A Developmental Analysis of Juxtavascular Microglia Dynamics and Interactions with the Vasculature

Abstract

Microglia, the resident macrophages of the central nervous system (CNS), are dynamic cells, 2 constantly extending and retracting their processes as they contact and functionally regulate 3 neurons and other glial cells. There is far less known about microglia-vascular interactions, 4 particularly under healthy steady-state conditions. Here, we use the male and female mouse 5 cerebral cortex to show that a higher percentage of microglia associate with the vasculature 6 during the first week of postnatal development compared to older ages and the timing of these 7 associations are dependent on the fractalkine receptor (CX3CR1). Similar developmental 8 microglia-vascular associations were detected in the prenatal human brain. Using live imaging 9 in mice, we found that juxtavascular microglia migrated when microglia are actively colonizing the cortex and became stationary by adulthood to occupy the same vascular space for nearly 2 months. Further, juxtavascular microglia at all ages contact vascular areas void of astrocyte endfeet and the developmental shift in microglial migratory behavior along vessels corresponded to when astrocyte endfeet more fully ensheath vessels. Together, our data provide a comprehensive assessment of microglia-vascular interactions. They support a mechanism by which microglia use the vasculature to migrate within the developing brain parenchyma. This migration becomes restricted upon the arrival of astrocyte endfeet when juxtavascular microglia then establish a long-term, stable contact with the vasculature.

Single-cell dissection of the human cerebrovasculature in health and disease

“…Endothelial cells have been shown to synthesize BDNF as a guidance cue for neuronal precursors to migrate along the vasculature in the adult forebrain 38 . Similarly, astrocytes have been shown to provide complementary scaffolds for neuroblasts 39 , and microglia migrate postnatally along the vasculature to occupy perivascular regions devoid of astrocytic end-feet 40 . How these particular subsets of neuronal and glial cell types are coupled to the vasculature and how their transcriptional profiles differ from non-coupled cells remain unanswered questions.…”

Neuropathobiology of COVID-19: The Role for Glia

“…of reactive oxygen species (molecular level), regulation of neurogenesis, synapse formation, maintenance and elimination (cellular and network levels), regulation of blood flow, glycogen synthesis and storage (metabolic level), as well as control of the BBB and glymphatic clearance (whole brain level) (Hanisch and Kettenmann, 2007;Tay et al, 2017bTay et al, , 2019Verkhratsky et al, 2015bVerkhratsky et al, , 2016Verkhratsky et al, , 2020Verkhratsky and Nedergaard, 2018;Mestre et al, 2020;Mondo et al, 2020). Astrocytes further contribute to the regulation of energy balance and food intake, blood pH and Na + concentration, as well as of sleep homeostat (Verkhratsky and Nedergaard, 2018).…”

“…They are, respectively, neural cells of ectodermic origin and innate immune cells of mesodermal origin, which together represent key elements of the CNS homoeostatic system ( Figure 2 ). Astrocytes and microglia sustain homeostasis ranging from the molecular to the whole organic levels, including via transport of ions, uptake of neurotransmitters, scavenging of reactive oxygen species (molecular level), regulation of neurogenesis, synapse formation, maintenance and elimination (cellular and network levels), regulation of blood flow, glycogen synthesis and storage (metabolic level), as well as control of the BBB and glymphatic clearance (whole brain level) (Hanisch and Kettenmann, 2007 ; Tay et al, 2017b , 2019 ; Verkhratsky et al, 2015b , 2016 , 2020 ; Verkhratsky and Nedergaard, 2018 ; Mestre et al, 2020 ; Mondo et al, 2020 ). Astrocytes further contribute to the regulation of energy balance and food intake, blood pH and Na + concentration, as well as of sleep homeostat (Verkhratsky and Nedergaard, 2018 ).…”

Neurovascular unit alterations in the growth restricted newborn are improved following ibuprofen treatment

“…Excess production of these inflammatory cytokines in both acute and chronic environments is associated with disease pathogenesis and brain dysfunction [19]. Microglia display dynamic motility behaviours following tissue damage, and preferentially associate with microvessels [29, 63]. Juxtavascular microglia have reported to be key players in BBB disruption following stroke [38], where inhibition of microglial activation after stroke promotes BBB integrity and viability [99].…”