The cerebello-hypothalamic-pituitary-adrenal axis dysregulation hypothesis in depressive disorder

Depressive disorder can be viewed as an adaptive defense mechanism in response to excessive stress that has gone awry. The hypothalamic-pituitary-adrenal (HPA) axis is an important node in the brain's stress circuit and suggested to play a role in several subtypes of depression. While the hippocampus, amygdala and prefrontal cortex are considered important regions implicated in stress regulation and depressive disorder, the existence of reciprocal monosynaptic cerebello-hypothalamic connections and the presence of dense glucocorticoid binding sites point towards the view that the cerebellum plays a functional role in the regulation of HPA-axis as well. The present hypothesis may further contribute to contemporary neurobiological views on stress regulation and depressive disorder, and may offer a potential biological basis for developing novel neurosomatic treatment protocols.