Emerging roles for microglia and microbiota in the development of social circuits

Abstract

Social withdrawal is a core component of the behavioral response to infection. This fact points to a deep evolutionary and biologic relationship between the immune system and the social brain. Indeed, a large body of literature supports such an intimate connection. In particular, immune activation during the perinatal period has been shown to have long-lasting consequences for social behavior, but the neuroimmune mechanisms by which this occurs are only partially understood. Microglia, the resident immune cells of the brain, influence the formation of neural circuits by phagocytosing synaptic and cellular elements, as well as by releasing chemokines and cytokines. Intriguingly, microbiota, especially those that reside within the gut, may also influence brain development via the release of metabolites that travel to the brain, by influencing vagal nerve signaling, or by modulating the host immune system. Here, I will review the work suggesting important roles for microglia and microbiota in social circuit formation during development. I will then highlight avenues for future work in this area, as well as technological advances that extend our capacity to ask mechanistic questions about the relationships between microglia, microbiota, and the social brain.

Editorial commentary on the special issue emerging psychoneuroimmunology research: Future leaders in focus

“…The role played by inflammation in regulating social behavior is explored by Smith (2021a) who interrogates the important roles for microglia and microbiota in social circuit formation during development and Muscatell and Inagaki (2021) strongly urge fellow researchers to move beyond a singular focus on inflammation and social withdrawal to allow a more comprehensive understanding of the effects of inflammation on a variety of social behaviors. Shattuck (2021) explored the exciting field of social immunology and how the COVID-19 pandemic has highlighted the need for a holistic understanding of the effects of social contexts on immune function and the patterning of morbidity and mortality related to disease.…”

The microbiota promotes social behavior by modulating microglial remodeling of forebrain neurons

“…However, these probiotic Lactobacillus strains were applied to adult zebrafish and do not normally populate the zebrafish intestine, so it is unclear whether microbial modulation occurs through a similar mechanism during normal neurodevelopment of circuits that regulate social behavior [45, 46]. Like many circulating immune cells, microglia are responsive to microbial signals, and the microbiota appears to influence normal microglial colonization, maturation, morphology, activation, and homeostasis [21,47,48]. However, how microbial modulation of microglial function feeds forward to influence neural circuit architecture, especially in brain regions that regulate social behavior, has not been studied.…”

“…Several distinct bacterial taxa are individually sufficient for normal microglial and neuronal phenotypes, suggesting that host neuroimmune development is sensitive to a feature common among many bacteria. Our results demonstrate that the microbiota influences zebrafish social behavior by stimulating microglial remodeling of forebrain circuits during early neurodevelopment, and suggest pathways for new interventions in multiple neurodevelopmental disorders.[ [19][20][21][22][23]. Microglia infiltrate the brain in multiple waves [24,25].…”

“…The classical complement cascade is one of the bestunderstood pathways employed by microglia to sculpt neural circuits [31]. For example, complement component C1q is thought to tag axons and synapses, initiating the complement cascade and subsequent synaptic pruning events.It is increasingly appreciated that host-associated microbes can shape social behavior by influencing neurodevelopment [21,32,33]. Mice raised germ-free (GF) or with an abnormal microbiota exhibit impaired social behavior, which is correlated with microbial modulation of neuronal gene expression, neurotransmitter levels, brain maturation, and myelination [34][35][36][37][38][39][40].…”

“…It is increasingly appreciated that host-associated microbes can shape social behavior by influencing neurodevelopment [21,32,33]. Mice raised germ-free (GF) or with an abnormal microbiota exhibit impaired social behavior, which is correlated with microbial modulation of neuronal gene expression, neurotransmitter levels, brain maturation, and myelination [34][35][36][37][38][39][40].…”