Posts tagged entorhinal cortex
Articles and news from the latest research reports.
The Nobel Assembly at Karolinska Institutet has decided to award the 2014 Nobel Prize in Physiology or Medicine with one half to John O´Keefe and the other half jointly to May-Britt Moser and Edvard I. Moser for their discoveries of cells that constitute a positioning system in the brain.
How do we know where we are? How can we find the way from one place to another? And how can we store this information in such a way that we can immediately find the way the next time we trace the same path? This year´s Nobel Laureates have discovered a positioning system, an “inner GPS” in the brain that makes it possible to orient ourselves in space, demonstrating a cellular basis for higher cognitive function.
In 1971, John O´Keefe discovered the first component of this positioning system. He found that a type of nerve cell in an area of the brain called the hippocampus that was always activated when a rat was at a certain place in a room. Other nerve cells were activated when the rat was at other places. O´Keefe concluded that these “place cells” formed a map of the room.
More than three decades later, in 2005, May-Britt and Edvard Moser discovered another key component of the brain’s positioning system. They identified another type of nerve cell, which they called “grid cells”, that generate a coordinate system and allow for precise positioning and pathfinding. Their subsequent research showed how place and grid cells make it possible to determine position and to navigate.
The discoveries of John O´Keefe, May-Britt Moser and Edvard Moser have solved a problem that has occupied philosophers and scientists for centuries – how does the brain create a map of the space surrounding us and how can we navigate our way through a complex environment?
How do we experience our environment?
The sense of place and the ability to navigate are fundamental to our existence. The sense of place gives a perception of position in the environment. During navigation, it is interlinked with a sense of distance that is based on motion and knowledge of previous positions.
Questions about place and navigation have engaged philosophers and scientists for a long time. More than 200 years ago, the German philosopher Immanuel Kant argued that some mental abilities exist as a priori knowledge, independent of experience. He considered the concept of space as an inbuilt principle of the mind, one through which the world is and must be perceived. With the advent of behavioural psychology in the mid-20th century, these questions could be addressed experimentally. When Edward Tolman examined rats moving through labyrinths, he found that they could learn how to navigate, and proposed that a “cognitive map” formed in the brain allowed them to find their way. But questions still lingered - how would such a map be represented in the brain?
John O´Keefe and the place in space
John O´Keefe was fascinated by the problem of how the brain controls behaviour and decided, in the late 1960s, to attack this question with neurophysiological methods. When recording signals from individual nerve cells in a part of the brain called the hippocampus, in rats moving freely in a room, O’Keefe discovered that certain nerve cells were activated when the animal assumed a particular place in the environment (Figure 1). He could demonstrate that these “place cells” were not merely registering visual input, but were building up an inner map of the environment. O’Keefe concluded that the hippocampus generates numerous maps, represented by the collective activity of place cells that are activated in different environments. Therefore, the memory of an environment can be stored as a specific combination of place cell activities in the hippocampus.
May-Britt and Edvard Moser find the coordinates
May-Britt and Edvard Moser were mapping the connections to the hippocampus in rats moving in a room when they discovered an astonishing pattern of activity in a nearby part of the brain called the entorhinal cortex. Here, certain cells were activated when the rat passed multiple locations arranged in a hexagonal grid (Figure 2). Each of these cells was activated in a unique spatial pattern and collectively these “grid cells” constitute a coordinate system that allows for spatial navigation. Together with other cells of the entorhinal cortex that recognize the direction of the head and the border of the room, they form circuits with the place cells in the hippocampus. This circuitry constitutes a comprehensive positioning system, an inner GPS, in the brain (Figure 3).
A place for maps in the human brain
Recent investigations with brain imaging techniques, as well as studies of patients undergoing neurosurgery, have provided evidence that place and grid cells exist also in humans. In patients with Alzheimer´s disease, the hippocampus and entorhinal cortex are frequently affected at an early stage, and these individuals often lose their way and cannot recognize the environment. Knowledge about the brain´s positioning system may, therefore, help us understand the mechanism underpinning the devastating spatial memory loss that affects people with this disease.
