Early and Delayed Changes in Neuroplasticity-Related Gene Expression after Postnatal Interleukin-1β and Lipopolysaccharide Administration in Rats

The brain is not a static organ that finishes its construction before a child takes their first breath. Instead, it continues to grow, rewire, and refine its connections well into early childhood, a process known as development. During this critical window, the brain is highly sensitive to its environment, including the body's immune system. When the body fights an infection, it releases chemical messengers called cytokines to coordinate the defense. One such messenger, interleukin-1β, acts like a signal flare, telling other cells to join the fight. While this response is vital for survival, scientists have long wondered if these inflammatory signals, if they occur while the brain is still building itself, might accidentally alter the brain's future architecture. Specifically, researchers are interested in whether early inflammation changes the levels of genes that help the brain stay flexible and form new memories, potentially leading to learning difficulties later in life.

A team of researchers at the Institute of Experimental Medicine in Saint Petersburg set out to investigate this question by comparing two different ways of triggering inflammation in young rats. They wanted to see if a direct injection of the inflammatory signal interleukin-1β produced the same long-term changes in the brain as an injection of lipopolysaccharide, a substance found on the surface of bacteria that triggers a broader immune response. The scientists focused on two specific brain regions: the medial prefrontal cortex, which helps with organizing memories and decision-making, and the dorsal hippocampus, which is essential for spatial learning and navigation. They examined the rats at two distinct times: shortly after the final injection while the animals were still young, and again when the rats had reached adulthood, roughly two and a half months old. By measuring the activity of genes responsible for neuroplasticity—the brain's ability to change and adapt—the researchers hoped to uncover whether these early inflammatory events leave a lasting molecular footprint.

The study involved fifty-four male rats divided into groups. One group received daily injections of interleukin-1β for a week, while another group received injections of the bacterial substance on three separate days. Control groups received harmless saline solutions on the same schedules. The researchers then harvested brain tissue from some animals just two hours after the last injection to catch the immediate reaction, and from the others when they were fully grown adults. They carefully measured the levels of four specific genetic messages in the brain tissue: Bdnf, Fgf2, Mmp9, and Timp1. These genes are known to play roles in how neurons grow, how they communicate, and how the physical structure around them is remodeled. To ensure their measurements were accurate, the team tested nine different internal reference genes to find the most stable ones for each brain region and age group, a crucial step to avoid false results caused by natural biological variations.

The results revealed that the two types of inflammation did not leave the same mark on the developing brain. In the young rats, just two hours after the final injection, the group that received interleukin-1β showed a significant rise in the genetic message for Fgf2 within the medial prefrontal cortex. This suggests that the brain tissue immediately responded to the direct inflammatory signal by ramping up production of this growth factor. However, this immediate spike did not last into adulthood for this group; when the researchers checked the adult rats that had received interleukin-1β, their Fgf2 levels in that same brain region were no longer different from the healthy controls.

In contrast, the rats exposed to the bacterial substance, lipopolysaccharide, showed a different pattern that persisted into adulthood. These adult rats had lower levels of the Fgf2 genetic message in the medial prefrontal cortex compared to the control animals. The same trend was observed in the dorsal hippocampus, where the levels were also lower, though the difference was right on the edge of statistical significance. Furthermore, the adult rats exposed to lipopolysaccharide showed a lower ratio of two other genetic messages, Mmp9 and Timp1, in the dorsal hippocampus. This ratio is important because these two genes work together to regulate the enzymes that remodel the space between neurons. A lower ratio suggests a shift in how the brain maintains its structural flexibility. Interestingly, the researchers found no significant changes in the levels of the Bdnf gene in any of the groups at any time point, indicating that this particular plasticity factor was not affected by the treatments in the way the others were.

The study concludes that while both inflammatory challenges can disrupt the brain's molecular balance, they do so through different mechanisms and at different times. The direct injection of interleukin-1β caused a quick, temporary surge in a growth factor gene in the young brain, whereas the bacterial substance led to a lasting reduction in that same gene and a change in the enzyme balance in the adult brain. The researchers note that because they measured genetic messages rather than the actual proteins or behaviors, the exact functional consequences of these changes remain to be fully understood. They also point out that the study was limited to male rats and did not include behavioral testing, so it is not yet clear how these molecular shifts translate to learning or memory abilities. Nevertheless, the findings provide a clear picture that the type of early-life inflammation matters, with different triggers leaving distinct molecular signatures that can endure well into adulthood.