Eric J. Nestler
Icahn School of Medicine at Mount Sinai, NY·Neuroscience
Stressful experiences and repeated drug use can change behavior for years, long after the exposure ends. That persistence suggests the brain stores a lasting molecular record.
- Fields
Neuroscience
Genetics
Pharmacology
- Topics
addiction
substance use disorder
opioids
- Grants
- 4 known grants, through Apr 2030
What they work on
- Identify stable "chromatin scars" left in the mouse nucleus accumbens by early life stress, using unbiased proteomic and next-generation sequencing screens in specific neuron types and keeping only marks also found in postmortem accumbens from depressed humans.
- Test whether DOT1L and KDM2B, the enzymes that add and remove the histone tag H3K79me2, mediate lifelong stress susceptibility, by raising or lowering each one virally in D2-receptor medium spiny neurons of male and female mice.
- Map where H3K79me2 sits across the genome in D2 neurons using CUT&RUN sequencing, to find the gene networks through which early life stress changes expression, and test whether a DOT1L inhibitor given systemically reverses stress susceptibility.
- Complete the characterization of RXRa, a DNA-binding transcription factor predicted from human and rodent RNA sequencing data, as a controller of neuronal physiology and cocaine and opioid self-administration in nucleus accumbens.
- Map genome-wide binding of RXRa, ∆FOSB and CREB in the nucleus accumbens with CUT&RUN to identify each factor's target genes in a cell-type-specific way, and link them to cell activity in slices and in awake behaving animals.
- Track neuronal ensembles tagged during a first versus a last cocaine or opioid exposure using Arc-CreERT2 mice, testing whether these distinct cell sets play different roles during drug self-administration and relapse.
- Characterize the gene expression of drug-activated ensembles with single-nucleus RNA sequencing, which captures larger affected neuron populations than activity-gene tagging alone, in both D1 and D2 medium spiny neurons.
- Extend ensemble analysis to glutamate-releasing inputs to the nucleus accumbens, including ventral hippocampus and the paraventricular nucleus of the thalamus, where drug-activated D1- and D2-expressing neurons have been defined.
More about the research
Research here asks what that record is made of, focusing on gene regulation in the brain's reward circuitry: which genes get turned on or off, which proteins do the switching, and how chromatin, the packaging that wraps DNA and controls access to it, holds changes in place. The work concentrates on the nucleus accumbens and dorsal striatum, regions central to motivation and reward, and distinguishes between the two main neuron types there, medium spiny neurons carrying either the D1 or the D2 dopamine receptor. A shared rule across projects is that findings in mice and rats are checked against postmortem brain tissue from people with depression or substance use disorders.
Why it matters
Addiction and stress-related disorders such as depression affect enormous numbers of people, and current treatments help only some of them. By pinpointing the specific enzymes, histone marks, transcription factors and neuron populations that keep the brain in an addicted or stress-susceptible state, this work could supply drug targets and diagnostic leads. One concrete example is an inhibitor of the DOT1L enzyme, already in cancer trials, being tested for its ability to reverse lasting stress vulnerability.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Mary Kay Lobo
University of Maryland, Baltimore, MD·Neuroscience
Map cellular, synaptic plasticity and molecular changes in defined cell subtypes of the medial prefrontal cortex and nucleus accumbens in mice exposed to fentanyl during the equivalent of human gestation, from weaning through adolescence.
Yasmin L. Hurd
Icahn School of Medicine at Mount Sinai, NY·Neuroscience
Determine how prenatal cannabis or THC exposure disturbs immune-related genes in the placenta and brain, using placentas from women who used cannabis during pregnancy and rats exposed to THC during development.
Heath Schmidt
University of Pennsylvania, PA·Neuroscience
Define how amylin receptors on specific cell types, dopamine and GABA neurons of the ventral tegmental area and D1- or D2-receptor medium spiny neurons of the nucleus accumbens, control oxycodone self-administration and relapse-like seeking, using viral gene delivery in transgenic rats.
The school
Icahn School of Medicine at Mount Sinai: 45 labs on PI Pages, $1.0B a year on research, 62 research doctorates a year.
Reach out
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