Gene Expression Shifts as Shrews Shrink and Regrow Their Brains

As winter approaches, humans in the higher latitudes might beat the cold by snuggling up under a pile of blankets or booking a timeshare in sunny Florida. Similarly, some animals cope with seasonal changes by slowing their metabolisms to a crawl to drop into hibernation or undertaking long migrations to more hospitable climes.

But Sorex araneus, also known as the common shrew, doesn’t seem to be able to put the brakes on its extraordinarily fast metabolism—it has one of the highest basal metabolic rates of any mammal—and its diminutive stature makes long-distance migrations highly impractical.¹ Instead, the shrew evolved a somewhat peculiar strategy: it shrinks. 

Scientists have observed reductions not just in overall body mass, but also in the size of the shrews’ livers, spleens, skulls, and brains.^2,3 Researchers hypothesize that reducing the mass of metabolically-costly tissues helps the shrews conserve energy, allowing them to survive on less food during the winter months when their prey—bugs, slugs, and worms—is more difficult to come by. 

This loss isn’t without consequences—their shrunken brains are less capable of spatial learning.⁴ Fortunately for the shrews, it is also reversible: After losing 20 percent of their brain mass in the fall, they regain about 10 percent the following spring, going through this process just once during their approximately year-long lifespans.³ Now, an international team of researchers has characterized differences in gene expression in the brain, both over time and between species, that could explain the shrew’s remarkable plasticity in brain and body mass, which is known as Dehnel’s phenomenon.⁵ They published their findings yesterday (November 19) as a reviewed preprint in eLife.

“It’s very exciting,” said Liliana Dávalos, an evolutionary biologist at Stony Brook University, who coauthored the study along with Dina Dechmann, a behavioral ecologist at the Max Planck Institute of Animal Behavior, and John Nieland, a neuroscientist at Aalborg University. “There’s a lot of potential for understanding the mechanics of brain reorganization in an organism that naturally shrinks and regrows, which is something that [humans] cannot do. We’re just on a one-way trip towards shrinking and degenerating.”

In previous work, the research team examined transcripts in the shrews’ cortex and hippocampus—brain regions that are crucial for learning and memory—but in the present study, they shifted their focus to the hypothalamus.⁶ “The hypothalamus is a relay center in the brain to maintain metabolic homeostasis,” explained William Thomas, a postdoctoral fellow in the Dávalos research group and coauthor of the study. “But we’re also looking at the hypothalamus because it is a region that shrinks and regrows as well.” Thus, the hypothalamus could provide insights into the metabolic signaling underlying the total-body restructuring as well as the size changes within the brain itself.

The researchers started by analyzing gene expression in shrews across different points in the lifecycle, including in autumn (when the shrews’ brains were shrinking) and in spring (when their brains were regrowing). Compared to autumn shrews, spring shrews displayed upregulation of transcripts that code for components of inhibitory synapses and downregulation of several genes in the apoptosis pathway.  While the implications of these differences remain to be determined, the findings suggested that synaptic plasticity in the hypothalamus may be related to Dehnel’s phenomenon. Furthermore, the authors speculated that pro- and anti-apoptotic factors may help the shrew control both cell death and cell proliferation during this process.

Dávalos and her team also compared the spring shrew gene expression profiles with publicly available data from species in several other mammalian orders, searching for genes or pathways that appeared to be uniquely up- or down-regulated in S. araneus. Compared to other mammals, two pathways were significantly enriched in the shrew hypothalamus: One of these involved genes related to intracellular signalling and the second included genes responsible for recycling proteins and other components within the cell. Finally, the researchers compared the results of the seasonal and cross-species analyses to identify individual genes that were differently expressed in both data sets. Five genes fit the profile, including CCDC22, which may play a role in the regulation of inflammatory signaling, and FAM57B, which regulates synaptic structure.^7,8

While this study identified many intriguing differences across species, Thomas noted that there are some limitations to the conclusions that can be drawn from this type of comparison. Since there were no publicly available hypothalamic RNA datasets for other species of shrew, the researchers were not able to compare S. araneus to its relatives. “So, we don’t know if all shrews experience this up-regulation or if it’s actually related to Dehnel’s phenomenon,” he noted. “It could just be some sort of up-regulation that’s associated with having high metabolisms or just being a shrew in general.”

Furthermore, since hypothalamic gene expression responds to environmental change, it may be difficult to tease apart the extent to which differences in gene expression are evolved adaptations or responses to an animal’s current environment. Nevertheless, a comprehensive characterization of gene expression over time in a species that displays such remarkable brain plasticity is still worthwhile. 

“What I like about this approach—using RNA [sequencing]—is that it’s sort of a broad stroke approach,” said Christine Schwartz, a hibernation biologist at the University of Wisconsin-La Crosse who was not involved in the study. In species about which relatively little is known, said Schwartz, investigating a single candidate gene might not turn up anything. “But, if you’re able to investigate many [genes] at a time over the course of relevant time points… then you’re able to see these big changes in groups of genes—or maybe genes that you wouldn’t have even thought of might be involved. So that’s really valuable from a scientific perspective.” 

Dávalos said that this is only just beginning; this study lays the groundwork for future explorations into gene functions and drivers of Dehnel’s phenomenon. She also noted that it is still unknown whether these drivers of brain shrinkage and regrowth will be applicable to human neurodegenerative disease.

“On one hand, we think that the shrew as a system is super exciting because it’s giving us insights into the limits of what a mammal can do,” said Dávalos. “On the other hand, we have to respect the fact that this is a shrew, and we’re not going to find some kind of magic bullet. This is simply not how biology works.”

While their work provides the foundation for mechanistic studies that could one day inform strategies to promote brain regeneration in humans, Dávalos said, “We’re also very passionate about the shrew, for the shrew’s sake.”