Behavioral Change in Response to Low-Grade Non-Infectious Stimuli: Findings and Potential Neuroimmune Mechanisms
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BEHAVIORAL CHANGE IN RESPONSE TO LOW-GRADE NON-INFECTIOUS STIMULI: FINDINGS AND POTENTIAL NEUROIMMUNE MECHANISMS BY JASON M. YORK DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Animal Sciences in the Graduate College of the University of Illinois at Urbana-Champaign, 2012 Urbana, Illinois Doctoral Committee: Professor Gregory G Freund, Chair Professor Rodney W Johnson Associate Professor Janeen L Salak-Johnson Assistant Professor Ryan N Dilger Sarah O Allison, DVM, DACLAM ABSTRACT Individuals afflicted with a pathogenic infection exhibit symptoms including lethargy, malaise, listlessness, loss of interest in social and environmental surroundings, and anorexia. Together, these symptoms comprise what is recognized as “sickness behavior.” Sickness behavior represents a conserved, motivational behavioral state that, with the induction of fever, serves to help an organism combat infection and ultimately survive. Long dismissed as an unavoidable consequence of the physiological changes resulting from pathogen-dependent immune activation, it is now well known that sickness behavior is a consequence of neuroimmune activation. Neuroimmunity serves as a bridge between the peripheral immune system and the central nervous system, acting to signal bi-directionally both centrally and humorally between these two systems. Proinflammatory cytokines, most often originating from innate immune cells, are the principle signaling molecules from the periphery to the brain. Sickness behavior is typically transient, resolving upon pathogen clearance. Exacerbated or unchecked proinflammation, such as occurs in chronic disease or autoimmune disorders, leads to maladaptive behaviors such as depression and anxiety. Neuroimmune activation often also causes cognitive impairments in addition to sickness, depressive or anxietal behaviors. It is widely recognized that non-infectious stimuli, such as ionizing radiation or hypoxia can activate the neuroimmune system and cause sickness behavior and other behaviors. This literature review focuses on the different ways activation of the neuroimmune system can occur, the inflammatory and behavioral consequences of its activation and some of the modulators of neuroimmune communication. Chapters 2 and 3 will provide evidence showing low dose ionizing radiation and chronic low-grade hypoxia can result in the display of typical neuroimmune-mediated behaviors, as well as other physiological changes. Taken together, these findings show that behavioral change can be induced by lower doses of ionizing radiation and hypoxia than have previously ii been reported, and that neuroimmune signaling can occur where and when it was previously unknown to. iii To my mother, father and stepfather. Throughout my life you have always shown me what it means to work hard and put your best effort forward. I will carry these lessons and your words of wisdom with me for the rest of my life. Thank you for your unending love, support and encouragement. iv ACKNOWLEDGEMENTS This completion of this work would not have been possible without the help and support of many people. I would first like to thank my advisor, Greg Freund, for giving me an opportunity to show my abilities and develop my skills as a scientist. Many others would have passed on me, but you did not, and I will never forget that. I would also like to thank all the Freund lab members, past and present, for their support and friendship, especially Chris Guest, Christina Sherry and Desiree Lavin. You all had a great influence on my development as a scientist and as a person and will be missed very much, but not forgotten. I would like to give a tremendous thanks to Neil Blevins. You traveled and helped run some seriously large behavioral experiments in California and Pennsylvania. When I needed someone I could count on in a pinch, you were always at the top of the list. In addition to your great skill and technical knowledge as a researcher, you are a great friend I hope to never lose contact with. Thank you to Keith Cengel, a great scientist, physician and person. I will always remember our work and time together fondly. To the members of my committee, Rod Johnson, Janeen Johnson, Ryan Dilger and Sarah Allison, thank you. You were all integral to my research and scientific upbringing and I would surely not possess the same knowledge and skill set without your individual and cumulative influences. The lessons I have learned from you – science, professional and life, will not soon be forgotten, if ever. Finally, I would like to thank my family and friends. You have all been nothing but instrumental in keeping my head up and my feet moving forward throughout