Gene Silencing Spurs Fountain of Youth in Mouse Brain

Feb. 7, 2013 — Cognitive decline in old age is linked to decreasing production of new neurons. Scientists from the German Cancer Research Center have discovered in mice that significantly more neurons are generated in the brains of older animals if a signaling molecule called Dickkopf-1 is turned off. In tests for spatial orientation and memory, mice in advanced adult age whose Dickkopf gene had been silenced reached an equal mental performance as young animals.

Newborn neurons (in green) in the brain of a 3 month old mouse. (Credit: German Cancer Research Center)

The hippocampus — a structure of the brain whose shape resembles that of a seahorse — is also called the “gateway” to memory. This is where information is stored and retrieved. Its performance relies on new neurons being continually formed in the hippocampus over the entire lifetime. “However, in old age, production of new neurons dramatically decreases. This is considered to be among the causes of declining memory and learning ability,” Prof. Dr. Ana Martin-Villalba, a neuroscientist, explains.

Martin-Villalba, who heads a research department at the German Cancer Research Center (DKFZ), and her team are trying to find the molecular causes for this decrease in new neuron production (neurogenesis). Neural stem cells in the hippocampus are responsible for continuous supply of new neurons. Specific molecules in the immediate environment of these stem cells determine their fate: They may remain dormant, renew themselves, or differentiate into one of two types of specialized brain cells, astrocytes or neurons. One of these factors is the Wnt signaling molecule, which promotes the formation of young neurons. However, its molecular counterpart, called Dickkopf-1, can prevent this.

“We find considerably more Dickkopf-1 protein in the brains of older mice than in those of young animals. We therefore suspected this signaling molecule to be responsible for the fact that hardly any young neurons are generated any more in old age.” The scientists tested their assumption in mice whose Dickkopf-1 gene is permanently silenced. Professor Christof Niehrs had developed these animals at DKFZ. The term “Dickkopf” (from German “dick” = thick, “Kopf” = head) also goes back to Niehrs, who had found in 1998 that this signaling molecule regulates head development during embryogenesis.

Martin-Villalba’s team discovered that stem cells in the hippocampus of Dickkopf knockout mice renew themselves more often and generate significantly more young neurons. The difference was particularly obvious in two-year old mice: In the knockout mice of this age, the researchers counted 80 percent more young neurons than in control animals of the same age. Moreover, the newly formed cells in the adult Dickkopf-1 mutant mice matured into potent neurons with multiple branches. In contrast, neurons in control animals of the same age were found to be more rudimentary already.

Blocking Dickkopf improves spatial orientation and memory

Several years ago, Ana Martin-Villalba had shown that mice lose their spatial orientation when neurogenesis in the hippocampus is blocked. Now, is it possible that the young neurons in Dickkopf-deficient mice improve the animals’ cognitive performance? The DKFZ researchers used standardized tests to study how the mice orient themselves in a maze. While in the control animals, the younger ones (3 months) performed much better in orienting themselves than the older ones (18 months), the Dickkopf-1-deficient mice showed no age-related decline in spatial orientation capabilities. Older Dickkopf-1 mutant mice also outperformed normal animals in tests determining spatial memory.

“Our result proves that Dickkopf-1 promotes age-related decline of specific cognitive abilities,” says Ana Martin-Villalba. “Although we had expected silencing of Dickkopf-1 to improve spatial orientation and memory of adult mice, we were surprised and impressed that animals in advanced adult age actually reach the performance levels of young animals.”

These results give rise to the question whether the function of Dickkopf-1 may be turned off using drugs. Antibodies blocking the Dickkopf protein are already being tested in clinical trials for treating a completely different condition. “It is fascinating to speculate that such a substance may also slow down age-related cognitive decline. But this is still a dream of the future, since we have only just started first experiments in mice to explore this question.”


Story Source:

The above story is reprinted from materials provided byHelmholtz Association of German Research Centres, via EurekAlert!, a service of AAAS.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.


