Biology subjects

Toth, M.

Publications and source records attributed to Toth, M..

22 records · Page 2Linked to original sources

bioRxiv2020

Somatostatin neurons of the bed nucleus of stria terminalis enhance associative fear memory consolidation in mice

Excessive fear learning and extinction-resistant fear memories are core symptoms of anxiety and trauma-related disorders. Despite significant evidence from clinical studies reporting hyperactivity of the bed nucleus of stria terminalis (BNST) under these conditions, the role of BNST in fear learning and expression is still not clarified. Here, we tested how BNST modulates fear learning in mice using a chemogenetic approach. Activation of GABAergic neurons of BNST during fear acquisition, more specifically the consolidation phase, resulted in enhanced cued fear recall. Importantly, BNST activation had no acute impact on fear expression during conditioning or recalls, but it enhanced cued fear recall subsequently, potentially via altered activity of downstream regions as indicated by c-Fos. Enhanced fear memory consolidation could be replicated by selectively activating somatostatin neurons (but not corticotropin releasing factor neurons), suggesting significant modulation of fear memory strength by specific circuits of BNST.

neuroscience↗

bioRxiv2020

YAP orchestrates heterotypic endothelial cell communication via HGF/c-MET signaling in liver tumorigenesis

Next to cell autonomous mechanisms, the oncogene yes-associated protein (YAP) controls liver tumor initiation and progression via cell extrinsic functions creating a tumor-supporting environment. However, how YAP affects the microenvironment and in particular the vascular niche, which contributes to liver disease and hepatocarcinogenesis, is poorly understood. In this study, histo-morphological and molecular characterization of murine liver endothelial cells (ECs) populations and human single cell data revealed the presence of liver sinusoidal endothelial cells (LSECs) and capillary endothelial cells (CECs) in healthy liver tissue. In YAPS127A-induced tumorigenesis, a gradual replacement of LSECs by CECs was associated with dynamic changes in the expression of genes involved in EC subtype-specific paracrine communication. The formation of new potential communication hubs connecting CECs and LSECs included the hepatocyte growth factor (Hgf)/c-Met signaling pathway. In hepatocytes and tumor cells, YAP/TEA domain transcription factor 4 (TEAD4)-dependent transcriptional induction of osteopontin (Opn) stimulated c-Met expression in ECs with CEC phenotype, which sensitized these cells to the pro-migratory effects of LSEC-derived Hgf. In human HCCs, the presence of a migration-associated tip-cell signature correlated with poor clinical outcome and the loss of LSEC marker gene expression. In addition, the replacement of LSECs by CECs with exclusive c-MET expression in a CEC subpopulation was confirmed at the single cell level. In summary, YAP-dependent changes of the liver vascular niche comprise the formation of heterologous communication hubs (e.g. the HGF/c-Met axis), in which tumor cell-derived factors modify the crosstalk between LSECs and CECs.

cancer biology↗

bioRxiv2019

Epigenetically bistable regions across neuron-specific genes govern neuron eligibility to a coding ensemble in the hippocampus

Episodic memories are stored in distributed neurons but how eligibility of individual neurons to coding ensembles is determined remains elusive. We identified thousands of predominantly bistable (CpG methylated or unmethylated) regions within neuronal gene bodies, established during the development of the mouse hippocampal dentate gyrus. Reducing DNA methylation and the proportion of the methylated epialleles at bistable regions compromised novel context-induced neuronal activation and spatial memory. Conversely, increasing methylation and the frequency of the methylated epialleles at bistable regions enhanced intrinsic excitability and spatial memory but impaired spatial working memory, indicating that the developmentally established methylated-unmethylated epiallelic balance at bistable regions is essential for proper neuronal excitability and hippocampal cognitive functions. Single-nucleus profiling revealed the enrichment of specific epialleles from a subset of bistable regions, primarily exonic, in encoding neurons. We propose a model in which epigenetically bistable regions create neuron heterogeneity, and specific constellations of exonic epialleles dictate, via modulating neuronal excitability, eligibility to a coding ensemble.

neuroscience↗

bioRxiv2018

Compartmentalized nonsense-mediated mRNA decay regulates synaptic plasticity and cognitive function via GluR1 signaling

Synaptic plasticity relies on new protein synthesis in dendrites that involves the selective translation of specific mRNAs. This requires a tight control of mRNA levels in dendrites. Consistently, RNA translation and degradation pathways have been recently linked to neurodevelopmental and neuropsychiatric diseases, suggesting a role for RNA regulation in synaptic plasticity and cognition. Despite being the only RNA regulatory pathway that is associated with multiple mental illnesses, the Nonsense-Mediated mRNA Decay (NMD) pathway presents an unexplored regulatory mechanism for synaptic function and plasticity. NMD is a highly conserved and selective RNA degradation pathway that exerts its function in a cell- and spatiotemporally-specific manner. Here, we show that neuron-specific disruption of NMD in adulthood attenuates learning, memory, hippocampal LTP, and potentiates perseverative/repetitive behavior. While it is known that local translation of specific mRNAs in dendrites enables synaptic plasticity, the tightly-controlled mechanisms that regulate local quantity of specific mRNAs remains poorly understood. We report that the NMD pathway operates within dendrites to regulate GluR1 surface levels. Specifically, NMD modulates the internalization of GluR1 and promotes its local synthesis in dendrites. We identified AMPK as a mechanistic substrate for NMD that contributes to the NMD-mediated regulation of GluR1 by limiting total GluR1 levels. These data establish that NMD regulates synaptic plasticity, cognition, and local protein synthesis in dendrites, providing fundamental insight into the neuron-specific function of NMD within the brain.

neuroscience↗