? PROJECT 1 Project 1 focuses on transcriptional and epigenetic mechanisms in the nucleus accumbens (NAc) and ventral tegmental area (VTA), key brain reward regions implicated in depression and other stress-related disorders. Over the past four years, we made significant progress in demonstrating the direct relevance of several modes of chromatin regulation to depression-related phenomena in VTA and NAc both in animal models and, with Project 4, in postmortem human brain. One of the primary rationales for focusing on chromatin mechanisms is their heuristic importance in mediating lifelong consequences of prior behavioral experience. Accordingly, with the Animal Models Core, we optimized a protocol where maternal separation (MS) during postnatal days P11- 20, but not other time windows, increases the susceptibility of male and female mice to subsequent stress in adulthood. This increase in stress susceptibility is latent: without subsequent stress the animals appear normal. This establishes an ideal system in which to study the chromatin mechanisms that mediate a lifelong increase in stress susceptibility, which we refer to colloquially as ?chromatin scars.? RNA-seq, with the Chromatin and Gene Analysis Core, revealed lasting gene expression abnormalities in VTA and NAc in MS-exposed mice before adult stress exposure. We focus here on two of the inferred top upstream regulators of these gene expression abnormalities, two transcription factors, OTX2 in dopamine neurons (DA) of VTA and ESR1 in D2- type medium spiny neurons (MSNs) of NAc. Indeed, we have found that both genes, upon their manipulation in the respective brain area and cell type, drive stress susceptibility. We are now characterizing the underlying mechanisms involved by defining chromatin changes that are induced at specific target genes in concert with alterations in OTX2 or ESR1 to control their lifelong expression in response to early life stress. We are also analyzing a small number of these target genes to understand how their lasting regulation controls the functioning of VTA DA neurons and D2 NAc MSNs to regulate stress susceptibility for a lifetime. Together, these studies are providing new insight into how early life stress controls stress susceptibility in males and females over the life cycle.
| Kaufman, Joan; Wymbs, Nicholas F; Montalvo-Ortiz, Janitza L et al. (2018) Methylation in OTX2 and related genes, maltreatment, and depression in children. Neuropsychopharmacology 43:2204-2211 |
| Takahashi, Aki; Flanigan, Meghan E; McEwen, Bruce S et al. (2018) Aggression, Social Stress, and the Immune System in Humans and Animal Models. Front Behav Neurosci 12:56 |
| Mitchell, A C; Javidfar, B; Pothula, V et al. (2018) MEF2C transcription factor is associated with the genetic and epigenetic risk architecture of schizophrenia and improves cognition in mice. Mol Psychiatry 23:123-132 |
| Hamilton, Peter J; Lim, Carissa J; Nestler, Eric J et al. (2018) Viral Expression of Epigenome Editing Tools in Rodent Brain Using Stereotaxic Surgery Techniques. Methods Mol Biol 1767:205-214 |
| Hamilton, Peter J; Lim, Carissa J; Nestler, Eric J et al. (2018) Neuroepigenetic Editing. Methods Mol Biol 1767:113-136 |
| Gandal, Michael J; Haney, Jillian R; Parikshak, Neelroop N et al. (2018) Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science 359:693-697 |
| Heshmati, Mitra; Aleyasin, Hossein; Menard, Caroline et al. (2018) Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility. Proc Natl Acad Sci U S A 115:1111-1116 |
| Wang, Jun; Hodes, Georgia E; Zhang, Hongxing et al. (2018) Epigenetic modulation of inflammation and synaptic plasticity promotes resilience against stress in mice. Nat Commun 9:477 |
| Akil, Huda; Gordon, Joshua; Hen, Rene et al. (2018) Treatment resistant depression: A multi-scale, systems biology approach. Neurosci Biobehav Rev 84:272-288 |
| Peña, Catherine J; Nestler, Eric J (2018) Progress in Epigenetics of Depression. Prog Mol Biol Transl Sci 157:41-66 |
Showing the most recent 10 out of 215 publications