Journal Reference:

  1. Désirée R.M. Seib, Nina S. Corsini, Kristina Ellwanger, Christian Plaas, Alvaro Mateos, Claudia Pitzer, Christof Niehrs, Tansu Celikel, Ana Martin-Villalba. Loss of Dickkopf-1 Restores Neurogenesis in Old Age and Counteracts Cognitive DeclineCell Stem Cell, 2013; 12 (2): 204 DOI: 10.1016/j.stem.2012.11.010
Helmholtz Association of German Research Centres (2013, February 7). Gene silencing spurs fountain of youth in mouse brain.ScienceDaily. Retrieved February 10, 2013, from http://www.sciencedaily.com/releases/2013/02/130207150911.htm

Newly Found ‘Volume Control’ in Brain Promotes Learning, Memory

Jan. 9, 2013 — Scientists have long wondered how nerve cell activity in the brain’s hippocampus, the epicenter for learning and memory, is controlled — too much synaptic communication between neurons can trigger a seizure, and too little impairs information processing, promoting neurodegeneration. Researchers at Georgetown University Medical Center say they now have an answer. In the January 10 issue of Neuron, they report that synapses that link two different groups of nerve cells in the hippocampus serve as a kind of “volume control,” keeping neuronal activity throughout that region at a steady, optimal level.


 

“Think of these special synapses like the fingers of God and man touching in Michelangelo’s famous fresco in the Sistine Chapel,” says the study’s senior investigator, Daniel Pak, PhD, an associate professor of pharmacology. “Now substitute the figures for two different groups of neurons that need to perform smoothly. The touching of the fingers, or synapses, controls activity levels of neurons within the hippocampus.”

The hippocampus is a processing unit that receives input from the cortex and consolidates that information in terms of learning and memory. Neurons known as granule cells, located in the hippocampus’ dentate gyrus, receive transmissions from the cortex. Those granule cells then pass that information to the other set of neurons (those in the CA3 region of the hippocampus, in this study) via the synaptic fingers.

Those fingers dial up, or dial down, the volume of neurotransmission from the granule cells to the CA3 region to keep neurotransmission in the learning and memory areas of the hippocampus at an optimal flow — a concept known as homeostatic plasticity. “If granule cells try to transmit too much activity, we found, the synaptic junction tamps down the volume of transmission by weakening their connections, allowing the proper amount of information to travel to CA3 neurons,” says Pak. “If there is not enough activity being transmitted by the granule cells, the synapses become stronger, pumping up the volume to CA3 so that information flow remains constant.”

There are many such touching fingers in the hippocampus, connecting the so-called “mossy fibers” of the granule cells to neurons in the CA3 region. But importantly, not every one of the billions of neurons in the hippocampus needs to set its own level of transmission from one nerve cell to the other, says Pak.

To explain, he uses another analogy. “It had previously been thought that neurons act separately like cars, each working to keep their speed at a constant level even though signal traffic may be fast or slow. But we wondered how these neurons could process learning and memory information efficiently, while also regulating the speed by which they process and communicate that information.

“We believe, based on our study, that only the mossy fiber synapses on the CA3 neurons control the level of activity for the hippocampus — they are like the engine on a train that sets the speed for all the other cars, or neurons, attached to it,” Pak says. “That frees up the other neurons to do the job they are tasked with doing — processing and encoding information in the forms of learning and memory.”

Not only does the study offer a new model for how homeostatic plasticity in the hippocampus can co-exist with learning and memory, it also suggests a new therapeutic avenue to help patients with uncontrollable seizures, he says.

“The CA3 region is highly susceptible to seizures, so if we understand how homeostasis is maintained in these neurons, we could potentially manipulate the system. When there is an excessive level of CA3 neuronal activity in a patient, we could learn how to therapeutically turn it down.”


Story Source:

The above story is reprinted from materials provided byGeorgetown University Medical Center, via EurekAlert!, a service of AAAS.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.


Georgetown University Medical Center (2013, January 9). Newly found ‘volume control’ in brain promotes learning, memory.ScienceDaily. Retrieved January 12, 2013, from http://www.sciencedaily.com/releases/2013/01/130109124154.htm

One Act of Remembering Can Influence Future Acts

ScienceDaily (July 26, 2012) — Can the simple act of recognizing a face as you walk down the street change the way we think? Or can taking the time to notice something new on our way to work change what we remember about that walk? In a new study published in the journal Science, New York University researchers show that remembering something old or noticing something new can bias how you process subsequent information.


This novel finding suggests that our memory system can adaptively bias its processing towards forming new memories or retrieving old ones based on recent experiences. For example, when you walk into a restaurant or for the first time, your memory system can both encode the details of this new environment as well as allow you to remember a similar one where you recently dined with a friend. The results of this study suggest that what you did right before walking into the restaurant can determine which process is more likely to occur.

