Exposed to events that never happen: Generalized unsafety, the default stress response, and prolonged autonomic activity

•The stress response is a default response, it is ‘always there’; it is not generated but disinhibited.•This default response is under tonic prefrontal inhibition as long as safety is perceived; and the conditions of safety are learned during an individual organisms lifespan.•This tonic inhibition is reflected by high tonic vagally mediated heart rate variability, and is relatively energy-economic.•Chronic stress responses are due to generalized unsafety (GU) rather than stressors.•GU is present in many other conditions, including obesity, old age and loneliness. Based on neurobiological and evolutionary arguments, the generalized unsafety theory of stress (GUTS) hypothesizes that the stress response is a default response, and that chronic stress responses are caused by generalized unsafety (GU), independent of stressors or their cognitive representation. Three highly prevalent conditions are particularly vulnerable to becoming ‘compromised’ in terms of GU, and carry considerable health risks: (1)‘Compromised bodies’: in conditions with reduced bodily capacity, namely obesity, low aerobic fitness and older age, GU is preserved due to its evolutionary survival value;(2)‘Compromised social network’: in loneliness the primary source of safety is lacking, i.e. being part of a cohesive social network;(3)‘Compromised contexts’: in case of specific stressors (e.g. work stressors), daily contexts that are neutral by themselves (e.g. office building, email at home) may become unsafe by previously being paired with stressors, via context conditioning. Thus, GUTS critically revises and expands stress theory, by focusing on safety instead of threat, and by including risk factors that have hitherto not been attributed to stress.