This study examined the influence of exercise intensity upon the cortisol response of the hypothalamic-pituitary-adrenal (HPA) axis. Specifically, we examined exercise at intensities of 40, 60, and 80% maximal oxygen uptake (VO2max) in an attempt to determine the intensity necessary to provoke an increase in circulating cortisol. Twelve active moderately trained men performed 30 min of exercise at intensities of 40, 60, and 80% of their VO2max, as well as a 30-min resting-control session involving no exercise on separate days. Confounding factors such as time of day--circadian rhythms, prior diet--activity patterns, psychological stress, and levels of exercise training were controlled. Cortisol and ACTH were assessed in blood collected immediately before (pre-) and after (post-) each experimental session. Statistical analysis involved repeated measures analysis of variance and Tukey post-hoc testing. The percent change in cortisol from pre- to post-sampling at each session was: resting-control, 40, 60, and 80% sessions (mean+/-SD) =-6.6+/-3.5%, +5.7+/-11.0%, +39.9+/-11.8%, and +83.1+/-18.5%, respectively. The 60% and 80% intensity magnitude of change was significantly greater than in the other sessions, as well as from one to another. The ACTH responses mirrored those of cortisol, but only the 80% exercise provoked a significant (p<0.05) increase pre- to post-exercise. The calculated changes in plasma volume for the resting-control, 40%, 60%, and 80% sessions were: +2.2+/-3.0%, -9.9+/-5.0%, -15.6+/-3.5%, and -17.2+/-3.3%, respectively. Collectively, the cortisol findings support the view that moderate to high intensity exercise provokes increases in circulating cortisol levels. These increases seem due to a combination of hemoconcentration and HPA axis stimulus (ACTH). In contrast, low intensity exercise (40%) does not result in significant increases in cortisol levels, but, once corrections for plasma volume reduction occurred and circadian factors were examined, low intensity exercise actually resulted in a reduction in circulating cortisol levels.

Significance Statement The protein tau is highly expressed in neurons and is involved in maintaining neuronal structure. In diseases such as Alzheimer's disease (AD), tau can form oligomers, which consist of tau molecules joined together. There is growing evidence that these tau oligomers are toxic to neurons, although their precise actions are still being characterized. We have taken the approach of introducing structurally-defined tau-441 oligomers into neurons via the recording electrode (a method previously published by Kaufmann et al., 2016). This method allowed us to provide detailed characterization of the concentration and time-dependent actions of tau oligomers on neuronal properties. We have found that tau interferes with the action potential wave form, modifies synaptic transmission and can block events that probably underlie memory storage.

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The development of therapeutic agonists for G protein-coupled receptors (GPCRs) is hampered by the propensity of GPCRs to couple to multiple intracellular signalling pathways. This promiscuous coupling leads to numerous downstream cellular effects, some of which are therapeutically undesirable. This is especially the case for adenosine A1 receptors (A1Rs) whose clinical potential is undermined by the sedation and cardiorespiratory depression caused by conventional agonists. We have discovered that the A1R-selective agonist, benzyloxy-cyclopentyladenosine (BnOCPA), is a potent and powerful analgesic but does not cause sedation, bradycardia, hypotension or respiratory depression. This unprecedented discrimination between native A1Rs arises from BnOCPA’s unique and exquisitely selective activation of Gob among the six Gαi/o subtypes, and in the absence of β-arrestin recruitment. BnOCPA thus demonstrates a highly-specific Gα-selective activation of the native A1R, sheds new light on GPCR signalling, and reveals new possibilities for the development of novel therapeutics based on the far-reaching concept of selective Gα agonism.