Inflammation-activated neuronal and astrocytic populations in the dorsal bed nucleus of the stria terminalis modulate peripheral immune response via the brain-spleen axis

The brain detects peripheral inflammatory signals and modulates immune responses, yet the forebrain mechanisms that participate in this process remain incompletely understood. Here, we find that the projection from the dorsal bed nucleus of the stria terminalis (dBNST) to the dorsal vagal complex (DVC) can regulate LPS-induced splenic immune responses. Using chemogenetic and optogenetic approaches, we show that lipopolysaccharide (LPS)-activated Fos + neuronal populations in the dBNST participate in the regulation of splenic immune cells. Inhibition of these neurons attenuates LPS-induced pro-inflammatory cytokine production and splenic nerve activation, and alters the number of splenic immune cells. Neural tracing combined with optogenetic functional validation provides evidence for a polysynaptic dBNST-DVC-spleen pathway through which Fos dBNST neurons can influence splenic nerve activity and the number of splenic immune cells. We further show that LPS recruits a subpopulation of dBNST astrocytes, and selective activation of these astrocytes is sufficient to enhance dBNST neuronal excitability and alter the number of splenic immune cells. Notably, the injection of LPS elevates adenosine triphosphate (ATP) levels around dBNST astrocytes, which activates P2Y 1 receptors and promotes glutamate release, thereby increasing local neuronal excitability. Together, our findings reveal a coordinated neuron-astrocyte mechanism in the dBNST that processes immune signals during acute LPS-induced inflammatory responses, implicate astrocytes as important modulators in forebrain regulation of peripheral immunity, and provide a new framework for understanding forebrain regulation of splenic immune responses under acute inflammatory conditions.