Neuroscience  

Neuroscientists have used a complex digital brain simulation of a rat brain that combines functional connectivity analysis and network modeling to investigate synaptic mechanisms of memory formation and pattern completion in hippocampal CA3 network.

Neuroscientists have used advanced brain simulations to unravel the complex synaptic mechanisms of pattern completion in hippocampus of the brain. The researchers' findings suggest that the rules of synaptic connectivity between CA3 pyramidal cells in the hippocampus contribute to the remarkable efficiency of pattern completion.

The hippocampal CA3 region is known to play a key role in learning and memory. One of the most remarkable properties of the network is its ability to retrieve previously stored memories from incomplete or degraded versions, a phenomenon that is widely known as pattern completion.

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It is widely accepted that the synapses between CA3 pyramidal cells, the recurrent CA3–CA3 synapses, play a key role in pattern completion, but how this exactly works is still a mystery.

"The results provide a nice demonstration of how the Hopfield quote “build it, and you understand it” can be successfully applied to important questions in neuroscience."

Now, in  recent research published in the journal Science, neuroscientists Jose Guzman, Alois Schlögl, Michael Frotscher, and Peter Jonas have investigated these mechanisms by combining functional connectivity analysis and network modeling. Their findings suggest that the rules of synaptic connectivity between CA3 pyramidal cells contribute to the remarkable efficiency of pattern completion.

Previous theories of the hippocampal formation often depicted the region as a network of highly interconnected cells. The neuroscientists from the Institute of Science and Technology Austria (IST Austria) tested this hypothesis using a technique that allows monitoring the connection between electrical signals in up to eight neurons at the same time.

They made several highly surprising observations. First, they found that connectivity was sparse, with an average connection probability of approximately 1%. This massively challenges the dogma of a network of highly connected cells. Even more surprisingly, they discovered that connectivity in the network is not random, but exhibits connectivity motifs that occur much more frequently than expected for a random network. The structure of the hippocampal CA3 network may be somewhat reminiscent of a “small world” architecture as found in social networks. Finally, the authors revealed that synaptic connections between two cells are mediated by only one or two synaptic contacts. This is also remarkable because much higher numbers have been found for excitatory synaptic connections in the neocortex.

What did these 'rules' man for memory formation? To address this question, Jonas,who leads the cellular neuroscience group and his team built a model of the CA3 network that incorporates many of these new experimental observations. In contrast to many previous studies, the network was implemented in full size, so that all 330,000 CA3 neurons of the rat hippocampus were simulated.

They found that a full-size network model with realistic connectivity of 1% was indeed able to perform the network computation of pattern completion. Also, they discovered that the presence of connectivity motives increased, under certain conditions, the performance of the network. Finally, the design of synaptic connections based on one or two synaptic contacts also seems useful for pattern completion, apparently because it minimizes redundancy in the flow of information in the network.

For the researchers, both macro- and microconnectivity facilitate pattern completion in the CA3 cell network. “The results provide a nice demonstration of how the Hopfield quote “build it, and you understand it” can be successfully applied to important questions in neuroscience,” states Jonas.

SOURCE  IST Austria

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Memory Implants  

A memory prosthesis being trialed next year could not only repair loss of long-term memory but could potentially be used as a model of how to upload new skills and memories directly into our brains.

A new human memory prosthesis will be tested next year could not only restore long-term recall but may eventually be used to upload new skills and memories directly to the brain according to researcher Theodore (Ted) Berger.

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The first trials will be undertaken on patients with epilepsy. Seizures can sometimes damage the hippocampus, causing the brain to be unable to form long-term memories.

To repair this functionality, Berger, a biomedical engineer and a developer of neuro-prosthesis technology models, will use brain implants to try to replace damaged or dysfunctional nerve tissue. His colleagues at the University of Southern California have already used electrodes implanted in people’s brains as part of epilepsy treatment to record electrical activity associated with memory.

The team has also developed an algorithm that could predict the neural activity thought to occur when a short-term memory becomes a long-term memory, as it passes through the hippocampus.

"There is good reason to believe that the sharing of memory can happen."

