Mg2+ regulates many physiological processes and signalling pathways. However, little is known about the mechanisms underlying the organismal balance of Mg2+. Capitalizing on a set of newly generated mouse models, we provide an integrated mechanistic model of the regulation of organismal Mg2+ balance during prenatal development and in adult mice by the ion channel TRPM6. We show that TRPM6 activity in the placenta and yolk sac is essential for embryonic development. In adult mice, TRPM6 is required in the intestine to maintain organismal Mg2+ balance, but is dispensable in the kidney. Trpm6 inactivation in adult mice leads to a shortened lifespan, growth deficit and metabolic alterations indicative of impaired energy balance. Dietary Mg2+ supplementation not only rescues all phenotypes displayed by Trpm6-deficient adult mice, but also may extend the lifespan of wildtype mice. Hence, maintenance of organismal Mg2+ balance by TRPM6 is crucial for prenatal development and survival to adulthood.DOI: http://dx.doi.org/10.7554/eLife.20914.001
Neural processing of sensory information is strongly influenced by context. For instance, cortical responses are reduced to predictable stimuli, while responses are increased to novel stimuli that deviate from contextual regularities. Such bidirectional modulation based on preceding sensory context is likely a critical component or manifestation of attention, learning, and behavior, yet how it arises in cortical circuits remains unclear. Using volumetric two-photon calcium imaging and local field potentials in primary visual cortex (V1) from awake mice presented with visual “oddball” paradigms, we identify both reductions and augmentations of stimulus-evoked responses depending, on whether the stimulus was redundant or deviant, respectively. Interestingly, deviance-augmented responses were limited to a specific subset of neurons mostly in supragranular layers. These deviance-detecting cells were spatially intermixed with other visually responsive neurons and were functionally correlated, forming a neuronal ensemble. Optogenetic suppression of prefrontal inputs to V1 reduced the contextual selectivity of deviance-detecting ensembles, demonstrating a causal role for top-down inputs. The presence of specialized context-selective ensembles in primary sensory cortex, modulated by higher cortical areas, provides a circuit substrate for the brain’s construction and selection of prediction errors, computations which are key for survival and deficient in many psychiatric disorders.
Summary The control of germline quality is critical to reproductive success and survival of a species; however, the mechanisms underlying this process remain unknown. Here we demonstrate that elongation factor 2 kinase (eEF2K), an evolutionarily conserved regulator of protein synthesis, functions to maintain germline quality and eliminate defective oocytes. We show that disruption of eEF2K in mice reduces ovarian apoptosis and results in the accumulation of aberrant follicles and defective oocytes at advanced reproductive age. Furthermore, the loss of eEF2K in Caenorhabditis elegans results in a reduction of germ cell death and significant decline in oocyte quality and embryonic viability. Examination of the mechanisms by which eEF2K regulates apoptosis shows that eEF2K senses oxidative stress and quickly downregulates short-lived anti-apoptotic proteins, XIAP and c-FLIPL by inhibiting global protein synthesis. These results suggest that eEF2K-mediated inhibition of protein synthesis renders cells susceptible to apoptosis, and functions to eliminate suboptimal germ cells.
Optical activation of neurons requires genetic manipulation or the use of chemical photoactivators with undesirable side effects. As a solution to these disadvantages, here, we demonstrate optically evoked neuronal activity in mouse cortical neurons in acute slices and in vivo by nonlinear excitation of gold nanoparticles. In addition, we use this approach to stimulate individual epitheliomuscular cells and evoke body contractions in Hydra vulgaris. To achieve this, we use a low-power pulsed near-infrared excitation at the double-wavelength of the plasmon resonance of gold nanoparticles, which enables optical sectioning and allows for high spatial precision and large penetration depth. The effect is explained by second-harmonic Mie scattering, demonstrating light absorption by a second-order nonlinear process, which enables photothermal stimulation of the cells. Our approach also minimizes photodamage, demonstrating a major advancement towards precise and harmless photoactivation for neuroscience and human therapeutics.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.