Latest Research Findings


Our Conte Translational Center on Epigenetic Mechanisms of Depression has made robust progress since it was first funded in 2012. See Publications for a list of our most high profile original research articles and reviews. Here we provide a brief synopsis of a small subset of our findings in the following categories.

Molecular Basis of Depression

2016

This recent article used RNA-sequencing, which provides a genome-wide map of all RNAs expressed in a tissue, in four brain regions linked to depression—nucleus accumbens, prefrontal cortex, hippocampus, and amygdala, at three time points after chronic social defeat stress in both mice susceptible to the stress as well as those which are more resilient, thus providing one of the most complete characterizations of gene expression changes induced in brain by chronic social stress. The study identified numerous gene networks and novel targets of stress which provide a path forward in drug discovery efforts.

Bagot RC et al. (2016) Circuit-wide transcriptional profiling reveals brain region-specific gene networks regulating depression susceptibility. Neuron 90:969-983. PMCID: PMC4896746

In this paper, which will be published soon, the authors show that SIRT1, a type of sirtuin, plays a critical role in the nucleus accumbens in mediating susceptibility to chronic stress. SIRT1 is categorized as a Class III histone deacetylase but regulates cell function by deacetylating non-histone proteins as well. This finding is interesting in light of recent work which has reported that variations in the SIRT1 gene confer risk for depression in some human populations.

Kim HD et al. (2016) SIRT1 mediates depression-like behaviors in the nucleus accumbens. J Neurosci, in press. Link to article will be made available soon.

This Conte team of investigators identified changes in the DNA methylation status of numerous genes in peripheral blood from individuals who suffered malnutrition during early life and show attention and cognition impairments as a result. The results suggest that early childhood malnutrition causes long-lasting epigenetic signatures associated with liability for neuropsychiatric symptoms.

Peter CJ et al. (2016) DNA methylation signatures of early childhood malnutrition associated with impairments in attention and cognition. Biol Psychiatry, in press. Advance online publication

2015

PsychENCODE is an exciting project, sponsored by NIMH, which is housed partly at Mount Sinai. The goal is to provide epigenetic maps for brain under normal conditions and in individuals with a psychotic disorder. Our Conte Center, by providing similar data for depression, thus complements PsychENCODE's focus, with the two efforts being highly synergistic.

Akbarian S and the PsychENCODE Consortium et al. (2015) The PsychENCODE project. Nat Neurosci 18:1707-1712. PMCID: PMC4675669

In this landmark paper, Conte investigators demonstrated that a variant form of histone H3, termed H3.3, gradually replaces other forms of the histone during postnatal development—in both animals and humans, and that this histone variant and its role in generating new nucleosomes is required for ongoing changes in gene expression throughout life.

Maze I et al. (2015) Critical role of histone turnover in neuronal transcription and plasticity. Neuron 87:77-94. PMCID: PMC4491146

L3MBTL1 is a type of "reader" protein which recognizes certain modifications of histone proteins and translates those changes into alterations in gene expression. This Conte team here shows the importance of this mechanism in behaviors related to depression.

Shen EY et al. (2015) Cognition and mood-related behaviors in L3mbtl1 null mutant mice. PLoS One 10:e0121252. PMCID: PMC4388653.

ACF is a type of chromatin remodeling complex, an ATPase-containing multi-protein complex which provides the molecular motor to move nucleosomes closer together or further apart. The authors found that ACF is induced in nucleus accumbens in animals susceptible to chronic stress and in depressed humans, with equivalent effects seen in both males and females. Reversal of this change induces antidepressant-like responses in animals, thus providing a new path for treatment research.

Sun H et al. (2015) ACF chromatin-remodeling complex mediates stress-induced depressive-like behavior. Nat Med 21:1146-1153. PMCID: PMC4598281

2014

It has recently been learned that the 3-dimensional (3D) structure of chromatin is an important determinant of gene expression. Here, the authors provide some of the first evidence that this 3D organization of chromatin is highly regulated in prefrontal cortical neurons, where the process plays a crucial role in controlling the expression of a gene tightly linked to depression and its treatment.

Bharadwaj R et al. (2014) Conserved higher-order chromatin regulates NMDA receptor gene expression and cognition. Neuron 84:997-1008. PMCID: PMC4258154

This multidisciplinary Conte team discovered that a transcription factor called β-catenin is a major determinant of stress resilience in mouse models and is deficient in the brains of depressed humans. The target genes through which β-catenin induces resilience, identified as part of this study, now provide a template for searching for new depression treatments.

