Details

Autor(en) / Beteiligte

• Feng, Jian
• Pena, Catherine J
• Purushothaman, Immanuel
• Engmann, Olivia
• Walker, Deena
• Brown, Amber N
• Issler, Orna
• Doyle, Marie
• Harrigan, Eileen
• Mouzon, Ezekiell
• Vialou, Vincent
• Shen, Li
• Dawlaty, Meelad M
• Jaenisch, Rudolf
• Nestler, Eric J

Titel

Tet1 in Nucleus Accumbens Opposes Depression- and Anxiety-Like Behaviors

Ist Teil von

• Neuropsychopharmacology, 2017-07, Vol.42 (8), p.1657-1669

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2017

Link zum Volltext

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• Depression is a leading cause of disease burden, yet current therapies fully treat <50% 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.