The discovery of the brain’s positioning system represents a paradigm shift in our understanding of how ensembles of specialized cells work together to execute higher cognitive functions. It has opened new avenues for understanding other cognitive processes, such as memory, thinking and planning.
(Source: nobelprize.org)
Epigenetic breakthrough bolsters understanding of Alzheimer’s disease
A team led by researchers at the University of Exeter Medical School and King’s College London has uncovered some of the strongest evidence yet that epigenetic changes in the brain play a role in Alzheimer’s disease.
Epigenetic changes affect the expression or activity of genes without changing the underlying DNA sequence and are believed to be one mechanism by which the environment can interact with the genome. Importantly, epigenetic changes are potentially reversible and may therefore provide targets for the development of new therapies.
Globally, more than 26 million people are currently affected by Alzheimer’s Disease. As this number grows in line with an increasingly aging population, the need to identify new disease mechanisms is more important than ever. Post-mortem examinations have revealed much about how Alzheimer’s damages the brain, with some regions, such as the entorhinal cortex, being particularly susceptible, while others, such as the cerebellum, remain virtually unscathed. However, little is yet known about how and why the disease develops in specific brain regions.
The current study found that chemical modifications to DNA within the ANK1 gene are strongly associated with measures of neuropathology in the brain. The study, published in Nature Neuroscience, found that people with more Alzheimer’s disease-related neuropathology in their brains had higher levels of DNA modifications within the ANK1 gene. The finding was particularly strong in the entorhinal cortex, and also detected in other cortical regions affected by the disease. In contrast, no significant changes were observed in less affected brain regions or blood.
Professor Jonathan Mill, of the University of Exeter Medical School and King’s College London, who headed the study, said: “This is the strongest evidence yet to suggest that epigenetic changes in the brain occur in Alzheimer’s disease, and offers potential hope for understanding the mechanisms involved in the onset of dementia. We don’t yet know why these changes occur – it’s possible that they are involved in disease onset, but they may also reflect changes induced by the disease itself.”
Dr Katie Lunnon, first author on the study, from the University of Exeter Medical School, added: “It’s intriguing that we find changes specifically in the regions of the brain involved in Alzheimer’s disease. Future studies will focus on isolating different cell-types from the brain to see whether these changes are neuron-specific.”
In addition to the University of Exeter Medical School and King’s College London, the team included contributors from The Icahn School of Medicine at Mount Sinai, the JJ Peters VA Medical Center, The Johns Hopkins University School of Medicine, Harvard Medical School, the University of Oxford, and Rush University Medical Center, Chicago. They used cutting-edge technology to examine brain tissue from different areas of the brain across three cohorts - the MRC London Brain Bank for Neurodegenerative Disease, the Oxford Thomas Willis Brain Bank, and the Mount Sinai Alzheimer’s Disease and Schizophrenia Brain Bank. They analysed three cortical regions, cerebellum, and blood obtained from several hundred individuals representing the spectrum of disease; from those with no evidence of dementia and neurodegeneration, through to patients with very advanced disease.
The research was primarily funded by the National Institutes of Health (NIH), U.S. Department of Health and Human Services, as part of its Epigenomics Roadmap Initiative (grant number R01-AG036039 awarded to Jonathan Mill). To learn more about the NIH initiative that seeks to accelerate research into the relatively new and fast-developing area of epigenetics, go to: https://commonfund.nih.gov/epigenomics/index.
Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, the UK’s leading dementia research charity, who also provided funding for the study said:“We know that changes to the DNA code of certain genes are associated with an increased risk of developing Alzheimer’s disease. Investigating how epigenetic changes influence genes in Alzheimer’s is still a relatively new area of study. The importance of understanding this area of research is highlighted by the fact that epigenetic changes have been associated with development of other diseases, including cancer.
