Norman Cousins Lecture. Mechanisms of cytokine-induced behavioral changes: psychoneuroimmunology at the translational interface

Abstract

Work in our laboratory has focused on the mechanisms by which cytokines can influence the brain and behavior in humans and non-human primates. Using administration of interferon (IFN)-alpha as a tool to unravel these mechanisms, we have expanded upon findings from the basic science literature implicating cytokine-induced changes in monoamine metabolism as a primary pathway to depression. More specifically, a role for serotonin metabolism has been supported by the clinical efficacy of serotonin reuptake inhibitors in blocking the development of IFN-alpha-induced depression, and the capacity of IFN-alpha to activate metabolic enzymes (indolamine 2,3 dioxygenase) and cytokine signaling pathways (p38 mitogen activated protein kinase) that can influence the synthesis and reuptake of serotonin. Our data also support a role for dopamine depletion as reflected by IFN-alpha-induced changes in behavior (psychomotor slowing and fatigue) and regional brain activity, which implicate the involvement of the basal ganglia, as well as the association of IFN-alpha-induced depressive-like behavior in rhesus monkeys with decreased cerebrospinal fluid concentrations of the dopamine metabolite, homovanillic acid. Neuroimaging data in IFN-alpha-treated patients also suggest that activation of neural circuits (dorsal anterior cingulate cortex) associated with anxiety and alarm may contribute to cytokine-induced behavioral changes. Taken together, these effects of cytokines on the brain and behavior appear to subserve competing evolutionary survival priorities that promote reduced activity to allow healing, and hypervigilance to protect against future attack. Depending on the relative balance between these behavioral accoutrements of an activated innate immune response, clinical presentations may be distinct and warrant individualized therapeutic approaches.

Figure 1. Potential Pathways Leading to Cytokine-Induced Changes in Serotonin Metabolism

Two pathways by which cytokines may reduce serotonin (5-HT) availability in the synapse are depicted. Cytokine-induced activation of indolamine 2,3 dioxygenase (IDO) can lead to decreased tryptophan (TRP), the primary amino acid precursor of 5-HT, which in turn can contribute to decreased 5-HT synthesis. In addition, activation of p38 mitogen activated protein kinase (MAPK) can upregulate the expression and activity of the membrane transporter for 5-HT, leading to increased 5-HT reuptake.

Figure 2. Potential Pathways Leading to Cytokine-Induced Changes in Dopamine Metabolism

Three pathways by which cytokines can reduce dopamine (DA) availability in the synapse are depicted. Cytokine-induced activation of nitric oxide (NO) can lead to decreased tetrahydrobiopterin (BH₄) which serves as a co-enzyme for tyrosine hydroxylase (TH), the rate limiting enzyme in DA synthesis. In addition, activation of mitogen activated protein kinase pathways (MAPK), including MAPK kinase (MEK), has been associated with upregulation of the activity of the DA transporter, which leads to increased DA reuptake. Finally, cytokine-induced activation of indolamine 2,3 dioxygenase (IDO) results in the breakdown of tryptophan into kynurenic acid (KA), which in turn has been associated with inhibition of the release of glutamate. Glutamate stimulates the release of DA, and therefore decreased glutamate release can lead to decreased DA release.

Figure 3. The Contribution of the Neurovegetative Syndrome and Anxiety, Arousal and Alarm to Cytokine-Induced Neuropsychiatric Disorders

Cytokine-induced inflammatory responses lead to a host of behavioral changes that can be grouped into 1) a “neurovegetative syndrome” that subserves shutting the organism down to facilitate fighting infection and would healing and 2) an “anxiety, arousal and alarm state” that subserves protection against future attack. These behavioral responses are mediated by the impact of cytokines on relevant neurobiological pathways and represent a reorganization of behavior to address competing survival priorities, the balance of which will determine the clinical manifestations of related cytokine-induced neuropsychiatric disorders.