Cool Stuff: How Sleep and Thermoregulation Influence Antidepressant-Induced Brain Plasticity Signaling

Current conventional medications have failed to curb the rising incidence of depression and are hindered by their side effects and slow onset of action. Electroconvulsive therapy (ECT) and the NMDA receptor antagonist ketamine are more effective but limited to treatment-resistant patients. The mechanism behind alleviation of depressive symptoms has been a subject of a lengthy debate, but brain plasticity appears to play a central role. Various therapeutic modalities converge on brain derived neurotrophic factor (BDNF) receptor TrkB signaling pathway targets, such as mTOR and GSK3β. However, targeting TrkB-signaling in drug development is complicated due to its involvement in fundamental physiological processes. Emerging evidence suggests that some of these physiological processes, particularly sleep physiology, may contribute to the antidepressant effect.

This thesis investigates the physiological responses to rapid-acting antidepressants, which have been overlooked in pharmacological research. We review literature showing overlaps between ketamine’s mechanisms and sleep physiology, suggesting that ignoring these overlaps may have confounded antidepressant research. Our original in vivo research examines neurotrophic signaling in antidepressant-induced physiological responses related to three sleep characteristics: electroencephalographic (EEG) activity, metabolic rate, and thermoregulation.

We demonstrate an inverse relationship between EEG activity and TrkB signaling pathway phosphorylation during isoflurane anesthesia. A screen of pharmacologically diverse drugs shows that the signaling is not associated with a single pharmacodynamic action, but a drowsy phenotype. We demonstrate that the effect is independent of any pharmacodynamic interaction by showing TrkB activation in animals undergoing recovery sleep after sleep deprivation. Through pharmacological manipulation experiments, we confirm that EEG slowing and TrkB signaling can occur independently, evidenced by negligible TrkB phosphorylation with EEG-slowing atropine and significant TrkB activation in medetomidine-anesthesia despite EEG normalization by amphetamine-pretreatment. Next, we show that TrkB activation coincides with a hypometabolic state using metabolomics and a functional imaging method developed in this thesis. Administering inhibitors of glycolysis and lipid β-oxidation confirms the causal link between TrkB activity and metabolomic alterations. We discovered that TrkB-activating treatments induce hypothermia. Investigating the hypothermic response, we find that drug-induced TrkB signaling is prevented by maintaining body temperature within a physiological range. Warm ambient temperature abolishes signaling produced by amitriptyline, previously considered as a TrkB agonist, and this signaling occurs regardless of impaired activity-dependent BDNF release. Finally, we demonstrate that this phenomenon also applies to the ketamine-like antidepressant nitrous oxide (N₂O), and that preventing the hypothermic response abolishes N₂O’s antidepressant-like behavioral effects in an animal model.

The thesis characterizes a novel thermosensitive regulatory mechanism for TrkB activity in vivo. As a result of the oversight of physiology in past preclinical research, it is conceivable that the phenomenon has been erroneously interpreted as a marker of antidepressant effect, which would explain the high rates of translational failures in the field. The discovery sheds light on the enigmatic mechanisms of antidepressant action and opens fascinating new avenues to investigate physiological regulation of neuroplasticity for developing more effective and safer treatments for psychiatric disorders such as depression.