“This innovative research has discovered a potential new mechanism involved in Alzheimer’s by linking the ANK1 gene to the disease. We will be interested to see further research into the role of ANK1 in Alzheimer’s and whether other epigenetic changes may be involved in the disease.
“Alzheimer’s affects millions of people worldwide and we need pioneering research to understand exactly why the disease occurs. Alzheimer’s Research UK is helping to fund research which will take us a step closer to understanding and defeating this devastating disease.”
(Source: exeter.ac.uk)
How brains remember and correct
Information processing in the brain is complex and involves both the processing of sensory inputs and the conversion of those inputs into behavior. The passing of electrical oscillations between networks of neurons in different parts of the brain is thought to be a critical component of cognition as well as conscious perception and awareness, but so far there has been little direct evidence linking specific neuronal oscillations to discrete thinking and behavior events.
Jun Yamamoto and colleagues from the RIKEN–MIT Center for Neural Circuit Genetics have now detected a brief burst of nerve activity oscillating in two specific parts of the mouse brain just before a correct choice is made, either when planning an action or when correcting a mistake.
The researchers searched for evidence of specific neuronal oscillations by studying mice navigating a T-shaped maze with a reward at the end of one arm of the T. Just before trained mice made the correct choice of direction, Yamamoto and his colleagues observed a brief burst of synchronized high-frequency gamma waves oscillating in specific parts of the entorhinal cortex and hippocampus.
Yamamoto was fascinated to notice that the burst of gamma waves also occurred just before mice that had originally turned in the wrong direction realized their mistake and turned round. He called this the “oops” moment, and the results indicate that similar neuronal activity occurs when making a correct choice either immediately or on realization of an error. No such gamma-wave activity was detected when mice made the wrong choice without correcting it.
To further test the link between the gamma synchrony and the memory recall process, the researchers genetically engineered mice with light-activated ion channels that could block the gamma waves. When these channels were activated, the gamma waves ceased and the mice could no longer accurately choose the right direction or correct their wrong choices.
“Our work is telling us about how the brain recalls remembered information at critical moments,” says Yamamoto. “It suggests that synchronized gamma oscillations actually contribute to the animal’s correct choice rather than being a consequence of their choice.” The finding sheds light on the fundamental mechanism underlying the successful retrieval of working memory. Yamamoto now intends to see if these initial findings apply to other brain regions.
The results also provide new insight into the phenomenon of animal consciousness. “Our findings provide evidence that animals employ a behavior monitoring process called metacognition that typically requires conscious awareness,” says Yamamoto.
Oops! Researchers find neural signature for mistake correction
Culminating an 8 year search, scientists at the RIKEN-MIT Center for Neural Circuit Genetics captured an elusive brain signal underlying memory transfer and, in doing so, pinpointed the first neural circuit for “oops”—the precise moment when one becomes consciously aware of a self-made mistake and takes corrective action.
The findings, published in Cell, verified a 20 year old hypothesis on how brain areas communicate. In recent years, researchers have been pursuing a class of ephemeral brain signals called gamma oscillations, millisecond scale bursts of synchronized wave-like electrical activity that pass through brain tissue like ripples on a pond. In 1993, German scientist Wolf Singer proposed that gamma waves enable binding of memory associations. For example, in a process called working memory, animals store and recall short-term memory associations when exploring the environment.
In 2006, the MIT team under the direction of Nobel Laureate Susumu Tonegawa began a study to understand working memory in mice. They trained animals to navigate a T maze and turn left or right at a junction for an associated food reward. They found that working memory required communication between two brain areas, the hippocampus and entorhinal cortex, but how mice knew the correct direction and the neural signal for memory transfer of this event remained unclear.
The study’s lead author Jun Yamamoto noticed that mice sometimes made mistakes, turning in the wrong direction then pausing, and turning around to go in the correct direction, trials he termed “oops” in his lab notebook. Intrigued, he recorded neural activity in the circuit and observed a burst of gamma waves just before the “oops” moment. He also saw gamma waves when mice chose the correct direction, but not when they failed to choose the correct direction or did not correct their mistakes.
