MAPPING IMMUNE-TO-NEURON DYNAMICS AND MOLECULAR MECHANISMS OF AFFECTIVE PROCESSING

Major Depressive Disorder (MDD) is a leading cause of disease burden worldwide, affecting roughly one in five over a lifetime. Although systemic inflammation is a well-established predictor for developing depressive symptoms, not everyone experiencing inflammatory disease will develop a mood disorder. Clearly, the healthy brain has ways to ensure affective resilience. We have developed an inflammatory model for acute sickness and negative affect, followed by a subsequent state of relief. 24 hours after acute sickness, mice show a relived affective state characterized by increased grooming and hedonic responding, and decreased immobility in the forced swim test.
Using O-link proteomics analysis, we have characterized systemic immune-signaling for both the acute sickness and the subsequent positive recovery. Here, we see that proinflammatory cytokines are strongly upregulated in blood during acute sickness, while anti-inflammatory cytokines are predominant during the relieved state, mirroring behavioral changes of our affective homeostasis model.
To explore immune-to-brain mechanisms of acute sickness and subsequent relief, we have generated whole‑brain activity maps of IBA1+ microglia and c-Fos+ neuronal activity using iDISCO+ clearing, light‑sheet imaging, and computational quantification.
We are currently exploring the neurocircuits and immune-to-neuron mechanisms involved in affective homeostasis following inflammatory insult. By uncovering the microglia-neuron pathways that regulate affective resilience, this work aims to uncover novel, mechanism-based targets for relieving inflammation-related negative affect in psychopathology, such as MDD.