Teenage boys like to wrestle. They bite at each other and will pin the other one down. But as they get older, this playful wrestling turns into a more dignified sniffing, and occasionally, a real fight. These aren’t human boys, of course. They’re rats. And a new study has shown that immune cells in their brains play some role in directing the transition from rough-and-tumble play to serious adult behaviors.
Young female rats don’t show nearly as much rough-and-tumble play as the guys their age. They don’t show the same style of style of brain development, either. That difference could help scientists learn more about how people’s brains mature — and what generally makes boys and girls behave so differently.
When humans hit adolescence, their behaviors change. As children, they valued adult attention most. As teens? Friends matter more. Teen rats are the same way, Ashley Kopec notes. She’s a neuroscientist — someone who studies the brain. She works at Harvard Medical School in Boston, Mass. “Adolescents [even rats] seem to be trying to get out on their own,” she says. Playing with friends is a part of that. “In rodents there’s a time when social play increases.”
And boy rats like to brawl. “It’s super cute,” Kopec says. “It’s rough-and-tumble wrestling.” The rats jump around the cage, pin each other down and nip at each other. Some of this pinning and nipping might be a way to practice attacking and defending themselves. Male rats will need such skills as they head out into the adult world.
It’s clear the play is also fun — and for a good reason. It activates dopamine (DOAP-uh-meen). This is a chemical that serves as a messenger between cells. Dopamine, in particular, is a messenger associated with things that feel good. It spikes in an area of the brain called the nucleus accumbens (NOO-klee-us Uh-KUM-benz) when a substance (such as food) or activity (such as play) is pleasing. In adult rats, play gives a brief dopamine zing. As they get older, however, the spikes in dopamine taper off. And now the antics aren’t so much fun. But in teen rats, the wrestling — and the dopamine surge — never get old.
Calling in the brain cops
Of course, adolescent rats eventually become adults. Teen boys go from all-night adventures to middle-aged dads who drone on about mowing the lawn. Rats go from the joy of rat wrestling to the dignified sniffed greetings of the old and boring. This means their brains must change. Their dopamine systems, in particular, must simmer down with time. Kopec wondered if immune cells in the brain might play a role in this.
The immune system works to keep the body from harm. It does this by chomping up dangerous bacteria and chasing down viral invaders. The precious brain is protected from most of this activity. It’s carefully tucked away behind a barrier to give it extra armor and prevent germs from getting in. But that extra barrier means that while most germy threats can’t invade, the body’s immune system also can’t get in. So the brain also has its own separate immune police force. It’s made up of cells called microglia (My-kroh-GLEE-uh).
These cells patrol the brain. They chow down on dead neurons (nerve cells in the brain) and swallow up invading germs. They also trim the ends of healthy neurons. Neurons are specialized cells with ends that connect to each other. They pass messages back and forth. Those conversations help us not only learn movements and store memories, but also do so much more. Such cellular connections change over time. Some become stronger. Others weaken. Eventually, some old connections aren’t needed anymore. So microglia step in as the neurons’ personal barbers. They prune off old, less useful, connections at the ends of cells so that new ones can emerge.
Of course the microglia need to know which neurons are due for a cellular styling and which aren’t. To do that, they rely on a chemical called complement three, or C3. Scientists aren’t always sure what makes a neuron know when a bit of it needs to go. But when a neuron is ready for a trim, it puts out a C3 “flag.”
“Microglia can identify C3,” Kopec explains. When one of these cells spots a C3 tag, it heads to the neuron and trims off the bit with the flag.
Kopec knew that as animals (including people) are developing, connections between neurons get trimmed and restyled. She and her colleagues began to wonder if microglia might be responsible for at least some of that.
Microglia chomp down dopamine
To find out, Kopec’s team looked at groups of rats of different ages. Life comes at rats fast. They grow from kids to adults in a matter of weeks. Age is measured in post-natal days, or the number of days after birth. Male rats hit their peak playfulness at 30 days after birth. Females grow up even faster. They hit peak wrestling time at post-natal day 22 (though they don’t ever wrestle as much). That’s 8 days earlier than males.
So Kopec’s team looked at rats between 22 and 54 days after birth. (That’s about the equivalent of a human teen.) They were especially interested in a dopamine receptor known as D1.