The critical experiment was to block gamma oscillations and prevent mice from making correct decisions. To do this, the researchers created a transgenic mouse with a light-activated protein called archaerhodopsin (ArchT) in the hippocampus. Using an optic fiber implanted in the brain, light was flashed into the hippocampal-entorhinal circuit, shutting off gamma activity. In accord, the mice could no longer accurately choose the right direction and the number of “oops” events decreased.
The findings provide strong evidence of a role for gamma oscillations in cognition, and raise the prospect of their involvement in other behaviors requiring retrieval and evaluation of working memory. This may open the door to a class of behaviors called metacognition, or “thinking about thinking”, the self-monitoring of one’s actions. Regarding the appearance of gamma oscillations in the “oops” cases, Dr. Tonegawa stated “our data suggest that animals consciously monitor whether their behavioral choices are correct and use memory recall to improve their outcomes”
Neurons in the Brain Tune into Different Frequencies for Different Spatial Memory Tasks
Your brain transmits information about your current location and memories of past locations over the same neural pathways using different frequencies of a rhythmic electrical activity called gamma waves, report neuroscientists at The University of Texas at Austin.
The research, published in the journal Neuron on April 17, may provide insight into the cognitive and memory disruptions seen in diseases such as schizophrenia and Alzheimer’s, in which gamma waves are disturbed.
Previous research has shown that the same brain region is activated whether we’re storing memories of a new place or recalling past places we’ve been.
“Many of us leave our cars in a parking garage on a daily basis. Every morning, we create a memory of where we parked our car, which we retrieve in the evening when we pick it up,” said Laura Colgin, assistant professor of neuroscience and member of the Center for Learning and Memory in The University of Texas at Austin’s College of Natural Sciences. “How then do our brains distinguish between current location and the memory of a location? Our new findings suggest a mechanism for distinguishing these different representations.”
Memory involving location is stored in an area of the brain called the hippocampus. The neurons in the hippocampus that store spatial memories (such as the location where you parked your car) are called place cells. The same set of place cells are activated both when a new memory of a location is stored and, later, when the memory of that location is recalled or retrieved.
When the hippocampus forms a new spatial memory, it receives sensory information about your current location from a brain region called the entorhinal cortex. When the hippocampus recalls a past location, it retrieves the stored spatial memory from a subregion of the hippocampus called CA3.
The entorhinal cortex and CA3 transmit these different types of information using different frequencies of gamma waves. The entorhinal cortex uses fast gamma waves, which have a frequency of about 80 Hz (about the same frequency as a bass E note played on a piano). In contrast, CA3 sends its signals on slow gamma waves, which have a frequency of about 40 Hz.
Colgin and her colleagues hypothesized that fast gamma waves promote encoding of recent experiences, while slow gamma waves support memory retrieval.
They tested these hypotheses by recording gamma waves in the hippocampus, together with electrical signals from place cells, in rats navigating through a simple environment. They found that place cells represented the rat’s current location when cells were active on fast gamma waves. When cells were active on slow gamma waves, place cells represented locations in the direction that the rat was heading.
“These findings suggest that fast gamma waves promote current memory encoding, such as the memory of where we just parked,” said Colgin. “However, when we need to remember where we are going, like when finding our parked car later in the day, the hippocampus tunes into slow gamma waves.”
Because gamma waves are seen in many areas of the brain besides the hippocampus, Colgin’s findings may generalize beyond spatial memory. The ability for neurons to tune into different frequencies of gamma waves provides a way for the brain to traffic different types of information across the same neuronal circuits.
Colgin said one of the next steps in her team’s research will be to apply technologies that induce different types of gamma waves in rats performing memory tasks. She imagines that they will be able to improve new memory encoding by inducing fast gamma waves. Conversely, she expects that inducing slow gamma waves will be detrimental to the encoding of new memories. Those slow gamma waves should trigger old memories, which would interfere with new learning.
