Make and break connections in the brain. (2023)

If you were to take a human brain and throw it into a blender, which you shouldn't, the resulting jumble of cells wouldn't be nearly as special as the human brain. No thoughts, no worries, no wonder or wonder.

That's because it's the connections between these cells that make the brain so amazing. By sending electrical signals from nerve cell to nerve cell within a vast network of connections, the brain generates thoughts as mundane as "Where are my keys?" or as deep as “I think, therefore I am”.

Kimberley McAllister has been fascinated by the human brain since college. As a graduate student in the 1990s studying developmental neurobiology, I was intrigued by the question of how the brain is built: how the individual brain cells of a growing fetus are somehow organized into an organ that may one day contemplate the life mysteries.

McAllister, who is now director of the Center for Neuroscience at the University of California, Davis, continues to study how nerve cells in the brain, called neurons, find, connect, and disconnect. she talked toKenbar magazineabout important discoveries in the study of brain networks and new work that shows their importance in diseases.

This interview has been edited for length and clarity.

The connections between neurons are called synapses. What exactly is a synapse and what happens there?

It's basically a connection: one cell talks to another. A brain cell, or neuron, has a large main body with tiny wires sticking out of it. So a neuron, the transmitter, uses a very thin wire called an axon. A second neuron, the receiving neuron, can receive contacts along its main body or along filaments that branch like a tree, called dendrites. When the tip of the axon connects from a transmitter to a receiver, that's a synapse.

Neurons run on electricity. When an electrical signal travels down an axon, its tip releases chemicals called neurotransmitters into the synapse. These neurotransmitters tell the receiving cell to turn on its own electrical charge, which sends the signal to the next neuron in the chain, or they tell the receiving cell to shut up.

But it's not as simple as one receiver for each transmitter. For example, the neurons in the frontal cortex, the part of the brain that houses skills like language that distinguish us from other animals, look beautiful, like trees. They can have 10,000 or more synapses on their branching dendrites, each of which can receive information from a different cell.

The activity of these thousands of inputs add up to make the neuron fire, or not, and thus the information is transmitted in the brain. This way of transmitting information through intricate networks formed by the 120 billion neurons of the human brain makes complex thoughts possible.

Axons and dendrites can move, especially when the brain is young. The way in which individual neurons connect creates the pathways of the network. During development, the 100 trillion synapses in the human cortex form at an estimated rate of 10,000 every 15 minutes. Together, all these synapses form a large network. And that makes us aware.

When I started, we didn't know anything about how synapses are formed. I have developed a technique to study the growth of dendrites. We realize that the shape of neurons and dendrites depends on it.activity at synapses🇧🇷 This means that if the brain does not receive information -from the senses and from the environment- and responds with conversations through the network, the neurons will not build the appropriate receptors and the brain will not develop properly.

Synapses are very small but incredibly complex molecular machines made up of proteins that direct, maintain and strengthen connections. One of the greatest advances of the last 20 years has been the identification of the wide range of proteins that make up these compounds. Biochemists estimate that there are thousands of different and distinct proteins in each synapse. The incredible diversity of these proteins allows the brain to fine-tune the strength and stability of synapses, allowing us to think complex thoughts and build memories.

We have learned that a genetic mutation that alters the function of one of these proteins can contribute to conditions such as autism, schizophrenia, and depression. We consider these conditions as synaptic disorders or synaptopathies.

Either way, neurons in a developing fetus or baby are thought to form many connections, as described in the delightful phrase "exuberant synaptogenesis." How does this process build an organized brain?

When neurons are born in the fetal brain, they migrate to their proper positions. Simply put, some go to the brain, which is involved in tasks like speaking and thinking, some to the cerebellum, which is involved in coordinating movement, and some to the brainstem, where physical actions take place. Skills like breathing are ingrained. 🇧🇷 Once positioned, the axons follow chemical trails to the target areas, either in the same part of the brain or elsewhere.

Textbooks state that once axons are in the basic target area, they form abundant connections; then the excess synapse is removed later in development. But now we know that there are molecules that limit synapse formation in the first place, that initial formation is more tightly controlled.

The brain's ability to strengthen or weaken synapses based on activity is often referred to as "plasticity." What is plasticity and why is it important?

Plasticity means that the brain can change, for example by changing the connections in its networks. Without plasticity we would not be able to learn or adapt to our environment. When you learn something, you have electrical activity going through different circuits. These electrical impulses change the strength of certain connections, making them stronger or weaker.

For example, when you learn that "hola" means "hello" in Spanish, certain synapses become stronger. This results from changes in the various proteins that make up the synapse.

