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.

No abstract

Tau is a predominantly neuronal protein that is normally bound to microtubules, where it acts to modulate neuronal and axonal stability. In humans, pathological forms of tau are implicated in a range of diseases that are collectively known as tauopathies. Kinases and phosphatases are responsible for maintaining the correct balance of tau phosphorylation to enable axons to be both stable and labile enough to function properly. In the early stages of tauopathies, this balance is interrupted leading to dissociation of tau from microtubules. This leaves microtubules prone to damage and phosphorylated tau prone to aggregation. Initially, phosphorylated tau forms oligomers, then fibrils, and ultimately neurofibrillary tangles (NFTs). It is widely accepted that the initial soluble oligomeric forms of tau are probably the most pathologically relevant species but there is relatively little quantitative information to explain exactly what their toxic effects are at the individual neuron level. Electrophysiology provides a valuable tool to help uncover the mechanisms of action of tau oligomers on synaptic transmission within single neurons. Understanding the concentration-, time-, and neuronal compartment-dependent actions of soluble tau oligomers on neuronal and synaptic properties are essential to understanding how best to counteract its effects and to develop effective treatment strategies. Here, we briefly discuss the standard approaches used to elucidate these actions, focusing on the advantages and shortcomings of the experimental procedures. Subsequently, we will describe a new approach that addresses specific challenges with the current methods, thus allowing real-time toxicity evaluation at the single-neuron level.

Summary The substantia nigra (SN) and ventral tegmental area (VTA) are vital for the control of movement, goal-directed behavior, and encoding reward. Here we show that the firing of specific neuronal subtypes in these nuclei can be modulated by physiological changes in the partial pressure of carbon dioxide (PCO 2 ). The resting conductance of substantia nigra dopaminergic neurons in young animals (postnatal days 7–10) and GABAergic neurons in the VTA is modulated by changes in the level of CO 2 . We provide several lines of evidence that this CO 2 -sensitive conductance results from connexin 26 (Cx26) hemichannel expression. Since the levels of PCO 2 in the blood will vary depending on physiological activity and pathology, this suggests that changes in PCO 2 could potentially modulate motor activity, reward behavior, and wakefulness.

Alpha-synuclein aggregates increase the conductance of substantia nigra dopamine neurons, an effect partly reversed by the KATP channel inhibitor glibenclamide.