Posts tagged mouse brain
Articles and news from the latest research reports.
Publication in Nature Showcases Most Comprehensive Wiring Diagram of the Mammalian Brain To Date
Researchers from the Allen Institute for Brain Science have published the first comprehensive, large-scale data set on how the brain of a mammal is wired, providing a groundbreaking data resource and fresh insights into how the nervous system processes information. Their landmark paper in this week’s issue of the journal Nature both describes the publicly available Allen Mouse Brain Connectivity Atlas, and demonstrates the exciting knowledge that can be gleaned from this valuable resource.
(Image: Connectivity Dot-o-Gram)
“Understanding how the brain is wired is among the most crucial steps to understanding how the brain encodes information,” explains Hongkui Zeng, Senior Director of Research Science at the Allen Institute for Brain Science. “The Allen Mouse Brain Connectivity Atlas is a standardized, quantitative, and comprehensive resource that will stimulate exciting investigations around the entire neuroscience community, and from which we have already gleaned unprecedented details into how structures are connected inside the brain.”
Using the data, Allen Institute scientists were able to demonstrate that there are highly specific patterns in the connections among different brain regions, and that the strengths of these connections vary with greater than five orders of magnitudes, balancing a small number of strong connections with a large number of weak connections. This publication comes just as the research team wraps up more than four years of work to collect and make publicly available the data behind the Allen Mouse Brain Connectivity Atlas project, with the completion of the Atlas announced in March 2014.
(Source: alleninstitute.org)
Analysis of 26 networked autism genes suggests functional role in the cerebellum
A team of scientists has obtained intriguing insights into two groups of autism candidate genes in the mammalian brain that new evidence suggests are functionally and spatially related. The newly published analysis identifies two networked groupings from 26 genes associated with autism that are overexpressed in the cerebellar cortex, in areas dominated by neurons called granule cells.
The team, composed of neuroscientists and computational biologists, worked from a database providing expression levels of individual genes throughout the mouse brain, as complied in the open-source Allen Mouse Brain Atlas. To promote reproducibility, the scientists surveyed expression data of over 3000 genes, about three-fourths of all the genes listed in the Atlas for which two independent sets of data have been complied.
The work was led by Professor Partha Mitra of Cold Spring Harbor Laboratory (CSHL) and scientists from MindSpec, a nonprofit research organization, founded by Dr. Sharmila Banerjee-Basu.
Despite obvious genetic and neuroanatomical differences between mouse and human, the team explains, mouse models are extremely effective in dissecting out the role of specific genes, pathways, neuronal subtypes and brain regions in specific abnormal behaviors manifested in both mice and people.
Based on years of studies in both species, scientists now know of mutations affecting more than 300 genes whose occurrence correlates with autism susceptibility; more are certain to be identified. Some of these candidate genes are more strongly correlated with the illness than others, although correlation is not the same thing as direct evidence of causation.
Nevertheless, “the key question as yet unanswered,” notes Dr. Mitra, “concerns the way or ways in which particular mutations, singly or in combination, cause pathologies that result in the complex combination of symptoms that characterizes autism in children.” It is assumed that autism pathologies are the result of insults — genetic, environmental, or most likely both — sustained at the time of conception and early in development.
Dr. Idan Menashe, now of Ben-Gurion University of the Negev in Israel, and Dr. Pascal Grange, a postdoctoral researcher in the Mitra lab, demonstrated that co-expression of 26 autism genes was “significantly higher” than would occur by chance. “This suggests that these 26 genes have common neuro-functional properties,” says Dr. Menashe.
The team found two co-expressed networks or “cliques” of genes that are significantly enriched with autism genes. They then asked where in the mouse brain these cliques are expressed. Notably, genes in both groups showed significant overexpression in the cerebellar cortex, and particularly in regions in which granule cells predominate. “This result supports prior studies pointing to involvement of the cerebellum in autism,” says Dr. Grange. Specifically, a recent neuroimaging study highlighted functional subregions in the cerebellum as playing a role in both motor and cognitive tasks. Other genes associated with autism have been shown in other studies to play a role in the development of this brain region.
“Our study provides insights into co-expression properties of genes associated with autism and suggests specific brain regions implicated in pathology. Complementing these findings with additional genomic and neuroimaging analyses from both mouse and human brains will help in obtaining a broader picture of the autistic brain,” the team concludes.
