The role of GABA in the in the dorsal striatum-raphe nucleus circuit regulating stress vulnerability in male mice with high levels of Shati/Nat8l

Depression is a frequent and serious illness and stress is considered the main risk factor for its onset. First-line antidepressants increase serotonin (5-hydroxytryptamine and 5-HT) levels in the brain. We previously reported that an N-acetyltransferase, Shati/Nat8l, is upregulated in the dorsal striatum (dSTR) of stress-susceptible mice exposed to repeated social defeat stress (RSDS) and that dSTR Shati/Nat8l overexpression in mice (dSTR-Shati OE) induces stress vulnerability and local reduction in 5-HT content. Male mice were used in this study, and we found that dSTR 5-HT content decreased in stress-susceptible but not in resilient mice. Moreover, vulnerability to stress in dSTR-Shati OE mice was suppressed by the activation of serotonergic neurons projecting from the dorsal raphe nucleus (dRN) to the dSTR, followed by upregulation of 5-HT content in the dSTR using designer receptors exclusively activated by designer drugs (DREADD). We evaluated the role of GABA in modulating the serotonergic system in the dRN. Stress-susceptible after RSDS and dSTR-Shati OE mice exhibited an increase in dRN GABA content. Furthermore, dRN GABA content was correlated with stress sensitivity. We found that the blockade of GABA signaling in the dRN suppressed stress susceptibility in dSTR-Shati OE mice. In conclusion, we propose that dSTR 5-HT and dRN GABA, controlled by striatal Shati/Nat8l via the dSTR-dRN neuronal circuitry, critically regulate stress sensitivity. Our study provides insights into the neural processes that underlie stress and suggests that dSTR Shati/Nat8l could be a novel therapeutic target for drugs against depression, allowing direct control of the dRN serotonergic system.Significance StatementGiven that 30% of depression patients have resistant to conventional antidepressants, finding novel therapeutic strategies for its disease is required. We previously demonstrated that the overexpression of Shati/Nat8l, N-acetyltransferase, in the dorsal striatum (dSTR) of mice induces stress vulnerability. dSTR 5-HT (5-hydroxytryptamine and 5-HT) levels are downregulated in stress-susceptible, non-resilient mice exposed to repeated social defeat stress. Stress vulnerability in dSTR Shati/Nat8l overexpression mice was suppressed by the activation of serotonergic neurons projecting from the dorsal raphe nucleus (dRN) to the dSTR. We discovered that dRN GABA content correlated with stress sensitivity and inhibited GABA signaling in dRN-induced stress resilience. We suggest that novel bidirectional dSTR-dRN circuits determine the stress sensitivity underlying depression pathology.

5-hydroxytryptamine; Shati/Nat8l; dorsal raphe nucleus; dorsal striatum; stress; stress sensitivity.