Study Uncovers Molecular Mechanisms During Shrew’s Brain Changes

Published in eLife, the research findings could provide insight to how certain genes change in human neurological diseases

STONY BROOK, NY, November 21, 2024 - New research led by William R. Thomas, PhD, with Professor Liliana M. Dávalos, PhD, in the Department of Ecology and Evolution at Stony Brook University, shows how the Eurasian common shrew (Sorex araneus) changes its brain and bodily size throughout the year. The study, published online in eLife, reveals how changes in gene expression enable these small mammals to shrink their brain in winter and regrow it in spring, defying the typical mammalian pattern where organ size does not change. Their findings offer genetic clues to neurological and metabolic health in mammals.

The Eurasian common shrew, which has a fast metabolism, has the ability to shrink its brain and other organs to survive winters, a rare metabolic phenomenon that preserves its energy.
Credit: Christian Ziegler of the Max Planck Institute of Animal Behavior

This research explores the molecular underpinnings of Dehnel's phenomenon, a rare adaptation in which the shrew's brain, skull, and other organs shrink by up to 30 percent, conserving energy in the face of low temperatures and scarce food. While most other small mammals hibernate or migrate to survive winter, the shrew remains active, relying on this size change to reduce energy demand while maintaining a hyperactive metabolism.

Thomas and colleagues focused on investigating the hypothalamus, a brain region that regulates energy balance. They measured how gene expression shifts both seasonally in the shrew and between various mammalian species, including humans.

"We generated a unique data set, with which we were able to compare the shrew hypothalamus across seasons and species," says Thomas. "We found a suite of genes that change across the seasons involved in the regulation of energy homeostasis, as well as genes that regulate cell death that we propose may be associated with reductions in brain size."

The team discovered that genes involved in maintaining the blood-brain barrier and calcium signaling were also found to be upregulated -more highly expressed -in the shrew compared to many other mammals. While the blood-brain barrier regulates what chemicals enter the brain, calcium signaling relays these signals across the brain. Therefore, these evolutionary changes may allow the hypothalamus to efficiently sense and manage energy, thus meeting the shrew's high metabolic demands.

Connecting the findings with human neurological diseases

Thomas and Dávalos believe the findings from the study present new opportunities for scientists to understand neurological diseases in humans and that particular genes identified in the shrew could be important candidates for future therapeutic treatment of certain diseases.

Several genes with roles in human neurological and metabolic disorders, including CCDC22, varied by season and were upregulated in the shrew. CCDC22 plays a key role in recycling proteins in cells. Improper recycling results in the aggregation of proteins in cells, which is a hallmark of several neurological diseases including ALS, Alzheimer's disease, and Parkinson's disease. Thomas and Dávalos propose that the regulation of this this gene in the shrew brain may serve as a neuroprotective mechanisms, that is especially important during the restoration of brain mass.

Thomas also explains that for humans, chronic metabolic dysfunction is often linked with the development and progression of neurological diseases. By studying how the hypothalamus shrinks and regrows in shrews, researchers can better understand how metabolic shifts influence brain size, with the hopes that these insights may one day inform strategies to reverse similar changes in humans as they age.

Multiple methods were used to identify the genes involved during the brain-shrinking process such as RNA extraction, sequencing, and identifying differential gene expression through seasons and between species.

The team aims to continue their research in two ways. First, along with collaborators they will continue to build the infrastructure to study the shrew's phenotype to better explore the physiological and anatomical changes associated with brain size. They are already working with collaborators and developed an MRI, histological, and gene expression atlas for the shrew.

Second, the researchers are continuing to research how genes have evolved within the shrew compared to other mammals. To address this, they plan to investigate how shrew genes have evolved in comparison to other mammals and conduct more functional tests in cell lines to determine whether gene expression changes play similar roles in brain physiology.

This international collaboration included researchers from the Max Planck Institute of Animal Behavior, the University of Massachusetts in Boston, Aalborg University in Denmark, John Jay College of Criminal Justice, and University Medical Center in Freiburg, Germany.

The work was funded in part by the Human Frontiers of Science Program and a Presidential Innovation and Excellence award to Dávalos from Stony Brook University.

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