Next year, Berger’s team will use this algorithm to communicate between the electrodes and the subjects' brains to help predict and then mimic the activity that should occur during long-term memories formation.

“Hopefully, it will repair their long-term memory,” says Berger. Previous studies using animals suggest that the prosthesis might even give people a better memory than they could expect naturally.

A similar approach could eventually be used to implant new memories into the brain. “There is good reason to believe that the sharing of memory can happen,” says Berger.

DARPA is also seeking to accelerate the development of memory implant technology.

Berger’s team recorded brain activity in a rat that had been trained to perform a specific task. The memory implant then replicated that activity in a rat that hadn’t been trained. The second rat was able to learn the task much faster than the first rat – as if it already had some memory of the task.

Are you thinking what we are?

SOURCE  New Scientist

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 Artificial Intelligence  

Speaking recently at Google's Zeitgeist event DeepMind's co-founder Demis Hassabis described his personal journey in exploring artificial intelligence and building general purpose learning machines.

According to Google DeepMind's Demis Hassabis, in order to find the theory of everything, we must first solve the question of intelligence. He spoke recently at Google's Zeitgeist event.

Hassabis is the man behind DeepMind Technologies, a neuroscience-inspired artificial intelligence company which was recently acquired by Google.

Hassabis was a chess master at the age of 12 who graduated with a double first from Cambridge before founding the pioneering videogames company Elixir Studios, producing award-winning games for Microsoft and Universal.

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His video games, which included the classic Theme Park, which he created at age 17 all featured an element of artificial intelligence, and he ascribes his ambition to unravel intelligence as a choice between, "the only two subjects really worth studying: physics and neuroscience." Physics, he points out, is the study of the outside world and neuroscience is the study of the internal world of our minds.

"When I thought about this more, I came the conclusion that the mind was more important, because that is the way we actually interpret the external world out there," says Hassabis. This philosophy echoes Emmanuel Kant's phrase, "the mind interprets the world."

After he sold his games company, Hassabis returned to school to obtain his PhD in Cognitive Neuroscience from University College London and then continued his neuroscience and artificial intelligence research for a period.  He focused on imagination, memory and the function of the hippocampus, because "these are two of the capabilities that we don't know how to do very well in AI." He wanted to use the study of neuroscience to inspire work in artificial intelligence.

In 2010 he co-founded DeepMind, a company with a lofty goal of being an "Apollo program mission for AI." The company how has over a hundred researchers working on neuroscience-inspired artificial general intelligence.

The company intends to create a general purpose learning machine, or artificial general intelligence (AGI). Hassabis refers to them as, "AI Scientists."  They plan to do this by 1) solving intelligence and 2) using the AI Scientists to solve everything else.  Going back to Hassabis' initial decision, he hopes solving intelligence will help solve the problems of physics.

All of DeepMind's work involves creating learning algorithms.  Famously, the company has recently showcased this general purpose learning algorithm in a paper in Nature where they created a system that has taught itself to play Atari video games, and become super-human in ability to do so.

The conceptual model Hassabis and the DeepMind team came up with for developing their learning algorithms is called Reinforcement Learning Framework.  In the video above the way the system plays games like Space Invaders  and Breakout is really astonishing.

Now the company is progressing and moving to work on other capabilities of intelligence like concepts and memory.  These are also based on a deep understanding of neuroscience as inspiration. "One way to think about artificial general intelligence is that it is a process that automatically converts unstructured information into actionable knowledge.

"By trying to distill intelligence into an algorithmic construct and comparing it to the human mind, that might help us to unlock some of the deepest mysteries of the mind, like consciousness, creativity and even dreams."

DeepMind is also working on learning systems beyond simple video games.  This includes 3D games, Go (considered to be a much harder game for AI compared to chess), simulations and even eventually robotics. The system is also being adapted in the near term for recommendation systems on YouTube and for predictive healthcare applications (look out Watson!)

Hassabis claims in the talk that human-level AI is still several decades away, but we need to start the debate about it now.  He is a signer of the recent open letter on the safety of artificial intelligence, and made the creation of an ethics board a central part of his deal with Google.

