Posts tagged LTP
Articles and news from the latest research reports.
When we learn, we associate a sensory experience either with other stimuli or with a certain type of behaviour. The neurons in the cerebral cortex that transmit the information modify the synaptic connections that they have with the other neurons. According to a generally-accepted model of synaptic plasticity, a neuron that communicates with others of the same kind emits an electrical impulse as well as activating its synapses transiently. This electrical pulse, combined with the signal received from other neurons, acts to stimulate the synapses. How is it that some neurons are caught up in the communication interplay even when they are barely connected? This is the crucial chicken-or-egg puzzle of synaptic plasticity that a team led by Anthony Holtmaat, professor in the Department of Basic Neurosciences in the Faculty of Medicine at UNIGE, is aiming to solve. The results of their research into memory in silent neurons can be found in the latest edition of Nature.
Learning and memory are governed by a mechanism of sustainable synaptic strengthening. When we embark on a learning experience, our brain associates a sensory experience either with other stimuli or with a certain form of behaviour. The neurons in the cerebral cortex responsible for ensuring the transmission of the relevant information, then modify the synaptic connections that they have with other neurons. This is the very arrangement that subsequently enables the brain to optimise the way information is processed when it is met again, as well as predicting its consequences.
Neuroscientists typically induce electrical pulses in the neurons artificially in order to perform research on synaptic mechanisms.
The neuroscientists from UNIGE, however, chose a different approach in their attempt to discover what happens naturally in the neurons when they receive sensory stimuli. They observed the cerebral cortices of mice whose whiskers were repeatedly stimulated mechanically without an artificially-induced electrical pulse. The rodents use their whiskers as a sensor for navigating and interacting; they are, therefore, a key element for perception in mice.
An extremely low signal is enough
By observing these natural stimuli, professor Holtmaat’s team was able to demonstrate that sensory stimulus alone can generate long-term synaptic strengthening without the neuron discharging either an induced or natural electrical pulse. As a result – and contrary to what was previously believed – the synapses will be strengthened even when the neurons involved in a stimulus remain silent.In addition, if the sensory stimulation lasts over time, the synapses become so strong that the neuron in turn is activated and becomes fully engaged in the neural network. Once activated, the neuron can then further strengthen the synapses in a forwards and backwards movement. These findings could solve the brain’s “What came first?” mystery, as they make it possible to examine all the synaptic pathways that contribute to memory, rather than focusing on whether it is the synapsis or the neuron that activates the other.
The entire brain is mobilised
A second discovery lay in store for the researchers. During the same experiment, they were also able to establish that the stimuli that were most effective in strengthening the synapses came from secondary, non-cortical brain regions rather than major cortical pathways (which convey actual sensory information). Accordingly, storing information would simply require the co-activation of several synaptic pathways in the neuron, even if the latter remains silent. These findings may also have important implications both for the way we understand learning mechanisms and for therapeutic possibilities, in particular for rehabilitation following a stroke or in neurodegenerative disorders. As professor Holtmaat explains: “It is possible that sensory stimulation, when combined with another activity (motor activity, for example), works better for strengthening synaptic connections”. The professor concludes: “In the context of therapy, you could combine two different stimuli as a way of enhancing the effectiveness.”
Mechanism behind the activation of dormant memory cells discovered
The electrical stimulation of the hippocampus in in-vivo experiments activates precisely the same receptor complexes as learning or memory recall. This has been discovered for the first time and the finding has now been published in the highly respected journal “Brain Structure Function”. “This may form the basis for the use of medications aimed at powering up dormant or less active memory cells,” says Gert Lubec, Head of Fundamental Research / Neuroproteomics at the University Department of Paediatrics and Adolescent Medicine at the MedUni Vienna.
“This discovery has far-reaching consequences both for the molecular understanding of memory formation and the understanding of the clinical electrical stimulation, which is already possible, of areas of the brain for therapeutic purposes,” says the MedUni Vienna researcher. Similar principles are currently already being used in the field of deep brain stimulation. With this technology, an implanted device delivers electronic impulses to the patient’s brain. This physical stimulation allows neuronal circuits to be influenced that control both behaviour and memory.
