Research

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. To build on my doctoral work as well as my current projects at Williams College, my future research goals are the following: a) explore the relationship between the brain and the immune system when an organism is healthy and exposed to enriching, positive life events; and b) 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.

Past Research

During my doctoral studies, I sought to understand how immune signaling in both the normal and disordered brain affects hippocampal plasticity and its function in learning and memory. This theme underlies my current and future research as well.

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.

       a.          Microglia, the immune cells of the brain, are more reactive and inflammatory for the remainder of the animal’s life [1]. 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).

        b.          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).

        c.           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 [2].

        d.          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 [3].

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 [4].

 

Current Research

In my current position at Williams College, I have focused on 3 main questions:

a)      Is a rich, varied environment sufficient to reduce brain inflammation equally in middle-aged males and females? Male and female rats were exposed to 7 weeks of environmental enrichment and given an immune challenge before tissue harvest. Several undergraduate research assistants have worked on this lab-wide project by assisting with tissue harvest, tissue slicing and immunohistochemistry.

b)      Is inflammation that causes memory deficits the result of a cascade of inflammatory signals or is a single molecule to blame? One of my honors thesis students is extending work from an empirical project to ask if interleukin-1β (IL-1β, an inflammatory cytokine) is responsible for previously described memory impairments on a context-object discrimination task following immune challenge with lipospolysaccharide (LPS; dead bacteria) [5]. We will block IL-1β signaling during a context-object discrimination task, which is hippocampally dependent. We will also assess protein levels of inflammatory cytokines during the behavioral task and analyze microglial morphology in response to immune challenge, learning and IL-1ra. We predict that blocking IL-1β signaling during memory retrieval will eliminate the impairing effect of LPS on memory.

c)      Does selective breeding for communication and anxiety-like phenotypes link phenotypically with altered immune function within the brain? Does immune activation during infancy result in altered communication and anxiety-like behavior in lines of rats selectively bred for altered neonatal ultrasonic vocalizations? In collaboration with Dr. Betty Zimmerberg, my other honors thesis student will assess the effects of neonatal inflammation on neonatal ultrasonic communication and adult anxiety-like behavior, as measured by the open field task and the elevated zero maze. We will also compare RNA expression of inflammatory molecules within the brains of each line’s neonatal offspring. We predict that the low-anxiety line will be affected more than the high-anxiety line by the early-life immune challenge, resulting in increased anxiety-like behavior and stress during adulthood.

 

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.