Two things emerge from this talk.  First DeepMind's work points to the soon-to-arrive future of artificial intelligence and the importance of the subject.  Second, the lecture really demonstrates the intelligence of Hassabis himself.  Some may consider naming your lecture after a movie about arguably the most brilliant minds of our time, as a pure act of ego.

Considering the accomplishments this man has already achieved at his young age though, he is deserving of being mentioned in the same breath as Alan Turing and Stephen Hawking.  As DeepMind continues to build their general purpose learning machine, his personal recognition is sure to escalate until he too is a house-hold name.

"I think that by trying to distill intelligence into an algorithmic construct and comparing it to the human mind, that might help us to unlock some of the deepest mysteries of the mind, like consciousness, creativity and even dreams," Hassabis concludes.


SOURCE  ZeitgeistMinds

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 Neuroscience  

Scientists have implanted new memories into mice while they slept.  They hope this technique can be developed to alter problematic memories in people. The idea is to attach good thoughts to bad memories, such as those that linger after traumatic experiences.

M

ice can recall artificial memories created during sleep once they’re awake, researchers from the French National Center for Scientific Research (CNRS) and their colleagues have reported in Nature Neuroscience. The findings support a causal role between the firing of specialized neurons called place cells and the ability of these neurons to represent a particular location in space.

Place cells, part of the brain’s “inner GPS,” were first discovered by John O’Keefe, are a type of pyramidal neuron within the hippocampus that become active when an animal enters a particular place in an environment.

"The animal developed a goal-directed strategy for the [location], as if the animal had a conscious recollection that there was a reward there."

Karim Benchenane, a neuroscience researcher at CNRS and ESPCI-ParisTech and his colleagues first identified a single place cell in the hippocampus of each mouse that fired when the animal was in a specific location and measured the average time each mouse spent in that location prior to any manipulation.

Then, when that particular place cell became spontaneously active during either an awake or sleep state, an automatic stimulation of the medial forebrain bundle—a part of the brain associated with positive reward sensations—was executed through a brain-computer interface. This stimulation has long been known to result in the release of dopamine neurotransmitters, similar to what happens when the mouse receives a food or some other reward. Each mouse received the stimulation either during an awake or sleeping state, but not both.

a. Wake pairing protocol. The paradigm consisted in four sessions: 1) free exploration and place field identification, 2) basal exploration (PRE), 3) 15 minutes exploration with pairing where online detected spikes of a given place cell triggered MFB stimulation, and 4) test exploration (POST). In PRE and POST session a minimum of eight 60s—trials with changing starting point (gray circles) is performed. Analyses were carried on the first 4 trials where animal was actively exploring. b. Sleep pairing protocol. As in panel a, the sleep protocol is composed of the same four sessions except that spike—stimulation pairing is performed during 1h of sleep. This protocol was always followed by free exploration to erase the learning (extinction exploration) and a control wake pairing. c. Classical Place preference task. Mouse position was tracked in real time with a video camera during a session lasting 15 minutes. Rewarding stimulations were then delivered when mice reached a pre—established area, covering around 5% of the total surface of exploration. This stimulation phase was preceded by a basal exploration (PRE) and followed by a probe exploration (POST) as described in panel a. d. Method for the choice of the 4 starting points used in PRE and POST sessions of all place preference paradigms. Image Benchenane et al./Nature Neuroscience

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The linkage of a specific place cell with rewarding stimulation resulted in the animals spending about five times more time in the area associated with the place cell activity compared to the time they spent in that location prior to the stimulation experiment.

When this link between the place cell and reward trigger occurred during sleep in a second set of mice, the animals were more likely to go directly to the location associated with that place cell upon waking.

“The animal developed a goal-directed strategy for the [location], as if the animal had a conscious recollection that there was a reward there,” explained Benchenane.

In awake animals, the activity of place cells has been associated with being in a specific location, but so far, it has been difficult to directly attribute place cell activity to a representation of that physical location by the animal’s brain. Focusing on the animal’s place cell activity during sleep, when only replay is active, Benchenane and his colleagues were able to directly link place cell firing to spatial navigation.

