Eric J. Nestler is the Dean for Academic and Scientific Affairs and Director of the Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai in New York. His research is focused on a molecular approach to drug addiction and depression. He is the co-author of four books and more than 650 peer-reviewed articles, and he serves as principal investigator on 6 NIH grants.
Each month The Brain & Behavior Research Foundation hosts a Meet the Scientist Webinar featuring a researcher discussing the latest findings related to mental illness. In March, 2019, the Foundation featured Dr. Eric J. Nestler of the Icahn School of Medicine at Mount Sinai. Description: Drugs of abuse target discrete collections of nerve cells—called circuits—in the brain that normally regulate responses to natural rewards in the environment, like food, sex, and social interactions. The areas of brain involved in these circuits are referred to as brain reward regions. Drugs corrupt these brain regions and circuits by activating them with abnormal power and persistence, actions that trigger adaptations at the molecular and cellular levels that are aimed to compensate for the drug-induced effects. These adaptations enable a drug to gradually and progressively take control over a vulnerable individual's life. During this Webinar, Dr. Nestler will describe these molecular, cellular, and circuit actions of drugs of abuse and how knowledge gained from this work can be used to develop more effective treatments of addiction.
Addiction can be viewed as a form of drug-induced neural plasticity. Given the stability of the behavioral abnormalities that characterize an addicted state, it makes sense that stable changes in gene expression are involved. Among several transcriptional mechanisms implicated in drug addiction, our laboratory has focused on two main pathways. First, chronic exposure to cocaine or certain other drugs of abuse causes prolonged activation of the transcription factor CREB within several brain regions, and this adaptation mediates aspects of tolerance and dependence. In contrast, induction of another transcription factor, termed ?FosB, in some of the same brain regions exerts the opposite effect and contributes to sensitized responses to drug exposure. Studies are underway to explore the detailed molecular mechanisms by which CREB and FosB regulate target genes and thereby contribute to the complex state of addiction. One way to approach such molecular mechanisms of drug action in vivo is through the study of chromatin remodeling, that is, changes in the acetylation or methylation of histones that bind to certain drug-regulated gene promoters, or changes in methylation of the promoters themselves, as revealed by chromatin immunoprecipitation (ChIP). We are utilizing ChIP to examine chromatin changes at specific candidate genes for CREB and ?FosB, as well as ChIP on chip (immunoprecipitated chromatin analyzed by gene promoter arrays) to gain a global view of target genes for these transcription factors. We are also investigating drug regulation of some of the enzymes that catalyze chromatin remodeling as additional drug targets. These findings establish chromatin remodeling as an important regulatory mechanism underlying drug-induced neural and behavioral plasticity, and promise to reveal fundamentally new insight into how CREB and ?FosB, and several other transcription factors, contribute to addiction by regulating the expression of specific target genes. The NIH Director's Wednesday Afternoon Lecture Series includes weekly scientific talks by some of the top researchers in the biomedical sciences worldwide.
When we try to get rid of a bad habit, whether it involves food or drugs or gambling, it often seems like we're fighting ourselves inside. The reality's not far off: Addiction twists the reward pathways of the brain to keep addicts tied to whatever gets them high. But can we use our knowledge of the brain to undo these neurological knots? Watch psychiatrist Nora Volkow, chemist Kim Janda, and neuroscientists Eric Nestler and Amir Levine explain the latest thinking in the science of addiction in the mind in "The Craving Brain".