University of Utah scientists have developed a genetically engineered line of mice that is expected to open the door to new research on epilepsy, Alzheimer’s and other diseases.
The mice carry a protein marker, which changes in degree of fluorescence in response to different calcium levels….
Scientists at Seattle Children’s Research Institute have discovered an area of the brain that could control a person’s motivation to exercise and participate in other rewarding activities – potentially leading to improved treatments for depression.
Dr. Eric Turner, a principal investigator in Seattle Children’s Research Institute’s Center for Integrative Brain Research, together with lead author Dr. Yun-Wei (Toni) Hsu, have discovered that a tiny region of the brain – the dorsal medial habenula – controls the desire to exercise in mice. The structure of the habenula is similar in humans and rodents and these basic functions in mood regulation and motivation are likely to be the same across species.
Exercise is one of the most effective non-pharmacological therapies for depression. Determining that such a specific area of the brain may be responsible for motivation to exercise could help researchers develop more targeted, effective treatments for depression.
“Changes in physical activity and the inability to enjoy rewarding or pleasurable experiences are two hallmarks of major depression,” Turner said. “But the brain pathways responsible for exercise motivation have not been well understood. Now, we can seek ways to manipulate activity within this specific area of the brain without impacting the rest of the brain’s activity.”
Dr. Turner’s study, titled “Role of the Dorsal Medial Habenula in the Regulation of Voluntary Activity, Motor Function, Hedonic State, and Primary Reinforcement,” was published today by the Journal of Neuroscience and funded by the National Institute of Mental Health and National Institute on Drug Abuse. The study used mouse models that were genetically engineered to block signals from the dorsal medial habenula. In the first part of the study, Dr. Turner’s team collaborated with Dr. Horacio de la Iglesia, a professor in University of Washington’s Department of Biology, to show that compared to typical mice, who love to run in their exercise wheels, the genetically engineered mice were lethargic and ran far less. Turner’s genetically engineered mice also lost their preference for sweetened drinking water.
“Without a functioning dorsal medial habenula, the mice became couch potatoes,” Turner said. “They were physically capable of running but appeared unmotivated to do it.”
In a second group of mice, Dr. Turner’s team activated the dorsal medial habenula using optogenetics – a precise laser technology developed in collaboration with the Allen Institute for Brain Science. The mice could “choose” to activate this area of the brain by turning one of two response wheels with their paws. The mice strongly preferred turning the wheel that stimulated the dorsal medial habenula, demonstrating that this area of the brain is tied to rewarding behavior.
Past studies have attributed many different functions to the habenula, but technology was not advanced enough to determine roles of the various subsections of this area of the brain, including the dorsal medial habenula.
“Traditional methods of stimulation could not isolate this part of the brain,” Turner said. “But cutting-edge technology at Seattle Children’s Research Institute makes discoveries like this possible.”
As a professor in the University of Washington Department of Psychiatry and Behavioral Sciences, Dr. Turner treats depression and hopes this research will make a difference in the lives of future patients.
“Working in mental health can be frustrating,” Turner said. “We have not made a lot of progress in developing new treatments. I hope the more we can learn about how the brain functions the more we can help people with all kinds of mental illness.”
New fundamental knowledge about the regulation of stem cells in the nerve tissue of zebrafish embryos results in surprising insights into neurodegenerative disease processes in the human brain. A new study by scientists at VIB and KU Leuven identifies the molecules responsible for this process.
Zebrafish as a model
The zebrafish is a small fish measuring 3 to 5 cm in length, with dark stripes along the length of its body. They are originally from India, but also a popular aquarium fish. Zebrafish have several unusual characteristics that make them popular for scientific research. Zebrafish eggs are fertilized outside the body, where they develop into embryos. This process occurs very quickly: the most important organs have formed after 24 hours and the young fish have hatched after 3 days. These fish are initially transparent, making them easy to study under the microscope. Zebrafish start reproducing after only 3 months. The genetic code of humans and zebrafish is more than 90 % identical. In addition, the genetic material of these fish is easy to manipulate, meaning that they are often used as a model in the study of all sorts of diseases.
