LATERAL HABENULA AS A NOVEL MECHANISM REGULATING SYSTEMIC IMMUNE RESPONSES

Mood can have a great impact on our physical health. In everyday life, stressful events increase the likelihood of becoming sick, and in clinical settings, patients with mood disorders such as depression have an increased risk of developing comorbid inflammatory diseases. This suggests that an individual’s affective state and immune system are closely related and dependent. How the brain specifically modulates peripheral immunity in the context of depression is, however, scarcely explored. My research aims to understand how, and through which circuits, brain regions regulate systemic inflammation and peripheral immunity during affective disorders. I focus on the lateral habenula (Lhb), a brain region critical for encoding and integrating aversive signals and clearly altered in depression, as dysregulation of Lhb circuitry has been proposed to mediate depressive symptomatology in humans and rodents. I hypothesize that increased neuronal activity in Lhb can lead to maladaptive changes in peripheral immunity and underlie associated negative affective states. Using an optogenetic approach to selectively activate Lhb neurons, I assessed immune function using an LPS challenge. Repeated Lhb activation induced a negative affective state in male and female mice and altered inflammatory responses in a sex-specific manner, potentiating LPS-induced inflammation in females while dampening it in males. Chemical sympathectomy completely blocked the enhanced inflammatory response in females, and Lhb projections to the brainstem were critical for conveying signals that regulate peripheral immunity. Overall, this study identifies a novel neuronal mechanism through which persistent Lhb activation drives maladaptive, sex-dependent immune responses during negative affective states.