Sickness behaviours like fatigue, anhedonia and reduced motivation, are active processes by the brain in response to an infection for shunting energy expenditure to the immune response; This sickness behaviour phenotype greatly overlaps with depressive behaviour. Even though a clear association between inflammation, metabolic dysregulation and depressive behaviour exists, the underlying mechanisms explaining the relation between these processes are unknown. We propose that chronic inflammation induces a shift in metabolic setpoints which results in depressive behaviours.
Our research with real-time monitoring of mice with prolonged, low-level, systemic inflammation showed this inflammation to drive energy expenditure to critical threshold levels. To preserve a viable metabolic balance, their physical activity was reduced while food and water intake remained largely unaffected. Upon chronic inflammation the body temperature circadian rhythm (36 to 38 °C) was lost and remained constant at approximately 36 °C, while occasionally falling to ambient temperature levels (~23 ºC) in a hypometabolic state (torpor). This inflammation-dependent hypometabolic state is orchestrated by the preoptic area (POA) of the hypothalamus, a central hub known for its role in thermoregulation and fasting-induced torpor. Activation of the POA by acute restraint stress upon chronic inflammation was sufficient to induce glucose-dependent hypothermia, showing that an inflammatory state renders the organism susceptible to psychogenic stress-induced metabolic shutdown.
It is our aim to determine mechanistically whether depressive disorders represent an energy-preserving behaviour in humans, and whether psychiatric breakdown parallels torpor as a coping mechanism to sustain vital body functions upon challenge. We aim to determine i) which signals induce shifts between metabolic setpoints, ii) if the energy-preserving behaviours represent depression iiI) which brain regions/circuits are involved
