My brain on a 24/7 schedule - impact on memory function
Luísa V. Lopes | iMM Lisboa, Portugal | [email protected]
The effects of a “24-7” schedule in our general physiology, as well as our cognitive capacities, are a growing social concern. A wealth of recent studies shows that the integrity of circadian rhythms is crucial for cognitive function possibly through direct disruption of its biological mechanism – neural plasticity.
Circadian release of cortisol from the adrenal cortex is under tight regulation of this hypothalamic–pituitary–adrenal (HPA) axis. The hippocampus plays a crucial role in regulating HPA axis; and excessive glucocorticoid production disrupts the regulatory feedback from the hippocampus onto the hypothalamus. Impaired cortisol levels are observed in post-traumatic stress syndrome or major depression. Increased glucocorticoid activity has also been associated with greater hippocampal atrophy and memory impairment in the elderly.
I will share evidence of age-related downregulation of glucocorticoid receptors (GR) in the hippocampus, and consequent desensitization of the regulatory feedback to the hypothalamus. Higher cortisol levels have been associated with more rapid Alzheimer’s disease (AD) progression and systemic administration of glucocorticoids or stress shown to potentiate memory impairments, hippocampal damage, β-amyloid formation and Tau accumulation in transgenic AD mice. We have recently described the interesting ability of novel drugs -adenosine A2A receptor (A2A) blockers- to rescue age-like memory deficits and anxiety in rodents, by re-establishing central GR levels, hippocampal feedback and consequent control of systemic CORT circadian levels. Plus, A2A deletion improved spatial memory and mitigates hippocampal Tau phosphorylation in AD-related THY-Tau22 mice.
Altogether, such observations strongly suggest that A2A over-activation and GR dysfunction are key events in age-related hippocampal deficits and raise the possibility that both pathways might be interconnected. We recently provided the first demonstration of a direct impact of A2A modulation on GR function, a mechanism never hypothesized before. We found that A2A overexpression in forebrain neurons is sufficient to promote HPA-axis dysfunction, namely loss of plasmatic corticosterone circadian oscillation, and reduced GR hippocampal levels, both being age-related phenotypes; by modulating GR nuclear translocation and transcriptional activity.
This supports the idea that the procognitive effects of A2AR antagonists, namely caffeine, on age-related cognitive impairments may be due, at least in part, to its ability to modulate GR actions and normalize HPA axis feedback. The concept of enhanced vulnerability to dementia by the existence of underlying circadian disorders is very appealing, supported by evidence and deserves further attention.
Modern schedules have led humans to be the only animal species that routinely ignores its biological clock. This is a socially pervasive phenomenon, whose consequences to mental and general health are not fully understood. By identifying circadian modulators with impact on cognition we may contribute to novel strategies to ameliorate the effects of the ’24/7’ schedule on modern societies.
Luísa V. Lopes | iMM Lisboa, Portugal | [email protected]
The effects of a “24-7” schedule in our general physiology, as well as our cognitive capacities, are a growing social concern. A wealth of recent studies shows that the integrity of circadian rhythms is crucial for cognitive function possibly through direct disruption of its biological mechanism – neural plasticity.
Circadian release of cortisol from the adrenal cortex is under tight regulation of this hypothalamic–pituitary–adrenal (HPA) axis. The hippocampus plays a crucial role in regulating HPA axis; and excessive glucocorticoid production disrupts the regulatory feedback from the hippocampus onto the hypothalamus. Impaired cortisol levels are observed in post-traumatic stress syndrome or major depression. Increased glucocorticoid activity has also been associated with greater hippocampal atrophy and memory impairment in the elderly.
I will share evidence of age-related downregulation of glucocorticoid receptors (GR) in the hippocampus, and consequent desensitization of the regulatory feedback to the hypothalamus. Higher cortisol levels have been associated with more rapid Alzheimer’s disease (AD) progression and systemic administration of glucocorticoids or stress shown to potentiate memory impairments, hippocampal damage, β-amyloid formation and Tau accumulation in transgenic AD mice. We have recently described the interesting ability of novel drugs -adenosine A2A receptor (A2A) blockers- to rescue age-like memory deficits and anxiety in rodents, by re-establishing central GR levels, hippocampal feedback and consequent control of systemic CORT circadian levels. Plus, A2A deletion improved spatial memory and mitigates hippocampal Tau phosphorylation in AD-related THY-Tau22 mice.
Altogether, such observations strongly suggest that A2A over-activation and GR dysfunction are key events in age-related hippocampal deficits and raise the possibility that both pathways might be interconnected. We recently provided the first demonstration of a direct impact of A2A modulation on GR function, a mechanism never hypothesized before. We found that A2A overexpression in forebrain neurons is sufficient to promote HPA-axis dysfunction, namely loss of plasmatic corticosterone circadian oscillation, and reduced GR hippocampal levels, both being age-related phenotypes; by modulating GR nuclear translocation and transcriptional activity.
This supports the idea that the procognitive effects of A2AR antagonists, namely caffeine, on age-related cognitive impairments may be due, at least in part, to its ability to modulate GR actions and normalize HPA axis feedback. The concept of enhanced vulnerability to dementia by the existence of underlying circadian disorders is very appealing, supported by evidence and deserves further attention.
Modern schedules have led humans to be the only animal species that routinely ignores its biological clock. This is a socially pervasive phenomenon, whose consequences to mental and general health are not fully understood. By identifying circadian modulators with impact on cognition we may contribute to novel strategies to ameliorate the effects of the ’24/7’ schedule on modern societies.