Dr. Staci Bilbo is the Director of Research for the Lurie Center for Autism at MassGeneral Hospital for Children. She received her Ph.D. in Psychological and Brain Sciences from Johns Hopkins University in 2003, and continued her training with a postdoctoral fellowship in the Center for Neuroscience at the University of Colorado at Boulder. She directed the Developmental Neuroimmunology Laboratory in the Department of Neuroscience at Duke University from 2007-2016, until joining the faculty at HMS in 2016. Her research is broadly focused on the mechanisms by which the immune and endocrine systems interact with the brain to impact health and behavior. Current research in her laboratory focuses on understanding the consequences of early life events, including infection, stress, environmental toxins, and maternal obesity on neural and immune system development.
Marcy Kingsbury, Senior Scientist/Member of the Faculty
I am interested in how maternal stressors and modifications of the perinatal environment alter neuroimmune interactions and how these alterations contribute to aberrant social behavior such as that observed in Autism Spectrum Disorder (ASD). I am also interested in the microbiota-gut-brain axis, gut-brain-immune interactions and mechanisms that contribute to neurodevelopmental and neuroinflammatory diseases. Currently, I am examining the role of oxytocin at birth as a neuroprotective and anti-inflammatory molecule. Contact me here.
I am broadly interested in microglial function. I am currently investigating sex differences in microglial development and reactivity, and their potential role in neurodevelopmental disorders such as autism, which has a sex bias in presentation (greater prevalence in males). Contact me here.
Phillip Rivera, Postdoctoral Fellow
I am interested in the synaptic plasticity mechanisms underlying learning and memory, and neural-glial interactions, especially in relation to addiction. Contact me here.
Ashley Kopec, Postdoctoral Fellow
I am interested in how microglia shape, maintain, and modify neural circuits during plasticity. I am currently investigating the role of microglia during nucleus accumbens development, and how this relates to social and addiction behaviors. Contact me here and here.
Evan Bordt, Postdoctoral Fellow
I am interested in how sex differences in mitochondrial function and inheritance influence microglial reactivity, and how this impacts neurodevelopmental disorders such as autism (greater incidence in males than females). Contact me here.
Caroline Smith, Postdoctoral Fellow
Broadly, I am interested in understanding the role of microglia in the organization and maintenance of neural circuits underlying social behavior. Currently, I am investigating the impact of maternal immune activation on the developmental trajectory of microglia and whether or not changes in microglial development may lead to alterations in social behavior. Contact me here.
Carina Block, Graduate Student
I am interested in the role of microglia in developing neural circuits. I am investigating whether sex differences in the number of microglia in the developing brain may reflect sex differences in synapse number or refinement during critical windows. Contact me here.
Fall 2016, in our new space at MGH
Bilbo Lab, Spring 2016
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.
MICROGLIA, NEURAL DEVELOPMENT, AND COGNITION THROUGHOUT THE LIFESPAN
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 the cellular source of IL-1β during normal learning, and thereby lend insight into the mechanism by which this cytokine is enduringly altered by early-life infection. Microglia are the primary immune cells of the brain, are long-lived, and have been linked to neurodegenerative disorders like AD. However, whether microglia and their inflammatory products are a cause or consequence of neural dysfunction remains subject to intense debate. Rapid isolation and separation of microglia (CD11b+ cells) from other CNS cell types (CD11b- cells; e.g., astrocytes, neurons) using cell sorting for analysis of IL-1β expression indicates that microglia are the sole source of exaggerated IL-1β in neonatally-infected rats within the hippocampus. Most exciting, these experiments also revealed that CD11b+ cells are the source of IL-1β during hippocampal-dependent learning. Taken together, these data directly implicate microglial-derived IL-1β in normal learning for the first time. Importantly, they suggest an individual’s risk or resilience to neuroinflammatory disorders may critically depend on their early lifeexperience, which can modulate normal cognition-dependent cytokine activity within the brain long after the initial insult.