Why your nose can be a pathfinder
When I was a child I used to sit in my grandfather’s workshop, playing with wood shavings. Freshly shaven wood has a distinct smell of childhood happiness, and whenever I get a whiff of that scent my brain immediately conjures up images of my grandfather at his working bench, the heat from the fireplace and the dog next to it.
Researchers at the Kavli Institute for Systems Neuroscience have recently discovered the process behind this phenomenon. The brain, it turns out, connects smells to memories through an associative process where neural networks are linked through synchronised brain waves of 20-40 Hz.
– We all know that smell is connected to memories, Kei Igarashi, lead author, explains.– We know that neurons in different brain regions need to oscillate in synchrony for these regions to speak effectively to each other. Still, the relationship between interregional coupling and formation of memory traces has remained poorly understood. So we designed a task to investigate how odour-place representation evolved in the entorhinal and hippocampal region, to figure out whether learning depends on coupling of oscillatory networks.
Smell guides the way in maze
The researchers designed a maze for rats, where a rat would see a hole to poke its nose into. When poking into the hole, the rat was presented with one of two alternative smells. One smell told the rat that food would be found in the left food cup behind the rat. The other smell told it that there was food in the right cup. The rat would soon learn which smell would lead to a reward where. After three weeks of training, the rats chose correctly on more than 85% of the trials. In order to see what happened inside the brain during acquisition, 16–20 electrode pairs were inserted in the hippocampus and in different areas of the entorhinal cortex.
After the associations between smell and place were well established, the researchers could see a pattern of brain wave activity (the electrical signal from a large number of neurons) during retrieval.
Coherent brain activity evolves with learning
– Immediately after the rat is exposed to the smell there is a burst in activity of 20–40 Hz waves in a specific connection between an area in the entorhinal cortex, lateral entorhinal cortex (LEC), and an area in the hippocampus, distal CA1 (dCA1), while a similar strong response was not observed in other connections, Igarashi explains.
This coherence of 20–40 Hz activity in the LEC and dCA1 evolved in parallel with learning, with little coherence between these areas before training started. By the time the learning period was over, cells were phase locked to the oscillation and a large portion of the cells responded specifically to one or the other of the smell-odour pairs.
Long distance communication in brain mediated by waves
– This is not the first time we observe that the brain uses synchronised wave activity to establish network connections, Edvard Moser, director of the Kavli Institute for Systems Neuroscience says. – Both during encoding and retrieval of declarative memories there is an interaction between these areas mediated through gamma and theta oscillations. However, this is the first study to relate the development of a specific band of oscillations to memory performance in the hippocampus. Together, the evidence is now piling up and pointing in the direction of cortical oscillations as a general mechanism for mediating interactions among functionally specialised neurons in distributed brain circuits.
So, there you have it – the signals from your nose translate and connect to memories in an orchestrated symphony of signals in your head. Each of these memories connects to a location, pinpointed on your inner map. So when you feel a wave of reminiscence triggered by a fragrance, think about how waves created this connection in the first place.
In the brain, timing is everything
Suppose you heard the sound of skidding tires, followed by a car crash. The next time you heard such a skid, you might cringe in fear, expecting a crash to follow — suggesting that somehow, your brain had linked those two memories so that a fairly innocuous sound provokes dread.
MIT neuroscientists have now discovered how two neural circuits in the brain work together to control the formation of such time-linked memories. This is a critical ability that helps the brain to determine when it needs to take action to defend against a potential threat, says Susumu Tonegawa, the Picower Professor of Biology and Neuroscience and senior author of a paper describing the findings in the Jan. 23 issue of Science.
“It’s important for us to be able to associate things that happen with some temporal gap,” says Tonegawa, who is a member of MIT’s Picower Institute for Learning and Memory. “For animals it is very useful to know what events they should associate, and what not to associate.”