Receptors are parts of a cell that “sniff out” chemical messengers and make cells take action based on what they “smell.” D1 receptors in the nucleus accumbens help cells take action in response to a dopamine surge. But Kopec and her colleagues found that as male rats move into their late teen years (er, days), neurons in their nucleus accumbens have fewer and fewer D1 receptors.
Where did those D1 receptors go? To find out, Kopec’s team used a drug known as NIF. (That’s short for neutrophil inhibitor factor.) This drug blocks the C3 tags in a rat’s brain. When NIF was present, the microglia could not spot C3. So they no longer trimmed the neurons. The D1 receptors remained, and that meant that the nucleus accumbens cells retained their ability to sense dopamine. The treated male rats now played just as rough as before, even though they should have been too old for such scuffles.
This research, then, showed microglia normally view the C3 flags on neurons as a call to chow down on a dinner of D1 receptors. And as D1 levels disappear, so will the male rats’ appetite for rough play.
But in females, it was a completely different story. Their D1 receptor levels were already low by post-natal day 22. Their rough-and-tumble days were over. So blocking microglia had no effect on how hard they played.
These results suggest that by chewing up D1 receptors, the brain’s immune system transforms adolescent male rats into chilled-out adults. Kopec and her team published their findings September 25 in Nature Communications.
Growing up rat
What makes the study especially interesting is that it links the way rats’ microglia chew up D1 receptors with how they play, says Ukpong Eyo. He’s a neuroscientist at the University of Virginia in Charlottesville. But, he asks, are microglia chewing up living cells’ D1 receptors? Or do the microglia only cut off the cellular ends that were already dead or dying? Put another way, are the immune cells helping to control brain development — or just taking out the trash?
“The play behavior is interesting because it shows sex differences,” says Kathryn Lenz. She’s a neuroscientist at Ohio State University in Columbus. This play is “also a social behavior,” she notes. “We know boys engage in more rough-and-tumble play than girls, [and] we know that’s due to hormones.” But hormones don’t act alone, she points out. And the role of microglia is especially exciting, she says, because the brain’s immune cells are activated by stress. Those cells also can play a role in mental illnesses.
Understanding more about the way microglia shape behavior in teens — both in rats and people — could help scientists understand why some mental illnesses (such as anxiety) tend to develop in adolescence. It also might eventually help explain why some disorders, such as autism or attention deficit hyperactivity disorder, are more common in males than in females, Lenz says.
Kopec now knows that microglia are trimming male rat brains as they develop. But what about in females? The role of those cells in them remains a mystery that she’s determined to solve. “Every time I look further at the females, they always have some kind of confusing result,” she says. They may have other behaviors, ones that matter much more than rough-and-tumble wrestling. Kopec just needs to figure out what to look for.
activate (in biology) To turn on, as with a gene or chemical reaction.
adolescence A transitional stage of physical and psychological development that begins at the onset of puberty, typically between the ages of 11 and 13, and ends with adulthood.
adolescent Someone in that transitional stage of physical and psychological development that begins at the onset of puberty, typically between the ages of 11 and 13, and ends with adulthood.
anxiety A nervous reaction to events causing excessive uneasiness and apprehension. People with anxiety may even develop panic attacks.
attention deficit hyperactivity disorder (ADHD) This is a disorder characterized by not being able to focus or pay attention, being physically overactive, not being able to control behavior, or a combination of these.
autism (also known as autism spectrum disorders ) A set of developmental disorders that interfere with how certain parts of the brain develop. Affected regions of the brain control how people behave, interact and communicate with others and the world around them. Autism disorders can range from very mild to very severe. And even a fairly mild form can limit an individual’s ability to interact socially or communicate effectively.
bacteria (singular: bacterium) Single-celled organisms. These dwell nearly everywhere on Earth, from the bottom of the sea to inside other living organisms (such as plants and animals).
behavior The way something, often a person or other organism, acts towards others, or conducts itself.
cell The smallest structural and functional unit of an organism. Typically too small to see with the unaided eye, it consists of a watery fluid surrounded by a membrane or wall. Depending on their size, animals are made of anywhere from thousands to trillions of cells. Most organisms, such as yeasts, molds, bacteria and some algae, are composed of only one cell.
chemical A substance formed from two or more atoms that unite (bond) in a fixed proportion and structure. For example, water is a chemical made when two hydrogen atoms bond to one oxygen atom. Its chemical formula is H2O. Chemical also can be an adjective to describe properties of materials that are the result of various reactions between different compounds.
