Adult hippocampal neurogenesis is age dependent and differently modulated in male and female wild house mice

The brain is not a static organ that finishes building itself in childhood; in many mammals, including humans, it continues to grow new nerve cells throughout life. This process, known as adult hippocampal neurogenesis, happens in a specific region called the hippocampus, which is vital for learning, memory, and emotional balance. Think of this region as a construction site where fresh neurons are born, mature, and then integrate into existing networks to help the brain adapt to new experiences. Scientists have long known that this construction slows down as animals get older, but most of what we understand comes from studying mice in sterile laboratories. These lab mice live in perfect, unchanging conditions, which raises a question: does the brain age the same way when an animal faces the real world, with its unpredictable weather, social struggles, and constant need to find food and avoid predators? To answer this, researchers needed to look at wild animals whose lives were fully documented from birth to death, allowing them to see how age and the body's own chemical signals interact in a natural setting.

A team of scientists set out to investigate this by studying a large population of wild house mice living in a barn near Zurich, Switzerland. This specific group of mice has been watched closely for over two decades, meaning the researchers knew the exact age of every individual they caught, ranging from two months to more than two years old. On a single day in December, they captured 73 of these mice—32 males and 41 females—and carefully collected their brains and small samples of hair. The goal was to count the number of new, young nerve cells in the hippocampus and see how those numbers changed with age. They also wanted to understand how the body's internal chemistry influenced this process. To do this, they analyzed the hair samples for levels of stress hormones, sex hormones, and signaling molecules called endocannabinoids. Unlike blood tests, which only show what is happening in the body at a single moment, hair acts like a slow tape recorder, preserving a record of hormone levels over the past two to three months. This allowed the scientists to see the long-term chemical environment each mouse had been living in.

The most striking finding was that age was the single strongest factor determining how many new brain cells were being made. As the mice got older, the production of new neurons dropped sharply, following a steep decline that was remarkably similar to what has been seen in laboratory mice. This drop happened in both males and females, and it was so consistent that age alone could explain nearly all the variation in the number of new cells found. Interestingly, while the number of new cells fell, the total number of mature nerve cells in the hippocampus remained stable, suggesting that the brain maintains its core structure even as it stops adding new parts. The researchers also checked if the stress of being caught and handled affected the results, but they found that the time the mice spent in cages before being examined, or the time between death and brain removal, had no impact on the counts. The decline was a natural part of aging, not an artifact of the study method.

When the scientists looked at the hormones stored in the hair, the picture became more complex and revealed surprising differences between the sexes. In isolation, higher levels of the stress hormone corticosterone were linked to fewer new brain cells, which matched previous ideas about stress being harmful to the brain. Similarly, higher levels of testosterone and progesterone were also associated with a drop in new cell production, a finding that contradicted the expectation that testosterone might protect the brain in males. However, when the researchers analyzed all the hormones together while accounting for the animal's age, the story changed. The stress hormone corticosterone lost its significance as a predictor. Instead, the influence of the other chemicals depended entirely on whether the mouse was male or female.

In female mice, the decline in new brain cells was driven primarily by age, followed by the levels of testosterone and progesterone. The researchers noted that progesterone levels in females rise with the number of pregnancies they have had, and they found that a history of many pregnancies was strongly linked to fewer new brain cells. This suggests that for females, the biological costs of reproduction may trade off against the brain's ability to generate new neurons. In male mice, the dynamic was different. The most important chemical predictor for new brain cells was not a hormone, but an endocannabinoid called 2-arachidonoylglycerol, or 2-AG. This molecule, which is part of the body's natural signaling system, showed a positive relationship with new cell growth in males. Even when age was taken into account, higher levels of 2-AG in males were associated with more new neurons, making it the strongest single factor for them. For females, this chemical did not play the same dominant role.

The study concludes that while aging is the universal force that slows down brain cell production, the chemical signals that modulate this process are not the same for everyone. The body does not use a single blueprint for both sexes; instead, the interplay between age, reproductive history, and specific chemical signals creates a unique landscape for males and females. The findings suggest that in the wild, the brain's plasticity is deeply tied to an individual's life history and sex-specific physiology. By moving beyond the controlled environment of the lab to observe animals in their natural habitat, the researchers uncovered that the rules governing brain health are more nuanced than previously thought. The brain does not just age; it ages differently depending on whether you are a male or a female mouse, shaped by the specific chemical signals that have accumulated over months of living in the wild.