The latest findings very much form part of the highly controversial subject of “cognitive enhancement”. Scientists are currently discussing the possibility of improving mental capacity through the use of drugs - including in healthy subjects of all age groups, but especially in patients with age-related impairments of cognitive processes.
With regard to the study design, two electrodes were implanted into the brain in an animal model. One transferred electrical impulses to stimulate the hippocampus, while the other transferred the electrical signals away. “These electrical potentials are the electrical equivalent of memory and are known as LTP (Long Term Potentiation),” explains Lubec. The generation of LTP in an in-vivo experiment was accompanied by specific changes in the receptor complexes - the same receptor complexes that are also activated during learning and memory formation.
Schizophrenia linked to abnormal brain waves
Neuroscientists discover neurological hyperactivity that produces disordered thinking
Schizophrenia patients usually suffer from a breakdown of organized thought, often accompanied by delusions or hallucinations. For the first time, MIT neuroscientists have observed the neural activity that appears to produce this disordered thinking.
The researchers found that mice lacking the brain protein calcineurin have hyperactive brain-wave oscillations in the hippocampus while resting, and are unable to mentally replay a route they have just run, as normal mice do.
Mutations in the gene for calcineurin have previously been found in some schizophrenia patients. Ten years ago, MIT researchers led by Susumu Tonegawa, the Picower Professor of Biology and Neuroscience, created mice lacking the gene for calcineurin in the forebrain; these mice displayed several behavioral symptoms of schizophrenia, including impaired short-term memory, attention deficits, and abnormal social behavior.
In the new study, which appears in the Oct. 16 issue of the journal Neuron, Tonegawa and colleagues at the RIKEN-MIT Center for Neural Circuit Genetics at MIT’s Picower Institute for Learning and Memory recorded the electrical activity of individual neurons in the hippocampus of these knockout mice as they ran along a track.
Previous studies have shown that in normal mice, “place cells” in the hippocampus, which are linked to specific locations along the track, fire in sequence when the mice take breaks from running the course. This mental replay also occurs when the mice are sleeping. These replays occur in association with very high frequency brain-wave oscillations known as ripple events.
In mice lacking calcineurin, the researchers found that brain activity was normal as the mice ran the course, but when they paused, their ripple events were much stronger and more frequent. Furthermore, the firing of the place cells was abnormally augmented and in no particular order, indicating that the mice were not replaying the route they had just run.
This pattern helps to explain some of the symptoms seen in schizophrenia, the researchers say.
“We think that in this mouse model, we may have some kind of indication that there’s a disorganized thinking process going on,” says Junghyup Suh, a research scientist at the Picower Institute and one of the paper’s lead authors. “During ripple events in normal mice we know there is a sequential replay event. This mutant mouse doesn’t seem to have that kind of replay of a previous experience.”
The paper’s other lead author is David Foster, a former MIT postdoc. Other authors are Heydar Davoudi and Matthew Wilson, the Sherman Fairchild Professor of Neuroscience at MIT and a member of the Picower Institute.
The researchers speculate that in normal mice, the role of calcineurin is to suppress the connections between neurons, known as synapses, in the hippocampus. In mice without calcineurin, a phenomenon known as long-term potentiation (LTP) becomes more prevalent, making synapses stronger. Also, the opposite effect, known as long-term depression (LTD), is suppressed.
“It looks like this abnormally high LTP has an impact on activity of these cells specifically during resting periods, or post exploration periods. That’s a very interesting specificity,” Tonegawa says. “We don’t know why it’s so specific.”
The researchers believe the abnormal hyperactivity they found in the hippocampus may represent a disruption of the brain’s “default mode network” — a communication network that connects the hippocampus, prefrontal cortex (where most thought and planning occurs), and other parts of the cortex.
This network is more active when a person (or mouse) is resting between goal-oriented tasks. When the brain is focusing on a specific goal or activity, the default mode network gets turned down. However, this network is hyperactive in schizophrenic patients before and during tasks that require the brain to focus, and patients do not perform well in these tasks.
Further studies of these mice could help reveal more about the role of the default mode network in schizophrenia, Tonegawa says.
