This proposal is designed to provide the applicant with supervised education and research training in translational neuroimaging to assess the impact of innate immune cytokines on basal ganglia dopamine (DA). Neuropsychiatric disorders including depression are common in medically ill patients, possibly as a result of chronic peripheral immune system activation and release of innate immune cytokines. Although innate immune cytokines have been shown to interact with virtually every pathophysiologic domain relevant to depression including neurotransmitter metabolism, the exact mechanisms by which these cytokines exert behavioral effects are unknown. Basal ganglia DA plays a pivotal role in regulating behaviors including mood, motor activity, motivation and reward, and mounting evidence indicates that the DA system may be targeted by innate immune cytokines. For example, administration of the innate immune cytokine, interferon (IFN)-alpha, is associated with behavioral changes consistent with DA depletion including depressive behavior, fatigue, and reduced locomotor activity. In addition, neuroimaging studies using positron emission tomography (PET) in patients undergoing IFN-alpha therapy have revealed increased basal ganglia glucose metabolism similar to that seen in Parkinson?s disease. Increased uptake and decreased release of the DA precursor, [18F]fluorodopa, in the caudate and putamen of IFN-alpha-treated patients has also been observed. Preliminary findings from in vivo microdialysis indicate decreased basal ganglia DA under resting conditions and following amphetamine (AMPH) administration via reverse microdialysis. The goal of the proposed research is to use neuroimaging techniques to examine DA availability and release in basal ganglia during IFN-alpha-treatment. The primary hypothesis of the study is that reduced DA availability and/or release is a key mechanism of cytokine-induced behavioral change. To test the hypothesis, [11C]raclopride neuroimaging with intravenous AMPH challenge will be used to indirectly measure DA availability and release during IFN-alpha or saline administration. This PET protocol will be complemented by direct measurement of extracellular DA using in vivo microdialysis in the striatum under basal conditions and in response to AMPH administered via reverse microdialysis. In addition to providing important insight into the effects of cytokines on basal ganglia DA, these studies will help the applicant develop an independent line of research in neuro-immune interactions, while fostering her career development. To accomplish her goals, the applicant?s training plan will include a combination of mentored research, coursework, seminars, and attendance at national and international meetings.
Medically ill patients experience high rates of depression, fatigue, and other neuropsychiatric disturbances possibly as a result of chronic exposure to innate immune cytokines that affect the brain and behavior. Recent data from our laboratory and others indicate that the basal ganglia dopamine system, known to regulate multiple behaviors including mood, motor activity, motivation and reward, is involved in cytokine-induced behavioral change. This postdoctoral training project will provide education and research experience in translational neuroimaging to assess the impact of innate immune system activation on basal ganglia dopamine availability and release using an animal model of chronic cytokine administration.
|Felger, Jennifer C; Hernandez, Carla R; Miller, Andrew H (2015) Levodopa reverses cytokine-induced reductions in striatal dopamine release. Int J Neuropsychopharmacol 18:|
|Miller, Andrew H; Haroon, Ebrahim; Raison, Charles L et al. (2013) Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety 30:297-306|
|Felger, Jennifer C; Mun, Jiyoung; Kimmel, Heather L et al. (2013) Chronic interferon-? decreases dopamine 2 receptor binding and striatal dopamine release in association with anhedonia-like behavior in nonhuman primates. Neuropsychopharmacology 38:2179-87|
|Felger, Jennifer C; Li, Li; Marvar, Paul J et al. (2013) Tyrosine metabolism during interferon-alpha administration: association with fatigue and CSF dopamine concentrations. Brain Behav Immun 31:153-60|
|Felger, Jennifer C; Miller, Andrew H (2012) Cytokine effects on the basal ganglia and dopamine function: the subcortical source of inflammatory malaise. Front Neuroendocrinol 33:315-27|
|Felger, J C; Cole, S W; Pace, T W W et al. (2012) Molecular signatures of peripheral blood mononuclear cells during chronic interferon-? treatment: relationship with depression and fatigue. Psychol Med 42:1591-603|