Stem cells in the brain
Evgenia Salta, scientist in the team of Bart De Strooper (VIB – KU Leuven), used zebrafish as a model in molecular brain research and discovered a previously unknown regulatory process for the development of nerve cells. Evgenia Salta explains: “The human brain contains stem cells, which are cells that have not matured into nerve cells yet, but do have the potential to do this.” Stem cells are of course crucial in the development of the brain. Similar stem cells also exist in zebrafish. Therefore, these fish form an ideal model to study the behavior of these cells. A so-called Notch signaling pathway regulates the further ripening of these cells during early embryonic development. Scientists are still largely in the dark about Notch processes in the brains of Alzheimer patients, but the research by Evgenia Salta is changing this situation.
The expression of genes, which form the basis of the Notch signaling pathway, is regulated in part by microRNAs (miRNAs), which are short molecules that can inhibit or activate genes. Evgenia Salta: “We specifically studied how miRNA-132 regulates the Notch signaling pathway in stem cells.”
MiRNA-132 appears to play a role in maintaining the plasticity of the adult human brain. The adult brain still contains stem cells, but these are limited in number. The activity of miRNA-132 is reduced in diseases of the nervous system that involve the death of nerve cells, such as Alzheimer’s dementia. “We wanted to study the effect of the reduction in miRNA-132 in the nervous system. Zebrafish are an ideal model for this, because we can easily reduce levels of this miRNA in them. The development of stem cells is impaired in these altered fish. We mapped the molecules that play a role in this process”, explains Evgenia Salta.
The concentration of miRNA-132 is also reduced in the brains of patients with Alzheimer’s disease. Therefore, the zebrafish allow you to mimic a condition that also occurs in Alzheimer’s dementia. Evgenia Salta: “To our surprise, the reduced activity of miRNA-132 in the zebrafish blocks the further ripening of stem cells into nerve cells. This new knowledge about the molecular signaling pathway that underlies this process gives us an insight into the exact blocking mechanism. Thanks to this work in zebrafish, we can now examine in detail what exactly goes wrong in the brains of patients with Alzheimer’s disease.” The research team has therefore started a follow-up study in mice and the brains of deceased patients.
As this research can raise many questions, we would you to refer in your report or article to the e-mail address that VIB has made available for this purpose. Anyone with questions about this research and other medically oriented research can contact: firstname.lastname@example.org.
This research was performed by the research team of Bart De Strooper, who is head of the Leuven Laboratory for Research into Degenerative Diseases and is affiliated with the VIB Center for the Biology of Disease.
A self-organizing miR-132/Ctbp2 circuit regulates bimodal Notch signals and glial progenitor fate choice during spinal cord maturation.Salta E et al. Developmental Cell.
Jane Goodall - studied chimpanzees and has created community-centered conservation programs that not only protect chimpanzees of Gombe National Park in Tanzania, but also take into account the needs of the people crucial to their protection
Hayat Sindi - created low-tech diagnostic tools to aid in the improvement of healthcare in the world’s poorest communities, has a Cambridge University Ph.D. in biotechnology
Kakenya Ntaiya - teacher building the first school for girls in her rural Kenyan village, refuses to accept Maasai woman’s traditionally subservient role, hopes that expanding education and leadership opportunities for girls will also improve life for the entire village
Nalini Nadkarni - uses mountain climbing gear to climb into the rainforest canopies of Costa Rica and researches the threats of global warming
Sarah McNair-Landry - youngest person to ski to the South Pole, sledged to the North Pole, and crossed ~1,400 miles of the Greenland ice cap to draw attention to the dangers of global warming
Dian Fossey - studied endangered gorillas in the Virunga Volcanoes of Rwanda, her devotion to their care and protection cost her her life and she was probably murdered by poachers who she fought relentlessly.
I hope that one day I can be added to this list of incredible and inspiring women.
Photographs by Hugo Van Lawick, Kris Krug, Philip Scott Andrews, Michael and Patricia Fogden, John Stetson, Robert I. M. Campbell