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Microglia and Microbiota: Tiny cells with big impacts on brain development

I, like so many other students in the field of Neuroscience, spent the vast majority of my graduate training studying neurons — the primary information transmitting cells of the brain. It is the intricate circuits of neurons in the brain that give rise to all animal behaviors — from very basic things like breathing, eating, and drinking, to the most complex human thoughts such as moral reasoning and falling in love.

But neurons are not the only cell type in the brain. Nor are they the only cells in the body that are responsible for shaping how we think, feel, and act. In recent years, my own personal scientific interest has mirrored that of the field of Neuroscience in general — turning attention towards another, often overlooked cell type in the brain — microglia.

The prefix ‘micro’ comes from the ancient Greek word for ‘small’. Microglia are the tiniest cells that reside within the brain. Santiago Ramon y Cajal (1852–1934), a Spanish pathologist who is widely considered to be the father of neuroscience, famously overlooked microglia, thinking they were unlikely to be of any important consequence. It was not until his student Pio del Rio-Hortega (1882–1945) that someone began to take notice of this tiny cell type. I am an incoming Assistant Professor at Boston College, and my lab will study microglia, their role in development, and their interactions with the gut microbiome — which is the topic of this blog post.

Nicolas Achucarro (a) and Pio del Rio Hortega (b) and their drawings. Photo source: Researchgate.

Microglia help to build the developing brain

Microglia are a kind of immune cell called a ‘macrophage’ which comes from the Greek for big (macro) eaters (phages). As such, their job is to “eat” things within the brain — mainly the debris of other cells. However, work in recent decades has shown that microglia also eat synapses, the connections between neurons, during their development, a process called pruning. This ‘pruning’ of synapses is critical to the proper wiring of neural connections during development.

What happens when microglial developmental pruning goes array?

Why is it so important that we understand the role of microglia in sculpting the brain?

The reason this is such a critical question is that indicators of abnormal microglial function, such as eating away at synapses, have been found in brain tissue from human patients with neurodevelopmental and neuropsychiatric conditions ranging from autism spectrum disorder to schizophrenia. Impaired social behavior is a symptom of these conditions. Studies in mice show that getting rid of microglial genes, such as P2Y12 and CX3CR1, reduces synaptic pruning. Furthermore, these mice display abnormal patterns of social interaction — reminiscent of disorders in humans such as autism.

These findings, and others, suggest that a better understanding of microglial sculpting of the developing brain may be key to finding treatments and therapeutic interventions for neurodevelopmental disorders such as autism.

Microbiota play important roles during development

Microglia are not the only ‘micro’ cells with big impacts on brain development. The term ‘microbiota’ refers to the bacteria that live on and within our bodies. While it is common to view all bacteria as dangerous pathogenic invaders, many bacteria actually help us in a variety of sometimes surprising ways. For example, species of bacteria that live within our gut help us by breaking down foods that would be otherwise indigestible, communicating with our immune system and sensory nerves, and even by killing more dangerous microbes and viruses! During development, bacteria also train our immune systems and help shape brain organization.

Microbiota in neuropsychiatric disorders

As with microglia, gut microbiota are shifted in human neuropsychiatric disorders including autism, depression, and anxiety. But just because the microbiome is different, doesn’t necessarily mean that it causes the changes in brain function and behavior in these conditions. However, experimental manipulation of the gut microbiome has shown promising results so far. For instance, transferring typical microbiota to the guts of human patients with autism reduces their behavioral symptoms. Conversely, transferring microbiota from human autism patients into mice induces social behavior impairments in those animals.

The term ‘Psychobiotics has been coined by John Cryan and colleagues to refer to bacteria with the potential to positively impact mental health.

How do microglia and microbiota interact with one another?

There are many outstanding questions as to how microbiota and microglia sculpt the brain during development. For example, microglia appear to be uniquely responsive to signals from the gut microbiome.

How are those signals conveyed?

There are many potential routes. For instance, when bacteria break down the food we ingest, there are byproducts of this process called metabolites. Studies have shown that these metabolites are often secreted into the bloodstream and can enter the brain. Another potential route is via the vagus nerve. This nerve relays information from the gut, as well as other parts of the body, to the brain.

Importantly, bacteria within the gut function as part of a complex ecosystem of bacterial species. Not all bacterial changes are for the better. Therefore, it is essential that we more completely understand the complex interplay within the bacterial communities inside and around us.

Much of the work to date has been done in male mice. However, in many cases when females have been studied, the results are not the same. How sex-specific are these findings? This is critically important as many disorders are more commonly diagnosed in males (autism spectrum disorder) or in females (anxiety and depression).

Finally, many environmental exposures such as air pollution, pesticides, and even stress, are associated with a higher risk of many of these disorders. How do such environmental exposures impact microglia and the microbiome? Exciting work is currently being done to address these questions.

Hopefully, the next decades will see significant advances in our ability to treat neuropsychiatric disorders. Better understanding of microglia, microbiota, and their interactions with one another may hold the key to some of these advances.


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