Previous scholarship has demonstrated that both encoding new memories and retrieving old ones depend on the same specific brain region — the hippocampus. However, computational models suggest that encoding and retrieval occur under incompatible network processes. In other words, how can the same part of the brain perform two tasks that are at odds with each other?

At the heart of this paradox is distinction between encoding, or forming a new memory, and memory retrieval, or recalling old information. Specifically, encoding is thought to rely on pattern separation, a process that makes overlapping, or similar, representations more distinct, whereas retrieval is thought to depend on pattern completion, a process that increases overlap by reactivating related memory traces.

With this in mind, the researchers saw a potential resolution to this neurological paradox — that the hippocampus can be biased towards either pattern completion or pattern separation, depending on the current context?

To address this question, the researchers conducted an experiment in which participants rapidly switched between encoding novel objects and retrieving recently presented ones. The researchers hypothesized that processing the novel objects would bias participants’ memory systems towards pattern separation while processing the old ones would evoke pattern completion biases.

Specifically, they were shown a series of objects that fell into three categories: novel objects (i.e., an initial presentation of an image, such as an apple or a face), repeated objects, or objects that were similar but not identical to previously presented ones (e.g., an apple with slightly different shape from the initial image). Participants were then asked to identify each as new (first presentation), old (exact repetition), or similar (not exact repetition). The similar items were the critical study items since they contained a little old and little new information. Thus, participants could either notice the novel details or incorrectly identify these stimuli as old.

The researchers found that participants’ ability to notice the new details and correctly label those stimuli as ‘similar’ depended on what they did on the previous trial. Specifically, if they encountered a new stimulus on the preceding trial, participants were more likely to notice the similar trials were similar, but not old, items.

By contrast, in another experiment, the researchers demonstrated that the same manipulation can also influence how we form new memories. In this study, the researchers tested how well participants were able to form links between overlapping memories. They found that participants were more likely to construct these links when the overlapping memories were formed immediately after retrieving an unrelated old object as compared to identifying a new one. This suggests that after processing old objects, participants were more likely to retrieve the associated memories and link them to an ongoing experience.

“We’ve all had the experience of seeing an unexpected familiar face as we walk down the street and much work has been done to understand how it is that we can come to recognize these unexpected events,” said Lila Davachi, an associate professor in NYU’s Department of Psychology and the study’s senior author. “However, what has never been appreciated is that simply seeing that face can have a substantial impact on your future state of mind and can allow you, for example, to notice the new café that just opened on the corner or the new flowers in the garden down the street.”

“We spend most of our time surrounded by familiar people, places, and objects, each of which has the potential to cue memories,” added Katherine Duncan, the study’s first author who was an NYU doctoral student at the time of the study and is now a postdoctoral researcher at Columbia University. “So why does the same building sometimes trigger nostalgic reflection but other times can be passed without notice? Our findings suggest that one factor maybe whether your memory system has recently retrieved other, even unrelated, memories or if it was engaged in laying down new ones.”

Co-author Arhanti Sadanand assisted with the research as an NYU undergraduate. She begins medical school at Virginia Commonwealth University this fall.

Link:

http://www.newswise.com/articles/one-act-of-remembering-can-influence-future-acts-nyu-researchers-find

Journal Reference:

  1. K. Duncan, A. Sadanand, L. Davachi. Memory’s Penumbra: Episodic Memory Decisions Induce Lingering Mnemonic Biases. Science, 2012; 337 (6093): 485 DOI: 10.1126/science.1221936

Citation:

New York University (2012, July 26). One act of remembering can influence future acts. ScienceDaily. Retrieved July 28, 2012, from http://www.sciencedaily.com­ /releases/2012/07/120726142045.htm

Spatial Knowledge Vs. Spatial Choice: The Hippocampus as Conflict Detector?

ScienceDaily (July 19, 2012) — Hippocampal NMDA receptors in the brain help to make the right decision when faced with complex orientation problems.


Synapses are modified through learning. Up until now, scientists believed that a particular form of synaptic plasticity in the brain’s hippocampus was responsible for learning spatial relations. This was based on a receptor type for the neurotransmitter glutamate: the NMDA receptor. Researchers at the Max Planck Institute for Medical Research in Heidelberg and Oxford University have now observed that mice develop a spatial memory, even when the NMDA receptor-transmitted plasticity is switched off in parts of their hippocampus. However, if these mice have to resolve a conflict while getting their bearings, they are not successful in resolving it; the hippocampal NMDA receptors are clearly needed to detect or resolve the conflict. This has led the researchers involved in this experiment to refute a central tenet of neuroscience regarding the function of hippocampal NMDA receptor-transmitted plasticity in spatial learning.