Dias C et al. (2014) β-catenin mediates stress resilience through Dicer1/microRNA regulation. Nature 516:51-55. PMCID: PMC4257892

This paper provided a major technical advance in the field. The authors developed new tools with which to induce a single type of epigenetic modification at a single gene of interest within nerve cells of a single brain region of interest. In this way, the authors dramatically elevated the quality of proof linking epigenetic regulation in the brain to behavioral outcomes, including depression-like behavior.

Heller EA et al. (2014) Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors. Nat Neurosci 17:1720-1727. PMCID: PMC4241193

2013

Histone proteins are modified in many ways. In this study, the authors characterized the consequences of a newly discovered form of modification which they show plays an important role in controlling gene expression.

Casadio F et al. (2013) H3R42me2a is a histone modification with positive transcriptional effects. Proc Natl Acad Sci U S A 110:14894-14899. PMCID: PMC3773778

The authors discovered that chronic social stress alters levels of a protein called RAC1 in nucleus accumbens, with a similar effect seen in depressed humans. RAC1 is a type of protein called GTPase, which plays an important role in regulating synapses. They also characterized the epigenetic mechanisms through which stress and depression control expression levels of RAC1.

Golden SA et al. (2013) Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression. Nat Med 19:337-344. PMCID: PMC3594624

Mechanisms of Action of Antidepressant Medications

2016

The authors used RNA-sequencing to characterize the effects of two antidepressant treatments on gene expression in four brain regions: nucleus accumbens, prefrontal cortex, hippocampus, and amygdala. The two antidepressants studied were: chronic imipramine (a standard treatment used in humans) or acute ketamine (an experimental treatment now in clinical development). The findings show that the two drugs work largely via distinct mechanisms, in both cases reversing some gene expression changes seen in susceptible mice as well as recapitulating other changes in gene expression seen in resilient mice.

Bagot TC et al. (2016) Ketamine and imipramine reverse transcriptional signatures of susceptibility and induce resilience-specific gene expression profiles. Biol Psychiatry, in press. Advance online publication

2015

This Conte group of investigators provided further evidence for the involvement of a transcription factor called ∆FosB in mediating either antidepressant-like effects or pro-depression-like effects depending on the brain region involved.

Vialou V et al. (2015) Differential induction of FosB isoforms throughout the brain by fluoxetine and chronic stress. Neuropharmacology 99:28-37. PMCID: PMC4655122

2014

The investigators used animal models and postmortem brain tissue from depressed humans to implicate the transcription factor, ∆FosB, and its regulation by an enzyme called calcium/calmodulin-dependent protein kinase 2α (CaMKIIα), in mediating pro-resilient effects within the nucleus accumbens. The ability to validate key findings from animal models in human depression is a major strength of our Center's efforts.

Robison AJ et al. (2014) Fluoxetine epigenetically alters the CaMKIIα promoter in nucleus accumbens to regulate ΔFosB binding and antidepressant effects. Neuropsychopharmacology 39:1178-1186. PMCID: PMC3957112

HDACs—or histone deacetylases—are enzymes that remove acetyl groups from histones and thereby repress gene expression. In this study, the authors showed that one particular form of HDAC is important in mediating the effects of early life exposure to fluoxetine (an SSRI antidepressant) on lasting changes in gene expression.

Sarkar A et al. (2014) Hippocampal HDAC4 contributes to postnatal fluoxetine-evoked depression-like behavior. Neuropsychopharmacology 39:2221-2232. PMCID: PMC4104341

Early Leads on New Treatments for Depression

Although our Conte Center does not directly sponsor clinical trials, its work is tightly connected to the clinic, with several findings over the years driving highly novel clinical trials in patients with depression. These advances underscore the translational nature of the Center.

2016

Advances made in this mouse study provided the rationale to test a potentiator of one type of potassium channel, called a KCNQ channel, in depression. Early results are encouraging.

Friedman AK et al. (2016) KCNQ channel openers reverse depressive symptoms via an active resilience mechanism. Nat Commun, in press. PMCID: PMC4890180

2015

This study follows up several earlier studies from the same group which discovered that HDAC inhibitors exert antidepressant-like effects in mouse models. Since several HDAC inhibitors are in clinical development for non-CNS purposes, the work provides a rationale for testing these compounds in depression.

Covington HE 3rd et al. (2015) Antidepressant action of HDAC inhibition in the prefrontal cortex. Neuroscience 298:329-335. PMCID: PMC4441835

The investigators, along with other Conte Center members, over the past decade have provided basic research evidence from animal models that antagonists of kappa opioid receptors might be novel antidepressants. This study provides further support for this possibility, now in clinical testing.

