Immune-brain plasticity underpins stress and affective behaviors

The lifetime prevalence of mood disorders such as major depressive disorder (MDD) is thought to approach up to 50% of the world's population. Traditionally, research into the mechanisms of these disorders has focused on neurotransmission, but emerging evidence highlights neuroimmune interactions-the molecular signaling between immune and brain cells-as key regulators of brain plasticity, affective behavior, and potential vulnerability to mood disorders. Chronic stress models have unearthed how immune cell responses modify neural circuit activity, synaptic connectivity, and behaviors relevant for mood disorders by acting on brain-resident cell types. This perspective synthesizes basic principles of neuroimmune communication derived from animal studies relevant for mood disorders and assesses their relevance in MDD and post-traumatic stress disorder (PTSD). We describe cellular neuroimmune interactions important for behavior as well as the molecular mechanisms that govern immune-brain plasticity across different cell types. We also explore how therapeutic interventions, including anti-inflammatory biologics and psychedelics, can target these pathways. Finally, we chart how the field could dissect neuroimmune interactions across biological scales in the near future by highlighting the conceptual frontiers and emerging technologies. Understanding the modulation of neuroimmune interactions promises to inform next-generation treatments for mood disorders.