Research

Funding

Research Focus

Psychoneuroimmunology, the study of the interactions between the brain, the immune system and behavior, is a field that acknowledges the whole organism and its external environment. A large body of evidence has demonstrated that the immune system and brain directly interact with and influence one another. We have each experienced the effect of our immune systems on our brains and behavior when we get sick, as our own behavior is changed by illness, resulting often in lethargy and reduced social interactions. I began my research career interested in the long-term effects of infections that occur during development and I have evolved to consider how the immune system affects the normal, healthy brain. Specifically, my primary interest is how these interactions affect the normal function of the hippocampus in learning and memory.

My research goals are the following:

1. explore the relationship between the brain and the immune system when an organism is healthy and exposed to enriching, positive life events
2. determine the effects of maternal parasites on neuroimmune development and function in her offspring
3. examine the developing brain and the unique influence of the immune system on its developmental trajectory.

My background and training provide me with a deep understanding of interactions between the nervous and immune systems and the effects of immune stimulation on neural development and adult neural function. My range of techniques extends from behavioral assays and surgeries to preparation of primary neuronal/glial cultures and the analysis of gene expression and protein expression in discrete brain regions. I have trained dozens undergraduate students on these techniques, allowing them to participate in data collection and experiment design.  Thus, I am able to ask specific short-term and long-term mechanistic questions regarding neuronal and glial function from a developmental perspective, and also able to test these mechanisms and their effects on behavior in adulthood with extensive undergraduate participation.

Current Research

1. The effects of maternal helminths on offspring neuroinflammation, response to neonatal infection, and learning in adulthood. Commensalist parasites are a possible avenue for reducing inflammation, especially in the developed world that has largely eliminated parasite loads in the general population. We are treating dams with helminths (Hymenolepis diminuta) and assessing their offspring at several time points. This work is a follow-up to earlier work during my Ph.D. (Williamson et al 2016).
   • Do maternal helminths alter the neuroinflammatory response to neonatal E. coli infection?
   • Do maternal helminths alter microglia development and proliferation in neonates?
   • Do maternal helminths rescue cognitive impairments in adult offspring?
2. The effects of sex in a model of inflammation-induced cognitive impairment. We are extending the findings from previous work (Czerniawski et al 2015) that demonstrated that LPS (lipopolysaccharide, a cell wall component of Gram-negative bacteria) disrupted memory retrieval in a context-object discrimination task in males. We will assess these findings in females and also assess the effects of blocking specific cytokines on learning and memory outcomes.

Past Research

During my doctoral studies at Duke University and VAP position at Williams College, I sought to understand how immune signaling in both the normal and disordered brain affects hippocampal plasticity and its function in learning and memory.

1. A single infection with Escherichia coli in early life (postnatal day 4) causes profound and enduring changes in the brain and on behavior during adulthood.
   • Microglia, the immune cells of the brain, are more reactive and inflammatory for the remainder of the animal’s life. Rats that experience early-life infection are more sensitive to immune challenges (e.g., dead bacteria) that occur during adulthood. A single immune challenge during adulthood can cause memory impairments on a fear-conditioning task (dependent on the hippocampus) (Williamson et al 2011).
   • One inflammatory signaling molecule, interleukin-1β (IL-1β), is the underlying molecular mechanism for the learning impairment. Blocking IL-1β with caspase-1 inhibitors or minocycline, a known microglia inhibitor, eliminates the memory impairments observed in rats that were infected as infants and given an immune challenge as adults (Williamson et al 2011).
   • Rats that experience early-life infection are faster and more accurate on a Morris water maze task than non-infected controls, and their better memory is associated with reduced neuronal activation in the dentate gyrus (DG), a sub-region of the hippocampus. However, their increased accuracy also results in decreased flexibility, such that a reversal task that changes the platform location results in poorer memory than controls (Williamson & Bilbo 2014).
   • Helminth exposure with rat tapeworms (H. diminuta) in parents and offspring prevents the learning impairments observed in neonatally infected rats that also receive adult immune challenges. The helminths prevent the inflammatory response to E. coli within the brains of pups whose mothers were treated with the worms, and the worms also prevented fear-conditioning impairments in the adult offspring (Williamson et al 2016).
2. Environmental enrichment, a positive intervention, markedly reduces the inflammatory response within the hippocampus after an immune challenge. Home cage controls have a robust pro-inflammatory response within the hippocampus, expressing many inflammatory signals. Rats that had 7 weeks of environmental enrichment, however, have an attenuated expression of a subset of pro-inflammatory molecules, and this attenuated response occurs exclusively within the hippocampus, and not in adjacent cortex. Microglial and astrocytic marker density is also increased in the hippocampi of enriched rats, indicating a possible change in morphology in these cell types (Williamson, Chao & Bilbo, 2012).
3. Neonatal lipopolysaccharide (LPS) alters neuroinflammation and anxiety-like behavior in rats bred for the infantile trait of increased or decreased ultrasonic vocalization during the neonatal period. In two lines of rats bred for infantile USV levels, we assessed the effects of neonatal inflammation on the immediate immune response as well as adult anxiety-like behavior. Neonatal inflammation caused a prolonged peripheral immune response in high-vocalizing rats within 24H of their last LPS injection. Furthermore, early-life inflammation increased anxiety-like behavior in the low-vocalizing (i.e., less phenotypic anxiety) rats and decreased anxiety-like behavior in the high-vocalizing rats on the open field test. LPS treatment also reduced anxiety-like behavior in both lines on the elevated plus maze (Claypoole, Zimmerberg & Williamson, 2017).
4. Maternal high fructose diet alters offspring response to neonatal inflammation, adult anxiety-like behavior and adult cognitive behavior. In offspring born to dams on a high-fructose diet, neonatal inflammation caused a prolonged peripheral immune response. Maternal high fructose diet increased anxiety-like behavior in juveniles and reduced anxiety-like behavior in adult offspring. Neonatal inflammation and maternal high fructose diet altered microglial density within the hippocampus (Bukhari, Clark & Williamson, 2018).

