Tet1 in Nucleus Accumbens Opposes Depression- and Anxiety-Like Behaviors
| Autor: | Marie A. Doyle, Ezekiell Mouzon, Eileen Harrigan, Immanuel Purushothaman, Catherine Jensen Pena, Meelad M. Dawlaty, Amber Brown, Li Shen, Vincent Vialou, Eric J. Nestler, Deena M. Walker, Rudolf Jaenisch, Jian Feng, Olivia Engmann, Orna Issler |
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| Přispěvatelé: | Icahn School of Medicine at Mount Sinai [New York] (MSSM), Florida State University [Tallahassee] (FSU), Albert Einstein College of Medicine [New York], Whitehead Institute, Massachusetts Institute of Technology (MIT), vialou, vincent |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Gene Expression Anxiety Nucleus accumbens Nucleus Accumbens Social defeat Mice 03 medical and health sciences 0302 clinical medicine Proto-Oncogene Proteins Gene expression medicine Animals Epigenetics Mice Knockout Pharmacology Behavior Animal Depression [SCCO.NEUR]Cognitive science/Neuroscience [SCCO.NEUR] Cognitive science/Neuroscience medicine.disease Up-Regulation DNA-Binding Proteins Disease Models Animal Psychiatry and Mental health 030104 developmental biology Schizophrenia Antidepressant Original Article Brain stimulation reward Psychopharmacology Psychology Neuroscience Stress Psychological 030217 neurology & neurosurgery Clinical psychology |
| Zdroj: | Neuropsychopharmacology Neuropsychopharmacology, 2017, 42 (8), pp.1657-1669. ⟨10.1038/npp.2017.6⟩ |
| ISSN: | 0893-133X 0007-0920 |
| DOI: | 10.1038/npp.2017.6⟩ |
| Popis: | International audience; Depression is a leading cause of disease burden, yet current therapies fully treat o50% of affected individuals. Increasing evidence implicates epigenetic mechanisms in depression and antidepressant action. Here we examined a possible role for the DNA dioxygenase, ten-eleven translocation protein 1 (TET1), in depression-related behavioral abnormalities. We applied chronic social defeat stress, an ethologically validated mouse model of depression-like behaviors, and examined Tet1 expression changes in nucleus accumbens (NAc), a key brain reward region. We show decreased Tet1 expression in NAc in stress-susceptible mice only. Surprisingly, selective knockout of Tet1 in NAc neurons of adult mice produced antidepressant-like effects in several behavioral assays. To identify Tet1 targets that mediate these actions, we performed RNAseq on NAc after conditional deletion of Tet1 and found that immune-related genes are the most highly dysregulated. Moreover, many of these genes are also upregulated in the NAc of resilient mice after chronic social defeat stress. These findings reveal a novel role for TET1, an enzyme important for DNA hydroxymethylation, in the brain's reward circuitry in modulating stress responses in mice. We also identify a subset of genes that are regulated by TET1 in this circuitry. These findings provide new insight into the pathophysiology of depression, which can aid in future antidepressant drug discovery efforts. |
| Databáze: | OpenAIRE |
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