Dysfunction of the rostral lateral septum GABAergic neurons induces mania-like behavior in male mice

Manic episodes in bipolar disorder are characterized by hyperactivity, elevated mood, and sleep disturbances. The precise brain regions and neuronal populations underlying these behaviors remain elusive. We demonstrated that chemogenetic inhibition or ablation of rostral lateral septum (LS) GABAergic neurons induced mania-like behaviors in mice, encompassing hyperactivity, reduced anxiety, anti-depressive-like behaviors, and shortened sleep duration. Chronic administration of lithium and valproic acid effectively attenuated hypermobility and normalized elevated mood in these mice. Regarding neural circuit mechanisms, we identified that mania-like behaviors induced by LS GABAergic neuronal dysfunction primarily involve the lateral hypothalamic circuit and, to a lesser extent, the diagonal band of Broca. These findings elucidate the neurobiological mechanisms of manic episodes and identify the LS GABAergic-lateral hypothalamic pathway as a potential therapeutic target for bipolar disorder.