Scientists can see this by mimicking learning in brain slices in laboratory dishes and even in live animals. The dendrites have little protrusions called spines that act as signaling receptors. Once learned, these spikes grow larger and are more likely to persist. This type of change is part of plasticity.

Young children are great at absorbing new information and skills. As adults, we're often not that good at it. How does plasticity change with age?

The brains of young animals have a lot of plasticity. For every skill in the brain, like learning a language, there is a critical period when learning is easy. During this critical period, the brain undergoes many changes. If you look at those dendritic spines in a young brain, they move like crazy.

But if you look at the brain of an adult, the spines don't move much. That's because the material, which acts like glue, penetrates and holds the neurons in place. The critical period for each brain region ends at a different time. For example, the critical period for language development begins around age 5. But the brain's ability to make rational judgments doesn't fully develop until the age of 25.

Therefore, in adults, the connections are quite stable, but the plasticity does not disappear completely. In adults, it's not so much about adding or removing connections as it is about adjusting the strength of synapses by using all those synaptic proteins.

One of the great mysteries iswhyAdults lose this ability to learn so easily. In some cases, such as parts of the visual system in frogs and goldfish, this plasticity does not go away. Scientists are trying to understand what happens inside these creatures. If we could reopen the critical period in someone whose nerves are damaged or impaired, perhaps we could reactivate the connections.

To study synapses, the scientists first looked at the neuromuscular junction, where specific neurons meet muscles to control movement. Where did the investigators go from there?

In the 1990s and early 2000s, the field was completely dominated by studies of neuromuscular connections. It is a much simpler synapse than the one in the brain. We learned a lot.

But in the brain, synapses are much more diverse. Focusing on the brain became possible with the development oftechniquesThis allowed us to extract neurons from the brain and watch them form networks in a dish. We can then begin to assess how synapses form, function, and disappear in the complex networks they form outside the brain.

We discovered that there are big differences between the brain and the neuromuscular junction. There are many, many more diverse types of synapses in the brain and more types of neurotransmitters. This makes the brain much more complicated, not to distract from the complexity of the neuromuscular junction! - and super interesting.

The researchers also discovered a new class of molecules that hold the two sides of the synapse together. Because they are important?

These molecules bridge the gap between the two sides of the synapse, hold the sending and receiving cells together like zippers, and are very important forFormation and removal of synapses..

It turns out that mutations that change many of these "zipper" molecules make synapses dysfunctional and have been linked to brain diseases such as epilepsy, Down syndrome, and Alzheimer's disease. For example, there were defects in the gene for a zipper protein called neuroligin.associated with autism🇧🇷 So the researchers found mutations in the same genein people with schizophrenia.

But you too can have these mutations and not a brain disorder. One of the pressing questions now is: what causes someone with a Zipper protein mutation to show symptoms, and why do different people with the same mutations show different symptoms (ie, autism vs. schizophrenia)?

I think these zipper proteins could become even more interesting than other parts of the synapse. Scientists now want to understand: How can we design drugs to repair dysfunctional synapses?

The brain is believed to be somewhat isolated from the body's immune system. However, she and others are studying the role of immune cells and molecules in the brain. What they do?

There is tremendous excitement around a certain type of immune cell called microglia. These cells remove dead cells and other materials used in the brain. Microglia can eliminate synapses by eating them. we know what they areimplicated in brain disorders such as Alzheimer's disease, because they are switched to their active anti-infective state in people with these disorders. But how exactly they contribute remains a mystery.

I examined the brain functions of the so-called immune molecules.MHC1🇧🇷 These molecules protrude from the surface of almost all cells. His traditional job is to tell the immune system that these cells are part of the body and do not need to be attacked. MHC1 molecules are tooinvolved in synaptic plasticity🇧🇷 Youprevent synapses from formingearly, making brain development less exuberant and more tightly controlled.

I also believe that the MHC1 molecules are involved in chemicals or infections.affect brain development🇧🇷 I am part of a group that studies how infections occur in pregnant womenincrease risk to babyfor possible autism spectrum disorder or schizophrenia. In one project, we are studying the offspring of mother mice after the mothers have been exposed to a virus-like substance.provokes an immune response🇧🇷 Mice pups have more MHC1 and fewer synapses in their brain than control animals. This suggests that infections involving the immune system may disrupt brain circuitry by altering the levels of immune molecules in synapses.

On the one hand, the fact that infections can alter brain development is surprising. On the other hand, most infectionsNoaffect the brain. If we better understand how, when, and why the immune system regulates brain development, we might one day develop drugs to alter the immune response and correct what's wrong with the brain.