Dynamic regulation of NMDAR function in the adult brain by the stress hormone corticosterone

Stress and corticosteroids dynamically modulate the expression of synaptic plasticity at glutamatergic synapses in the developed brain. Together with alpha-amino-3-hydroxy-methyl-4-isoxazole propionic acid receptors (AMPAR), N-methyl-D-aspartate receptors (NMDAR) are critical mediators of synaptic function and are essential for the induction of many forms of synaptic plasticity. Regulation of NMDAR function by cortisol/corticosterone (CORT) may be fundamental to the effects of stress on synaptic plasticity. Recent reports of the efficacy of NMDAR antagonists in treating certain stress-associated psychopathologies further highlight the importance of understanding the regulation of NMDAR function by CORT. Knowledge of how corticosteroids regulate NMDAR function within the adult brain is relatively sparse, perhaps due to a common belief that NMDAR function is stable in the adult brain. We review recent results from our laboratory and others demonstrating dynamic regulation of NMDAR function by CORT in the adult brain. In addition, we consider the issue of how differences in the early life environment may program differential sensitivity to modulation of NMDAR function by CORT and how this may influence synaptic function during stress. Findings from these studies demonstrate that NMDAR function in the adult hippocampus remains sensitive to even brief exposures to CORT and that the capacity for modulation of NMDAR may be programmed, in part, by the early life environment. Modulation of NMDAR function may contribute to dynamic regulation of synaptic plasticity and adaptation in the face of stress, however, enhanced NMDAR function may be implicated in mechanisms of stress-related psychopathologies including depression

Environmental Programming of Susceptibility and Resilience to Stress in Adulthood in Male Mice

Epidemiological evidence identifies early life adversity as a significant risk factor for the development of mood disorders. Much evidence points to the role of early life experience in susceptibility and, to a lesser extent, resilience, to stress in adulthood. While many models of these phenomena exist in the literature, results are often conflicting and a systematic comparison of multiple models is lacking. Here, we compare effects of nine manipulations spanning the early postnatal through peri-adolescent periods, both at baseline and following exposure to chronic social defeat stress in adulthood, in male mice. By applying rigorous criteria across three commonly used measures of depression- and anxiety-like behavior, we identify manipulations that increase susceptibility to subsequent stress in adulthood and other pro-resilient manipulations that mitigate the deleterious consequences of adult stress. Our findings point to the importance of timing of early life stress and provide the foundation for future studies to probe the neurobiological mechanisms of risk and resilience conferred by variation in the early life environment

On the effect of Ti on Oxidation Behaviour of a Polycrystalline Nickel-based Superalloy

Titanium is commonly added to nickel superalloys but has a well-documented detrimental effect on oxidation resistance. The present work constitutes the first atomistic-scale quantitative measurements of grain boundary and bulk compositions in the oxide scale of a current generation polycrystalline nickel superalloy performed through atom probe tomography. Titanium was found to be particularly detrimental to oxide scale growth through grain boundary diffusion

Modulation of Synaptic Plasticity by Stress Hormone Associates with Plastic Alteration of Synaptic NMDA Receptor in the Adult Hippocampus

Stress exerts a profound impact on learning and memory, in part, through the actions of adrenal corticosterone (CORT) on synaptic plasticity, a cellular model of learning and memory. Increasing findings suggest that CORT exerts its impact on synaptic plasticity by altering the functional properties of glutamate receptors, which include changes in the motility and function of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype of glutamate receptor (AMPAR) that are responsible for the expression of synaptic plasticity. Here we provide evidence that CORT could also regulate synaptic plasticity by modulating the function of synaptic N-methyl-D-aspartate receptors (NMDARs), which mediate the induction of synaptic plasticity. We found that stress level CORT applied to adult rat hippocampal slices potentiated evoked NMDAR-mediated synaptic responses within 30 min. Surprisingly, following this fast-onset change, we observed a slow-onset (>1 hour after termination of CORT exposure) increase in synaptic expression of GluN2A-containing NMDARs. To investigate the consequences of the distinct fast- and slow-onset modulation of NMDARs for synaptic plasticity, we examined the formation of long-term potentiation (LTP) and long-term depression (LTD) within relevant time windows. Paralleling the increased NMDAR function, both LTP and LTD were facilitated during CORT treatment. However, 1–2 hours after CORT treatment when synaptic expression of GluN2A-containing NMDARs is increased, bidirectional plasticity was no longer facilitated. Our findings reveal the remarkable plasticity of NMDARs in the adult hippocampus in response to CORT. CORT-mediated slow-onset increase in GluN2A in hippocampal synapses could be a homeostatic mechanism to normalize synaptic plasticity following fast-onset stress-induced facilitation

Point excess solute: A new metric for quantifying solute segregation in atom probe tomography datasets including application to naturally aged solute clusters in Al-Mg-Si-(Cu) alloys

Data availability: The raw and processed data required to reproduce these findings cannot be shared at this time due to legal reasons.Supplementary data are available online at: https://www.sciencedirect.com/science/article/pii/S1044580323007611#s0060 .Copyright © 2023 The Authors. Accurate, repeatable and quantitative analysis of nanoscale solute clustering in atom probe tomography (APT) datasets is a complex challenge which is made more difficult by the positional uncertainty and lack of absolute resolution inherent to the technique. In this work a new method, the point excess solute, is introduced for quantifying solute segregation in datasets with limited spatial resolution. This new method is based on measuring the matrix concentration using a dataset sampling method. We show the new method can accurately reproduce the values expected from synthetic datasets a priori and when the dataset spatial resolution and or phase contrast is too low for accurate quantification this is observable. The method is then applied to naturally aged solute clusters in the Al-Mg-Si-Cu system. Datasets were collected with a range of natural ageing times from 8 min to 76 weeks. The formation of the solute clusters is shown to be unaffected by the Cu content of the alloy.The authors would like to thank Constellium for providing the materials and financially supporting this research alongside the Engineering and Physical Science Research Council (EPSRC) through studentship 1922133. The authors are grateful to EPSRC for funding of the LEAP 5000XR for the UK National Atom Probe Facility through grant EP/M022803/1

Increased Expression of PLS3 Correlates with Better Outcome in Sézary Syndrome.

Dermatology-oncolog