Posts tagged animal model
Articles and news from the latest research reports.
The skin is a human being’s largest sensory organ, helping to distinguish between a pleasant contact, like a caress, and a negative sensation, like a pinch or a burn. Previous studies have shown that these sensations are carried to the brain by different types of sensory neurons that have nerve endings in the skin. Only a few of those neuron types have been identified, however, and most of those detect painful stimuli. Now biologists at the California Institute of Technology (Caltech) have identified in mice a specific class of skin sensory neurons that reacts to an apparently pleasurable stimulus.
More specifically, the team, led by David J. Anderson, Seymour Benzer Professor of Biology at Caltech, was able to pinpoint individual neurons that were activated by massage-like stroking of the skin. The team’s results are outlined in the January 31 issue of the journal Nature.
UCI neuroscientists create fiber-optic method of arresting epileptic seizures
UC Irvine neuroscientists have developed a way to stop epileptic seizures with fiber-optic light signals, heralding a novel opportunity to treat the most severe manifestations of the brain disorder.
Using a mouse model of temporal lobe epilepsy, Ivan Soltesz, Chancellor’s Professor and chair of anatomy & neurobiology, and colleagues created an EEG-based computer system that activates hair-thin optical strands implanted in the brain when it detects a real-time seizure.
These fibers subsequently “turn on” specially expressed, light-sensitive proteins called opsins, which can either stimulate or inhibit specific neurons in select brain regions during seizures, depending on the type of opsin.
The researchers found that this process was able to arrest ongoing electrical seizure activity and reduce the incidence of severe “tonic-clonic” events.
“This approach is useful for understanding how seizures occur and how they can be stopped experimentally,” Soltesz said. “In addition, clinical efforts that affect a minimum number of cells and only at the time of a seizure may someday overcome many of the side effects and limitations of currently available treatment options.”
Study results appear online in Nature Communications.
More than 3 million Americans suffer from epilepsy, a condition of recurrent spontaneous seizures that occur unpredictably, often cause changes in consciousness, and can preclude normal activities such as driving and working. In at least 40 percent of patients, seizures cannot be controlled with existing drugs, and even in those whose seizures are well controlled, the treatments can have major cognitive side effects.
Although the study was carried out in mice, not humans, Soltesz said the work could lead to a better alternative to the currently available electrical stimulation devices.
Stem Cell Research Helps to Identify Origins of Schizophrenia
New University at Buffalo research demonstrates how defects in an important neurological pathway in early development may be responsible for the onset of schizophrenia later in life.
The UB findings, published in Schizophrenia Research, test the hypothesis in a new mouse model of schizophrenia that demonstrates how gestational brain changes cause behavioral problems later in life – just like the human disease.
Partial funding for the research came from New York Stem Cell Science (NYSTEM).
The genomic pathway, called the Integrative Nuclear FGFR 1 Signaling (INFS), is a central intersection point for multiple pathways of as many as 160 different genes believed to be involved in the disorder.
“We believe this is the first model that explains schizophrenia from genes to development to brain structure and finally to behavior,” says lead author Michal Stachowiak, PhD, professor in the Department of Pathology and Anatomical Sciences in the UB School of Medicine and Biomedical Sciences. He also is director of the Stem Cell Engraftment & In Vivo Analysis Facility at the Western New York Stem Cell Culture and Analysis Center at UB.
A key challenge with the disease is that patients with schizophrenia exhibit mutations in different genes, he says.
“How is it possible to have 100 patients with schizophrenia and each one has a different genetic mutation that causes the disorder?” asks Stachowiak. “It’s possible because INFS integrates diverse neurological signals that control the development of embryonic stem cell and neural progenitor cells, and links pathways involving schizophrenia-linked genes.
“INFS functions like the conductor of an orchestra,” explains Stachowiak. “It doesn’t matter which musician is playing the wrong note, it brings down the conductor and the whole orchestra. With INFS, we propose that when there is an alteration or mutation in a single schizophrenia-linked gene, the INFS system that controls development of the whole brain becomes untuned. That’s how schizophrenia develops.”
Using embryonic stem cells, Stachowiak and colleagues at UB and other institutions found that some of the genes implicated in schizophrenia bind the FGFR1 (fibroblast growth factor receptor) protein, which in turn, has a cascading effect on the entire INFS.
A New Focus on the ‘Post’ in Post-Traumatic Stress
Psychological trauma dims tens of millions of lives around the world and helps create costs of at least $42 billion a year in the United States alone. But what is trauma, exactly?
Both culturally and medically, we have long seen it as arising from a single, identifiable disruption. You witness a shattering event, or fall victim to it — and as the poet Walter de la Mare put it, “the human brain works slowly: first the blow, hours afterward the bruise.” The world returns more or less to normal, but you do not.
In 1980, the Diagnostic and Statistical Manual of Mental Disorders defined trauma as “a recognizable stressor that would evoke significant symptoms of distress in almost everyone” — universally toxic, like a poison.