Human Brain Cells Developed in Lab, Grow in Mice
A key type of human brain cell developed in the laboratory grows seamlessly when transplanted into the brains of mice, UC San Francisco researchers have discovered, raising hope that these cells might one day be used to treat people with Parkinson’s disease, epilepsy, and possibly even Alzheimer’s disease, as well as and complications of spinal cord injury such as chronic pain and spasticity.
“We think this one type of cell may be useful in treating several types of neurodevelopmental and neurodegenerative disorders in a targeted way,” said Arnold Kriegstein, MD, PhD, director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF and co-lead author on the paper.
The researchers generated and transplanted a type of human nerve-cell progenitor called the medial ganglionic eminence (MGE) cell, in experiments described in the May 2 edition of Cell Stem Cell. Development of these human MGE cells within the mouse brain mimics what occurs in human development, they said.
Kriegstein sees MGE cells as a potential treatment to better control nerve circuits that become overactive in certain neurological disorders. Unlike other neural stem cells that can form many cell types — and that may potentially be less controllable as a consequence — most MGE cells are restricted to producing a type of cell called an interneuron. Interneurons integrate into the brain and provide controlled inhibition to balance the activity of nerve circuits.
To generate MGE cells in the lab, the researchers reliably directed the differentiation of human pluripotent stem cells — either human embryonic stem cells or induced pluripotent stem cells derived from human skin. These two kinds of stem cells have virtually unlimited potential to become any human cell type. When transplanted into a strain of mice that does not reject human tissue, the human MGE-like cells survived within the rodent forebrain, integrated into the brain by forming connections with rodent nerve cells, and matured into specialized subtypes of interneurons.
These findings may serve as a model to study human diseases in which mature interneurons malfunction, according to Kriegstein. The researchers’ methods may also be used to generate vast numbers of human MGE cells in quantities sufficient to launch potential future clinical trials, he said.
Kriegstein was a co-leader of the research, along with Arturo Alvarez-Buylla, PhD, UCSF professor of neurological surgery; John Rubenstein, MD, PhD, UCSF professor of psychiatry; and UCSF postdoctoral scholars Cory Nicholas, PhD, and Jiadong Chen, PhD.
Nicholas utilized key growth factors and other molecules to direct the derivation and maturation of the human MGE-like interneurons. He timed the delivery of these factors to shape their developmental path and confirmed their progression along this path. Chen used electrical measurements to carefully study the physiological and firing properties of the interneurons, as well as the formation of synapses between neurons.
Previously, UCSF researchers led by Allan Basbaum, PhD, chair of anatomy at UCSF, have used mouse MGE cell transplantation into the mouse spinal cord to reduce neuropathic pain, a surprising application outside the brain. Kriegstein, Nicholas and colleagues now are exploring the use of human MGE cells in mouse models of neuropathic pain and spasticity, Parkinson’s disease and epilepsy.
“The hope is that we can deliver these cells to various places within the nervous system that have been overactive and that they will functionally integrate and provide regulated inhibition,” Nicholas said.
The researchers also plan to develop MGE cells from induced pluripotent stem cells derived from skin cells of individuals with autism, epilepsy, schizophrenia and Alzheimer’s disease, in order to investigate how the development and function of interneurons might become abnormal — creating a lab-dish model of disease.
One mystery and challenge to both the clinical and pre-clinical study of human MGE cells is that they develop at a slower, human pace, reflecting an “intrinsic clock”. In fast-developing mice, the human MGE-like cells still took seven to nine months to form interneuron subtypes that normally are present near birth.
“If we could accelerate the clock in human cells, then that would be very encouraging for various applications,” Kriegstein said.
(Source: newswise.com)
Australian scientists map mouse brains in greatest detail yet
Hopes for a cure for many brain diseases may rest on the humble mouse, now that scientists can map the rodents’ brains more thoroughly than ever before.
Researchers at The University of Queensland’s Centre for Advanced Imaging (CAI) and Curtin University have created the most detailed atlas of the mouse brain, a development that is helping in the fight against brain disease.
This new tool will allow researchers to map what parts of the brain are affected in mouse models of brain disease – such as brain cancer, Parkinson’s disease and Alzheimers disease, which affect nearly 1 in 6 of the world’s population.
Lead author, Dr Jeremy Ullmann said that the new brain atlas provided a fundamental tool for the neuroscience community.
