Psychosocial stress is a major short- and long-term risk factor for psychiatric and neurodegenerative disorders. One potential mechanism is that stress induces chronic low-level inflammation which in turn leads to excitotoxic and oxidative-stress changes in the CNS. Animal models are essential to demonstrate and understand such aetio-pathophysiological pathways. Adult mice exposed to chronic social stress developed immune-inflammation responses including increases in: splenic inflammatory monocytes and T helper cells, plasma cytokines and kynurenines, CNS region-specific kynurenines and microglia. RNA sequencing identified down-regulated expression of genes characteristic of specific cell types in amygdala and prefrontal cortex, including: myelination genes in oligodendroyctes, parvalbumin gene in GABA interneurons, monoamine receptor and signalling-pathway genes in medium spiny neurons. Resting state fMRI identified increased connectivity within corticolimbic regions e.g. ACC, insula. Behaviourally, psychosocial stress led to reduced motivation to obtain rewarding stimuli and to control aversive stimuli, increased emotional responding to aversive stimuli, and decreased cognitive flexibility. Antidepressant drugs and anti-inflammatory compounds exhibit behavioural efficacy in the model, and novel targets are under investigation.