colleague Someone who works with another; a co-worker or team member.
complement To match or fit with something else to complete it. In genetics, a series of nucleotides that pairs exactly with another sequence of DNA or RNA is called the complement of that sequence.
develop (in biology) To grow as an organism from conception through adulthood, often undergoing changes in chemistry, size and sometimes even shape.
development (in biology) The growth of an organism from conception through adulthood, often undergoing changes in chemistry, size and sometimes even shape. (in economics and social sciences) The conversion of land from its natural state into another so that it can be used for housing, agriculture, or resource development.
disorder (in medicine) A condition where the body does not work appropriately, leading to what might be viewed as an illness. This term can sometimes be used interchangeably with disease.
dopamine A neurotransmitter, this chemical helps transmit signals in the brain.
germ Any one-celled microorganism, such as a bacterium or fungal species, or a virus particle. Some germs cause disease. Others can promote the health of more complex organisms, including birds and mammals. The health effects of most germs, however, remain unknown.
hormone (in zoology and medicine) A chemical produced in a gland and then carried in the bloodstream to another part of the body. Hormones control many important body activities, such as growth. Hormones act by triggering or regulating chemical reactions in the body. (in botany) A chemical that serves as a signaling compound that tells cells of a plant when and how to develop, or when to grow old and die.
immune (adj.) Having to do with the immunity. (v.) Able to ward off a particular infection. Alternatively, this term can be used to mean an organism shows no impacts from exposure to a particular poison or process. More generally, the term may signal that something cannot be hurt by a particular drug, disease or chemical.
immune system The collection of cells and their responses that help the body fight off infections and deal with foreign substances that may provoke allergies.
journal (in science) A publication in which scientists share their research findings with experts (and sometimes even the public). Some journals publish papers from all fields of science, technology, engineering and math, while others are specific to a single subject. The best journals are peer-reviewed: They send all submitted articles to outside experts to be read and critiqued. The goal, here, is to prevent the publication of mistakes, fraud or sloppy work.
microglia A type of cell found in the brain and spinal cord. It can move from place to place, and serve as part of the immune system, protecting the brain from infection.
neuron An impulse-conducting cell. Such cells are found in the brain, spinal column and nervous system.
neuroscientist Someone who studies the structure or function of the brain and other parts of the nervous system.
nucleus Plural is nuclei. (in biology) A dense structure present in many cells. Typically a single rounded structure encased within a membrane, the nucleus contains the genetic information. (in neuroscience) A concentration of cell bodies in a specific area of the brain. Those cell bodies are usually involved in the same function, such as feelings of reward, or how we see or hear. (in astronomy) The rocky body of a comet, sometimes carrying a jacket of ice or frozen gases. (in physics) The central core of an atom, containing most of its mass.
nucleus accumbens An area deep within the front part of the brain that is linked to pleasure and motivation.
receptor (in biology) A molecule in cells that serves as a docking station for another molecule. That second molecule can turn on some special activity by the cell.
rodent A mammal of the order Rodentia, a group that includes mice, rats, squirrels, guinea pigs, hamsters and porcupines.
sex An animal’s biological status, typically male or female. There are a number of indicators of biological sex, including sex chromosomes, gonads, internal reproductive organs, and external genitals. It can also be a term for some system of mating between male and female animals such that each parent organism contributes genes to the potential offspring, usually through the fertilization of an egg cell by a sperm cell.
social (adj.) Relating to gatherings of people; a term for animals (or people) that prefer to exist in groups. (noun) A gathering of people, for instance those who belong to a club or other organization, for the purpose of enjoying each other’s company.
stress (in psychology) A mental, physical, emotional or behavioral reaction to an event or circumstance (stressor) that disturbs a person or animal’s usual state of being or places increased demands on a person or animal; psychological stress can be either positive or negative.
synapse The junction between neurons that transmits chemical and electrical signals.
transition The boundary where one thing (paragraphs, ecosystems, life stage, state of matter) changes or converts into another. Some transitions are sharp or abrupt. Others slowly or gradually morph from one condition or environment to another
Journal: A.M. Kopec et al. Microglial dopamine receptor elimination defines sex-specific nucleus accumbens development and social behavior in adolescent rats. Nature Communications. Vol. 9, published online September 25, 2018. doi: 10.1038/s41467-018-06118-z.