Redrawing Papez' circuit: a theory about how acute stress becomes chronic and causes disease.

The diseases of chronic stress include migraine, essential hypertension, depression, and the metabolic syndrome. A theory is presented to explain how acute stress becomes chronic and causes these inter-related conditions. The theory is based on a new "circuit of emotion", which is derived from Papez' famous theory of emotion. The hypothesis is as follows: There is a basic circuit of emotion which runs from the hippocampus (defined as the dentate gyrus plus the CA regions), where emotion arises, to the amygdala and from there to serotonergic pacemaker cells in the dorsal raphe nucleus (DRN). The DRN projects back to the dentate gyrus in two ways: a direct route without a stop and an indirect route via pacemaker cells in the entorhinal cortex. The purpose of the direct route is to promote neurogenesis in the subgranular zone of the dentate; the indirect route has two purposes: to imprint ongoing moments of consciousness onto new dentate cells for retention as memory and to provide a negative feedback loop for regulation of the whole process. The hippocampus, the amygdala, and the DRN all project to the hypothalamus, which are branches off the basic loop that subserve the autonomic expression of emotion. Pathologic overdrive of the DRN causes overdrive of the entorhinal cortex, which leads to excitotoxic cell death of neurons in the hippocampus involved in the negative feedback loop. The disinhibited amygdala and DRN are then free to orchestrate the syndromes of chronic stress. Recovery from chronic stress requires repopulation of the dentate gyrus and restoration of the feedback loop. Excitotoxic cell death in the hippocampus results from either extraordinary acute stress or increased susceptibility to DRN overdrive, as might be caused, for example, by genetic factors, age, high cortisol levels, or incomplete recovery from previous damage. Three goals for therapeutic intervention are identified: inhibition of pacemaker cells in the DRN (which can be targeted by ethosuximide and other drugs that block serotonergic pacemaker currents), inhibition of pacemaker cells in the entorhinal cortex (which can be targeted by anti-epileptic drugs that block pacemaker currents in the entorhinal cortex, e.g. phenytoin), and restoration of serotonin levels in the dentate gyrus (which can be accomplished with anti-depressants). It is logical to use drugs from all three categories, either alone on in combination, to treat any of the four diseases of chronic stress. This leads to novel therapeutic recommendations, e.g. the use of ethosuximide, mood-stabilizers, and anti-depressants in synergy to treat essential hypertension.