Benchenane doesn't think the technique used in this study can be used to implant many other types of memories, like skills—at least for the time being. Spatial memories are easier to modify because they are among the best understood, and tied to specific neurons.

He hopes his technique can be developed to alter problematic memories in people. The idea is to attach good thoughts to bad memories, such as those that linger after traumatic experiences. "If you can identify where in the brain a person is reactivating a phobia-associated experience, you might be able to create a positive association," he says.


SOURCE  The Scientist

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Neuroscience  

The discovery that the human brain continues to produce new neurons in adulthood challenged a major dogma in the field of neuroscience, but the role of these neurons in behavior and cognition is still not clear. In a review article, researchers synthesize the vast literature on this topic, reviewing environmental factors that influence the birth of new neurons in the adult hippocampus.

The discovery that the human brain continues to produce new neurons in adulthood challenged a major dogma in the field of neuroscience, but the role of these neurons in behavior and cognition is still not clear. In a review article published in Trends in Cognitive Sciences, Maya Opendak and Elizabeth Gould of Princeton University synthesize the vast literature on this topic, reviewing environmental factors that influence the birth of new neurons in the adult hippocampus, a region of the brain that plays an important role in memory and learning.

The authors discuss how the birth of such neurons may help animals and humans adapt to their current environment and circumstances in a complex and changing world. They advocate for testing these ideas using naturalistic designs, such as allowing laboratory rodents to live in more natural social burrow settings and observing how circumstances such as social status influence the rate at which new neurons are born.

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"New neurons may serve as a means to fine-tune the hippocampus to the predicted environment," Opendak says. "In particular, seeking out rewarding experiences or avoiding stressful experiences may help each individual optimize his or her own brain. However, more naturalistic experimental conditions may be a necessary step toward understanding the adaptive significance of neurons born in the adult brain."

"New neurons may serve as a means to fine-tune the hippocampus to the predicted environment."

In recent years, it has become increasingly clear that environmental influences have a profound effect on the adult brain in a wide range of mammalian species. Stressful experiences, such as restraint, social defeat, exposure to predator odors, inescapable foot shock, and sleep deprivation, have been shown to decrease the number of new neurons in the hippocampus. By contrast, more rewarding experiences, such as physical exercise and mating, tend to increase the production of new neurons in the hippocampus.

The birth of new neurons in adulthood may have important behavioral and cognitive consequences. Stress-induced suppression of adult neurogenesis has been associated with impaired performance on hippocampus-dependent cognitive tasks, such as spatial navigation learning and object memory.

Stressful experiences have also been shown to increase anxiety-like behaviors that are associated with the hippocampus. In contrast, rewarding experiences are associated with reduced anxiety-like behavior and improved performance on cognitive tasks involving the hippocampus.

Gould and her collaborators recently proposed that stress-induced decreases in new neuron formation might improve the chances of survival by increasing anxiety and inhibiting exploration, thereby prioritizing safety and avoidant behavior at the expense of performing optimally on cognitive tasks. On the other hand, reward-induced increases in new neuron number may reduce anxiety and facilitate exploration and learning, leading to greater reproductive success.

"Because the past is often the best predictor of the future, a stress-modeled brain may facilitate adaptive responses to life in a stressful environment, whereas a reward-modeled brain may do the same but for life in a low-stress, high-reward environment," says Gould, a professor of psychology and neuroscience at Princeton University.

However, when aversive experiences far outnumber rewarding ones in both quantity and intensity, the system may reach a breaking point and produce a maladaptive outcome. For example, repeated stress produces continued reduction in the birth of new neurons, and ultimately the emergence of heightened anxiety and depressive-like symptoms.

"Such a scenario could represent processes that are engaged under pathological conditions and may be somewhat akin to what humans experience when exposed to repeated traumatic stress," Opendak says.

Because many studies that investigate adult neurogenesis use controlled laboratory conditions, the relevance of the findings to real-world circumstances remains unclear. The use of a visible burrow system—a structure consisting of tubes, chambers, and an open field--has allowed researchers to recreate the conditions that allow for the production of dominance hierarchies that rats naturally form in the wild, replicating the stressors, rewards, and cognitive processes that accompany this social lifestyle.

