Chronic stress can impact decision-making and lead to a preference for immediate rewards rather than long-term payoffs. Factors that may influence these effects of chronic stress on decision-making are under-explored. Here we used a mouse model to investigate the changes in decision-making caused by the experience of chronic stress and the role of social isolation in exaggerating these changes. To test decision-making, mice were trained to perform a Cost-Benefit Conflict (CBC) task on a T-maze, in which they could choose between a high-reward, high-risk alternative and a low-reward, low-risk alternative. Mice were either housed in groups or alone throughout the experiment. Both groups of mice underwent a seven-day period of repeated immobilization to induce chronic stress. Stress levels were confirmed using behavioral (open field test) and physiological (urine corticosterone ELISA) measures. We found a significant increase in frequency of high-risk decisions after exposure to chronic stress among both socially-and individually-housed mice. Crucially, socially-housed mice showed a significantly smaller increase in high-risk decision-making compared to singly-housed mice. These findings suggest that chronic stress leads to an increase in high-risk decision-making in mice, and that lack of social interaction may exacerbate this stress effect.

all-atom molecular dynamics simulations we provide extensive insight into microsecond dynamics of a villin solution at different concentrations, as a simple model of cellular environment. Since inaccuracies of current force fields are known to result in exaggerated protein aggregation we increase protein-water interactions to better reproduce available experimental results. The simulations show that protein rotational diffusion slows down more significantly than translational diffusion with increasing concentration, while protein internal dynamics remain largely unaltered. These findings correlate with observed formation of sub-microsecond persisting protein clusters which size distribution shifts toward larger clusters with increasing protein concentration. We show that diffusion coefficients estimated for simulation-derived cluster structures weighted by the cluster size distribution mostly reproduce the observed overall diffusion. It indicates the clusters formation as a primary determinant of diffusion slow-down upon crowding. Finally, we shed light on protein diffusion in a heterogeneous protein solution, near a lipid membrane and in the presence of metabolites. The most abundant NFkB family member, p65 (also called RelA), exerts its transcriptional regulatory function as a homo-or hetero-dimer with p50. The two dimers have different but overlapping DNA binding specificities, considered to be the key to fine control of gene regulation. Past crystallographic studies on NFkB-DNA complexes showed high structural homology among different NFkB dimers and left a puzzle: how do NFkB dimers bind to DNA with different affinities? In this study, we discovered drastically different conformational dynamics between two free NFkB dimers: p65p50 and p65 homodimer. Hydrogen-deuterium exchange mass spectrometry (HDXMS) revealed different exchange levels in the p65 DNA-binding domains (DBDs) of the homodimer as compared to the heterodimer, suggesting a sub-global conformational difference between p65 bound to p50 and p65 bound to another p65. Furthermore, molecular dynamics (MD) simulations elucidated the conformational ensembles that give rise to different HDX patterns. We found that when not bound to DNA, the two DBDs of the NFkB dimer can twist around the linker between the dimerization domain and the DBD with a large amplitude (30 Å ). Through MD simulations, we observed very distinct conformational relaxation processes from DNA-bound to free states for p65p50 and p65 homodimer. While the two DBDs in p65p50 move apart from each other, those in p65 homodimer come together and form new contacts. The new protein interface captured by MD in the p65 homodimer explains the different HDX behaviors between NFkB dimers. Moreover, we suggest that the differences in DNA-binding affinities are a consequence of distinct conformational dynamics displayed by the free NFkB dimers. By combining HDX-MS and MD simulations, we here provide an example of understanding how signaling proteins function from the standpoint of conformational dynam...

Chronic stress can impact decision-making and lead to a preference for immediate rewards rather than long-term payoffs. Factors that may mitigate these effects of chronic stress on decision-making are under-explored. Here we used a mouse model to investigate the changes in decision-making caused by the experience of chronic stress and the role of social interaction in attenuating these changes. To test decision-making, mice were trained to perform a Cost-Benefit Conflict (CBC) task on a T-maze, in which they could choose between a high-reward, high-risk alternative and a low-reward, low-risk alternative.Mice were either housed in groups or alone throughout the experiment. Both groups of mice underwent a seven-day period of repeated immobilisation to induce chronic stress. Stress levels were confirmed using behavioural (open field test) and physiological (urine corticosterone ELISA) measures. We found a significant increase in frequency of high-risk decisions after exposure to chronic stress among both sociallyand individually-housed mice. Crucially, socially-housed mice showed a significantly smaller increase in high-risk decision-making compared to singly-housed mice. These findings suggest that although chronic stress leads to an increase in high-risk decision-making in mice, access to social interaction may mitigate this stress effect.