Journal
JOURNAL OF NEUROSCIENCE
Volume 38, Issue 41, Pages 8845-8859Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1116-18.2018
Keywords
cytokine; dopamine; immune system; learning and memory; motivation; voltammetry
Categories
Funding
- Vanderbilt University School of Medicine
- Icahn School of Medicine at Mount Sinai
- National Institutes of Health
- National Institute of Drug Abuse [DA042111, DA044308]
- National Institute of Mental Health [MH111216]
- Brain and Behavior Research Foundation
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Deficits in motivation and cognition are hallmark symptoms of multiple psychiatric diseases. These symptoms are disruptive to quality of life and often do not improve with available medications. In recent years there has been increased interest in the role of the immune system in neuropsychiatric illness, but to date no immune-related treatment strategies have come to fruition. The cytokine granulocytecolony stimulating factor (G-CSF) is known to have trophic and neuroprotective properties in the brain, and we recently identified it as a modulator of neuronal and behavioral plasticity. By combining operant tasks that assess discrete aspects of motivated behavior and decision-making in male mice and rats with subsecond dopamine monitoring via fast-scan cyclic voltammetry, we defined the role of G-CSF in these processes as well as the neural mechanism by which it modulates dopamine function to exert these effects. G-CSF enhanced motivation for sucrose as well as cognitive flexibility as measured by reversal learning. These behavioral outcomes were driven by mesolimbic dopamine system plasticity, as systemically administered G-CSF increased evoked dopamine release in the nucleus accumbens independent of clearance mechanisms. Importantly, sustained increases in G-CSF were required for these effects as acute exposure did not enhance behavioral outcomes and decreased dopamine release. These effects seem to be a result of the ability of G-CSF to alter local inflammatory signaling cascades, particularly tumor necrosis factor a. Together, these data show G-CSF as a potent modulator of the mesolimbic dopamine circuit and its ability to appropriately attend to salient stimuli.
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