Research in the MicroglEyo Lab is focused on understanding microglial activity in neurodevelopment and neurodevelopmental pathologies. We work on the premise that to adequately appreciate how to treat injuries and disorders of the brain, an adequate understanding of development is important. Microglia are the brain’s primary resident-immune cell. They have emerged as critical cellular players in brain development, yet our understanding of the specific processes and molecular mechanisms employed by microglia in regulating proper development of the brain are in its infancy. Moreover, how microglia contribute to various pathologies of the developing and mature brain requires further research attention. The MicroglEyo lab’s objective is to identify and elucidate the mechanisms by which microglia regulate normal brain development and determine their reactivity and contributions during abnormal brain development, acute injury or diseased conditions.
Research in the Eyo Lab is focused on understanding microglial activity in neurodevelopment and neurodevelopmental pathologies. To this end, our research has four broad areas of focus:
The brain is made up of various cell types broadly divided into neurons, glia and vascular cells. Although microglia constitute 5-10% of the cells in the brain, they exist and function in concert with other resident brain cells. Processes and mechanisms by which microglia interact with these cell times are critical for a proper understanding of brain function. In our previous work, we have elucidated novel physical interactions and their underlying mechanisms between microglia and neurons (Eyo et al., 2014; Eyo et al., 2015; Eyo et al., 2017a; Eyo et al., 2018a) as well as microglial landscape dynamics in the brain (Eyo et al., 2018b). Studies into these and other novel microglial-neuronal physical interactions continue (Uweru et al., 2019; Sharma et al., 2020, Badimon et al, 2020). However, we are expanding our interests from these interactions to investigate interactions with other cell types including the vasculature (Eyo et al., 2018c, Bisht et al., 2020) including its developmental maturation, pericytes (Bisht et. al., 2020) and oligodendrocyte precursor cells (OPCs, Bisht et al., 2020) among others such as oligodendrocytes and astrocytes.
Microglia are unique immune cells that take up residence in the brain early in development. The represent the first glia to colonize the brain and persist in the brain thereafter. However, recent studies indicate that between development and maturity, microglia exhibit dramatic transcriptional and functional changes as a result of their maturation. For example, in the developing hippocampus, microglial mobilization is more dramatic in early development than in later development (Eyo et al., 2016) and significantly reduced in adulthood (Eyo et al., 2018b). Moreover, microglial susceptibility to ischemia is also developmentally regulated (Eyo et al., 2012) presumably as a result their maturation. Therefore, microglial functions are altered during developmental maturation which may be critical for brain development. Moreover, we seek to determined factors regulating these developmental changes having ruled out contributions from developmental apoptotic factors (Eyo et al., 2016). Understanding the mechanisms required for normal microglial maturation including their colonization of the brain can be employed to restore brain health especially in contexts of brain aging and neurodegeneration where microglial dysfunction and / or senescence has been reported.
Microglia are known as the brain’s first line of defense. They react and respond rapidly to various forms of acute injury. But debate exists as to whether their role is beneficial or detrimental in these acute injuries. Because of the relevance and prevalence of ischemia and seizures in developing children, the MicroglEyo lab is investigating microglial roles and interactions in these acute injuries. In a model of experimental ischemia, we developed an approach to visualize microglial demise in real-time in situ during development (Eyo et al., 2012) and implicated purinergic P2X7 receptors in the ischemic injury mechanism (Eyo et al., 2013). In a model of experimental seizures, we also document neuroprotective roles for microglia during acute seizures (Eyo et al., 2014; Eyo et al., 2017a). However, we also show that following the initial seizures, microglia promote features of epileptogenesis (Mo et al, 2019) suggesting that microglia may have different roles in acute seizures when compared to epileptic seizure development. Finally, we provided the first comprehensive review of microglial roles in epilepsy (Eyo et al., 2017b). We continue to investigate microglial roles in seizure disorders especially using a febrile seizure model as a naturalistic model of human childhood pathology. Our goal is to elucidate precise mechanisms by which microglia perform these neuroprotective functions in both ischemia and seizure disorders (including genetic seizure disorders. Understanding these could motivate novel approaches to enhanced (or suppress) microglial activities and improve stroke or seizure outcome(s).
The developing brain is exquisitely orchestrated to lead the optimal brain function in development and adulthood and emerging findings suggest that microglia are critical players in proper brain function during development and neurodevelopmental disorders. Since these disorders and the aberrant behaviors that are characteristic therein are often sexually dimorphic and microglia show sexual dimorphic functional differences, they are a promising candidate regulating sex-specific behaviors in health and neurodevelopmental disorders. Our work in this area is focused on perturbing microglial functions and determining influences on behavior that may be relevant in neurodevelopmental disorders such as autism spectrum disorders.
Microglial process extension in response to glutamate in brain slices
Microglia in a hippocampal brain slice of a CX3CR1-GFP expressing mouse extend their processes toward the region of neuronal cell bodies during glutamate (1mM) treatment. Time is displayed as hr:min. Read more in Eyo UB, Peng J, Przemyslaw S, Mukherjee A, Bispo A, Wu LJ (2014). Neuronal Hyperactivity Recruits Microglial Processes via Neuronal NMDA Receptors and Microglial P2Y12 Receptors after Status Epilepticus. Journal of Neuroscience, 34 (32): 10528-10540.
Microglial process convergence towards a neuronal dendrite in response to glutamate in brain slices
Microglial (green) processes in a brain slice of a CX3CR1-GFP expressing mouse converge on a neuronal dendrite (red) after glutamate (1mM) treatment. Time is displayed as hr:min. Read more in Eyo UB, Peng, J, Murugan M, Mo M, Lalani A, Xie P, Xu P, Margolis DJ, Wu LJ (2017). Regulation of Physical Microglia-Neuron Interactions by Fractalkine Signaling after Status Epilepticus. eNeuro. doi: 10.1523/ENEURO.0209-16.2016.
Microglial process convergence in response to extracellular calcium depletion in vivo
Microglial processes in the somatosensory cortex of a CX3CR1-GFP expressing mouse converge at certain “hotspot” when bathed in Ca2+-deficient ACSF with 2mM EGTA to eliminate the extracellular calcium concentrations. Time is displayed as hr:min. Read more in Eyo UB, Gu N, De S, Dong H, Richardson JR, Wu LJ (2015). Modulation of Microglial Process Convergence towards Neuronal Dendrites by Extracellular Calcium. Journal of Neuroscience, 35(6): 2417-2422.
Microglial landscape changes in by translocation in vivo
Microglial cells (four cells tracked with various colors) translocate to varying degrees through the naïve brain over several days. Read more in Eyo UB, Mo M, Yi M-H , Murugan M, Liu J, Yarlagadda R, Margolis DJ, Xu P, Wu LJ (2018). P2Y12R-Dependent Translocation Mechanisms Gate the Changing Microglial Landscape. Cell Rep. Apr 24; 23(4):979-966. doi: 1016/j.celrep.2018.04.001.