Stress-encoding neurons in the lateral habenula promote humoral immunity under eustress

The protective effects of initial stress responses are associated with stress-induced immune enhancement. The lateral habenula (LHb) is a key brain region involved in stress regulation; however, its role in stress-induced humoral immunomodulation remains unclear. We aimed to determine whether stress-responsive neurons in the LHb mediate eustress-induced enhancement of humoral immunity and to elucidate the underlying neural mechanisms. Under conditions of eustress that promote humoral immune responses, c-Fos expression and calcium signaling in LHb neurons were significantly increased. Chemogenetic activation of glutamatergic neurons in the LHb enhanced humoral immunity, whereas inhibition of these neurons attenuated stress-induced humoral immune responses. Furthermore, bidirectional manipulation of stress-activated LHb neurons using activity-dependent genetic labeling resulted in either promotion or suppression of humoral immunity, accompanied by corresponding changes in the neuronal activity of corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN/PVH) and circulating corticosterone levels. Inhibition of PVN/PVH neurons blocks stress-activated LHb neuron-mediated humoral immunity. In summary, this study reveals that stress-activated neurons in the LHb mediate stress-induced enhancement of humoral immunity, potentially through increased PVN/PVH neuronal activity and subsequent elevation of corticosterone levels. These findings identify the LHb as a previously unrecognized key brain region in stress-immune interactions and provide insight into the underlying mechanisms.