Peripheral cytokine-induced CNS immune activation and effects on mesolimbic dopamine Público

Abstract

Peripheral administration of inflammatory cytokines such as interferon alpha (IFNα) has been shown to reliably induce depressive behaviors in humans and non-human primates (NHPs) that are related to reduced motivation and anhedonia. Peripheral administration of inflammatory cytokines and cytokine-inducers (e.g. endotoxin) has also been shown to reduce neural activation of the ventral striatum to hedonic reward in humans. Our previous work in NHPs suggests that the effects of peripheral inflammation on reward circuitry and behavior may by due to decreased availability and release of dopamine. However, the immunologic and neurobiologic mechanisms by which peripheral cytokines affect the dopamine system is currently unknown. Herein immune activation was assessed in relation to effects on the dopamine system in the ventral and dorsal striatum in post-mortem brain tissue from rhesus monkeys (aged 10-14 yrs) exposed to chronic IFNα (20 MIU/m² s.c. for 4 weeks, n=7) compared to saline control (n=4). Significantly less tissue content of dopamine was observed in the nucleus accumbens (p=0.004) and putamen (p=0.009) of IFNα-treated animals. Whole-gene expression analysis revealed induction of limited immune signaling pathways by IFNα in association with activation of immune cells primarily in vascular and meningeal compartments in or near putamen. Whole genome and targeted analysis also revealed alterations in genes related to dopamine neurotransmission and receptor signaling. These results support our previous findings of decreased striatal dopamine release in IFNα-treated monkeys, and indicate that effects of peripheral IFNα on brain dopamine are likely driven by peripheral immune cells trafficking to the CNS.

Table of Contents

INTRODUCTION. 2

METHODS. 6

SUBJECTS AND BRAIN TISSUE COLLECTION. 6

HPLC FOR TISSUE DOPAMINE CONCENTRATIONS. 6

GENE EXPRESSION. 7

IMMUNOFLUORESCENCE. 8

STATISTICS. 9

RESULTS. 10

DECREASED TISSUE CONTENT OF DOPAMINE IN NUCLEUS ACUMBENS AND PUTAMEN. 10

CHANGES IN INFLAMMATORY AND NEUROTRANSMITTER-RELATED GENE EXPRESSION, WHOLE GENOME ANALYSIS. .11

DECREASED EXPRESSION OF DOPAMINE-RELATED GENES, TARGETED ANALYSIS. 13

INCREASED ACTIVATED IMMUNE CELLS IN AND AROUND PERIVASCULAR AND MENINGEAL SPACES. 14

DISCUSSION. 16

TABLES AND FIGURES. 20

TABLE 1. 20

TABLE 2. 22

FIGURE 1. 26

FIGURE 2. 27

FIGURE 3. 27

FIGURE 4. 28

FIGURE 5. .29

REFERENCES. 30

SUPPLEMENTAL MATERIALS. 36

FIGURE S1. 36

FIGURE S2. 37

FIGURE S3. 37

TABLE S1. 38

TABLE S2. 92

About this Honors Thesis

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School	Emory College
Department	Neuroscience and Behavioral Biology
Degree	BS
Submission	Honors Thesis
Language	English
Research Field	Biology, Neuroscience Psychology, Behavioral Health Sciences, Immunology
Palavra-chave	Depression Immune Activation Interferon Alpha Cytokine Peripheral Dopamine CNS
Committee Chair / Thesis Advisor	Felger, Jennifer, Emory University
Committee Members	Bosinger, Steven, Emory University O'Toole, Kate K, Emory University

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