The interaction of these two circuits allows the brain to maintain a balance between becoming too easily paralyzed with fear and being too careless, which could result in being caught off guard by a predator or other threat.
The paper’s lead authors are Picower Institute postdocs Takashi Kitamura and Michele Pignatelli.
Linking memories
Memories of events, known as episodic memories, always contain three elements — what, where, and when. Those memories are created in a brain structure called the hippocampus, which must coordinate each of these three elements.
To form episodic memories, the hippocampus also communicates with the region of the cerebral cortex just outside the hippocampus, known as the entorhinal cortex. The entorhinal cortex, which has several layers, receives sensory information, such as sights and sounds, from sensory processing areas of the brain and sends the information on to the hippocampus.
Previous research has revealed a great deal about how the brain links the place and object components of memory. Certain neurons in the hippocampus, known as place cells, are specialized to fire when an animal is in a specific location, and also when the animal is remembering that location. However, when it comes to associating objects and time, “our understanding has fallen behind,” Tonegawa says. “Something is known, but relatively little compared to the object-place mechanism.”
The new Science paper builds on a 2011 study from Tonegawa’s lab in which he identified a brain circuit necessary for mice to link memories of two events — a tone and a mild electric shock — that occur up to 20 seconds apart. This circuit connects layer 3 of the entorhinal cortex to the CA1 region of the hippocampus. When that circuit, known as the monosynaptic circuit, was disrupted, the animals did not learn to fear the tone.
In the new paper, the researchers report the discovery of a previously unknown circuit that suppresses the monosynaptic circuit. This signal originates in a type of excitatory neurons discovered in Tonegawa’s lab, dubbed “island cells” because they form circular clusters within layer 2. Those cells stimulate inhibitory neurons in CA1 that suppress the set of excitatory CA1 neurons that are activated by the monosynaptic circuit.
This circuit creates a counterbalance that limits the window of opportunity for two events to become linked. “This pathway might provide a mechanism for preventing constant learning of unimportant temporal associations,” says Michael Hasselmo, a professor of psychology at Boston University who was not part of the research team.
The findings are “an important demonstration of the functional role of different populations of neurons in entorhinal cortex that provide input to the hippocampus,” Hasselmo adds.
Deciphering circuits
The researchers used optogenetics, a technology that allows specific populations of neurons to be turned on or off with light, to demonstrate the interplay of these two circuits.
In normal mice, the maximum time gap between events that can be linked is about 20 seconds, but the researchers could lengthen that period by either boosting activity of layer 3 cells or suppressing layer 2 island cells. Conversely, they could shorten the window of opportunity by inhibiting layer 3 cells or stimulating input from layer 2 island cells, which both result in turning down CA1 activity.
The researchers hypothesize that prolonged CA1 activity keeps the memory of the tone alive long enough so that it is still present when the shock takes place, allowing the two memories to be linked. They are now investigating whether CA1 neurons remain active throughout the entire gap between events.
Study Shows Where Alzheimer’s Starts and How It Spreads
Using high-resolution functional MRI (fMRI) imaging in patients with Alzheimer’s disease and in mouse models of the disease, Columbia University Medical Center (CUMC) researchers have clarified three fundamental issues about Alzheimer’s: where it starts, why it starts there, and how it spreads. In addition to advancing understanding of Alzheimer’s, the findings could improve early detection of the disease, when drugs may be most effective. The study was published today in the online edition of the journal Nature Neuroscience.
“It has been known for years that Alzheimer’s starts in a brain region known as the entorhinal cortex,” said co-senior author Scott A. Small, MD, Boris and Rose Katz Professor of Neurology, professor of radiology, and director of the Alzheimer’s Disease Research Center. “But this study is the first to show in living patients that it begins specifically in the lateral entorhinal cortex, or LEC. The LEC is considered to be a gateway to the hippocampus, which plays a key role in the consolidation of long-term memory, among other functions. If the LEC is affected, other aspects of the hippocampus will also be affected.”
