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.
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.”
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- 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 Decline. Cell Stem Cell, 2013; 12 (2): 204 DOI: 10.1016/j.stem.2012.11.010
Jan. 30, 2013 — It takes a lot to make a memory. New proteins have to be synthesized, neuron structures altered. While some of these memory-building mechanisms are known, many are not. Some recent studies have indicated that a unique group of molecules called microRNAs, known to control production of proteins in cells, may play a far more important role in memory formation than previously thought.
Now, a new study by scientists on the Florida campus of The Scripps Research Institute has for the first time confirmed a critical role for microRNAs in the development of memory in the part of the brain called the amygdala, which is involved in emotional memory. The new study found that a specific microRNA — miR-182 — was deeply involved in memory formation within this brain structure.
“No one had looked at the role of microRNAs in amygdala memory,” said Courtney Miller, a TSRI assistant professor who led the study. “And it looks as though miR-182 may be promoting local protein synthesis, helping to support the synapse-specificity of memories.”
In the new study, published in theJournal of Neuroscience, the scientists measured the levels of all known microRNAs following an animal model of learning. A microarray analysis, which enables rapid genetic testing on a large scale, showed that more than half of all known microRNAs are expressed in the amygdala. Seven of those microRNAs increased and 32 decreased when learning occurred.
The study found that, of the microRNAs expressed in the brain, miR-182 had one of the lowest levels and these decreased further with learning. Despite these very low levels, its overexpression prevented the formation of memory and led to a decrease in proteins that regulate neuronal plasticity (neurons’ ability to adapt) through changes in structure.
These findings suggest that learning-induced suppression of miR-182 is a main supporting factor in the formation of long-term memory in the amagdala, as well as an underappreciated mechanism for regulating protein synthesis during memory consolidation, Miller said.
Further analysis identified miR-182 as a repressor of proteins that control actin — a major component of the cytoskeleton, the scaffolding that holds cells together.
“We know that memory formation requires changes in dendritic spines on the neurons through regulation of the actin cytoskeleton,” Miller said. “When miR-182 is suppressed through learning it halts, at least in part, repression of actin-regulating proteins, so there’s a good chance that miR-182 exerts important control over the actin cytoskeleton.”
Miller is now interested in whether or not high levels of miR-182 accumulate in the aging brain, something that would help to explain a tendency toward memory loss in the elderly. She also notes that other research has shown that animal models lacking miR-182 had no significant physical or cellular abnormalities, suggesting that miR-182 could be a viable target for drug discovery.
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- E. M. Griggs, E. J. Young, G. Rumbaugh, C. A. Miller.MicroRNA-182 Regulates Amygdala-Dependent Memory Formation. Journal of Neuroscience, 2013; 33 (4): 1734 DOI: 10.1523/JNEUROSCI.2873-12.2013
Jan. 29, 2013 — Working with patients with electrodes implanted in their brains, researchers at the University of California, Davis, and The University of Texas Health Science Center at Houston (UTHealth) have shown for the first time that areas of the brain work together at the same time to recall memories. The unique approach promises new insights into how we remember details of time and place.
“Previous work has focused on one region of the brain at a time,” said Arne Ekstrom, assistant professor at the UC Davis Center for Neuroscience. “Our results show that memory recall involves simultaneous activity across brain regions.” Ekstrom is senior author of a paper describing the work published Jan. 27 in the journalNature Neuroscience.
Ekstrom and UC Davis graduate student Andrew Watrous worked with patients being treated for a severe seizure condition by neurosurgeon Dr. Nitin Tandon and his UTHealth colleagues.
To pinpoint the origin of the seizures in these patients, Tandon and his team place electrodes on the patient’s brain inside the skull. The electrodes remain in place for one to two weeks for monitoring.
Six such patients volunteered for Ekstrom and Watrous’ study while the electrodes were in place. Using a laptop computer, the patients learned to navigate a route through a virtual streetscape, picking up passengers and taking them to specific places. Later, they were asked to recall the routes from memory.
Correct memory recall was associated with increased activity across multiple connected brain regions at the same time, Ekstrom said, rather than activity in one region followed by another.
However, the analysis did show that the medial temporal lobe is an important hub of the memory network, confirming earlier studies, he said.
Intriguingly, memories of time and of place were associated with different frequencies of brain activity across the network. For example, recalling, “What shop is next to the donut shop?” set off a different frequency of activity from recalling “Where was I at 11 a.m.?”
Using different frequencies could explain how the brain codes and recalls elements of past events such as time and location at the same time, Ekstrom said.
“Just as cell phones and wireless devices work at different radio frequencies for different information, the brain resonates at different frequencies for spatial and temporal information,” he said.
The researchers hope to explore further how the brain codes information in future work.
The neuroscientists analyzed their results with graph theory, a new technique that is being used for studying networks, ranging from social media connections to airline schedules.
“Previously, we didn’t have enough data from different brain regions to use graph theory. This combination of multiple readings during memory retrieval and graph theory is unique,” Ekstrom said.
Placing electrodes inside the skull provides clearer resolution of electrical signals than external electrodes, making the data invaluable for the study of cognitive functions, Tandon said. “This work has yielded important insights into the normal mechanisms underpinning recall, and provides us with a framework for the study of memory dysfunction in the future.”
Additional authors of the study are Chris Connor and Thomas Pieters at the UTHealth Medical School. The work was supported by the Sloan Foundation, the Hellman Foundation and the NIH.
Note: Materials may be edited for content and length. For further information, please contact the source cited above.
