“Maladaptive stress-coping behavior in CX3CR1-deficient mice: Impact of adolescent stress and alcohol exposure on neuroimmune responses and inflammation”

The CX₃CL1/CX₃CR1 chemokine axis regulates synaptic pruning, plasticity, and stress-related behaviors, influencing resilience or vulnerability to psychiatric disorders. Adolescence, a critical period for neuroimmune development, increases susceptibility to stressors. This study investigated how adolescent restraint stress and alcohol exposure affect stress-coping behavior, neuroimmune signaling, and systemic inflammation in adult wild-type (WT) and CX₃CR1 knock-out (KO) mice. Eighty-one male and female WT and KO mice were assigned to control (non-stressed, saline-treated), stress (stressed, saline-treated), alcohol (non-stressed, alcohol-treated), and stress + alcohol (stressed, alcohol-treated) groups. Behavioral responses were evaluated using the tail suspension test. Hypothalamic gene expression of CX₃CL1/CX₃CR1, corticotropin-releasing hormone (CRH), and neuropeptide Y (NPY) systems was analyzed alongside plasma corticosterone, adrenocorticotropic hormone (ACTH), CX₃CL1, and inflammatory mediators. Adolescent stress-but not alcohol-increased plasma CX₃CL1 levels, which inversely correlated with immobility time in WT mice. KO mice displayed higher baseline immobility than WT mice, whereas stress and/or alcohol paradoxically reduced immobility. These behavioral effects were reproduced by pharmacological inhibition of CX₃CR1. Additionally, KO mice showed disrupted hypothalamic expression of multiple genes in the CRH pathway and Npy1r, attenuated corticosterone responses to stress, and abolished ACTH-corticosterone correlation, suggesting HPA axis dysregulation. KO mice also exhibited exacerbated inflammatory responses to stress and alcohol, including elevated IL-17A/F, IL-11, and IFN-β1 levels. CX₃CR1 deficiency disrupts neuroimmune homeostasis, leading to maladaptive stress-coping behaviors and heightened inflammatory reactivity. These findings underscore the protective role of the CX₃CL1/CX₃CR1 axis in neuroinflammatory regulation and stress resilience, supporting CX₃CR1 as a potential therapeutic target in stress-related disorders.