The Influence of Microglia on Neuroplasticity and Long-Term Cognitive Sequelae in Long COVID: Impacts on Brain Development and Beyond.

Microglial cells, the immune cells of the central nervous system, are key elements regulating brain development and brain health. These cells are fully responsive to stressors, microenvironmental alterations and are actively involved in the construction of neural circuits in children and the ability to undergo full experience-dependent plasticity in adults. Since neuroinflammation is a known key element in the pathogenesis of COVID-19, one might expect the dysregulation of microglial function to severely impact both functional and structural plasticity, leading to the cognitive sequelae that appear in the pathogenesis of Long COVID. Therefore, understanding this complex scenario is mandatory for establishing the possible molecular mechanisms related to these symptoms. In the present review, we will discuss Long COVID and its association with reduced levels of BDNF, altered crosstalk between circulating immune cells and microglia, increased levels of inflammasomes, cytokines and chemokines, as well as the alterations in signaling pathways that impact neural synaptic remodeling and plasticity, such as fractalkines, the complement system, the expression of SIRPα and CD47 molecules and altered matrix remodeling. Together, these complex mechanisms may help us understand consequences of Long COVID for brain development and its association with altered brain plasticity, impacting learning disabilities, neurodevelopmental disorders, as well as cognitive decline in adults.

Environmental Signals on Microglial Function during Brain Development, Neuroplasticity, and Disease.

Recent discoveries on the neurobiology of the immunocompetent cells of the central nervous system (CNS), microglia, have been recognized as a growing field of investigation on the interactions between the brain and the immune system. Several environmental contexts such as stress, lesions, infectious diseases, and nutritional and hormonal disorders can interfere with CNS homeostasis, directly impacting microglial physiology. Despite many encouraging discoveries in this field, there are still some controversies that raise issues to be discussed, especially regarding the relationship between the microglial phenotype assumed in distinct contexts and respective consequences in different neurobiological processes, such as disorders of brain development and neuroplasticity. Also, there is an increasing interest in discussing microglial-immune system cross-talk in health and in pathological conditions. In this review, we discuss recent literature concerning microglial function during development and homeostasis. In addition, we explore the contribution of microglia to synaptic disorders mediated by different neuroinflammatory outcomes during pre- and postnatal development, with long-term consequences impacting on the risk and vulnerability to the emergence of neurodevelopmental, neurodegenerative, and neuropsychiatric disorders.

Rapid plasticity of intact axons following a lesion to the visual pathways during early brain development is triggered by microglial activation.

Lesions in the central nervous system (CNS) can often induce structural reorganization within intact circuits of the brain. Several studies show advances in the understanding of mechanisms of brain plasticity and the role of the immune system activation. Microglia, a myeloid derived cell population colonizes the CNS during early phases of embryonic development. In the present study, we evaluated the role of microglial activation in the sprouting of intact axons following lesions of the visual pathways. We evaluated the temporal course of microglial activation in the superior colliculus following a contralateral monocular enucleation (ME) and the possible involvement of microglial cells in the plastic reorganization of the intact, uncrossed, retinotectal pathway from the remaining eye. Lister Hooded rats were enucleated at PND 10 and submitted to systemic treatment with inhibitors of microglial activation: cyclosporine A and minocycline. The use of neuroanatomical tracers allowed us to evaluate the time course of structural axonal plasticity. Immunofluorescence and western blot techniques were used to observe the expression of microglial marker, Iba-1 and the morphology of microglial cells. Following a ME, Iba-1 immunoreactivity showed a progressive increase of microglial activation in the contralateral SC at 24 h, peaking at 72 h after the lesion. Treatment with inhibitors of microglial activation blocked both the structural plasticity of intact uncrossed retinotectal axons and microglial activation as seen by the decrease of Iba-1 immunoreactivity. The local blockade of TNF-α with a neutralizing antibody was also able to block axonal plasticity of the intact eye following a ME. The data support the hypothesis that microglial activation is a necessary step for the regulation of neuroplasticity induced by lesions during early brain development.