The study also shows that, over time, Alzheimer’s spreads from the LEC directly to other areas of the cerebral cortex, in particular, the parietal cortex, a brain region involved in various functions, including spatial orientation and navigation. The researchers suspect that Alzheimer’s spreads “functionally,” that is, by compromising the function of neurons in the LEC, which then compromises the integrity of neurons in adjoining areas.
A third major finding of the study is that LEC dysfunction occurs when changes in tau and amyloid precursor protein (APP) co-exist. “The LEC is especially vulnerable to Alzheimer’s because it normally accumulates tau, which sensitizes the LEC to the accumulation of APP. Together, these two proteins damage neurons in the LEC, setting the stage for Alzheimer’s,” said co-senior author Karen E. Duff, PhD, professor of pathology and cell biology (in psychiatry and in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain) at CUMC and at the New York State Psychiatric Institute.
In the study, the researchers used a high-resolution variant of fMRI to map metabolic defects in the brains of 96 adults enrolled in the Washington Heights-Inwood Columbia Aging Project (WHICAP). All of the adults were free of dementia at the time of enrollment.
“Dr. Richard Mayeux’s WHICAP study enables us to follow a large group of healthy elderly individuals, some of whom have gone on to develop Alzheimer’s disease,” said Dr. Small. “This study has given us a unique opportunity to image and characterize patients with Alzheimer’s in its earliest, preclinical stage.”
The 96 adults were followed for an average of 3.5 years, at which time 12 individuals were found to have progressed to mild Alzheimer’s disease. An analysis of the baseline fMRI images of those 12 individuals found significant decreases in cerebral blood volume (CBV) — a measure of metabolic activity — in the LEC compared with that of the 84 adults who were free of dementia.
A second part of the study addressed the role of tau and APP in LEC dysfunction. While previous studies have suggested that entorhinal cortex dysfunction is associated with both tau and APP abnormalities, it was not known how these proteins interact to drive this dysfunction, particularly in preclinical Alzheimer’s.
To answer this question, explained first author Usman Khan, an MD-PhD student based in Dr. Small’s lab, the team created three mouse models, one with elevated levels of tau in the LEC, one with elevated levels of APP, and one with elevated levels of both proteins. The researchers found that the LEC dysfunction occurred only in the mice with both tau and APP.
The study has implications for both research and treatment. “Now that we’ve pinpointed where Alzheimer’s starts, and shown that those changes are observable using fMRI, we may be able to detect Alzheimer’s at its earliest preclinical stage, when the disease might be more treatable and before it spreads to other brain regions,” said Dr. Small. In addition, say the researchers, the new imaging method could be used to assess the efficacy of promising Alzheimer’s drugs during the disease’s early stages.
A Brake in the Head: German researchers gain new insights into the working of the brain
Scientists of the Charité – Universitätsmedizin Berlin and the German Center for Neurodegenerative Diseases (DZNE) have managed to acquire new insights into the functioning of a region in the brain that normally is involved in spatial orientation, but is damaged by the Alzheimer’s disease. They investigated how nerve signals are suppressed inside the so-called entorhinal cortex. According to the researchers, this neuronal inhibition leads nerve cells to synchronize their activity. The results of this study are now published in Neuron.
The entorhinal cortex is a link between the brain’s memory centre, the hippocampus, and the other areas of the brain. It is, however, more than an interface that only transfers nervous impulses. The entorhinal cortex also has an independent role in learning and thinking processes. This is particularly applicable for spatial navigation. “We know precious little about how this happens,” says Prof. Dietmar Schmitz, a researcher at the Cluster of Excellence NeuroCure at the Charité – Universitätsmedizin Berlin and Site Speaker for the DZNE in Berlin. “This is why we are investigating in animal models how the nerve cells within the entorhinal cortex are connected with each other.“
Signals wander inside the brain as electrical impulses from nerve cell to nerve cell. In general, signals are not merely forwarded. Rather, operation of the brain critically depends on the fact that the nerve impulses in some situations are activated and in other cases suppressed. A correct balance between suppression and excitation is decisive for all brain processes. “Until now research has mainly concentrated on signal excitation within the entorhinal cortex. This is why we looked into inhibition and detected a gradient inside the entorhinal cortex,” explains Dr. Prateep Beed, lead author of the study. “This means that nerve signals are not suppressed equally. The blockage of the nerve signals is weaker in certain parts of the entorhinal cortex and stronger in others. The inhibition has, so to speak, a spatial profile.”