this whole process. Your interest, encouragement, love and support made all this possible. v TABLE OF CONTENTS LIST OF TABLES…………………………………………………………………………......viii LIST OF FIGURES……………………………………………………………………………..ix CHAPTER ONE: LITERATURE REVIEW………………………………………………......1 I) INFLAMMATION AND NEUROIMMUNE ACTIVATION…………………………...1 II) NEUROIMMUNE ACTIVATION-INDUCED BEHAVIORAL CHANGE…………….3 A) SICKNESS BEHAVIOR………………………………………………………………3 B) DEPRESSIVE-LIKE BEHAVIOR…………………………………………………….4 C) COGNITIVE BEHAVIOR…………………………………………………………….6 D) ANXIETY-LIKE BEHAVIOR………………………………………………………..6 III) STRESS AND NEUROIMMUNITY……………………………………………………..7 A) BASIC MECHANISM OF THE STRESS RESPONSE………………………………7 B) ACUTE STRESS………………………………………………………………………8 C) CHRONIC STRESS…………………………………………………………………...9 IV) NEUROIMMUNE AND BEHAVIORAL EFFECTS OF IONIZING RADIATION EXPOSURE……………………………………………………………………………...10 A) IONIZING RADIATION FUNDAMENTALS……………………………...………10 B) NEUROIMMUNE EFFECTS OF IONIZING RADIATION………………………..12 C) BEHAVIORAL EFFECTS OF IONIZING RADIATION…………………………...12 V) NEUROIMMUNE AND BEHAVIORAL EFFECTS OF HYPOXIC EXPOSURE……13 A) HYPOXIA FUNDAMENTALS……………………………………………………...13 B) NEUROIMMUNE AND BEHAVIORAL EFFECTS OF ACUTE HYPOXIA……..14 C) NEUROIMMUNE AND BEHAVIORAL EFFECTS OF CHRONIC HYPOXIA…..14 VI) MOUSE TESTING METHODS IN PSYCHONEUROIMMUNOLOGY: AN OVERVIEW OF HOW TO MEASURE SICKNESS, DEPRESSIVE/ANXIETAL COGNITIVE AND PHYSICAL ACTIVITY BEHAVIORS……………………………15 A) INTRODUCTION……………………………………………………………………15 B) PRE-EXPERIMENTAL CONSIDERATIONS………………………………………17 vi C) SICKNESS BEHAVIORS……………………………………………………………25 D) DEPRESSIVE/ANXIETY-LIKE BEHAVIORS…………………………………….34 E) COGNITIVE BEHAVIORS………………………………………………………….45 F) PHYSICAL ACTIVITIES……………………………………………………………57 G) CONCLUSION……………………………………………………………………….60 VII) SUMMARY……………………………………………………………………………...61 VIII) REFERENCES…………………………………………………………………………..62 CHAPTER TWO: THE BIOBEHAVIORAL AND NEUROIMMUNE IMPACT OF LOW- DOSE IONIZING RADIATION………………………………………………………………76 I) ABSTRACT……………………………………………………………………………...76 II) INTRODUCTION……………………………………………………………………….77 III) METHODS………………………………………………………………………………79 IV) RESULTS………………………………………………………………………………..83 V) DISCUSSION……………………………………………………………………………86 VI) FIGURES………………………………………………………………………………...93 VII) REFERENCES…………………………………………………………………………104 CHAPTER THREE: INDIVIDUALLY VENTILATED CAGES CAUSE CHRONIC LOW-GRADE HYPOXIA IMPACTING MICE HEMATOLOGICALLY AND BEHAVIORALLY…………………………………………………………………………….108 I) ABSTRACT…………………………………………………………………………….108 II) INTRODUCTION……………………………………………………………………...109 III) METHODS……………………………………………………………………………..110 IV) RESULTS………………………………………………………………………………115 V) DISCUSSION…………………………………………………………………………..116 VI) FIGURES……………………………………………………………………………….120 VII) REFERENCES…………………………………………………………………………125 vii LIST OF TABLES Table 2.1: Impact of high-dose rate gamma radiation on TNF-α, IL-1RA and Arc gene transcripts in cerebral hippocampus, hypothalamus, cortex and cerebellum at 4, 8, 12 and 24 h post irradiation………………………………………………………101 Table 2.S1: Impact of radiation on social exploration…………………………………………102 Table 2.S2: Comparison of locomotor activity between restraint-10 and restraint-240 mice exposed to high-dose rate gamma radiation……………………………………...103 Table 3.1: Oxygen (O2) percentages in ambient room air and within AEC or IVC housing conditions…………………………………………………………………………120 Table 3.2: Relative humidity (RH) percentages in ambient room air and within AEC or IVC housing conditions………………………………………………………………..120 Table 3.3 Red blood cell (RBC) counts and related RBC parameters from AEC- and IVC- housed mouse blood draws……………………………………………………….121 Table 3.4 Leukocyte counts, differentials and platelet count/volume from AEC- and IVC- housed mouse whole blood draws………………………………………………..121 Table 3.5 Percent change in body weight, food and water consumption (g) following relocation from group-housed IVC or AEC cages to novel AEC housing 24, 48 and 72 h following relocation…………………………………………………………122 viii LIST OF FIGURES Figure 2.1: Gamma radiation but not proton radiation reduces mouse locomotor activity…….93 Figure 2.2: Gamma radiation up-regulates gene transcripts for TNF-α and Arc in whole brain 6 h post irradiation…………………………………………………………………...95 Figure 2.3: Gamma radiation up-regulates gene transcripts for IL-1β and IL-1RA in blood 8 h post irradiation……………………………………………………………………..97 Figure 2.4: Restraint-240 inhibits the impact of 200 cGy gamma radiation on locomotor activity……………………………………………………………………………...99 Figure 3.1: IVC mice show an increased preference for a saccharin and consume more total fluid than AEC mice……………………………………………………………...123 ix CHAPTER ONEa LITERATURE REVIEW I INFLAMMATION AND NEUROIMMUNE ACTIVATION Neuroimmunology as a field of study is relatively new with respect to the individual fields of neuroscience