Figure 3
The biphasic actions of mediators of allostasis to promote adaptation and also damage is described in an inverted-U-shaped dose–response curve, in which acutely activated physiological levels of mediators enhance synaptic functions and memory, whereas more intense acute activation has the opposite effect. Chronic activation by repeated stressors or circadian disruption produces adaptive plasticity, with resilience, in the healthy brain. Loss of resilience is found in anxiety and depressive disorders where IR has a role and contributes to cognitive impairment. With damage, involving excessive activation of excitatory amino acids, potentiated by glucocorticoids, irreversible damage occurs; this is postulated to be a key step in the irreversible activation of the cascade leading to Alzheimer’s disease involving inactivation of the adaptive insulin receptor mechanism.5 In contrast, normal brain aging involves potentially reversible loss of resilience, which, for example, can be overcome by regular physical activity.25 IR, insulin resistance.
