Research

Our laboratory seeks to understand how neuron-glia communication facilitates the formation, elimination and plasticity of synapses—the points of communication between neurons—during both healthy development and disease. A major goal is to elucidate the cellular and molecular mechanisms underlying activity-dependent synapse elimination during health and disease, with emphasis on the role of microglia and immune molecules in this process. Using the visual system as our primary model system,  we employ a combination of live imaging, molecular, biochemical and neuroanatomical approaches.

IMMUNE CELLS IN THE HEALTHY AND DISEASED BRAIN

Microglia are brain parenchyma-resident macrophages that critically regulate neurodevelopment and whose dysregulation has been linked to the etiology of neurodevelopmental disorders and neurodegeneration. A major research focus of the lab is to understand how microglia interact with other cell types of the brain to regulate neurodevelopment and how dysregulation of these interactions contributes to neurological disease.

 

Furthermore, we wish to identify molecules that

instruct how microglia recognize and engulf

synapses, investigate the novel functions that

are performed by distinct microglia

subpopulations, explore contributions of other

immune populations and their interactions with

microglia to maintain health brain functionality

and respond to brain injury, and define how

microglia and other immune cells contribute to

neurodegenerative disorders. The synaptic

pruning functions of microglia are critical for

normal development and establishment of

neural circuits. Importantly, synapse loss and aberrant connectivity are common features of neuropsychiatric disorders, such as autism and schizophrenia, as well as neurodegenerative diseases, that exhibit both high levels of inflammation and microglial activation, such as Alzheimer’s disease and multiple sclerosis. The ability to ask detailed mechanistic questions about microglial engulfment of synaptic material in these contexts relies on the availability of robust and reproducible tools, which we are working to further develop. 

MICROGLIA STATES AND FUNCTION

In addition to pruning synapses for proper brain wiring, microglia have been shown to perform other critical functions in the developing and healthy brain. These include promoting the survival of other brain cells, clearing unnecessary and damaging debris and ensuring that neurons communicate rapidly with each other. Our previous work has identified the presence of subpopulations of microglia that each express a unique combination of genes, which suggests that they contribute to distinct functions. For example, we identified a microglial subpopulation that is only detected during the first week of life in mice and is only found in structures called axon tracts. These Axon-Tract associated Microglia (ATM) express genes with unknown functions that have been linked to neurodevelopmental disorders such as autism. Moreover, axon tracts defects have been identified in patients with autism. Intriguingly, many of the genes expressed in ATM are also increased in microglia that are triggered in response to neurodegeneration. Another population called chemokine-secreting microglia express genes that are important for triggering an immune response. These microglia are low in number in the developing brain but increase with aging and in injury. 

To dissect the contributions of these microglial subsets, we will use mouse models lacking key functional genes and investigate how loss of these genes alters microglial behavior, the behavior of the surrounding cells and the structural features of the brain where they reside. We will use live-imaging of labeled microglia from these subpopulations to specifically track and observe how they physically interact with their environment. We will also use cutting-edge sequencing tools to determine the mechanisms governing the precise window of emergence of microglial populations such as ATM. Understanding the specific functions and regulation of these microglial subpopulations to the brain will broaden our understanding of how microglia regulate normal neurodevelopment; in turn, these insights will inform our understanding of how their dysregulation leads to neuropsychiatric and neurodegenerative disease. 

 

NEUROIMMUNOLOGY GROUP AT THE BROAD AND DEVELOPMENT

In addition to our lab facilities at Boston Children's Hospital, half of our lab utilizes facilities at the Broad Institute of Harvard and MIT. The Neurimmunology Group in the Stanley Center for Psychiatric Research at Broad Institute studies the synaptic pruning functions of microglia, complement, and other immune signaling molecules in the context of the "pruning hypothesis" of schizophrenia. The pruning hypothesis, first proposed by psychiatrist Irwin Feinberg more than thirty years ago, posits that abberant synaptic pruning during adolescent brain develipment contributes to the etiology of schizophrenia and is supported by several suggestive lines of evidence: 

  1. Synapitic pruning and grey matter loss are prominent features of healthy brain development during late childhood and adolescence, leading up to the age when psychiatric symptoms most commonly appear.

  2. Some evidence suggests that individuals with schizophrenia, or who will go on to develop psychosis, experience accelerated grey matter loss during this period and have fewer synapses in brain areas known to be important for cognition and psychiatric symptoms. 

  3. Genetic variation impacting molecules known to mediate synaptic pruning, most prominently complement component C4 have been associated with increased risk for schizophrenia. 

The Neuroimmunology Group is working to understand the impact of neuroimmune mechanisms on adolescent brain development at a variety of levels, from molecules to complex cognition, using models ranging from stem cells to non-human primates; and is building tools and technologies to support this research, includingviral vectors, synaptic quantification methods, stem cell-derived human genetic models and more.

NEURODEGENERATION 

The immune response which occurs in neurodegenerative disease was long considered a secondary response to underlying disease processes. However, emerging evidence from both genetic and functional studies has implicated the immune system, and microglia, specifically as central players in disease onset and progression. Using a multi-pronged approach including transcriptomics, proteomics, and functional assays across both in vivo mouse models and in vitro patient-derived iPSC models the Stevens lab seeks to understand how microglia and other immune populations modulate disease pathogenesis in Alzheimer’s and other neurodegenerative conditions.

TOOL DEVELOPMENT

The Stevens lab is always in the process of implementing, building on, and developing new tools that can n expand how we approach new and ongoing problems within the field. These tools are not only limited to physical methodology used at the bench, but extend to utilization of our technological resources to write new analysis and visualization scripts, These make data acquisition and exploration easier, more intuitive, more efficient, and more insightful. You can read more about the specific tools we're developing on the Ongoing Projects page.