Donahue RJ et al. (2015) Effects of acute and chronic social defeat stress are differentially mediated by the dynorphin/kappa-opioid receptor system. Behav Pharmacol 26(7 Spec No):654-663. PMCID: PMC4586263

Conte-related research has directly implicated several cytokines—hormones of the immune system—in mediating susceptibility to chronic stress in animals, with confirming evidence in depressed humans. These findings provided a good part of the rationale for current testing of antibodies to these cytokines as a novel treatment for depression.

Hodes GE et al. (2015) Neuroimmune mechanisms of depression. Nat Neurosci 18:1386-1393. NIHMS ID: 775272

2014

These Conte investigators discovered a novel means of inducing resilience in mouse models. The mechanism involves regulation of a type of ion channel for which small molecule inhibitors and activators are available, thus demonstrating the potential utility of these drugs as new antidepressants. Friedman AK et al. (2014) Enhancing depressio

n mechanisms in midbrain dopamine neurons achieves homeostatic resilience. Science 344:313-319. PMCID: PMC4334447

Sex Differences in Depression

Sex differences have long been known in stress responses in animals and in depression in humans, however, the molecular basis of these differences remain poorly understood. A major theme of our Conte Center research is to better understand the nature of these sex differences, with the goal of identifying novel means of treating depression in females or males. These are some of the Center's first studies that have appeared on this topic, with several more now in preparation.

2015

This multi-disciplinary Conte team first demonstrated that female mice are more susceptible to chronic variable stress than males and then went on to demonstrate that one important mediator of this greater susceptibility is higher levels of an epigenetic enzyme called DNMT3a, which methylates DNA. Depressed humans, like stressed mice, show abnormally high levels of DNMT3a in nucleus accumbens, with experimental knockout of the enzyme inducing antidepressant-like effects in both sexes.

Hodes GE et al. (2015) Sex differences in nucleus accumbens transcriptome profiles associated with susceptibility versus resilience to subchronic variable stress. J Neurosci 35:16362-16376. PMCID: PMC4679819

In this collaborative study with Dr. Margaret McCarthy at the University of Maryland, the authors provided further evidence for the importance of DNA methylation in mediating sex differences in stress responses.

Nugent BM et al. (2015) Brain feminization requires active repression of masculinization via DNA methylation. Nat Neurosci 18:690-697. PMCID: PMC4519828

In a second collaborative study, this one with Dr. Nancy Forger and colleagues at Georgia State University, the investigators mapped sex differences in epigenetic marks in mouse brain. We believe that epigenetic marks generated through development maintain gene expression differences seen between males and females.

Shen EY et al. (2015) Epigenetics and sex differences in the brain: A genome-wide comparison of histone-3 lysine-4 trimethylation (H3K4me3) in male and female mice. Exp Neurol 268:21-29. PMCID: PMC4329105

Insights into Other Brain Diseases

Novel Bioinformatic Approaches

The Conte Center's use of advanced next generation sequencing methods, such as RNA-sequencing, ChIP (chromatin immunoprecipitation)-sequencing, whole genome bisulfite sequencing, and ATAC (assay for transposase-accessible chromatin)-sequencing, among others, generates extremely large datasets involving terabytes of information. Accordingly, the Center's bioinformatics team has made important contributions in developing new tools to analyze this vast data, the analysis of which is still not routine. Here are some examples.

2015

Dincer et al. Deciphering H3K4me3 broad domains associated with gene-regulatory networks and conserved epigenomic landscapes in the human brain. Transl Psychiatry. 2015 Nov 17;5:e679. doi: 10.1038/tp.2015.169. PMCID: PMC5068762

2014

This article provides an overview of the current approaches used in analyzing epigenetic sequencing data as well as of the challenges that remain in making optimal use of such large datasets. A major theme of the review is a discussion of the several unique challenges in analyzing epigenetic data from brain, in particular, human brain.

Maze I et al. (2014) Analytical tools and current challenges in the modern era of neuroepigenomics. Nat Neurosci 17:1476-1490. PMCID: PMC4262187

Ngs.plot is another novel software program developed by Conte investigators and also used by hundreds of research groups worldwide. This program provides several novel features for visually displaying RNA-seq, ChIP-seq, and related data.

