Immune Signaling and Neurobehavioral Regulation: Dissecting the Roles of Complement Receptors and Regulatory T Cells in Neuroinflammation

Neuroimmune communication is fundamentally important to the regulation of brain function and Behaviours. The current thesis explores the contribution of C3aR and C5aR complement receptors and Tregs to neuroimmune responses and anxiety-like behavior, using genetically modified mice. The primary goals for this work were to investigate the behavioral and inflammatory effects of C3aR-deficiency in response to systemic inflammation induced by lipopolysaccharide (LPS). Characterize the behavioral phenotype of C5aR KO mice in different regimes. Examine Treg depletion effects on stress hormones and anxiety-like behavior in the FoxP3-DTR model. Approaches utilized a combination of behavioral (open field test, elevated plus maze, acoustic startle response, spontaneous alternation), biochemical (multiplex ELISA measurement of serum cytokines and chemokines), and histological (immunohistochemistry of astrocyte activation and colocalization of cytokines) methods. Our main findings indicated that in the absence of C3aR, astrocyte activation and cytokine colocalization in the brain were reduced in the face of severe peripheral inflammation, implicating C3aR in central neuroimmune signaling. Genotype- and sex-specific C5aR deletion impacted locomotion, anxiety-like behavior, as well as sensorimotor gating, indicating a bi-phasic mechanism of C5aR in the modulation of emotional and cognitive processing. Furthermore, the ablation of Tregs in FoxP3-DTR mice resulted in enhanced anxiety-like behavior and corticosterone levels, especially during stress, which suggested the involvement of Tregs in the control of the neuroendocrine stress response. All these results extend our knowledge of how immune signaling pathways affect brain function and behavior and may not be specific to neuropsychiatric and neurodegenerative diseases. These findings emphasize the role of complement receptors and Tregs in neuroimmune regulation and provide novel therapeutic options for controlling central immune responses without compromising systemic inflammation.