Ketamine, an NMDA receptor antagonist, rapidly relieves symptoms of depression within hours. While neuroplasticity in the medial prefrontal cortex (mPFC) is known to be critical for these effects, the downstream brain circuits involved were unclear. Using optogenetic and chemogenetic techniques in rodent models, researchers identified two distinct pathways. Activation of mPFC projections to the basolateral amygdala (BLA) and then to the ventral hippocampus mediated ketamine's effects on passive coping behavior, but not on anxiety or reward-seeking. In contrast, mPFC projections to the bed nucleus of stria terminalis (BNST) were necessary and sufficient for effects on anxiety-like and reward-seeking behaviors, but not passive coping. This suggests separate downstream circuits produce different antidepressant-like behavioral responses.
Psilocin, the active metabolite of psilocybin, produces antidepressant effects in mice by activating serotonin 5-HT2A receptors on GABAergic neurons in the lateral septum that project to the dorsomedial hypothalamic nucleus. Selectively inhibiting this pathway eliminated the antidepressant-like effect in forced-swim and social defeat stress tests, while activating it induced antidepressant-like effects. Microinjection of bicuculline, a GABAA receptor antagonist, into the dorsomedial hypothalamic nucleus diminished psilocin's antidepressant effect. These findings suggest that this specific neural network underlies the antidepressant action of serotonergic psychedelics, separate from their hallucinatory effects mediated by the visual cortex.
The FDA has approved psilocybin, the psychoactive compound in magic mushrooms, as a breakthrough therapy for depression, but its detailed mechanism remains unknown. Serotonergic psychedelics like psilocybin and LSD produce hallucinatory effects by stimulating the serotonin 5-HT2A receptor. In mice, 5-HT2A agonists such as DOI and psilocin (the active metabolite of psilocybin) reduced immobility time in the forced-swim test, an effect absent when the 5-HT2A gene was knocked down in the lateral septum. Activating Gq signaling in 5-HT2A-positive neurons in the lateral septum produced antidepressant and anxiolytic effects. Most 5-HT2A-positive cells in the lateral septum are GABAergic inhibitory neurons, suggesting their activation underlies the antidepressant effect.
Brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) in the medial prefrontal cortex (mPFC) work together to produce antidepressant effects. In cultured cortical neurons, BDNF stimulates VEGF release and VEGF stimulates BDNF release. BDNF increases dendritic complexity, but this effect is blocked by inhibiting the VEGF receptor Flk-1; similarly, VEGF's effect on dendrites is blocked by inhibiting the BDNF receptor TrkB. A single infusion of either BDNF or VEGF into the mPFC of mice produces antidepressant effects lasting at least 5 days in three behavioral tests. These effects are blocked by neutralizing the other factor, indicating that mutual signaling between BDNF and VEGF is required for rapid and sustained antidepressant responses.