Immune System Sculpts Rat Brains During Development

Newswise — Researchers have established that biological sex plays a role in determining an individual’s risk of brain disorders. For example, boys are more likely to be diagnosed with behavioral conditions like autism or attention deficit disorder, whereas women are more likely to suffer from anxiety disorders, depression, or migraines. However, experts do not fully understand how sex contributes to brain development, particularly in the context of these conditions. They think, in part, it may have something to do with the differing sizes of certain brain regions.

University of Maryland School of Medicine researchers now believe they have identified the mechanism for why and how one brain region differs in size between males and females, according to a February study published in PNAS. The study conducted in rats found that immune system cells in the brains of females consume and digest neurons to sculp this brain region during development.

The researchers also found that tinkering with the size of this brain region, which forms in the first couple days of life, affected whether female rats still preferred the odor of male rats. In rodents, this “odor preference” is an indicator of sexual partner preference with female rats typically preferring the odors of males. Although these rat inclinations do not directly apply to human sexual partner preferences, the findings demonstrate that changes to the brain that are determined by the immune system can later affect behavior.

Understanding in detail how biological sex and the immune system contribute to shaping the developing brain may one day help experts understand why certain brain diseases occur more likely in one sex versus another and could shed light on better ways to treat or prevent these conditions.

“Although there is much overlap between the brains of males and females, it seems to be the immune system that supplies much of the natural variation.  This may occur because the immune system is designed for variability to be able to respond to a wide range of attacks from the outside world,” said UMSOM Dean Mark Gladwin, MD, Vice President for Medical Affairs at the University of Maryland, Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor.

For the current study, Dr. McCarthy and her colleagues examined a region located deep inside the brain that in male rats is two to four times larger than in female rats. This size difference also appears in the brains of people in a similar region, but the sex difference is not as pronounced.

When they closely examined different cell types in the male and female brain, they noticed that the immune cells in the female rat’s brains had formed more of the structures on their surface that immune cells use to eat other cells, called phagocytic cups. They also observed these immune cells digesting neurons. Typically, these immune cells eat debris, dead or dying cells, and cells infected with viruses or bacteria, rather than healthy brain cells.

When the researchers used a drug or an antibody to block the immune cells’ ability to eat neurons in rat brains, they found that this region in the female rat brains developed larger, similar to the size of the region in male rat brains.

“For almost 50 years, we had thought that the cells just died in the females and not the males and thought this was due to steroid hormones,” said senior investigator Margaret McCarthy, PhD, the James and Carolyn Frenkil Dean’s Professor and Chair of the Department of Pharmacology at UMSOM. “In an open field of cells all touching each other, we’ll see a microglia immune cell shoot up through the other cells and eat one particular cell. The cells that these microglia eat aren’t random, but we don’t know why they are chosen. These are the kinds of questions we still need to investigate.”

The brain region analyzed in this study is known for controlling rat’s reproductive behaviors. For example, female rats typically prefer the odors of male rats when given a choice, and male rats prefer the odors of females. The researchers found that females with the larger brain region due to their immune cells eating function being blocked no longer preferred the male rat odor and instead picked the female odor or had no preference at all.  

“This finding adds to the evidence that the immune system plays a major role in determining certain sex differences in the brain that may ultimately lead to differences in the prevalence of developmental brain disorders,” said Dr. McCarthy. "Whether this process can be manipulated to develop new treatments for autism or anxiety remains to be seen, but it’s a promising avenue of research to explore.”  

Dr. McCarthy is also the Director of the newly formed University of Maryland-Medicine Institute for Neuroscience Discovery (UM-MIND), which was founded to bring basic and clinical scientists together to better facilitate translating discoveries about the brain into new treatments for diseases of the brain. Her area of expertise falls among the institutional strengths of neurodevelopment and psychiatric disorders. The other focuses of the institute are neurotrauma and brain injury, as well as aging and neurodegeneration.

National Institutes of Health's National Institute of Neurological Disorders and Stroke (F31NS093947), the National Institute of Mental Health (F31MH123025 and R01MH52716), and the National Institute on Drug Abuse (R01DA039062).

About the University of Maryland School of Medicine

Now in its third century, the University of Maryland School of Medicine was chartered in 1807 as the first public medical school in the United States. It continues today as one of the fastest growing, top-tier biomedical research enterprises in the world — with 46 academic departments, centers, institutes, and programs, and a faculty of more than 3,000 physicians, scientists, and allied health professionals, including members of the National Academy of Medicine and the National Academy of Sciences, and a distinguished two-time winner of the Albert E. Lasker Award in Medical Research. With an operating budget of more than $1.3 billion, the School of Medicine works closely in partnership with the University of Maryland Medical Center and Medical System to provide research-intensive, academic, and clinically based care for nearly 2 million patients each year. The School of Medicine has nearly $600 million in extramural funding, with most of its academic departments highly ranked among all medical schools in the nation in research funding. As one of the seven professional schools that make up the University of Maryland, Baltimore campus, the School of Medicine has a total population of nearly 9,000 faculty and staff, including 2,500 students, trainees, residents, and fellows. The combined School of Medicine and Medical System (“University of Maryland Medicine”) has an annual budget of over $6 billion and an economic impact of nearly $20 billion on the state and local community. The School of Medicine, which ranks as the 8th highest among public medical schools in research productivity (according to the Association of American Medical Colleges profile) is an innovator in translational medicine, with 606 active patents and 52 start-up companies. In the latest U.S. News & World Report ranking of the Best Medical Schools, published in 2021, the UM School of Medicine is ranked #9 among the 92 public medical schools in the U.S., and in the top 15 percent (#27) of all 192 public and private U.S. medical schools. The School of Medicine works locally, nationally, and globally, with research and treatment facilities in 36 countries around the world. Visit medschool.umaryland.edu