"This more realistic setting has revealed individual differences in adult neurogenesis, with more new neurons produced in dominant versus subordinate male rats," Gould says. "Taking findings from laboratory animals to the next level by exploring complex social interactions in settings that maximize individual variability, a hallmark of the human experience, is likely to be especially illuminating."


SOURCE  Cell Press via EurekAlert

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 Neuroscience  

An international team led by researchers has successfully determined the location, where memories are generated in the brain with a level of precision never achieved before.

The human brain continuously collects information. However, we have only basic knowledge of how new experiences are converted into lasting memories. Now, an international team led by researchers of the University of Magdeburg and the German Center for Neurodegenerative Diseases (DZNE) has successfully determined the location, where memories are generated with a level of precision never achieved before. The team was able to pinpoint this location down to specific circuits of the human brain.

To this end the scientists used a particularly accurate type of magnetic resonance imaging (MRI) technology. The researchers hope that the results and method of their study might be able to assist in acquiring a better understanding of the effects Alzheimer’s disease has on the brain.

The study was published in the journal Nature Communications.

For the recall of experiences and facts, various parts of the brain have to work together. Much of this interdependence is still undetermined, however, it is known that memories are stored primarily in the cerebral cortex and that the control center that generates memory content and also retrieves it, is located in the brain’s interior.

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This happens in the hippocampus and in the adjacent entorhinal cortex. “It is been known for quite some time that these areas of the brain participate in the generation of memories. This is where information is collected and processed.

"We have been able to locate the generation of human memories to certain neuronal layers within the hippocampus and the entorhinal cortex. We were able to determine which neuronal layer was active. This revealed if information was directed into the hippocampus or whether it traveled from the hippocampus into the cerebral cortex...this is the first time we have been able to show where in the brain the doorway to memory is located."

Our study has refined our view of this situation,” explains Professor Emrah Düzel, site speaker of the DZNE in Magdeburg and director of the Institute of Cognitive Neurology and Dementia Research at the University of Magdeburg. “We have been able to locate the generation of human memories to certain neuronal layers within the hippocampus and the entorhinal cortex. We were able to determine which neuronal layer was active. This revealed if information was directed into the hippocampus or whether it traveled from the hippocampus into the cerebral cortex. Previously used MRI techniques were not precise enough to capture this directional information. Hence, this is the first time we have been able to show where in the brain the doorway to memory is located.”

For this study, the scientists examined the brains of persons who had volunteered to participate in a memory test. The researchers used a special type of magnetic resonance imaging technology called 7 Tesla ultra-high field MRI. This enabled them to determine the activity of individual brain regions with unprecedented accuracy.

This work may lead to new findings about Alzheimer's and other neurodegenerative disorders.

“This measuring technique allows us to track the flow of information inside the brain and examine the areas that are involved in the processing of memories in great detail,” comments Düzel. “As a result, we hope to gain new insights into how memory impairments arise that are typical for Alzheimer’s. Concerning dementia, is the information still intact at the gateway to memory? Do troubles arise later on, when memories are processed? We hope to answer such questions.”


SOURCE  German Center for Neurodegenerative Diseases

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 Neuroscience  

Researchers have found that the brain's wiring is more complex than expected – one set of neural wires can trigger different reactions, depending on how it fires. The work opens new questions for scientists trying to map the brain's connections.

Scientists at Stanford's Bio-X have raised an entirely new set of questions when they sought answers about connections between two brain regions.

"There's a lot of excitement about being able to make a map of the brain with the idea that if we could figure out how it is all connected we could understand how it works,"  researcher Joanna Mattis said. "It turns out it's so much more dynamic than that."

Mattis is a co-first author on a paper describing the work published recently in the Journal of Neuroscience. Julia Brill, then a postdoctoral scholar, was the other co-first author.

