How Your Brain’s Immune System Affects Your Mood and Memory

With all the focus on COVID-19, immunity has become a fixture in the news and conversation. Yes, immunity is key to fighting off infections. But it’s actually a much bigger deal. In fact, it plays a major role in conditions like diabetes, cancer, and heart disease. More surprising still, it shapes our thinking.

To alter our thoughts, the immune system has to reach the brain. We usually only hear about brain cells called neurons. But as it turns out, the brain actually has its own resident immune cells. These are called microglia. Researchers discovered microglial cells around a century ago. However, we’ve only recently understood their immense importance.

Microglial cells are implicated in a wide assortment of brain diseases. These include Alzheimer’s, Parkinson’s, multiple sclerosis, and many others. There’s an easy connection: these brain problems are characterized by neuronal damage and death. Microglial cells are involved with neuron repair, as well as keeping them alive.

With this in mind, the link between microglia and our thoughts becomes clearer. Our thoughts and actions are a reflection of the brain’s wiring. The core of this wiring is made of neurons, which are influenced by microglia. So, having healthy microglia is essential to healthy cognition. But here’s the thing about these cells: they’re very temperamental.

Microglial cells are like reserve troops. They wait in an inactive state until they are needed. When they get the right signal, they undergo a dramatic shift. This includes changing shape, moving to where they’re needed, and manufacturing a specific set of chemicals. In this cascade of events, the initial molecular signal determines the final personality of the cell.

Once exposed to a certain set of molecules, microglia become specialized. One of these specialized forms is called M2 microglial cells. These help to grow new neurons and heal brain damage. If presented with another set of messages, they can morph into another specialized form called M1 microglial cells. These appear to aid in removing pathogens like bacteria from the brain. But there’s a catch: a sustained elevation of the M1 cells may spell disaster. Left unchecked, they appear to damage and disable good brain function.

A central theme leads to both M1 activation and its negative consequences. As it turns out, this may also be a key in connecting microglial cells with our mood and cognition. What is the link? In a word: inflammation.

In the presence of inflammation, microglia preferentially turn into the M1 subtype. These cells then produce more inflammation. This is really important because elevated levels of inflammation are associated with neurodegenerative diseases like Alzheimer’s and Parkinson’s. So, it’s no surprise that M1 microglial cells are thought to play a role in these conditions. More recently, this same brain inflammation has been connected to mood disorders. As you might then expect, M1 microglial cells are implicated in depression.

Over the course of the last few decades, various trials have confirmed that inflammation contributes to depression. Early research noted that patients receiving interferon for hepatitis displayed depressive symptoms. And it’s been repeatedly confirmed that inflammatory markers in the blood are higher in people with depression. Lastly, giving volunteers an injection that increases inflammation leads to depressive symptoms. All of this indicates that inflammation may indeed cause depression. But the question is: How? For some possible answers, we again turn to the microglia.

Microglial cells can be seen as signal amplifiers — when they hear a message, they promote it widely. This is especially relevant for inflammation and its downstream effects. When inflammation reaches the brain, it induces microglial cells to create even more inflammation. This damages neurons. More importantly, it may actually block their creation. That’s because a decrease in new neuron production (called neurogenesis) in a certain part of the brain may have a role in both depression and cognitive decline.

You’ve likely heard of the “memory center” of the brain. It’s called the hippocampus. We actually have two hippocampi, one on each side of the brain. Volume loss in the hippocampus predicts the severity of cognitive decline. In fact, atrophy of this part of the brain is used to diagnose Alzheimer’s disease. Interestingly, volume loss in the hippocampus is also seen in major depressive disorder. Finally, higher levels of inflammation predict a smaller hippocampus. And of course, microglial cells have a central role in all of this.

Let’s tie all of this together. Our cognitive ability and our mood is a reflection of the wiring of our brains. This is majorly influenced by our immune systems, especially the cells called microglia. Microglial cells are differentially activated by the signals they receive. When exposed to inflammation, microglial cells start generating inflammation in the brain, which has been linked to cognitive decline and to depression. This may specifically be the result of damage to the hippocampus.

This story is fascinating and certainly incomplete. There remains much to learn about the factors influencing our cognition and mood. But while new data continue to be generated, it’s important for us to act with what we do know. Understanding the connections between inflammation, mood and cognitive decline makes it all the more important to lower systemic inflammation in our bodies.

The most universally relevant methods of reaching this goal include avoidance of the standard American diet, moderate levels of exercise, adequate sleep, and stress-reduction techniques. Individuals may benefit from a more personalized plan including gut-healing strategies, specific dietary protocols, and more formal assessments of inflammatory status.




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Austin Perlmutter, MD

Austin Perlmutter, MD

Dr. Austin Perlmutter, co-author of BRAIN WASH, is a board-certified internal medicine physician.

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