Locus Coeruleus-Dorsolateral Septum Projections Modulate Depression-Like Behaviors via BDNF But Not Norepinephrine

Locus coeruleus (LC) dysfunction is involved in the pathophysiology of depression; however, the neural circuits and specific molecular mechanisms responsible for this dysfunction remain unclear. Here, it is shown that activation of tyrosine hydroxylase (TH) neurons in the LC alleviates depression-like behaviors in susceptible mice. The dorsolateral septum (dLS) is the most physiologically relevant output from the LC under stress. Stimulation of the LCTH-dLSSST innervation with optogenetic and chemogenetic tools bidirectionally can regulate depression-like behaviors in both male and female mice. Mechanistically, it is found that brain-derived neurotrophic factor (BDNF), but not norepinephrine, is required for the circuit to produce antidepressant-like effects. Genetic overexpression of BDNF in the circuit or supplementation with BDNF protein in the dLS is sufficient to produce antidepressant-like effects. Furthermore, viral knockdown of BDNF in this circuit abolishes the antidepressant-like effect of ketamine, but not fluoxetine. Collectively, these findings underscore the notable antidepressant-like role of the LCTH-dLSSST pathway in depression via BDNF-TrkB signaling. Optogenetic and chemogenetic activation of LCTH neurons after chronic social defeat stress increases the expression of BDNF, which in turn acts on SST neurons in the dLS and promotes resilience to stress. These findings highlight the notable antidepressant-like role of the LCTH-dLSSST pathway in depression which can serve as prominent targets for neurostimulation.image