Understanding Addiction w/ Eric Nestler, MD, PhD

Transcriptional and Epigenetic Mechanisms of Addiction

Drug addiction can be viewed as a stable form of drug-induced neural plasticity, whereby long-lasting changes in gene expression mediate some of the stable behavioral abnormalities that define an addicted state. Our laboratory has focused on transcriptional pathways in addiction, deduced from large RNA-sequencing datasets of RNAs that show altered expression in brain reward regions of mice as a consequence of drug self-administration, withdrawal, and relapse. Activation or induction of certain transcription factors represent homeostatic adaptations that oppose drug action and mediate aspects of drug tolerance and dependence. In contrast, induction of other transcription factors exerts the opposite effect and contributes to sensitized responses to drug exposure.

Studies are underway to explore the detailed molecular mechanisms by which these various transcription factors regulate target genes and thereby contribute to the complex state of addiction. We are approaching this question by studying a range of chromatin mechanisms genome-wide, including post-translational modifications of histones, DNA methylation, nucleosome positioning, and the 3-dimensional structure of chromatin. These studies are identifying many of the molecular targets of drug self-administration in brain reward regions and the biochemical pathways most prominently affected. Among these targets are those that regulate synaptic function and plasticity as well as the morphology of drug-regulated neurons and other cell types, thus linking transcriptional and chromatin regulation to neural and behavioral plasticity. Parallel work has focused on homologous regions in the brains of addicted humans examined postmortem.

This work establishes transcriptional and chromatin regulation as important mechanisms underlying the ways in which a history of drug use causes lasting changes in targeted brain reward neurons, and the circuits in which they operate, to result in addiction-related behavioral abnormalities. These advances can now be mined to develop improved diagnostic tests and treatments for addictive disorders.

Dr. Nestler is the Nash Family Professor of Neuroscience, Director of the Friedman Brain Institute and Dean for Academic and Scientific Affairs. His laboratory studies the molecular mechanisms of drug addiction and depression in animal models.

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[vivekjain]

I have a question about the Walker/Calipari paper from 2018: how was sleep (total duration, phases of sleep, etc) affected by cocaine exposure? How does the sleep cycle in mice vary from that of humans?

[mengistuferede]

it was a good and insightful lecture.



I wish this lecture can give a CE certificate of attendance.

Thank you
mengistu Ferede