Kaplick, P. M. | bioRxiv Science

bioRxiv2018

How much fear is in anxiety?

The selective breeding for extreme behavior on the elevated plus-maze (EPM) resulted in two mouse lines namely high-anxiety behaving (HAB) and low-anxiety behaving (LAB) mice. Using novel behavioral tests we demonstrate that HAB animals additionally exhibit maladaptive escape behavior and defensive vocalizations, whereas LAB mice show profound deficits in escaping from approaching threats which partially results from sensory deficits. We could relate these behavioral distortions to tonic changes in brain activity within the periaqueductal gray (PAG) in HAB mice and the superior colliculus (SC) in LAB mice, using in vivo manganese-enhanced MRI (MEMRI) followed by pharmacological or chemogenetic interventions. Therefore, midbrain-tectal structures govern the expression of both anxiety-like behavior and defensive responses. Our results challenge the uncritical use of the anthropomorphic terms anxiety or anxiety-like for the description of mouse behavior, as they imply higher cognitive processes, which are not necessarily in place.

neuroscience↗

bioRxiv2017

The role of m6A-RNA methylation in stress response regulation

N6-Methyladenosine (m6A) is an abundant internal RNA modification that regulates transcript processing and translation. The regulation of brain m6A by stressful stimuli in vivo and its role in the stress response are currently unknown.\n\nHere, we provide a detailed analysis of the stress-epitranscriptome using m6A-Seq, global and gene-specific m6A measurements. We show that stress exposure and glucocorticoids alter m6A and its regulatory network in a region- and time-specific manner. We demonstrate that depletion of the methyltransferase Mettl3 and the demethylase Fto in adult neurons increases fear memory, and alters the transcriptome response to fear as well as synaptic plasticity. Finally, we report that regulation of m6A is impaired in major depressive disorder patients following glucocorticoid receptor activation.\n\nOur findings indicate that brain m6A represents a novel layer of complexity in gene expression regulation after stress and that dysregulation of the m6A-response may contribute to the pathophysiology of stress-related psychiatric disorders.\n\nHighlightsO_LIm6A RNA methylation in adult mouse brain is regulated by stress\nC_LIO_LIBrain m6A levels are temporally and spatially regulated by stress\nC_LIO_LIMettl3 and Fto-KO alter fear memory, transcriptome response and synaptic plasticity\nC_LIO_LIThe m6A-glucocorticoid-response is impaired in major depressive disorder patients\nC_LI\n\neTOC blurbEngel et al. demonstrate a brain-area-specific and time-dependent role for the mRNA modification, m6A, in stress-response regulation. Manipulating m6A-enzymes alters fear-memory, transcriptome-response and synaptic-plasticity. Altered m6A dynamics in depressed patients suggest an involvement of m6A-modifications in stress-related psychiatric disorders.

neuroscience↗