“The mouse is now the most widely used animal model for neuroscience research and magnetic resonance imaging (MRI) is fundamental to investigating changes in the brain,” Dr Ullman said.
“Our atlas is already much in demand internationally because it allows researchers to use MRI to automatically map brain structures.”
The atlas was created in the laboratory of Professor David Reutens, CAI Director.
“In making these world-first maps, we had the advantage of using the most powerful MRI scanners in the Southern Hemisphere, backed up by leaders in digital image analysis, resulting in remarkably clear images of the brain,” Professor Reutens said.
The project’s lead neuroanatomist, Professor Charles Watson from Curtin University, believes that the study will open the door to accurate analysis of gene targeting in the mouse brain.
“The invention of gene targeting in the mouse has made this species the centrepiece of studies on models of human brain disease. MRI allows researchers to follow changes in the brain over time in the same animals,” Professor Watson said.
The atlas was recently described in an article published in the journal NeuroImage.
See-through brains clarify connections
Technique to make tissue transparent offers three-dimensional view of neural networks.
A chemical treatment that turns whole organs transparent offers a big boost to the field of ‘connectomics’ — the push to map the brain’s fiendishly complicated wiring. Scientists could use the technique to view large networks of neurons with unprecedented ease and accuracy. The technology also opens up new research avenues for old brains that were saved from patients and healthy donors.
“This is probably one of the most important advances for doing neuroanatomy in decades,” says Thomas Insel, director of the US National Institute of Mental Health in Bethesda, Maryland, which funded part of the work. Existing technology allows scientists to see neurons and their connections in microscopic detail — but only across tiny slivers of tissue. Researchers must reconstruct three-dimensional data from images of these thin slices. Aligning hundreds or even thousands of these snapshots to map long-range projections of nerve cells is laborious and error-prone, rendering fine-grain analysis of whole brains practically impossible.
The new method instead allows researchers to see directly into optically transparent whole brains or thick blocks of brain tissue. Called CLARITY, it was devised by Karl Deisseroth and his team at Stanford University in California. “You can get right down to the fine structure of the system while not losing the big picture,” says Deisseroth, who adds that his group is in the process of rendering an entire human brain transparent.
The technique, published online in Nature on 10 April, turns the brain transparent using the detergent SDS, which strips away lipids that normally block the passage of light. Other groups have tried to clarify brains in the past, but many lipid-extraction techniques dissolve proteins and thus make it harder to identify different types of neurons. Deisseroth’s group solved this problem by first infusing the brain with acrylamide, which binds proteins, nucleic acids and other biomolecules. When the acrylamide is heated, it polymerizes and forms a tissue-wide mesh that secures the molecules. The resulting brain–hydrogel hybrid showed only 8% protein loss after lipid extraction, compared to 41% with existing methods.
Applying CLARITY to whole mouse brains, the researchers viewed fluorescently labelled neurons in areas ranging from outer layers of the cortex to deep structures such as the thalamus. They also traced individual nerve fibres through 0.5-millimetre-thick slabs of formalin-preserved autopsied human brain — orders of magnitude thicker than slices currently imaged.
“The work is spectacular. The results are unlike anything else in the field,” says Van Wedeen, a neuroscientist at the Massachusetts General Hospital in Boston and a lead investigator on the US National Institutes of Health’s Human Connectome Project (HCP), which aims to chart the brain’s neuronal communication networks. The new technique, he says, could reveal important cellular details that would complement data on large-scale neuronal pathways that he and his colleagues are mapping in the HCP’s 1,200 healthy participants using magnetic resonance imaging.
Francine Benes, director of the Harvard Brain Tissue Resource Center at McLean Hospital in Belmont, Massachusetts, says that more tests are needed to assess whether the lipid-clearing treatment alters or damages the fundamental structure of brain tissue. But she and others predict that CLARITY will pave the way for studies on healthy brain wiring, and on brain disorders and ageing.
Researchers could, for example, compare circuitry in banked tissue from people with neurological diseases and from controls whose brains were healthy. Such studies in living people are impossible, because most neuron-tracing methods require genetic engineering or injection of dye in living animals. Scientists might also revisit the many specimens in repositories that have been difficult to analyse because human brains are so large.
The hydrogel–tissue hybrid formed by CLARITY — stiffer and more chemically stable than untreated tissue — might also turn delicate and rare disease specimens into reusable resources, Deisseroth says. One could, in effect, create a library of brains that different researchers check out, study and then return.