The Role of the Immune System in Translating Early-Life Experience to Later-Life Brain and Behavior STACI D. BILBO DEPARTMENT OF PSYCHOLOGY AND NEUROSCIENCE DUKE UNIVERSITY
Thanks to! Dr. Mark Hutchinson Dr. Jaclyn Schwarz Dr. Nicole Huff Dr. Susan Smith Lauren Williamson Rishi Mistry Verne Tsang Paige Sholar John Horton Agnes Chao Dr. Steven Maier Dr. Linda Watkins Dr. Jerry Rudy Dr. Sondra Bland Funding: NIMH R01MH083698 NIDA R01DA025978 NIEHS P30ES011961
Microglia Nervous Endocrine Immune BRAIN & BEHAVIOR Maier & Watkins, 1998
Take home message 1. The immune privilege of the brain is a myth. 2. Crosstalk between the nervous and immune systems is constant, and is critical for the normal function of both systems. 3. Brain development may be key to setting the life-long trajectory of these interactions, and therefore the physical & mental health of the individual.
Biomarkers we assess: Cytokines Chemokines Cellular sources of these factors: Peripheral immune cells Lymphocytes, monocytes Resident CNS immune cells Microglia, astrocytes Neurogenesis, immediate-early genes (Arc), growth factors (BDNF), behavior
So what is the evidence that cytokines can influence neural function and behavior? This is your brain on bugs
This is your brain on bugs Fatigue and increased sleep Decreased eating and drinking Reduced grooming & personal care Reduced social interactions Reduced motivation Anhedonia/depression Warmth seeking due to fever Sickness behaviors
This is your brain on bugs 1. Cytokines cause sickness behavior. 2. Sickness behaviors help us to recover from infections faster (they are adaptive).
But, cytokines are also implicated in: Interleukin-1 (IL-1) Chronic Fatigue Mood disorders (depression) Psychopathology (schizophrenia) Neurodegeneration (Alzheimer s) Obesity/ metabolic syndrome Memory impairment Drug addiction/abuse Neuropathic pain Why not inhibit IL-1 altogether? We need IL-1 in order to form memories
IL-1β is critical for LTP IL-1 X X Long-term potentiation
IL-1 and memory Memory function IL-1 X Optimal memory function Alzheimer s disease IL-1 concentration (Goshen et al., Psychoneuroendocrinology 32; 2007)
Role of Cytokines in the Brain In Disease: Chronic Fatigue Mood disorders (depression) Psychopathology (schizophrenia) Neurodegeneration (Alzheimer s) Obesity/ metabolic syndrome Memory impairment Drug addiction/abuse Neuropathic pain And in Health: Sleep Reproduction Growth Metabolism Cell division Synapse pruning Neurogenesis Cognition
Cytokines DISEASE? HEALTH
Microglial cell activity peaks during the perinatal period. Increasing Microglial Activation IL-1β Infiltrationof MononuclearCells fromtheperiphery What is the long-term consequence of injury or infection? IL-6 TNF α IL-1β Infection Drugs of abuse Maternal obesity Maternal stress Environmental toxins Amoeboid/Activated Normal AdultImmune Challenges Ramified/Quiescent E14 E18 P0 P5 P30 Age P60 (Bilbo & Schwarz, Frontiers in Behavioral Neuroscience, 2009)
Microglial cell activity peaks during the perinatal period. Increasing Microglial Activation IL-1β Infiltrationof MononuclearCells fromtheperiphery P0 What is the long-term consequence of injury or infection? TNF α P60 IL-6 IL-1β Infection Drugs of abuse Maternal obesity Maternal stress Environmental toxins Amoeboid/Activated Normal AdultImmune Challenges Ramified/Quiescent E14 E18 P0 P5 P30 Age P60 (Bilbo & Schwarz, Frontiers in Behavioral Neuroscience, 2009)
Neonatal Infection Paradigm PBS control E. coli E14 P4 P30 MEMORY Adult
Gram-negative bacteria (e.g., E. coli) are the #1 cause of infection in newborn infants world-wide Infection is a leading cause and consequence of premature birth.
