Russian silver foxes that have been tamed show changes in their brains. | photo provided by Anna Kukekova

Bond LSC scientist delves into how domestication alters the fox brain

By Roger Meissen | Bond Life Sciences Center

You might be familiar with the idiom “don’t bite the hand that feeds you,” but when it comes to a certain lineage of tame Russian silver foxes it’s quite literal.

After more than 50 generations of breeding, these tame foxes likely offer insight into how selective breeding leads to domestication, and scientists dove deeper to look at what this trait might mean in terms of changes in the brain and the genes behind them.

“These silver foxes act like domesticated dogs and are assumingly a good model to look at the process of domestication, tracing what happened as the wolves became domesticated into what we recognize today as the domesticated dog. Wouldn’t that be fascinating to know all the things that coincide with that?” said Cheryl Rosenfeld, a Bond Life Sciences Center principal investigator at the University of Missouri and co-lead author on the study. “Presumably, to become domesticated the one biggest organ that would have to change is the brain, because that’s where fearfulness, aggression, and social behaviors emerge from, so my interest is in the brain and how various factors might affect it.”

The path away from aggression

While this story eventually focuses on the brain, the path to a modern model of tameness starts in Soviet Russia in the 1950s.

Russian geneticist Dmitry K. Belyaev bred hundreds of foxes in Siberia, initially selecting them based on their willingness to approach humans in their cage. In its beginning only 10 percent of those tested showed a weakened wild response, and those foxes were bred together to reinforce this docile nature. In later generations, their behavior was further evaluated based on their likelihood to interact with humans approaching their cage, their territorial behavior, response to attempts to pet them and reaction to the experimenter leaving the interaction.  Lyudmila Trut, his intern now in her 80s and an author on this study, continues the breeding project.

“Those that showed a muted wild response would get bred together, so with each passing generation, the foxes showed diminished fear response. Once they established this tame fox population, they eventually developed the aggressive ones doing just the opposite in that they paired those foxes showing the most aggressive responses to an experimenter approaching the cage,” Rosenfeld said. “They repeated this over time and, ultimately, what they have now, going out 50 generations, are tame foxes that act and even look in some ways like pet dogs.”

The tame silver foxes love human interaction from attention to belly rubs, and exhibit traits like tail wagging, gazing into the faces of humans and a change in their barks. Physical changes accompanied these behavioral changes, with coat color shifting from silvered-black fur to a more mottled, piebald pattern, and tails becoming curly despite these traits not being intentional selected for by breeders. In contrast, those bred for aggression showed hyper aggressive responses to humans, as indicated by lunging at the cage.

The taming of the brain

A change in behavior as observed in these silver foxes likely comes with unseen shifts in genetics and brain function. Rosenfeld decided to look at these changes in the hypothalamus region of the brain with the help of researchers from the University of Illinois at Urbana-Champaign, Cornell University, the Broad Institute of MIT and Harvard and the Institute of Cytology and Genetics in Novosibirsk, Russia.

“We are interested in changes in gene expression associated with the hypothalamic-pituitary-adrenal axis, the main hormonal system involved in stress-response and it was very exciting and productive to collaborate with Dr. Rosenfeld and her colleagues on the analysis of gene expression in the hypothalamus of tame and aggressive foxes” said Anna Kukekova, the senior author and associate professor in the Department of Animal Sciences at the University of Illinois at Urbana-Champaign.

Rosenfeld compared genes in the hypothalamus between tame foxes and aggressive foxes as well as comparing them to genes in two other brain regions — the prefrontal cortex and the basal forebrain — significant in terms of learning and memory.

“The hypothalamus was a good target organ, because it controls social behaviors like getting along or gregariousness and usually hormones like the pro-social hormone oxytocin tends to increase in animals who are social,” Rosenfeld said. “We basically did a global approach, looking at every gene we could identify and how they differ in terms of expression between the tame and aggressive foxes.”

Among genes with differential hypothalamic expression in tame and aggressive foxes they found seven identical genes with the same pattern of expression between all three brain regions. It suggests that when you select for tameness that some genes will change regardless of brain region.

“It was interesting to us because these genes were involved in processes including cell division and making more neurons, differentiation, adhesion like how the cells contact each other, and the most surprising, carbohydrate processing.”

Rosenfeld commented that some of these involved — such as, carbohydrate processing — suggest potential changes to accommodate domestication between the tame and aggressive foxes.  This falls in line with how scientists believe dogs became domesticated 10,000 years ago, growing ever closer to human populations and developing to scavenge their scraps and garbage, although in this study both tame and aggressive foxes were maintained on the same diet.

“As animals get domesticated, they have to also accommodate different diets than what they’ve been eating in the wild because now they’re getting scraps from humans,” Rosenfeld said. “They’re selecting for genes that are involved in carbohydrate process, like metabolism processing, so it’s sort of telling us when you consider domestication that we might have to think about how the animal may have to then turn on a whole set of other genes to accommodate this new diet.”

But there were other brain differences as well.

“We also found genes suppressed in tame foxes associated in inflammation processes we call interleukin signaling, cytokines production and communication between cells to each other, and this gene expression linked to whether they were tame versus aggressive.”

The researchers’ original idea that genes related to hormones like oxytocin ended up not panning out when they saw little change between tame and aggressive foxes. But, she said it was interesting that the prevalent changes they did see involved more genes down-regulated or suppressed in tame than aggressive foxes.

“Most of the genes in the hypothalamus actually we found were suppressed in tame relative to hyper aggressive foxes, you know, squashing a hyperactive response, Rosenfeld said. “So, it’s an interesting question to consider that, as dogs became more domesticated, did they become more prone to disease because they don’t have such a heightened immune response? We can’t really answer that question just yet.”

Read more about this work in the journal article “Hypothalamic transcriptome of tame and aggressive silver foxes (Vulpes vulpes) identifies gene expression differences shared across brain regions.” This research published in October 2019 in the journal Genes, Brain and Behavior.

Cheryl Rosenfeld is a principal investigator in MU’s Bond Life Sciences Center and a professor of biomedical sciences at the University of Missouri.