longitudinal-two-photon-imaging-of-dorsal-hippocampal-ca1-in-live-mice

Longitudinal Two-Photon Imaging of Dorsal Hippocampal CA1 in Live Mice

Two-photon microscopy is a fundamental tool for neuroscience as it permits investigation of the brain of live animals at spatial scales ranging from ...

Max Planck Institute of Psychiatry

Weizmann Institute of Science

Anorexia nervosa (AN) is a devastating eating disorder characterized by self-starvation that mainly affects women. Its etiology is unknown, which impedes successful treatment options leading to a limited chance of full recovery. Here, we show that gestation is a vulnerable window that can influence the predisposition to AN. By screening placental microRNA expression of naive and prenatally stressed (PNS) fetuses and assessing vulnerability to activity-based anorexia (ABA), we identify miR-340 as a sexually dimorphic regulator involved in prenatal programming of ABA. PNS caused gene-body hypermethylation of placental miR-340, which is associated with reduced miR-340 expression and increased protein levels of several target transcripts, GR, Cry2 and H3F3b. MiR-340 is linked to the expression of several nutrient transporters both in mice and human placentas. Using placenta-specific lentiviral transgenes and embryo transfer, we demonstrate the key role miR-340 plays in the mechanism involved in early life programming of ABA.

Placental miR-340 mediates vulnerability to activity based anorexia in mice.

N-methyladenosine (mA) and N,2'-O-dimethyladenosine (mAm) are abundant mRNA modifications that regulate transcript processing and translation. The role of both, here termed mA/m, in the stress response in the adult brain in vivo is currently unknown. Here, we provide a detailed analysis of the stress epitranscriptome using mA/m-seq, global and gene-specific mA/m measurements. We show that stress exposure and glucocorticoids region and time specifically alter mA/m and its regulatory network. We demonstrate that deletion of the methyltransferase Mettl3 or the demethylase Fto in adult neurons alters the mA/m epitranscriptome, increases fear memory, and changes the transcriptome response to fear and synaptic plasticity. Moreover, we report that regulation of mA/m is impaired in major depressive disorder patients following glucocorticoid stimulation. Our findings indicate that brain mA/m represents a novel layer of complexity in gene expression regulation after stress and that dysregulation of the mA/m response may contribute to the pathophysiology of stress-related psychiatric disorders.

The Role of mA/m-RNA Methylation in Stress Response Regulation.

Vulnerability to eating disorders (EDs) is broadly assumed to be associated with early life stress. However, a careful examination of the literature shows that susceptibility to EDs may depend on the type, severity and timing of the stressor and the sex of the individual. We aimed at exploring the link between chronic prenatal stress and predisposition to EDs and metabolic disease.

Article	Year
Placental miR-340 mediates vulnerability to activity based anorexia in mice. Nature communications\| PubMed ID: 29686286	2018
The Role of mA/m-RNA Methylation in Stress Response Regulation. Neuron\| PubMed ID: 30048615	2018
Sex dependent impact of gestational stress on predisposition to eating disorders and metabolic disease. Molecular metabolism\| PubMed ID: 30174229	2018

Alon Chen

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