The Role of the Immune System in Translating Early-Life Experience to Later-Life Brain and Behavior

Transcription

1 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

2 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 R01MH NIDA R01DA NIEHS P30ES011961

3 Microglia Nervous Endocrine Immune BRAIN & BEHAVIOR Maier & Watkins, 1998

4 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.

5 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

6 So what is the evidence that cytokines can influence neural function and behavior? This is your brain on bugs

7 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

8 This is your brain on bugs 1. Cytokines cause sickness behavior. 2. Sickness behaviors help us to recover from infections faster (they are adaptive).

9 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

10 IL-1β is critical for LTP IL-1 X X Long-term potentiation

11 IL-1 and memory Memory function IL-1 X Optimal memory function Alzheimer s disease IL-1 concentration (Goshen et al., Psychoneuroendocrinology 32; 2007)

12 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

13 Cytokines DISEASE? HEALTH

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15 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)

16 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)

17 Neonatal Infection Paradigm PBS control E. coli E14 P4 P30 MEMORY Adult

18 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.

19 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)

20 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

21 Neonatal Infection Paradigm No challenge LPS after pre-exposure PBS control E. coli Percent Freezing PBS E. coli Neonatal Treatment Percent Freezing * PBS E. coli Neonatal Treatment E14 P4 P30 Adult

22 Neonatal Infection Paradigm PBS control IL-1 (pg/100 µg protein) * 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

23 Neonatal Infection Paradigm PBS control IL-1 (pg/100 µg protein) 0.17 later-life cognitive impairment, the so-called * 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

24 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

25 Adult neurogenesis is suppressed by LPS only in rats infected early in life with bacteria. Dentate Gyrus What is their function? CA * 350 BrdU+ NeuN+ cells * BrdU+ NeuN+ cells * 0 PBS E. COLI 0 PBS E. COLI SAL LPS (Bland et al., 2010)

26 Adult neurogenesis is suppressed by LPS only in rats infected early in life with bacteria. BrdU+ NeuN+ cells Low Dentate levels Gyrus of inflammation * increase neurogenesis (via secretion of growth factors, etc.) PBS * E. COLI BrdU+ NeuN+ cells High 50 levels of inflammation 0 PBS CA1 decrease neurogenesis (via cell death, etc.) * E. COLI SAL LPS (Bland et al., 2010)

27 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

28 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. *

29 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)

30 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

31 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.