Mattis had been a graduate student in the lab of Karl Deisseroth, professor of bioengineering and of psychiatry and behavioral sciences, where she helped work on a new technique called optogenetics. That technique allows neuroscientists to selectively turn parts of the brain on and off to see what happens. She wanted to use optogenetics to understand the wiring of a part of the brain involved in spatial memory – it's what makes a mental map of your surroundings as you explore a new city, for example.

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Scientists already knew that when an animal explores habitats, two parts of the brain are involved in the initial exploring phase and then in solidifying a map of the environment – the hippocampus and the septum.

When an animal is exploring an environment, the neurons in the hippocampus fire slow signals to the septum, essentially telling the septum that it's busy acquiring information. Once the animal is done exploring, those same cells fire off intense signals letting the septum know that it's now locking that information into memory. The scientists call this phase consolidation. The septum uses that information to then turn around and regulate other signals going into the hippocampus.

"I wanted to study the hippocampus because on the one hand so much was already known – there was already this baseline of knowledge to work off of. But then the question of how the hippocampus and septum communicate hadn't been accessible before optogenetics," Mattis said.

Neural wiring diagrams are even more complex than initially speculated according to new research

Neurons in the hippocampus were known to fire in a rhythmic pattern, which is a particular expertise of John Huguenard, a professor of neurology. Mattis obtained an interdisciplinary fellowship through Stanford Bio-X, which allowed her to combine the Deisseroth lab's expertise in optogenetics with the rhythmic brain network expertise of Julia Brill from the Huguenard lab.

"There's a lot of excitement about being able to make a map of the brain with the idea that if we could figure out how it is all connected we could understand how it works."

Mattis and Brill used optogenetics to prompt neurons of the hippocampus to mimic either the slow firing characteristic of information acquisition or the rapid firing characteristic of consolidation. When they mimicked the slow firing they saw a quick reaction by cells in the septum. When they mimicked the fast consolidation firing, they saw a much slower response by completely different cells in the septum.

Same set of wires – different outcome. That's like turning on different lights depending on how hard you flip the switch. "This illustrates how complex the brain is," Mattis said.

This research has raised a whole new set of questions, Mattis said. They more or less understand the faster reaction, but what is causing the slower reaction? How widespread is this phenomenon in the brain?

"The other big picture thing that we opened up but didn't answer is: How can you then tie this back to the circuit overall and learning memory?" Mattis said. "Those would be exciting things to follow up on for future projects."


SOURCE  Stanford

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 Memory  

New research has found that stimulating a specific gene could prompt growth – in adults – of new neurons in this critical region, leading to faster learning and better memories.

Learning and memory are regulated by a region of the brain known as the hippocampus. New research from City of Hope has found that stimulating a specific gene could prompt growth – in adults – of new neurons in this critical region, leading to faster learning and better memories.

Understanding the link between this gene and the growth of new neurons – or neurogenesis – is an important step in developing therapies to address impaired learning and memory associated with neurodegenerative diseases and aging. The new research was published in the Proceedings of the National Academy of Sciences.

"We manipulated the expression of this receptor by introducing an additional copy of the gene – which obviously we cannot do outside the laboratory setting. The next step is to find the drug that can target this same gene."

The study, which used an animal model, found that over-expressing the gene – a nuclear receptor called TLX – resulted in smart, faster learners that retained information better and longer.

"Memory loss is a major health problem, both in diseases like Alzheimer's, but also just associated with aging," said Yanhong Shi, Ph.D., lead author of the study and a neurosciences professor at City of Hope. "In our study, we manipulated the expression of this receptor by introducing an additional copy of the gene – which obviously we cannot do outside the laboratory setting. The next step is to find the drug that can target this same gene."

Neural Stem Cells
Image Source - Kiyohito Mura et al./PNAS

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The discovery creates a new potential strategy for improving cognitive performance in elderly patients and those who have a neurological disease or brain injury.

The bulk of the brain's development happens before birth, and there are periods –largely in childhood and young adulthood – when the brain experiences bursts of new growth. In the past couple of decades, however, scientists have found evidence of neurogenesis in later adulthood – occurring mostly in the hippocampus, the region of the brain associated with learning and memory.

The new study is the first to firmly link the TLX gene to a potential for enhancing learning and memory.