Methodology

The experimental methods that I use are practical and feasible. My experimental animals are rats and mice standard in any animal facility, and much of the hardware required for tissue analysis is often already present and shared by several researchers. Bacterial and viral mimetics, such as LPS and polyI:C, are safe for undergraduates to handle at the doses required for small mammals and do not require specialized safety precautions for their use. I will actively pursue grants from federal and private agencies to develop an exciting and enduring research program that involves undergraduates at every part of the research process.

        In my tenure-track position, I plan to continue pursuing several of these same questions. Environmental enrichment has significant effects on immune signaling within the brain and I plan to use it as a preventative intervention prior to immune challenge or infection in adults. The effects of enrichment demonstrate that the adult brain is capable of remarkable plasticity and that this plasticity extends to neuroimmune interactions. In addition to my current work on sex differences in enrichment, I plan to assess hippocampal-dependent behavioral tests following enrichment and immune challenge. What positive effects might enrichment have on a brain that is then exposed to inflammation? What positive, preventative effects might enrichment have in models of autoimmune disease, such as experimental autoimmune encephalomyelitis (EAE), the rodent model of multiple sclerosis? What are the molecular and cellular mechanisms by which environmental enrichment alters neuroimmune signaling? In addition to adult plasticity, I also plan to study the effects of immune changes and infections on brain and immune system development. Infections during early life are common, but their effects can be profound. What role do commensalist organisms, such as helminths, have on neuroimmune function in the developing brain? How does the introduction of these organisms to the “macrobiome” of the gut alter brain development and function? With these questions, I plan to examine neuroimmune function across the lifespan in ways that can easily include undergraduate research assistants and undergraduate co-authors. I am very enthusiastic about the possibilities that a tenure track position will afford me in these future projects. 

Publications

Title	Year
Maternal high fructose diet and neonatal immune challenge alter offspring anxiety-like behavior and inflammation across the lifespan SHF Bukhari, OE Clark, LL Williamson Life sciences 197, 114-121	2018
Neonatal lipopolysaccharide treatment alters hippocampal neuroinflammation, microglia morphology and anxiety-like behavior in rats selectively bred for an infantile trait LD Claypoole, B Zimmerberg, LL Williamson Brain, behavior, and immunity 59, 135-146	2017
Got worms? Perinatal exposure to helminths prevents persistent immune sensitization and cognitive dysfunction induced by early-life infection LL Williamson, EA McKenney, ZE Holzknecht, C Belliveau, JF Rawls, … Brain, behavior, and immunity 51, 14-28	2016
Alteration of the rat cecal microbiome during colonization with the helminth Hymenolepis diminuta EA McKenney, L Williamson, AD Yoder, JF Rawls, SD Bilbo, W Parker Gut Microbes 6 (3), 182-193	2015
116. Sex differences in microglial morphology and number: Implications for function and behavior R Hanamsagar, J Schwarz, L Williamson, S Bilbo Brain, Behavior, and Immunity 40, e34	2014
30. Biome reconstitution as a novel mechanism of preventing neonatal infection-induced cognitive dysfunction L Williamson, E McKenney, W Parker, S Bilbo Brain, Behavior, and Immunity 40, e9	2014
Neonatal infection modulates behavioral flexibility and hippocampal activation on a Morris Water Maze task LL Williamson, SD Bilbo Physiology & behavior 129, 152-159	2014
Early-Life Programming of Neuroendocrine Function by the Immune System: Plasticity or Autoimmunity due to Biome Depletion? SD Bilbo, LL Williamson, W Parker INTEGRATIVE AND COMPARATIVE BIOLOGY 54, E19-E19 (Poster Presentation)	2014
Neuroimmune Signaling in the Hippocampus: Mechanisms of Risk and Resilience LL Williamson – Dissertation Duke University	2014
Chemokines and the hippocampus: a new perspective on hippocampal plasticity and vulnerability LL Williamson, SD Bilbo Brain, behavior, and immunity 30, 186-194	2013
Modulation of immune cell function by an early life experience (167.11) S Smith, L Williamson, P Sholar, S Bilbo The Journal of Immunology 188 (1 Supplement), 167.11-167.11	2012
Environmental enrichment alters glial antigen expression and neuroimmune function in the adult rat hippocampus LL Williamson, A Chao, SD Bilbo Brain, behavior, and immunity 26 (3), 500-510	2012
Microglia and memory: modulation by early-life infection LL Williamson, PW Sholar, RS Mistry, SH Smith, SD Bilbo Journal of Neuroscience 31 (43), 15511-15521	2011
Enduring consequences of neonatal infection on adult neuronal survival and activation in the dentate gyrus LL Williamson, SD Bilbo Brain Behavior and Immunity, S195	2011
“Speed” warps time: methamphetamine’s interactive roles in drug abuse, habit formation, and the biological clocks of circadian and interval timing LL Williamson, RK Cheng, M Etchegaray, WH Meck Current drug abuse reviews 1 (2), 203-212	2008