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.