Researchers found that over-expression of the gene was actually associated with a physically larger brain, as well as the ability to learn a task quickly. Furthermore, over-expression of the gene was linked with the ability to remember, over a longer period of time, what had been learned.

Founded in 1913, City of Hope is one of only 41 comprehensive cancer centers in the nation, as designated by the National Cancer Institute. Their role as leaders in patient care, basic and clinical research, and the translation of science into tangible benefit is widely acknowledged.


SOURCE  City of Hope

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 Neuroscience  

Researchers have announced they are now able to 'film' a brain as it forms memories. The feat was accomplished by using mRNA molecules, which are crucial to forming memories, fluorescent "tags", so they could be watched more easily.

In two studies in the January 24 issue of Science, researchers at Albert Einstein College of Medicine of Yeshiva University used advanced imaging techniques to provide a window into how the brain makes memories.

These insights into the molecular basis of memory were made possible by a technological tour de force never before achieved in animals: a mouse model developed at Einstein in which molecules crucial to making memories were given fluorescent "tags" so they could be observed traveling in real time in living brain cells.

The research has been published in two articles, "Visualization of Dynamics of Single Endogenous mRNA as Labeled in Live Mouse," and "Single Beta-actin mRNA Detection in Neurons Reveals a Mechanism for Regulating Its Translatability," in the journal Science.

Efforts to discover how neurons make memories have long confronted a major roadblock: Neurons are extremely sensitive to any kind of disruption, yet only by probing their innermost workings can scientists view the molecular processes that culminate in memories. To peer deep into neurons without harming them, Einstein researchers developed a mouse model in which they fluorescently tagged all molecules of messenger RNA (mRNA) that code for beta-actin protein – an essential structural protein found in large amounts in brain neurons and considered a key player in making memories. mRNA is a family of RNA molecules that copy DNA's genetic information and translate it into the proteins that make life possible.

Robert Singer, Ph.D. Image Source: Albert Einstein College of Medicine

Robert Singer, Ph.D., is the senior author of both papers and professor and co-chair of Einstein's department of anatomy & structural biology and co-director of the Gruss Lipper Biophotonics Center at Einstein.

In the research described in the two Science papers, the Einstein researchers stimulated neurons from the mouse's hippocampus, where memories are made and stored, and then watched fluorescently glowing beta-actin mRNA molecules form in the nuclei of neurons and travel within dendrites, the neuron's branched projections. They discovered that mRNA in neurons is regulated through a novel process described as "masking" and "unmasking," which allows beta-actin protein to be synthesized at specific times and places and in specific amounts.

Singer states, "we know the beta-actin mRNA we observed in these two papers was ‘normal' RNA, transcribed from the mouse's naturally occurring beta-actin gene and attaching green fluorescent protein to mRNA molecules did not affect the mice, which were healthy and able to reproduce."

Neurons come together at synapses, where slender dendritic "spines" of neurons grasp each other, much as the fingers of one hand bind those of the other. Evidence indicates that repeated neural stimulation increases the strength of synaptic connections by changing the shape of these interlocking dendrite "fingers." Beta-actin protein appears to strengthen these synaptic connections by altering the shape of dendritic spines.

Memories are thought to be encoded when stable, long-lasting synaptic connections form between neurons in contact with each other.

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The first paper describes the work of Hye Yoon Park, Ph.D., a postdoctoral student in Dr. Singer's lab. Her research was instrumental in developing the mice containing fluorescent beta-actin mRNA—a process that took about three years.

Dr. Park stimulated individual hippocampal neurons of the mouse and observed newly formed beta-actin mRNA molecules within 10 to 15 minutes, indicating that nerve stimulation had caused rapid transcription of the beta-actin gene. Further observations suggested that these beta-actin mRNA molecules continuously assemble and disassemble into large and small particles, respectively. These mRNA particles were seen traveling to their destinations in dendrites where beta-actin protein would be synthesized.

In the second paper, lead author and graduate student Adina Buxbaum of Dr. Singer's lab showed that neurons may be unique among cells in how they control the synthesis of beta-actin protein.