Newly Discovered ‘Switch’ Plays Dual Role In Memory Formation
Researchers at Johns Hopkins have uncovered a protein switch that can either increase or decrease memory-building activity in brain cells, depending on the signals it detects. Its dual role means the protein is key to understanding the complex network of signals that shapes our brain’s circuitry, the researchers say. A description of their discovery appears in the July 31 issue of the Journal of Neuroscience.
“What’s interesting about this protein, AGAP3, is that it is effectively double-sided: One side beefs up synapses in response to brain activity, while the other side helps bring synapse-building back down to the brain’s resting state,” says Richard Huganir, Ph.D., a professor and director of the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins University School of Medicine and co-director of the Brain Science Institute at Johns Hopkins. “The fact that it links these two opposing activities indicates AGAP3 may turn out to be central to controlling the strength of synapses.”
Huganir has long studied how connections between brain cells, known as synapses, are strengthened and weakened to form or erase memories. The new discovery came about when he and postdoctoral fellow Yuko Oku, Ph.D., investigated the chain reaction of signals involved in one type of synaptic strengthening.
In a study of the proteins that interact with one of the known proteins from that chain reaction, the previously unknown AGAP3 turned up. It contained not only a site designed to bind another protein involved in the chain reaction that leads from brain stimulation to learning, but also a second site involved in bringing synapse-building activity down to normal levels after a burst of activity.
Although it might seem the two different functions are behaving at cross-purposes, Oku says, it also could be that nature’s bundling of these functions together in a single protein is an elegant way of enabling learning and memory while preventing dangerous overstimulation. More research is needed, Oku says, to figure out whether AGAP3’s two sites coordinate by affecting each other’s activity, or are effectively free agents.
Scientists identify brain’s ‘molecular memory switch’
Scientists have identified a key molecule responsible for triggering the chemical processes in our brain linked to our formation of memories. The findings, published in the journal Frontiers in Neural Circuits, reveal a new target for therapeutic interventions to reverse the devastating effects of memory loss.
The BBSRC-funded research, led by scientists at the University of Bristol, aimed to better understand the mechanisms that enable us to form memories by studying the molecular changes in the hippocampus — the part of the brain involved in learning.
Previous studies have shown that our ability to learn and form memories is due to an increase in synaptic communication called Long Term Potentiation [LTP]. This communication is initiated through a chemical process triggered by calcium entering brain cells and activating a key enzyme called ‘Ca2+ responsive kinase’ [CaMKII]. Once this protein is activated by calcium it triggers a switch in its own activity enabling it to remain active even after the calcium has gone. This special ability of CaMKII to maintain its own activity has been termed ‘the molecular memory switch’.
Until now, the question still remained as to what triggers this chemical process in our brain that allows us to learn and form long-term memories. The research team, comprising scientists from the University’s School of Physiology and Pharmacology, conducted experiments using the common fruit fly [Drosophila] to analyse and identify the molecular mechanisms behind this switch. Using advanced molecular genetic techniques that allowed them to temporarily inhibit the flies’ memory the team were able to identify a gene called CASK as the synaptic molecule regulating this ‘memory switch’.
Dr James Hodge, the study’s lead author, said: “Fruit flies are remarkably compatible for this type of study as they possess similar neuronal function and neural responses to humans. Although small they are very smart, for instance, they can land on the ceiling and detect that the fruit in your fruit bowl has gone off before you can.”
“In experiments whereby we tested the flies’ learning and memory ability, involving two odours presented to the flies with one associated with a mild shock, we found that around 90 per cent were able to learn the correct choice remembering to avoid the odour associated with the shock. Five lessons of the odour with punishment made the fly remember to avoid that odour for between 24 hours and a week, which is a long time for an insect that only lives a couple of months.“
By localising the function of the key molecules CASK and CaMKII to the flies’ equivalent brain area to the human hippocampus, the team found that the flies lacking these genes showed disrupted memory formation. In repeat memory tests those lacking these key genes were shown to have no ability to remember at three hours (mid-term memory) and 24 hours (long-term memory) although their initial learning or short-term memory wasn’t affected.
