The Bilbo Lab focuses on the study of neuroimmune interactions in brain development, using pre-clinical models. We collaborate with clinical research groups to translate our findings to human populations. We are particularly interested in the role of immune molecules in both normal and disrupted brain development, based on evidence from human and animal studies that immune system dysfunction or inflammation may be critical in a number of neurodevelopmental disorders, including schizophrenia, cognitive and mood disorders, and autism. A particular focus is on the resident immune cells of the brain, microglia, including their development and function in response to early life inflammatory signals.
Research Areas:
(1) Microglia, Neural Development, and Cognition Throughout the Lifespan
Evidence from both animal and human studies implicates the immune system in a number of disorders with known or suspected developmental origins, including schizophrenia, anxiety/depression, and autism. I developed a model of neonatal bacterial infection during my post-doc and early years as an assistant professor that demonstrated that neonatal bacterial infection in rats leads to marked hippocampal-dependent memory deficits in adulthood. However, deficits are only observed if unmasked by a subsequent immune challenge (peripheral LPS) 24 h prior to learning or immediately after learning. These data suggest the infection induces a long-term change within the immune system that, upon activation with the “second hit”, LPS, acutely impacts the neural processes underlying memory. Indeed, preventing the synthesis of brain IL-1β prior to the LPS challenge completely prevents the memory impairment in neonatally-infected rats. Subsequent experiments determined microglia as the sole cellular source of the exaggeraeted IL-1β signal, and thereby lend insight into the mechanism by which this cytokine is enduringly altered by early-life infection. Taken together, these data suggest an individual’s risk or resilience to later-life disorders may critically depend on their early lifeexperience, which can modulate cytokine activity within the brain long after the initial insult.
Representative Publications:
1. Bilbo, SD, Biedenkapp, JC, Der-Avakian, A, Watkins, LR, Rudy, JW, & Maier, SF. (2005) Neonatal infection-induced memory impairment following lipopolysaccharide in adulthood is prevented via caspase-1 inhibition. The Journal of Neuroscience, 25, 8000-8009. PMC Exempt
2. Bland, ST, Beckley JT, Young S, Tsang V, Watkins LR, Maier SF, & Bilbo SD. (2010) Enduring consequences of early-life infection on glial and neural cell genesis within cognitive regions of the brain. Brain, Behavior, & Immunity, 24, 329-338. PMCID: PMC2826544
3. Bilbo, SD. (2010) Early-life infection is a vulnerability factor for aging-related immune changes and cognitive decline. Neurobiology of Learning & Memory, 94(1); 57-64. PMCID: PMC2881165
4. Williamson, LL, Sholar, PW, Mistry RS, Smith, SH, & Bilbo, SD. (2011) Microglia and memory: modulation by early-life infection. Journal of Neuroscience,31(43): 15511-21. PMCID: PMC3224817
(2) Environmental and Social Toxins and the Developmental Origins of Disease
It is increasingly evident that diverse genes and environmental exposures combine or synergize to produce a spectrum of health outcomes later in life dependent upon critical developmental windows. For instance, multiple prenatal/maternal environmental toxins have been linked to autism spectrum disorder (ASD), but the associations of single agents have been relatively weak. This suggests it is the combination of multiple maternal exposures that increases vulnerability in offspring. We now recognize that non-chemical stressors, such as limited resources or social support of the mother, can increase vulnerability of the fetus to chemical stressor exposures (e.g., pollution or toxins), which could explain why a single exposure or risk factor in isolation is a modest predictor of autism risk. To explore these issues I developed a new rodent model that employs the combined effects of an ethologically relevant maternal stressor and environmentally relevant pollutant, diesel exhaust, both of which have been implicated in autism. We have shown that maternal diesel exhaust particle (DEP) exposure combined with maternal stress (MS) (but neither in isolation) produces early-life communication deficits, and long-term social, cognitive, and emotional deficits in male but not female offspring. Conversely, females show increased depressive-like behavior in adulthood. We have also shown that DEP exposure significantly alters microglial colonization of the male but not female embryonic brain, and combined prenatal DEP and MS exposure leads to persistent changes in the function of microglia of the same brain regions of males.
