Cowan, E. T. | Search bioRxiv

bioRxiv2021

RNA and the Goldilocks Zone: Where Mg2+ concentration is just right

Magnesium, the most abundant divalent cation in cells, catalyzes RNA cleavage but also promotes RNA folding. Because folding can protect RNA from cleavage, we predicted a "Goldilocks peak", which is a local maximum in RNA lifetime at the Mg2+ concentration required for folding. Here we use simulation and experiment to discover an innate yet sophisticated mechanism of control of RNA lifetime. By simulation we characterized the RNA Goldilocks peak and its dependence on cleavage parameters and extent of folding. Supporting experiments with yeast tRNAPhe and Tetrahymena ribozyme P4-P6 domains show that structured RNA can inhabit a Goldilocks peak in vitro. The Goldilocks peaks are tunable by differences in cleavage rate constants, Mg2+ binding cooperativity, and Mg2+ affinity. Broad ranges of those folding and cleavage parameters produce Goldilocks peaks of different intensities. Goldilocks behavior allows ultrafine control of RNA chemical lifetime, whereas non-folding RNAs do not display a Goldilocks peak. In sum, the effects of Mg2+ on RNA persistence are expected to be pleomorphic, both protecting and degrading RNA. In evolutionary context, Goldilocks behavior may have shaped RNA in an early Earth environment containing Mg2+ and other metals.

biochemistry↗

bioRxiv2021

Novelty-related engagement of VTA and anterior hippocampus propagate changes in cortical network plasticity at different scales

The detection of novelty indicates changes in the environment and the need to update existing representations. In response to novelty, interactions across the ventral tegmental area (VTA)-hippocampal circuit support experience-dependent plasticity in the hippocampus. While theories have broadly suggested plasticity-related changes are also instantiated in the cortex, research has also shown evidence for functional heterogeneity in cortical networks. It therefore remains unclear how the hippocampal-VTA circuit engages cortical networks, and whether novelty targets specific cortical regions or diffuse, large-scale cortical networks. To adjudicate the role of the VTA and hippocampus in cortical network plasticity, we used human functional magnetic resonance imaging (fMRI) to compare resting state functional coupling before and following exposure to novel scene images. Functional coupling between right anterior hippocampus and VTA was enhanced following novelty exposure. However, we also found evidence for a double dissociation, with anterior hippocampus and VTA showing distinct patterns of post-novelty functional coupling enhancements, targeting task-relevant regions versus large-scale networks, respectively. Further, significant correlations between these networks and the novelty-related plasticity in the anterior hippocampal-VTA functional network suggest the central hippocampal-VTA network may facilitate the interactions with the cortex. These findings support an extended model of novelty-induced plasticity, in which novelty elicits plasticity-related changes in both local and global cortical networks. Significance StatementNovelty detection is critical for adaptive behavior, signaling the need to update existing representations. By engaging the bi-directional hippocampal-VTA circuit, novelty has been shown to induce plasticity-related changes in the hippocampus. However, it remains an open question how novelty targets such plasticity-related changes in cortical networks. We show that anterior hippocampus and VTA target cortical networks at different spatial scales, with respective enhancements in post-novelty functional coupling with a task-relevant cortical region and a large-scale memory network. The results presented here support an extended model of novelty-related plasticity, in which engaging the anterior hippocampal-VTA circuit through novelty exposure propagates cortical plasticity through hippocampal and VTA functional pathways at distinct scales, targeting specific or diffuse cortical networks.

neuroscience↗