Shaping Minds: How the Immune System Molds Rat Brains in Development

Summary: Immune system cells in female rat brains consume and digest neurons, sculpting a specific brain region during development and potentially impacting behavior.

This insight into the interplay between biological sex, the immune system, and brain development may pave the way for understanding why certain brain disorders are more prevalent in one sex and could inform future treatments or prevention strategies.

Key Points:

  1. Immune system cells in female rat brains consume and digest neurons, shaping a specific brain region during development.
  2. This process could impact behavior, such as odor preference, which is an indicator of sexual partner preference in rodents.
  3. Understanding the role of biological sex and the immune system in brain development may help explain the prevalence of certain brain disorders in one sex over another.

Source: University of Maryland

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 diseases. 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.

This shows a brain slice
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. Credit: The Researchers

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.

Funding: 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 this neurodevelopment research news

Author: Vanessa McMains
Source: University of Maryland
Contact: Vanessa McMains – University of Maryland
Image: The image is credited to the researchers

Original Research: Closed access.
Microglia phagocytosis mediates the volume and function of the rat sexually dimorphic nucleus of the preoptic area” by Mark Gladwin et al. PNAS


Microglia phagocytosis mediates the volume and function of the rat sexually dimorphic nucleus of the preoptic area

The sexually dimorphic nucleus of the preoptic area (SDN-POA) is the oldest and most robust sex difference reported in mammalian brain and is singular for its presence across a wide range of species from rodents to ungulates to man. This small collection of Nissl-dense neurons is reliably larger in volume in males.

Despite its notoriety and intense interrogation, both the mechanism establishing the sex difference and the functional role of the SDN have remained elusive. Convergent evidence from rodent studies led to the conclusion that testicular androgens aromatized to estrogens are neuroprotective in males and that higher apoptosis (naturally occurring cell death) in females determines their smaller SDN. In several species, including humans, a smaller SDN correlates with a preference for mating with males.

We report here that this volume difference is dependent upon a participatory role of phagocytic microglia which engulf more neurons in the female SDN and assure their destruction. Selectively blocking microglia phagocytosis temporarily spared neurons from apoptotic death and increased SDN volume in females without hormone treatment.

Increasing the number of neurons in the SDN in neonatal females resulted in loss of preference for male odors in adulthood, an effect paralleled by dampened excitation of SDN neurons as evidenced by reduced immediate early gene (IEG) expression when exposed to male urine.

Thus, the mechanism establishing a sex difference in SDN volume includes an essential role for microglia, and SDN function as a regulator of sexual partner preference is confirmed.

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