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
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
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
Williamson, LL, Sholar, PW, Mistry RS, Smith, SH, and Bilbo, SD. (2011) Microglia and memory: modulation by early-life infection. Journal of Neuroscience, 31(43): 15511-21. PMCID: PMC3224817
SEX DIFFERENCES IN GLIAL DEVELOPMENT AND 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. At present, no sex-based differences have been described that can fully explain the sexual dimorphism of neuropsychiatric disorders.
Female microglia mature more quickly than male microglia. We used a novel data simplification strategy to analyze whole transcriptome profiling of purified developing male and female mouse microglia to identify a developmental gene expression program involving thousands of genes whose expression levels change significantly (up or down) across development. We discovered the percentage of genes that increase over normal development (a proxy for maturation) is delayed in males relative to females, and that acute immune stimulation accelerated this normal microglial maturation only in males. Next, we mined the same developmentally-regulated genes identified in mouse microglia from several human brain transcriptome datasets to test the hypothesis that variability in microglial developmental trajectory is associated with human disease. Microglial development was significantly increased in both Alzheimer’s disease and in autism compared to age-matched healthy controls, suggesting that accelerated or altered microglial development, and not simply “inflammation”, contributes to neuropathology. Finally, the same developmentally regulated genes enriched in both autism and in human microglia show accelerated maturity in males compared to females. Thus, we identified a microglia-specific gene expression program in mice that reveals insight into microglial developmental trajectory in heterogeneous human datasets, in health and in disease, and between males and females
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; 1504-1520. go HERE for a video abstract of this paper!
Other relevant pubs on sex differences in neuroimmune function:
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
Bilbo, SD & Tsang, V. (2010) Enduring consequences of maternal obesity for brain inflammation and behavior of offspring. TheFASEB J, 24(6); 2104-15. PMC Exempt (free full text online)
Bolton, JL, Smith SH, Huff NC, Gilmour MI, Foster WM, Auten RL, & Bilbo, SD. (2012) Prenatal air pollution exposure induces neuroinflammation and predisposes offspring to weight gain in adulthood in a sex-specific manner. The FASEB J, 26(11):4743-54. *Recommended by Faculty of 1000*. PMC Exempt (free full text online)
Bolton, JL, Auten RL, & Bilbo, SD. Prenatal Air Pollution Exposure Induces Sexually Dimorphic Fetal Programming of Metabolic and Neuroinflammatory Outcomes in Adult Offspring. Brain, Behavior, and Immunity, 37:30-44. PMC Exempt
Bolton, JL, Huff, NC, Smith, SH, Potts-Kant, EN, Mason, SN, Foster WM, Auten RL, & Bilbo, SD. (2013) Maternal stress worsens effects of prenatal air pollution on offspring mental health outcomes. Environmental Health Perspectives, 121(9): 1075-82. PMCID: PMC3764088
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. Specifically, we have shown that: (1) Morphine profoundly activates glia within the adult rat NAc, inducing a rapid (minutes) increase in chemokines; (2) Inhibiting this morphine-induced chemokine response with a glial modulator, Ibudilast, completely prevents morphine-induced reinstatement of CPP assessed months later, without altering initial CPP which remains high; and (3)Neonatal handling (which induces nurturing maternal care) mimics the glial modulator by completely preventing morphine-induced chemokine expression within the NAc in adulthood, and prevents the reinstatement of morphine CPP. Moreover, neonatally handled rats exhibit increased basal expression of the anti-inflammatory cytokine IL-10 within the brain compared to non-handled control rats, which is established early in life and maintained into adulthood via decreased methylation of the IL-10 gene specifically within microglia.
1. 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, in press.
2. Lacagnina, ML, Rivera, PD, Bilbo, SD. (2017) Glial and neuroimmune-mediated changes in plasticity as critical modulators of drug use and abuse. Neuropsychopharmacology Reviews, 42(1): 156-177.
3. Schwarz, JM & Bilbo SD. (2013) FACS analysis of neuronal-glial interactions in the nucleus accumbens following morphine administration. Psychopharmacology, 230(4): 525-35.
4. 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.
5. 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.
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CHECK OUT THE VIDEO ABSTRACT HERE OF OUR RECENT PAPER ON SEX DIFFERENCES IN MICROGLIAL DEVELOPMENT!
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