The hippocampus is part of the forebrain and processes a large amount of information from various parts of the brain. Incoming signals are transmitted by granule cells in the dentate gyrus to pyramid cells in the CA3 region and from these to pyramid cells in the CA1 region. NMDA receptors can optimise or weaken the transmission efficiency of the neurotransmitter glutamate at the synapses involved at the signal flow. It has long been speculated that this form of synaptic plasticity is needed when learning about spatial associations. Rolf Sprengel and Peter H. Seeburg from the Max Planck Institute for Medical Research worked with colleagues from Oxford and Oslo to refute this theory.

The scientists studied genetically modified mice lacking NMDA receptors in dentate gyrus granule cells and pyramid cells in the CA1 region. They were thus able to observe for the first time ever what happens when NMDA receptor-dependent plasticity is switched off almost exclusively at these synapses in the hippocampus. They analysed the learning behaviour of the mice and noted that learning capacity depended on the experimental setup. In a standard swimming test (the so called Morris Water Maze), the spatial memory of the genetically modified animals was just as good as the spatial memory of the normal controls. In this test, the animals had to learn the location of an escape platform placed just under the surface of water in a pool of milky water using external cues and had to find the hidden platform after a few attempts.

In a second spatial orientation test in which the animals could find food in three of six identical arms of a “six arm dry maze,” the mice lacking NMDA receptors in the dentate gyrus and CA1 region of the hippocampus repeatedly visited arms without food, while, after a number of attempts, the controls — as in the case of the swimming test — used markings outside of the maze to enter the three arms where there was food.

Although both tests demand spatial learning, the genetically modified animals performed worse only in the maze arm than the controls, apparently irritated by the fact that arms were rewarded or not rewarded with food. David Bannerman from Oxford therefore designed a second swimming test. In this test, the location of the hidden platform was marked with a beacon. A second identical, beacon was placed at another location in the pool as a decoy — there was no platform under the water at this second location. The mice had to learn that only the spatial orientation and not the location of the beacons — like the visually identical arms in the maze — was crucial for finding the platform that would allow them to escape. As the beacons were used by the animals with a preference for hippocampus-independent orientation, it was also difficult for the controls to unerringly find the hidden platform after numerous trials. Mice lacking the NMDA receptors in the dentate gyrus and the CA1 region could not resolve this problem. If both beacons were removed or the shape of the decoy beacons was modified, all the animals quickly selected the location of the invisible platform.

“This clearly shows that, after a number of runs, even our genetically modified mice know the exact location of the hidden escape platform or can purposefully get their bearings in the swimming pool when searching for various beacons. Our mice therefore have no learning or memory problems in either of the two tasks. If, however, the tasks are temporally superimposed and if the location of identical beacons in the swimming pool does not have to be evaluated as distinct items of information, our mice are not capable of making the right decision to resolve the problem,” says Rolf Sprengel.

The NMDA receptors in the CA1 region of the hippocampus therefore seem to perform a conflict detection or decision-making role in the event of conflicts.

This is an extremely surprising result. It runs contrary to a textbook tenet that has prevailed for more than 15 years, namely that NMDA receptors in the CA1 region of the hippocampus are needed to develop spatial memory. “Thanks to Rolf Sprengel’s new complex genetic technique of switching off the NMDA receptors only in specific parts of the hippocampus in adult mice and to David Bannerman’s intelligently linked behavioural experiments, we now know that NMDA receptors in other parts of the brain are probably responsible for learning spatial relations,” explains Peter H. Seeburg. The researchers assume, therefore, that hippocampal NMDA receptors are also significant in other non-spatial conflicts.

 

Journal Reference:

  1. David M Bannerman, Thorsten Bus, Amy Taylor, David J Sanderson, Inna Schwarz, Vidar Jensen, Øivind Hvalby, J Nicholas P Rawlins, Peter H Seeburg, Rolf Sprengel. Dissecting spatial knowledge from spatial choice by hippocampal NMDA receptor deletion. Nature Neuroscience, 2012; DOI: 10.1038/nn.3166

 

Max-Planck-Gesellschaft (2012, July 19). Spatial knowledge vs. spatial choice: The hippocampus as conflict detector?. ScienceDaily. Retrieved July 21, 2012, from http://www.sciencedaily.com­ /releases/2012/07/120719103524.htm