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  • Contract grant sponsor: National Institute of Mental Health; contract grant numbers: R01MH087604, R01MH083746, R01MH075102, R21 MH0771172, K23 MH091254, and F32 MH093054; contract grant sponsor: National Institutes of Health; contract grant number: UL1 RR025008.

Correspondence to: Andrew H. Miller, M.D., Department of Psychiatry and Behavioral Sciences, Winship Cancer Institute, School of Medicine, Emory University, 1365-B Clifton Rd., NE, 5th Floor, Room B5101, Atlanta, GA 30322. E-mail:


Increasing attention has been paid to the role of inflammation in a host of illnesses including neuropsychiatric disorders such as depression and anxiety. Activation of the inflammatory response leads to release of inflammatory cytokines and mobilization of immune cells both of which have been shown to access the brain and alter behavior. The mechanisms of the effects of inflammation on the brain have become an area of intensive study. Data indicate that cytokines and their signaling pathways including p38 mitogen-activated protein kinase have significant effects on the metabolism of multiple neurotransmitters such as serotonin, dopamine, and glutamate through impact on their synthesis, release, and reuptake. Cytokines also activate the kynurenine pathway, which not only depletes tryptophan, the primary amino acid precursor of serotonin, but also generates neuroactive metabolites that can significantly influence the regulation of dopamine and glutamate. Through their effects on neurotransmitter systems, cytokines impact neurocircuits in the brain including the basal ganglia and anterior cingulate cortex, leading to significant changes in motor activity and motivation as well as anxiety, arousal, and alarm. In the context of environmental challenge from the microbial world, these effects of inflammatory cytokines on the brain represent an orchestrated suite of behavioral and immune responses that subserve evolutionary priorities to shunt metabolic resources away from environmental exploration to fighting infection and wound healing, while also maintaining vigilance against attack, injury, and further pathogen exposure. Chronic activation of this innate behavioral and immune response may lead to depression and anxiety disorders in vulnerable individuals.