The Effects of Whole-Body Heating on Serotonergic Systems: A Novel Mechanism for Treating Depression

Major depressive disorder (MDD) is projected to be the 2nd leading cause of disability-adjusted life years (DALYs) by 2020. One hypothesis is that dysfunction of serotonergic systems in the brain, particularly serotonergic systems in the dorsal raphe nucleus, plays a role in the etiology and pathophysiology of depression. Current antidepressant therapies include drug therapies such as selective serotonin reuptake inhibitors (SSRIs). Although SSRIs have antidepressant effects in severely depressed patients, they also have many deleterious side effects. Thus, there is a need for more effective treatments that have fewer negative side effects. To develop more effective treatments for depression, a greater understanding of the underlying physiological mechanisms involved in activation of brainstem serotonergic systems and antidepressant responses is needed. Previous studies have demonstrated that whole-body heating in rats can activate a putative antidepressant-related subset of serotonergic neurons in the interfascicular part of the dorsal raphe nucleus. However, the pathway(s) involved in 1) activation of serotonergic neurons, and 2) activation of forebrain systems implicated in MDD, by warm temperature are not known. Here we explored neural systems activated by whole-body heating in rats, particularly spinoparabrachial and spinothalamic pathways, in hopes of identifying potential mechanisms through which whole-body heating activates forebrain systems implicated in antidepressant responses. We exposed rats to an incubation chamber at either warm ambient temperature (37 °C) or room temperature (RT; 23 °C) for 105 min. Brains then were removed and processed for immunohistochemical detection of the protein product of the immediate-early gene c-fos (as a marker of neuronal activation) and tryptophan hydroxylase (as a marker of serotonergic neurons). Our data suggest that the spinoparabrachial pathway plays a primary role in activation of brainstem serotonergic systems, while the medial spinothalamic pathway plays a direct role in activation of prefrontal cortical structures implicated in the pathophysiology of MDD and antidepressant responses. Together, these results provide evidence for multiple pathways through which warm temperature may influence affective and cognitive function, including 1) activation of prefrontal circuits via the spinoparabrachial pathway and serotonergic systems, and 2) modulation of affective and cognitive circuits via the medial spinothalamic pathway. Furthermore, these findings demonstrate the potential of whole-body heating as a novel mechanism for treating depression