A team of researchers has built a mathematical model that describes the molecular events associated with the beginning stage of learning and memory formation in the human brain.
The research, published in the journal Proceedings of the National Academy of Sciences, paves the way for understanding cognitive function and neurodegenerative diseases—at the molecular and cellular levels.
The study focuses on the dynamics of dendritic spines, which are thorny structures that allow neurons to communicate with each other. When a spine receives a signal from another neuron, it responds by rapidly expanding in volume—an event called transient spine expansion.
Transient spine expansion is one of the early events leading up to learning and memory formation. It consists of a cascade of molecular processes spanning four to five minutes, beginning when a neuron sends a signal to another neuron.
Many of the molecular processes leading up to transient spine expansion have already been identified experimentally and reported in the literature. Here, the authors built a map of many of these known processes into a computational framework.
“Spines are dynamic structures, changing in size, shape and number during development and aging. Spine dynamics have been implicated in memory, learning and various neurodegenerative and neurodevelopmental disorders, including Alzheimer’s, Parkinson’s and autism. Understanding how the different molecules can affect spine dynamics can eventually help us demystify some of these processes in the brain,” said Padmini Rangamani, a mechanical engineering professor at the University of California San Diego and first author of the study.
“This work shows that dendritic spines, which are sub-micrometer compartments within individual neurons, are the prime candidates for the initial tag of transient, millisecond synaptic activity that eventually orchestrates memory traces in the brain lasting tens of years,” said Shahid Khan, senior scientist at the Molecular Biology Consortium at Lawrence Berkeley National Laboratory and a co-author on the PNAS paper.
In this study, researchers constructed a mathematical model, based on ordinary differential equations, linking the different molecular processes associated with spine expansion together. They identified the key components (molecules and enzymes) and chemical reactions that regulate spine expansion.
As a result, they observed an interesting pattern—that the same components could both turn on and off some of the steps in the sequence—a phenomenon called paradoxical signaling. Further, they linked the chemical reactions of the different molecules to the reorganization of the actin cytoskeleton, which gives the cell its shape.
Both of these features—paradoxical signaling and linking spine expansion to actin reorganization—make this model robust, Rangamani explained. “By putting all these complicated pieces together in a simple mathematical framework, we can start to understand the underlying mechanisms of spine expansion. This is one of the benefits of combining mechanics of the cytoskeleton and biochemistry. We can bring together pieces of experimental work that are often not seen. However, we should note that we are only at the beginning stages of understanding what spines, neurons and the brain can do.”
“This work is notable for bringing together aspects from diverse disciplines (systems biology, cell signaling, actin mechanobiology and proteomics) and should motivate similar multi-disciplinary efforts for other problems in fundamental cellular neuroscience,” Khan said.
A new low-cost and non-invasive eye test could detect Parkinson’s disease before symptoms including tremors and muscle stiffness develop, according to new research in rats led by scientists at UCL.
Researchers at the UCL Institute of Ophthalmology have discovered a new method of observing changes in the retina which can be seen in Parkinson’s before changes in the brain occur and the first symptoms become evident.
Using ophthalmic instruments that are routinely used in optometrists and eye clinics, the scientists were able to use the new imaging technique to observe these retinal changes at an early stage.
This method, published in Acta Neuropathologica Communications, would allow earlier diagnosis of Parkinson’s and also could be used to monitor how patients respond to treatment. The technique has already been tested in humans for glaucoma and trials are due to start soon for Alzheimer’s.
“This is potentially a revolutionary breakthrough in the early diagnosis and treatment of one of the world’s most debilitating diseases,” said Professor Francesca Cordeiro, UCL Professor of Glaucoma & Retinal Neurodegeneration Studies, who led the research.
“These tests mean we might be able to intervene much earlier and more effectively treat people with this devastating condition.”
Parkinson’s disease affects 1 in 500 people and is the second most common neurodegenerative disease worldwide. Symptoms typically become apparent only once over 70 percent of the brain’s dopamine-producing cells have been destroyed.
The condition results in muscle stiffness, slowness of movement, tremors and a reduced quality of life.
Following the observation of retinal changes in the experimental model, Professor Cordeiro and her team treated the animals with a newly formulated version of the anti-diabetic drug Rosiglitazone, which helps to protect nerve cells. After using this drug, there was clear evidence of reduced retina cell death as well as a protective effect on the brain which suggests that it could have potential as a treatment for Parkinson’s disease.
“These discoveries have the potential to limit and perhaps eliminate the suffering of thousands of patients if we are able to diagnose early and to treat with this new formulation,” said first author Dr Eduardo Normando, Consultant Ophthalmologist at Western Eye Hospital and UCL.
“The evidence we have strongly suggests that we might be able to intervene much earlier and more effectively in treating people with this devastating condition, using this non-invasive and affordable imaging technique”, said Dr Normando.
Rutgers and Stanford scientists develop novel way to inject healthy human nerve cells into the brain
The scaffolds, loaded with healthy, beneficial neurons that can replace diseased cells, were injected into mouse brains. Neurons, or nerve cells, are critical for human health and functioning. Human brains have about 100 billion neurons, which serve as messengers that transmit signals from the body to the brain and vice versa.