Neonate: Context Pre-Exposure Paradigm: E. coli or PBS Adult: Group 1: no challenge or control injection Group 2: systemic bacterial LPS injection (25 µg/kg ip)
Bacterial infection early in life might: 1) Permanently disrupt the neural mechanisms supporting memory -or- 2) Alter how the adult animal responds to the second hit, the dead bacterial challenge, and this altered immune reaction itself (e.g., cytokine production?) could impair memory
Neonatal Infection Paradigm No challenge LPS after pre-exposure 60 60 PBS control E. coli Percent Freezing 50 40 30 20 10 0 PBS E. coli Neonatal Treatment Percent Freezing 50 40 30 20 10 0 * PBS E. coli Neonatal Treatment E14 P4 P30 Adult
Neonatal Infection Paradigm PBS control IL-1 (pg/100 µg protein) 0.35 0.26 0.17 0.09 * Preventing IL-1 synthesis or blocking microglial activation restores the memory. E. coli 0 HP PAR PFC Neonatal Treatment: PBS E. coli E14 P4 P30 Adult
Neonatal Infection Paradigm PBS control IL-1 (pg/100 µg protein) 0.17 later-life cognitive impairment, the so-called 0.35 0.26 0.09 * Preventing IL-1 synthesis or blocking microglial activation restores the memory. Early-life infection is a vulnerability factor for two-hit hypothesis. E. coli 0 HP PAR PFC Neonatal Treatment: PBS E. coli E14 P4 P30 Adult
Are there any longer-term consequences? Learning and memory Depression, anxiety, schizophrenia Hippocampal neurogenesis PBS control E. coli SAL or LPS + BrdU E14 P4 Adult 4-6 weeks
Adult neurogenesis is suppressed by LPS only in rats infected early in life with bacteria. Dentate Gyrus What is their function? CA1 3500 * 350 BrdU+ NeuN+ cells 3000 2500 2000 1500 1000 500 * BrdU+ NeuN+ cells 300 250 200 150 100 50 * 0 PBS E. COLI 0 PBS E. COLI SAL LPS (Bland et al., 2010)
Adult neurogenesis is suppressed by LPS only in rats infected early in life with bacteria. BrdU+ NeuN+ cells 3500 3000 2500 2000 1500 1000 500 0 Low Dentate levels Gyrus of inflammation * increase neurogenesis (via secretion of growth factors, etc.) PBS * E. COLI BrdU+ NeuN+ cells 350 300 250 200 150 100 High 50 levels of inflammation 0 PBS CA1 decrease neurogenesis (via cell death, etc.) * E. COLI SAL LPS (Bland et al., 2010)
Activity-regulated-cytoskeleton associated protein (Arc) Neuronal activation marker Critical for long-term memory Water maze task: PBS control Hippocampal dependent learning & memory E. coli SAL or LPS 48 h memory probe test Collect tissue for Arc analysis E14 P4 Adult 6 weeks
Total Arc + neurons Arc protein expression, a neuronal activation marker, is decreased during the memory probe in the early-infected rats 6 weeks after an LPS injection. *
Early brain development is a sensitive period for long-term changes in glial cell function and subsequent neural function. Increasing Microglial Activation IL-1β Infiltrationof MononuclearCells fromtheperiphery NeonatalImmuneChallenge Subsequent AdultImmune Challenge TNFα IL-6 IL-6 TNF α IL-1β Over -Activation IL-1β Amoeboid/Activated/ Primed Amoeboid/Activated Normal AdultImmune Challenges Altered neural function & behavioral changes Ramified/Quiescent E14 E18 P0 P5 P30 Age P60 (Bland et al., 2010; Bilbo & Schwarz, 2009)
Cognitive impairment may be the tip of the iceberg. Rats infected as newborns exhibit as adults: Decreased social behavior Impaired discrimination abilities in complex tasks Faster cognitive decline with aging Better ability to fight off infections & increased fever Better coping after stress
Challenges to the field Equating neural development in a rodent to a human. Nature of the challenge each infection/challenge may result in its own phenotype (common problem with neurotoxicology screening) Changes within the periphery may not reflect what is happening in brain.