But it turns out that most trauma victims — even survivors of combat, torture or concentration camps — rebound to live full, normal lives. That has given rise to a more nuanced view of trauma — less a poison than an infectious agent, a challenge that most people overcome but that may defeat those weakened by past traumas, or other factors.
Now, a significant body of work suggests that even this view is too narrow — that the environment just after the event, particularly other people’s responses, may be just as crucial as the event itself.
The idea was demonstrated vividly in two presentations this fall at the Interdisciplinary Conference on Culture, Mind and Brain at the University of California, Los Angeles. Each described reframing a classic model of traumatic experience — one in lab rats, the other in child soldiers.
Resistance to cocaine addiction may be passed down from father to son
Research from the Perelman School of Medicine at the University of Pennsylvania and Massachusetts General Hospital (MGH) reveals that sons of male rats exposed to cocaine are resistant to the rewarding effects of the drug, suggesting that cocaine-induced changes in physiology are passed down from father to son. The findings are published in the latest edition of Nature Neuroscience.
"We know that genetic factors contribute significantly to the risk of cocaine abuse, but the potential role of epigenetic influences – how the expression of certain genes related to addiction is controlled – is still relatively unknown," said senior author R. Christopher Pierce, PhD, associate professor of Neuroscience in Psychiatry at Penn. "This study is the first to show that the chemical effects of cocaine use can be passed down to future generations to cause a resistance to addictive behavior, indicating that paternal exposure to toxins such as cocaine can have profound effects on gene expression and behavior in their offspring."
In the current study, the team used an animal model to study inherited effects of cocaine abuse. Male rats self-administered cocaine for 60 days, while controls were administered saline. The male rats were mated with females that had never been exposed to the drug. To eliminate any influence that the males’ behavior would have on the pregnant females, they were separated directly after they mated.
The rats’ offspring were monitored to see whether they would begin to self-administer cocaine when it was offered to them. The researchers discovered that male offspring of rats exposed to the drug, but not the female offspring, acquired cocaine self-administration more slowly and had decreased levels of cocaine intake relative to controls. Moreover, control animals were willing to work significantly harder for a single cocaine dose than the offspring of cocaine-addicted rats, suggesting that the rewarding effect of cocaine was decreased.
In collaboration with Ghazaleh Sadri-Vakili, MS, PhD, from MGH, the researchers subsequently examined the animals’ brains and found that male offspring of the cocaine-addicted rats had increased levels of a protein in the prefrontal cortex called brain-derived neurotrophic factor (BDNF), which is known to blunt the behavioral effects of cocaine.
"We were quite surprised that the male offspring of sires that used cocaine didn’t like cocaine as much," said Pierce. "While we identified one change in the brain that appears to underlie this cocaine resistance effect, there are undoubtedly other physiological changes as well and we are currently performing more broad experiments to identify them. We also are eager to perform similar studies with more widely used drugs of abuse such as nicotine and alcohol."
The findings suggest that cocaine use causes epigenetic changes in sperm, thereby reprogramming the information transmitted between generations. The researchers don’t know exactly why only the male offspring received the cocaine-resistant trait from their fathers, but speculate that sex hormones such as testosterone, estrogen and/or progesterone may play a role.
(Source: eurekalert.org)
Kentucky team inhibits Alzheimer’s biomarkers in animal model by targeting astrocytes
A research team composed of University of Kentucky researchers has published a paper which provides the first direct evidence that activated astrocytes could play a harmful role in Alzheimer’s disease. The UK Sanders-Brown Center on Aging has also received significant new National Institutes of Health (NIH) funding to further this line of study.
Chris Norris, an associate professor in the UK College of Medicine Department of Molecular and Biomedical Pharmacology, as well as a member of the faculty at the UK Sanders-Brown Center on Aging, is the senior author on a paper published recently in the Journal of Neuroscience, entitled “Targeting astrocytes to ameliorate neurologic changes in a mouse model of Alzheimer’s disease.” The first author on the article, Jennifer L. Furman, was a graduate student in the Norris laboratory during completion of the study.
The astrocyte is a very abundant non-neuronal cell type that performs absolutely critical functions for maintaining healthy nervous tissue. However, in neurodegenerative diseases, like Alzheimer’s disease, many astrocytes exhibit clear physical changes often referred to as “astrocyte activation.” The appearance of activated astrocytes at very early stages of Alzheimer’s has led to the idea that astrocytes contribute to the emergence and/or maintenance of other pathological markers of the disease, including synaptic dysfunction, neuroinflammation and accumulation of amyloid plaques.
Using an animal model, researchers directly modulated the activation state of hippocampal astrocytes using a form of gene therapy.
Mice received the gene therapy at a very young age, before the development of extensive amyloid plaque pathology, and were assessed 10 months later on a variety of Alzheimer’s biomarkers.
The research team found that inhibition of astrocyte activation blunted the activation of microglia (a cell that mediates neuroinflammation), reduced toxic amyloid levels, improved synaptic function and plasticity, and preserved cognitive function.