Research that could lead to new medical imaging methods and better treatments for stroke and other brain conditions
A technique Stanford Linear Accelerator Center (SLAC) scientists invented for scanning ancient manuscripts is now being used to probe the human brain, in research that could lead to new medical imaging methods and better treatments for stroke and other brain conditions.
The studies, taking place at SLAC’s Stanford Synchrotron Radiation Lightsource, are led by cell biologist Helen Nichol, of the University of Saskatchewan, with $2.5 million in funding from the Canadian government and the Heart and Stroke Foundation of Canada.
Her team, which includes a Stanford neurosurgeon and stem cell expert, other medical doctors and experts in stroke research and medical imaging, reflects the broad ambitions of this research: to give doctors a better understanding of what they’re seeing in MRI scans of stroke patients; to improve diagnosis and guide treatments; and maybe even to develop new ways to peer inside the living brain. What all these goals have in common is that they depend on the ability to track movements and deposits of tiny traces of metal in human tissue. That’s a job the SSRL technique, known as rapid-scanning XRF, is exquisitely suited to do.
At a synchrotron equipped with this technology, “you can see a large sample of brain, and you have the high resolution the technique offers to actually zoom in on your single cells,” said Dr. Raphael Guzman, a pediatric neurosurgeon and stem cell expert at Stanford University Medical Center who is leading part of the study.
Regular XRF, or X-ray fluorescence imaging, uses the SSRL’s powerful X-ray beam to knock electrons out of the inner shells of atoms in a sample. As more electrons fall in to fill the gaps, they give off light—fluoresce—and the color of that light reveals which chemical elements are present.
In the mid-2000s, SLAC scientists had a chance to use this technique to examine a priceless manuscript—the Archimedes palimpsest, a 10th century parchment containing copies of works by the ancient Greek mathematician that had been erased by monks and recycled as a prayer book. But they soon realized that to examine something this big in a reasonable amount of time, they would have to make the scanning go much faster.
Led by physicist Uwe Bergmann, they developed a way to move the beam continually over the sample, rather than imaging one spot at a time. This allowed them to proceed 300 times faster—a scan that used to take 12 days could now be done in an hour—and opened up the possibility of examining much bigger samples, from art objects and cultural artifacts to fossils of early birds. In 2006, Bergmann and an international team of researchers used rapid-scanning XRF to reveal the words of Archimedes, including passages that had been lost for centuries, beneath the prayer writings on the old parchment.
When she read about this research, Nichol said, “It just grabbed me. I thought, if he could map something as big as a sheet of paper, we could map a brain.”
She and her colleagues began using rapid-scanning XRF at the SSRL to look at metals in the preserved brains of people who had died with Alzheimer’s disease, Parkinson’s disease or multiple sclerosis. The healthy brain needs metals like iron, zinc, manganese and copper to work properly, and some studies had indicated that in people with neurodegenerative diseases, the normal distribution of these metals was out of whack. But did these changes cause the disease, or were they a result of it? And were they consistent enough to offer a tool for diagnosis?
To the team’s disappointment, scans of brain slices from eight people with Parkinson’s disease found no clear pattern—nothing that could help doctors diagnose their brain conditions or understand how they came about. “What we found is that the changes you see in Parkinson’s and Alzheimer’s are sort of variations on normal,” Nichol said.
She decided that beam time on the SSRL was better spent studying a disorder that caused clear, obvious damage in the brain. Stroke fit the bill.
When a stroke blocks the flow of blood to the brain, it produces striking lesions, almost like bruises, caused by bleeding and tissue death. Blood contains iron, which is part of the hemoglobin that carries oxygen in red blood cells. When bleeding occurs, the iron leaks out in a form that can damage surrounding cells, so the body quickly tucks the iron away in various chemical compounds for safe storage.
Standard MRI scans can image and identify those iron compounds and show doctors where bleeding has taken place. But they may not catch the very smallest bleeds, Nichol said, or identify other elements that may be disrupted during a stroke.
That’s where RS-XRF comes in. As the first practical tool for imaging a number of different metals in all of their chemical forms at the same time—and over a large section of the brain—it “opens up a lot of doors to things you can’t see with medical imaging,” Nichol said. It also can tell one form of iron from another; the spectrum of iron in hemoglobin will look different than free-floating iron or the iron compounds produced by bleeding, for instance.
The idea behind the study is that iron in its varied forms can be used as a marker to reveal changes in molecules and cells that follow a stroke, evaluate stroke damage and follow the migration of stem cells that are injected into patients in experimental stroke treatments. The scientists will also look at sulfur compounds that are thought to play a role in protecting the brain from damage, and evaluate the effects of the few stroke treatments available, such as chilling the brain, on the distribution of iron and sulfur.
Members of the team come to the SSRL about three weeks per year to scan brain tissue from rats, including some that have been bred to make them unusually susceptible to stroke, as well as human brain tissue from the National Institutes of Health brain bank. Additional experiments are being done at the Canadian Light Source at the University of Saskatchewan.
While they are not putting live patients in a synchrotron, the scientists hope their findings will someday result in the ability to scan live patients with methods that are much more sensitive to damage from tiny strokes that now go unnoticed.