Finally, the team introduced a copy of the human CASK gene — it is 80 per cent identical to the fly CASK gene — into the genome of a fly that completely lacked its own CASK gene and was therefore not usually able to remember. The researchers found that flies which had a copy of the human CASK gene could remember like a normal wildtype fly.
Dr Hodge, from the University’s School of Physiology and Pharmacology, said: “Research into memory is particularly important as it gives us our sense of identity, and deficits in learning and memory occur in many diseases, injuries and during aging”.
“CASK’s control of CaMKII ‘molecular memory switch’ is clearly a critical step in how memories are written into neurons in the brain. These findings not only pave the way for to developing new therapies which reverse the effects of memory loss but also prove the compatibility of Drosophila to model these diseases in the lab and screen for new drugs to treat these diseases. Furthermore, this work provides an important insight into how brains have evolved their huge capacity to acquire and store information.”
These findings clearly demonstrate that neuronal function of CASK is conserved between flies and human, validating the use of Drosophila to understand CASK function in both the healthy and diseased brain. Mutations in human CASK gene have been associated with neurological and cognitive defects including severe learning difficulties.
(Source: bristol.ac.uk)
Eliminating useless information important to learning, making new memories
As we age, it just may be the ability to filter and eliminate old information – rather than take in the new stuff – that makes it harder to learn, scientists report.
“When you are young, your brain is able to strengthen certain connections and weaken certain connections to make new memories,” said Dr. Joe Z. Tsien, neuroscientist at the Medical College of Georgia at Georgia Regents University and Co-Director of the GRU Brain & Behavior Discovery Institute.
It’s that critical weakening that appears hampered in the older brain, according to a study in the journal Scientific Reports.
The NMDA receptor in the brain’s hippocampus is like a switch for regulating learning and memory, working through subunits called NR2A and NR2B. NR2B is expressed in higher percentages in children, enabling neurons to talk a fraction of a second longer; make stronger bonds, called synapses; and optimize learning and memory. This formation of strong bonds is called long-term potentiation. The ratio shifts after puberty, so there is more NR2A and slightly reduced communication time between neurons.
When Tsien and his colleagues genetically modified mice that mimic the adult ratio – more NR2A, less NR2B – they were surprised to find the rodents were still good at making strong connections and short-term memories but had an impaired ability to weaken existing connections, called long-term depression, and to make new long-term memories as a result. It’s called information sculpting and adult ratios of NMDA receptor subunits don’t appear to be very good at it.
“If you only make synapses stronger and never get rid of the noise or less useful information then it’s a problem,” said Tsien, the study’s corresponding author. While each neuron averages 3,000 synapses, the relentless onslaught of information and experiences necessitates some selective whittling. Insufficient sculpting, at least in their mouse, meant a reduced ability to remember things short-term – like the ticket number at a fast-food restaurant – and long-term – like remembering a favorite menu item at that restaurant. Both are impacted in Alzheimer’s and age-related dementia.
All long-term depression was not lost in the mice, rather just response to the specific electrical stimulation levels that should induce weakening of the synapse. Tsien expected to find the opposite: that long-term potentiation was weak and so was the ability to learn and make new memories. “What is abnormal is the ability to weaken existing connectivity.”
Acknowledging the leap, this impaired ability could also help explain why adults can’t learn a new language without their old accent and why older people tend to be more stuck in their ways, the memory researcher said.
“We know we lose the ability to perfectly speak a foreign language if we learn than language after the onset of sexual maturity. I can learn English but my Chinese accent is very difficult to get rid of. The question is why,” Tsien said.
Tsien and his colleagues already have learned what happens when NR2B is overexpressed. He and East China Normal University researchers announced in 2009 the development of Hobbie-J, a smarter than average rat. A decade earlier, Tsien reported in the journal Nature the development of a smart mouse dubbed Doogie using the same techniques to over-express the NR2B gene in the hippocampus.
Doogie, Hobbie-J and their descendants have maintained superior memory as they age. Now Tsien is interested in following the NR2A over-expressing mouse to see what happens.
(Source: news.georgiahealth.edu)