Representative Publications:
1. Bolton JL, Smith SH, Huff NC, Gilmour MI, Foster WM, Auten RL, Bilbo SD. Prenatal air pollution exposure induces neuroinflammation and predisposes offspring to weight gain in adulthood in a sex-specific manner. FASEB J, 2012; 26(11):4743-54. PMCID Exempt
2. Bolton JL, Huff NC, Smith SH, Mason SN, Foster WM, Auten RL, Bilbo SD. Maternal stress worsens effects of prenatal air pollution on offspring mental health outcomes. EHP, 2013; 121(9):1075-82. PMCID:PMC3764088
3. Bolton JL, Auten RL, Bilbo SD. Prenatal Air Pollution Exposure Induces Sexually Dimorphic Fetal Programming of Metabolic and Neuroinflammatory Outcomes in Adult Offspring. Brain Behav Immun, 2014; 37:30-44.PMCID Exempt
4. Bolton JL, Marinero S, Hassanzadeh T, Natesan D, Le D, Belliveau C, Mason SN, Auten RL, Bilbo SD. Gestational exposure to air pollution alters cortical volume, microglial morphology, and microglia-neuron interactions in a sex-specific manner. Frontiers in Synaptic Neuroscience, 2017, 31:10. PMCID:PMC5449437
(3) Sex Differences in Glial Function
Many neuropsychiatric disorders exhibit marked sex differences in prevalence and age of onset. Males are more likely to have disorders that arise in early childhood, including autism and learning disabilities. Females more often have disorders that arise during puberty, including anxiety and depression. This epidemiology suggests that there are sex-based neurobiological differences, which are likely to arise during development, that either directly promote specific neuropsychiatric disorders or increase the susceptibility to environmental factors that lead to such disorders. We have reported that male neonatal (postnatal day (P) 4) mice and rats display a markedly increased number of microglia in brain regions important for emotion and cognition. More recently, we used whole transcriptome profiling with Next Generation sequencing of purified developing microglia to identify a microglial developmental gene expression program involving thousands of genes whose expression levels change monotonically (up or down) across development. Importantly, the gene expression program was delayed in males relative to females and exposure of adult male mice to LPS, a potent immune activator, accelerated microglial development in males. Next, a microglial developmental index (MDI) generated from gene expression patterns obtained from purified mouse microglia, was applied to human brain transcriptome datasets to test the hypothesis that variability in microglial development is associated with human diseases such as Alzheimer’s and autism where microglia have been suggested to play a role. MDI was significantly increased in both Alzheimer’s Disease and in autism, suggesting that accelerated microglial development may contribute to neuropathology.
Representative Publications:
a. Schwarz, JM, Sholar, P, & Bilbo SD. (2012) Sex differences in microglial colonization of the developing rat brain. Journal of Neurochemistry, 120(6): 948-63. PMCID: PMC3296888
b. Hanamsagar, R, Alter, MD, Block, CS, Sullivan, H, Bolton, JL, Bilbo SD. (2017) Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity. GLIA, 65(9): 1504-1520. PMCID: PMC5540146
c. Bilbo SD. Sex differences in microglial appetites during development: inferences and implications. Brain Behav Immun, 2017; 64:9-10. PMCID Exempt
(4) Neural-Glial Interactions in Addiction
Increasing evidence suggests the activation of glia, including microglia and astrocytes, by drugs of abuse can markedly impact their physiological and addictive properties. For instance, it has recently been demonstrated that opioids directly activate glial cells within the CNS in a nonclassical opioid receptor manner, via the innate immune system’s pattern recognition receptor, toll-like receptor (TLR) 4, and that this opioid-induced glial activation contributes strongly to their rewarding properties. We have extended this literature by demonstrating that microglial-driven cytokine & chemokine expression within the nucleus accumbens (NAc) underlies morphine-induced relapse in a model of addiction, and moreover that nurturing maternal care early in life induces resilience of the pups to drug relapse in adulthood by inducing an anti-inflammatory phenotype in microglia. More recently we demonstrated that neonatal handling attenuates intravenous self-administration of the opioid remifentanil, and intracranial injections of plasmid DNA encoding IL-10 (pDNA-IL-10) into the NAc of non-handled rats reduces remifentanil self-administration, similar to the effect of handling. These collective observations suggest that neuroimmune signaling mechanisms in the NAc are shaped by early-life experience and may modify motivated behaviors for opioid drugs.
Our ongoing work is focused on the role of microglia in shaping the normal development of the NAc. We made the striking discovery that microglia specifically prune dopamine D1 receptors during adolescence, and that this glial activity is necessary for the development of normal social behavior in male rats. We believe these data may have profound implications for the impact of early-life events that persistently impact glial development and function, and thus their response to drugs of abuse (e.g., during adolescence).
Representative Publications:
a. Schwarz, JM, Hutchinson, MR, Bilbo, SD. (2011) Early-life experience decreases drug-induced reinstatement of morphine CPP in adulthood via microglial-specific epigenetic programming of anti-inflammatory IL-10 expression. Journal of Neuroscience, 31(49): 17835-47. PMCID: PMC3259856
b. Schwarz, JM, & Bilbo SD. (2013) Adolescent morphine exposure affects long-term microglial function and later-life relapse liability in a model of addiction. Journal of Neuroscience, 33(3):961-71. PMCID: PMC3713715
c. Lacagnina, ML, Kopec, AM, Cox SS, Hanamsagar, R, Wells C, Slade S, Grace, PM, Watkins LR, Levin, ED, Bilbo, SD. (2017) Opioid self-administration is attenuated by early-life experience and gene therapy for anti-inflammatory IL-10 in the nucleus accumbens. Neuropsychopharmacology, 42(11): 2128-2140. PMCID:PMC5603817
d. Kopec, AM, Smith, CJ, Ayre, NR, Sweat, SC, Bilbo, SD. Microglial elimination of dopamine D1 receptors defines sex-specific changes in nucleus accumbens development and social play behavior during adolescence. Nature Communications, in press. bioRxiv 211029; doi: https://doi.org/10.1101/211029