors, which are the primary brain target for ketamine and phencyclidine, and the posttranscriptional editing of the serotonin receptor transcript, which is an epigenetic mechanism that may be a risk factor in liability to drug-seeking behaviors. At the systems level, the effect of drug self-administration on activity in dopaminergic pathways is being studied through dialysis of brain regions that have been implicated in reward and addiction. The complementary interests of the investigators in this area, spanning cellular mechanisms from receptor-effector coupling to regulated gene expression, and involving multiple brain regions that are critical in addiction, will encourage trainees to formulate interdisciplinary projects that combine the expertise and capabilities from multiple laboratories.
  
  
• Adaptation, Plasticity and Memory in Drug Addiction
  Mentors: Benson, Blitzer, Ehrlich, Nestler
  This area focuses on the fundamental processes that mediate adaptive responses to drugs of abuse by analyzing them at the synaptic, cellular, and behavioral levels. Combinations of transgenic, biochemical, immunocytochemical, electrophysiological, and behavioral techniques are used to study problems of relevance to addiction, including: (1) Transcriptional control mechanisms that are engaged by drug-reinforced learning and chronic drug exposure, particularly the roles of the transcription factors C/EBP and deltaFosB; (2) The contribution of BDNF-responsive TrkB receptors to cocaine-induced acute and adaptive responses; (3) The role of protein synthesis in the reconsolidation of recently recalled memories, and the control of dendritic translation during persistent forms of synaptic plasticity; and (4) Analysis of intracellular signaling initiated by cell adhesion molecules, which participate in neuronal development, plasticity, and potentially the developmental defects associated with prenatal exposure to drugs of abuse. Trainees who conduct research in this area will be encouraged to interact with members of the Systems Biology of Addiction group, both to generate signaling network models, and to design experiments that will improve the accuracy of those models.
  
  
• Systems Biology of Drug Addiction
  Mentors: Devi, Hurd, Iyengar, Ma’ayan, Sealfon
  This area applies computational analyses of data from proteomic studies (such as those conducted by the Devi laboratory) and gene expression microarrays (such as those conducted by the Hurd or Sealfon laboratories) to study the functional alterations in cell-signaling and gene-regulatory networks due to drug abuse. Specifically, quantitative proteomics studies in the Devi laboratory compare changes in the presynapse proteome of rats addicted to morphine with their non-addicted littermates. Microarray analysis to examine gene expression changes in postmortem brains from heroin addicts has been applied by the Hurd laboratory. Gene expression analysis has been applied by the Sealfon laboratory to compare the changes in expression profiles specifically activated by LSD. These studies only provide lists of genes that change in their abundance levels under the addictive vs. normal states. The Ma’ayan and Iyengar laboratories use these genes as anchors to build networks based on careful literature mining, as well as integration with other large-scale studies. Graph-analysis algorithms and statistical tests are used to identify pathways and key regulators that could represent potential biomarkers and novel drug-targets. The Ma’ayan laboratory is focused on developing tools for extracting cell-signaling and gene-regulation pathways from neuroscience literature and developing mathematical approaches to integrate and analyze diverse datasets to construct novel hypotheses. Such tools are currently being used by Iyengar, Devi and Diversè laboratories to integrate and analyze networks of proteins associating with important signaling proteins such as calcium channels.
  
  
• Genetics and Genomics in Drug Addiction
  Mentors: Dracheva, Ehrlich, Fossella, Hurd, Nestler, Sealfon
  Under this strong interdisciplinary research topic, trainees will be able to investigate molecular and biochemical characterization of genes and their gene products in relation to genetic contributions to addiction disorders. Significant training will be obtained in molecular genetics of human disease, use of genetic animal models, genomics, and proteomics technologies. Current studies conducted by faculty within this program involve investigations into the mechanisms of transcription, gene expression, chromatin structure, and protein-protein interactions that regulate gene activity in relation to drug abuse disorders. With the recruitment of Dr. Nestler who will add to the research activities other current mentors such as Dr. Dracheva, there will be greater focus within this training area on studies of epigenetic mechanisms (such as DNA methylation, histone modification, RNA editing and microRNA expression) relevant to the regulation of gene transcription and other cellular functions in the development and expression of addictive states. Investigators interact with the Genetics and Genomics Center and have strong collaborations with clinical teams in order to investigate genetic polymorphisms in clinical drug abuse cohorts as well as populations at risk for addiction disorders. Molecular and biochemical studies of the postmortem human brain as well as in vivo functional brain activity measures are also assessed in relation to individual genotype in attempts to identify discrete neurobiological correlates directly in the human brain associated with genetic polymorphisms associated with addiction. In addition to the possibility of combining genetics with the molecular neurobiological studies of the human brain, trainees will utilize mouse and other eukaryotic model systems to integrate basic genomic research with clinical and translational genetics.
  
  
• Neuroimaging and Neurocognition in Addictive Disorders
  Mentors: Fan, Fossella, Fowler, Halperin, Wang
  This research topic offers the opportunity to investigate the neurobiology of substance abuse disorders directly in the living human brain. A major aspect of this research area is to apply findings from basic neuroscience to guide clinical research using imaging technologies such as functional magnetic resonance imaging (fMRI) and Positron Emission Tomography (PET) in order to investigate in vivo brain function in relation to addiction disorders. Current drug abuse research studies in this discipline are focused on examining the contribution of risk factors such as behavioral traits (e.g., inhibitory control deficit, sensation-seeking), genetics, environmental factors (e.g., stress), and early drug exposure on in vivo neural systems relevant to addiction disorders. Trainees will obtain state-of-the-art imaging equipment experience with neuroimaging technologies (fMRI, PET, DTI), neurocognitive psychology, and genetics. As such knowledge can be obtained as to the in vivo neural networks and neurotransmitter systems associated with specific behaviors and genotypes of normal and addicted individuals. A number of faculty in this discipline have significant experience with studying children and adolescents, thus exploring CNS development in relation to addiction vulnerability is a significant theme of this research area. In vivo rodent PET studies have been initiated at the Brookhaven laboratory and this program is expected to be expanded in the future which will provide significant translational insights for bridging basic and clinical research.