When the brain is busy, nerve cells often coordinate their operation. In an electroencephalogram (EEG) – a recording of the brain’s electrical activity – the synchronous rhythm of the nerve cells manifests as a periodic pattern. “It is a moot question as to how nerve cells synchronize their behavior and how they bring about such rhythms,” says Beed. As he explains, it is also unclear whether these oscillations are only just a side effect or whether they trigger other phenomena. “But it has been demonstrated that neuronal oscillations accompany learning processes and even happen during sleep. They are a typical feature of the brain’s activity,” describes the scientist. “In our opinion, the inhibitory gradient, which we detected, plays an important role in creating the synchronous rhythm of the nerve cells and the related oscillations.”
In the case of Alzheimer’s, the entorhinal cortex is among the regions of the brain that are the first to be affected. “In recent times, studies related to this brain structure have increased. Here, already in the early stages of Alzheimer’s, one finds the protein deposits that are typical of this disease,” explains Schmitz, who headed the research. “It is also known that patients affected by Alzheimer’s have a striking EEG. Our studies help us to understand how the nerve cells in the entorhinal cortex operate and how electrical activities might get interrupted in this area of the brain.”
A Major Cause of Age-Related Memory Loss Identified
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 today in the online edition of Science Translational Medicine.
“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 is University Professor & Kavli Professor of Brain Science, co-director of Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute, director of the Kavli Institute for Brain Science, and senior investigator, Howard Hughes Medical Institute, at CUMC. Dr. Kandel received a share of the 2000 Nobel Prize in Physiology or Medicine for his discoveries related to the molecular basis of memory.
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 current study was designed to look for more direct evidence that age-related memory loss differs from Alzheimer’s disease. The researchers began by performing microarray (gene expression) analyses of postmortem brain cells from the DG of eight people, ages 33 to 88, all of whom were free of brain disease. The team also analyzed cells from their EC, which served as controls since that brain structure is unaffected by aging. The analyses identified 17 candidate genes that might be related to aging in the DG. The most significant changes occurred in a gene called RbAp48, whoseexpressiondeclined steadily with aging across the study subjects.
To determine whether RbAp48plays an active role in age-related memory loss, the researchers turned to mouse studies. “The first question was whether RbAp48is downregulated in aged mice,” said lead author Elias Pavlopoulos, PhD, associate research scientist in neuroscience at CUMC. “And indeed, that turned out to be the case—there was a reduction of RbAp48 protein in the DG.”
When the researchers genetically inhibited RbAp48inthe brains ofhealthy young mice, they found the same memory loss as in aged mice, as measured by novel object recognition and water maze memory tests. When RbAp48inhibition was turned off, the mice’s memory returned to normal.
The researchers also did functional MRI (fMRI) studies of the mice with inhibited RbAp48 and found a selective effect in the DG, similar to that seen in fMRI studies of aged mice, monkeys, and humans. This effect of RbAp48 inhibition on the DG was accompanied by defects in molecular mechanisms similar to those found in aged mice. The fMRI profile and mechanistic defects of the mice with inhibited RbAp48 returned to normal when the inhibition was turned off.
In another experiment, the researchers used viral gene transfer and increased RbAp48expression inthe DG of aged mice. “We were astonished that not only did this improve the mice’s performance on the memory tests, but their performance was comparable to that of young mice,” said Dr. Pavlopoulos.
“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.”