Shen L et al. (2014) ngs.plot: Quick mining and visualization of next-generation sequencing data by integrating genomic databases. BMC Genomics 15:284. PMCID: PMC4028082

2013

The Conte's bioinformatics team developed a novel software program called diffReps—made freely available to the general public and now utilized by hundreds of investigators worldwide—to analyze differences in ChIP-seq datasets across different conditions.

Shen L et al. (2013) diffReps: Detecting differential chromatin modification sites from ChIP-seq data with biological replicates. PLoS One 8:e65598. PMCID: PMC3677880

Neural Circuitry of Depression

2016

Chronic social defeat stress is one of the primary depression models used by Center investigators. The model involves exposure of test mice to more aggressive mice. This novel study examined the aggressors and identified a novel neural circuit in the most aggressive mice that makes aggressive behavior rewarding for them.

Golden SA et al. (2016) Ventral striatal projections to the lateral habenula modulate aggression reward. Nature 534:688-692. PMCID PMC4930107

Conte investigators have long established an important role played by a growth factor termed brain-derived neurotrophic factor or BDNF in mediating the susceptibility of mice to chronic social stress. The source of this BDNF are midbrain dopamine neurons. In this most recent publication on the subject, the authors showed that chronic social stress causes changes in these dopamine neurons—which are normally rewarding—such that after stress they mediate depression-related behavioral abnormalities through greater release of BDNF rather than dopamine.

Koo JW et al. (2016) Essential role of mesolimbic brain-derived neurotrophic factor in chronic social stress-induced depressive behaviors. Biol Psychiatry, in press. PMCID: PMC49099591

2015

This study showed that different excitatory inputs to the nucleus accumbens mediate different functional effects during chronic social stress. Inputs from the prefrontal cortex promote resilience, while those from ventral hippocampus promote susceptibility. The findings have important implications for understanding the neural circuitry of depression.

Bagot RC et al. (2015) Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression. Nat Commun 6:7062. PMCID: PMC4430111

In a related study, the authors showed that a third input to the nucleus accumbens—from the thalamus—also controls behavioral responses to chronic social stress.

Christoffel DJ et al. (2015) Excitatory transmission at thalamo-striatal synapses mediates susceptibility to social stress. Nat Neurosci 18:962-964. PMCID: PMC4482771

2014

This follow up to the Chaudhury 2013 paper demonstrated that BDNF in the ventral tegmental area to nucleus accumbens circuit mediates the pro-susceptible effects of these neurons in response to acute stresses. A later paper by Koo 2016 found the same for chronic stress.

Walsh JJ et al. (2014) Stress and CRF gate neural activation of BDNF in the mesolimbic reward pathway. Nat Neurosci17:27-29. PMCID: PMC3984932

2013

This landmark study—using advanced optogenetic tools—demonstrated that hyperexcitability of midbrain dopamine neurons (specifically those in the ventral tegmental area) induces susceptibility to social stress in mice, whereas suppression of this excitability induces resilience. The study further established that this effect is mediated by those dopamine neurons that innervate the nucleus accumbens, with those that innervate prefrontal cortex exerting different functional effects.

Chaudhury D et al. (2013) Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 493:532-536. PMCID: PMC3554860

Review Articles and Books

Please refer to these review articles and books for more general discussion of themes related to this Conte Center.

2016

Ménard C et al. (2016) Pathogenesis of depression: Insights from human and rodent studies. Neuroscience 321:138-162. PMCID: PMC4664582

Nestler EJ et al. (2016) Epigenetic basis of mental illness. Neuroscientist, in press. PMCID: PMC4826318

Nestler EJ (2016) Transgenerational epigenetic contributions to stress responses: Fact or fiction? PLoS Biol, in press. PMCID: PMC4807775

Kundakovic M et al. (2016) Practical guidelines for high-resolution epigenomic profiling of nucleosomal histones in postmortem human brain tissue. Biol Psychiatry, in press. NIHMS ID: 767217

2014

Maze I et al. (2014) Every amino acid matters: essential contributions of histone variants to mammalian development and disease. Nat Rev Genet 15:259-271. PMCID: PMC4082118

Mitchell AC et al. (2014) The genome in three dimensions: a new frontier in human brain research. Biol Psychiatry 75:961-969. PMCID: PMC3925763

2013

Sweatt JD, Meaney MJ, Nestler EJ, Akbarian S (eds) (2013) Epigenetic Regulation in the Nervous System, Academic Press. (Book—PMCID exempt)

Vialou V et al. (2013) Epigenetic mechanisms of depression and antidepressant action. Annu Rev Pharmacol Toxicol 53:59-87. PMCID: PMC3711377