Norris and collaborators suggest that similar astrocyte-based approaches could be developed to treat humans suffering from Alzheimer’s disease, or possibly other neurodegenerative diseases. This study provides proof of principle that therapeutically targeting astrocytes can be beneficial.
(Source: eurekalert.org)
Lithium rescues synaptic plasticity and memory in Down syndrome mice
Down syndrome (DS) patients exhibit abnormalities of hippocampal-dependent explicit memory, a feature that is replicated in relevant mouse models of the disease. Adult hippocampal neurogenesis, which is impaired in DS and other neuropsychiatric diseases, plays a key role in hippocampal circuit plasticity and has been implicated in learning and memory. However, it remains unknown whether increasing adult neurogenesis improves hippocampal plasticity and behavioral performance in the multifactorial context of DS. We report that, in the Ts65Dn mouse model of DS, chronic administration of lithium, a clinically used mood stabilizer, promoted the proliferation of neuronal precursor cells through the pharmacological activation of the Wnt/β-catenin pathway and restored adult neurogenesis in the hippocampal dentate gyrus (DG) to physiological levels. The restoration of adult neurogenesis completely rescued the synaptic plasticity of newborn neurons in the DG and led to the full recovery of behavioral performance in fear conditioning, object location, and novel object recognition tests. These findings indicate that reestablishing a functional population of hippocampal newborn neurons in adult DS mice rescues hippocampal plasticity and memory and implicate adult neurogenesis as a promising therapeutic target to alleviate cognitive deficits in DS patients.
Iron deficiency and cognitive development: New insights from piglets
University of Illinois researchers have developed a model that uses neonatal piglets for studying infant brain development and its effect on learning and memory. To determine if the model is nutrient-sensitive, they have done some research on the effects of iron-deficient diets.
“Iron deficiency is a major problem worldwide,” said Rodney Johnson, professor of animal sciences and director of the Division of Nutritional Sciences. “Infants who experience iron deficiency during the first 6 to 12 months of age can have irreversible developmental delays in cognition.”
He said that, even in the United States, iron deficiency is a significant problem. “Babies born to obese mothers are at risk for iron deficiency,” said Johnson. “Furthermore, the incidence of child obesity is increasing, and being overweight or obese is a risk factor for iron deficiency. Overweight toddlers are nearly three times more likely to suffer from iron deficiency than are those with a healthy weight.”
Johnson said that this work highlights a new translational model for studying micronutrient deficiencies. Traditional rodent models are less suited for examining these kinds of questions because they cannot be weaned early and placed on experimental diets. Pigs, however, are a precocial species, which means that their motor and sensory skills are quite well developed at birth. This facilitates early weaning and behavioral testing.
An article describing this research, “Early Life Iron Deficiency Impairs Spatial Cognition in Neonatal Piglets” by Jennifer L. Rytych, Monica R. P. Elmore, Michael D. Burton, Matthew S. Conrad, Sharon M. Donovan, Ryan N. Dilger, and Rodney W. Johnson has recently been published in The Journal of Nutrition.
University of Minnesota researchers find new target for Alzheimer’s drug development
Researchers at the University of Minnesota’s Center for Drug Design have developed a synthetic compound that, in a mouse model, successfully prevents the neurodegeneration associated with Alzheimer’s disease.
In the pre-clinical study, researchers Robert Vince, Ph.D.; Swati More, Ph.D.; and Ashish Vartak, Ph.D., of the University’s Center for Drug Design, found evidence that a lab-made compound known as psi-GSH enables the brain to use its own protective enzyme system, called glyoxalase, against the Alzheimer’s disease process.
The discovery is published online in the American Chemical Society journal ACS Chemical Neuroscience and presents a new target for the design of anti-Alzheimer’s and related drugs.
“While most other drugs under development and on the market attempt to slow down or reverse the Alzheimer’s processes, our approach strikes at a root cause by enabling the brain itself to fight the disease at a very early stage,” said Vince, the study’s lead researcher and director of the Center for Drug Design. “As is the case with all drug development, these studies need to be replicated in human patients before coming to any firm conclusions.”
New Treatment Aids Weight Loss, Improves Diabetes in Monkeys
A new, lab-created antibody that mimics the action of a naturally occurring molecule causes weight loss in monkeys, researchers report.
The engineered antibody also appears to improve insulin sensitivity, which could fight type 2 diabetes, and it decreases levels of triglycerides, a blood fat that contributes to hardening of the arteries.
"The results we describe in animal models are profound and very encouraging," said study senior author Yang Li, scientific director at Amgen, Inc., in Thousand Oaks, Calif. "While we’re excited about these findings, we’re still evaluating the results."
Li said it’s important to remember these findings were in monkeys and only in a preclinical setting. It’s not yet clear how this treatment might act in humans.
The study was funded by Amgen, the developer of the new treatment. The findings are published in the Nov. 28 issue of Science Translational Medicine.
(Image: Courtesy of iStockphoto/GlobalP)