These findings suggest that neurons have developed an ingenious strategy for controlling how memory-making proteins do their job. "This observation that neurons selectively activate protein synthesis and then shut it off fits perfectly with how we think memories are made," said Dr. Singer. "Frequent stimulation of the neuron would make mRNA available in frequent, controlled bursts, causing beta-actin protein to accumulate precisely where it's needed to strengthen the synapse."

To gain further insight into memory's molecular basis, the Singer lab is developing technologies for imaging neurons in the intact brains of living mice. Since the hippocampus resides deep in the brain, they hope to develop infrared fluorescent proteins that emit light that can pass through tissue. Another possibility is a fiberoptic device that can be inserted into the brain to observe memory-making hippocampal neurons.




SOURCE  Albert Einstein College of Medicine

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 Memory Loss  

The results of a new study points to possible treatments and confirms distinction between memory loss due to aging and that of Alzheimer's.

A team of Columbia University Medical Center (CUMC) researchers, led by Nobel laureate Eric R. Kandel, MD, has found that deficiency of a protein called RbAp48 in the hippocampus is a significant contributor to age-related memory loss and that this form of memory loss is reversible.

The study, conducted in postmortem human brain cells and in mice, also offers the strongest causal evidence that age-related memory loss and Alzheimer’s disease are distinct conditions. The findings were published in the online edition of Science Translational Medicine.

The researchers have identified a protein—RbAp48—that, when increased in aged wild-type mice, improves memory back to that of young wild-type mice. In the image above, yellow shows the increased RbAp48 in the dentate gyrus.

“Our study provides compelling evidence that age-related memory loss is a syndrome in its own right, apart from Alzheimer’s. In addition to the implications for the study, diagnosis, and treatment of memory disorders, these results have public health consequences,” said Dr. Kandel, who received a share of the 2000 Nobel Prize in Physiology or Medicine for his discoveries related to the molecular basis of memory.

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The hippocampus, a brain region that consists of several interconnected subregions, each with a distinct neuron population, plays a vital role in memory. Studies have shown that Alzheimer’s disease hampers memory by first acting on the entorhinal cortex (EC), a brain region that provides the major input pathways to the hippocampus. It was initially thought that age-related memory loss is an early manifestation of Alzheimer’s, but mounting evidence suggests that it is a distinct process that affects the dentate gyrus (DG), a subregion of the hippocampus that receives direct input from the EC.

“Until now, however, no one has been able to identify specific molecular defects involved in age-related memory loss in humans,” said co-senior author Scott A. Small, MD, the Boris and Rose Katz Professor of Neurology and director of the Alzheimer’s Research Center at CUMC.

“The fact that we were able to reverse age-related memory loss in mice is very encouraging,” said Dr. Kandel. “Of course, it’s possible that other changes in the DG contribute to this form of memory loss. But at the very least, it shows that this protein is a major factor, and it speaks to the fact that age-related memory loss is due to a functional change in neurons of some sort. Unlike with Alzheimer’s, there is no significant loss of neurons.”

Finally, the study data suggest that RbAp48 protein mediates its effects, at least in part, through the PKA-CREB1-CBP pathway, which the team had found in earlier studies to be important for age-related memory loss in the mouse. According to the researchers, RbAp48 and the PKA-CREB1-CBP pathway are valid targets for therapeutic intervention. Agents that enhance this pathway have already been shown to improve age-related hippocampal dysfunction in rodents.

“Whether these compounds will work in humans is not known,” said Dr. Small. “But the broader point is that to develop effective interventions, you first have to find the right target. Now we have a good target, and with the mouse we’ve developed, we have a way to screen therapies that might be effective, be they pharmaceuticals, nutraceuticals, or physical and cognitive exercises.”

“There’s been a lot of handwringing over the failures of drug trials based on findings from mouse models of Alzheimer’s,” Dr. Small said. “But this is different. Alzheimer’s does not occur naturally in the mouse. Here, we’ve caused age-related memory loss in the mouse, and we’ve shown it to be relevant to human aging.”



SOURCE  Columbia University Top Image credit: Elias Pavlopoulos, PhD/Columbia University Medical Center

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