- Andrew J Watrous, Nitin Tandon, Chris R Conner, Thomas Pieters, Arne D Ekstrom. Frequency-specific network connectivity increases underlie accurate spatiotemporal memory retrieval. Nature Neuroscience, 2013; DOI: 10.1038/nn.3315
Jan. 23, 2013 — People with color-grapheme synesthesia experience color when viewing written letters or numerals, usually with a particular color evoked by each grapheme (i.e., the letter ‘A’ evokes the color red). In a new study, researchers Nathan Witthoft and Jonathan Winawer of Stanford University present data from 11 color grapheme synesthetes who had startlingly similar color-letter pairings that were traceable to childhood toys containing magnetic colored letters.
Their findings are published inPsychological Science, a journal of the Association for Psychological Science.
Matching data from the 11 participants showed reliably consistent letter-color matches, both within and between testing sessions (data collected online athttp://www.synesthete.org/). Participants’ matches were consistent even after a delay of up to seven years since their first session.
Participants also performed a timed task, in which they were presented with colored letters for 1 second each and required to indicate whether the color was consistent with their synesthetic association. Their data show that they were able to perform the task rapidly and accurately.
Together, these data suggest that the participants’ color-letter associations are specific, automatic, and relatively constant over time, thereby meeting the criteria for true synesthesia.
The degree of similarity in the letter-color pairings across participants, along with the regular repeating pattern in the colors found in each individual’s letter-color pairings, indicates that the pairings were learned from the magnetic colored letters that the participants had been exposed to in childhood.
According to the researchers, these are the first and only data to show learned synesthesia of this kind in more than a single individual.
They point out that this does not mean that exposure to the colored letter magnets was sufficient to induce synesthesia in the participants, though it may have increased the chances. After all, many people who do not have synesthesia played with the same colored letter magnets as kids.
Based on their findings, Witthoft and Winawer conclude that a complete explanation of synesthesia must incorporate a central role for learning and memory.
- N. Witthoft, J. Winawer. Learning, Memory, and Synesthesia. Psychological Science, 2013; DOI:10.1177/0956797612452573
Jan. 9, 2013 — As we age, it just may be the ability to filter and eliminate old information — rather than take in the new stuff — that makes it harder to learn, scientists report.
“When you are young, your brain is able to strengthen certain connections and weaken certain connections to make new memories,” said Dr. Joe Z. Tsien, neuroscientist at the Medical College of Georgia at Georgia Regents University and Co-Director of the GRU Brain & Behavior Discovery Institute.
It’s that critical weakening that appears hampered in the older brain, according to a study in the journal Scientific Reports.
The NMDA receptor in the brain’s hippocampus is like a switch for regulating learning and memory, working through subunits called NR2A and NR2B. NR2B is expressed in higher percentages in children, enabling neurons to talk a fraction of a second longer; make stronger bonds, called synapses; and optimize learning and memory. This formation of strong bonds is called long-term potentiation. The ratio shifts after puberty, so there is more NR2A and slightly reduced communication time between neurons.
When Tsien and his colleagues genetically modified mice that mimic the adult ratio — more NR2A, less NR2B — they were surprised to find the rodents were still good at making strong connections and short-term memories but had an impaired ability to weaken existing connections, called long-term depression, and to make new long-term memories as a result. It’s called information sculpting and adult ratios of NMDA receptor subunits don’t appear to be very good at it.
“If you only make synapses stronger and never get rid of the noise or less useful information then it’s a problem,” said Tsien, the study’s corresponding author. While each neuron averages 3,000 synapses, the relentless onslaught of information and experiences necessitates some selective whittling. Insufficient sculpting, at least in their mouse, meant a reduced ability to remember things short-term — like the ticket number at a fast-food restaurant — and long-term — like remembering a favorite menu item at that restaurant. Both are impacted in Alzheimer’s and age-related dementia.
All long-term depression was not lost in the mice, rather just response to the specific electrical stimulation levels that should induce weakening of the synapse. Tsien expected to find the opposite: that long-term potentiation was weak and so was the ability to learn and make new memories. “What is abnormal is the ability to weaken existing connectivity.”
Acknowledging the leap, this impaired ability could also help explain why adults can’t learn a new language without their old accent and why older people tend to be more stuck in their ways, the memory researcher said.
“We know we lose the ability to perfectly speak a foreign language if we learn than language after the onset of sexual maturity. I can learn English but my Chinese accent is very difficult to get rid of. The question is why,” Tsien said.
Tsien and his colleagues already have learned what happens when NR2B is overexpressed. He and East China Normal University researchers announced in 2009 the development of Hobbie-J, a smarter than average rat. A decade earlier, Tsien reported in the journal Nature the development of a smart mouse dubbed Doogie using the same techniques to over-express the NR2B gene in the hippocampus.
Doogie, Hobbie-J and their descendants have maintained superior memory as they age. Now Tsien is interested in following the NR2A over-expressing mouse to see what happens.
Tsien is the Georgia Research Alliance Eminent Scholar in Cognitive and Systems Neurobiology. The research was funded by the National Institutes of Health and the GRA.
- Zhenzhong Cui, Ruiben Feng, Stephanie Jacobs, Yanhong Duan, Huimin Wang, Xiaohua Cao, Joe Z. Tsien.Increased NR2A:NR2B ratio compresses long-term depression range and constrains long-term memory.Scientific Reports, 2013; 3 DOI: 10.1038/srep01036
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.
- 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
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
ScienceDaily (July 24, 2012) — Neuroscientists from Wayne State University and the Massachusetts Institute of Technology (MIT) are taking a deeper look into how the brain mechanisms for memory retrieval differ between adults and children. While the memory systems are the same in many ways, the researchers have learned that crucial functions with relevance to learning and education differ.
The team’s findings were published on July 17, 2012, in the Journal of Neuroscience.
According to lead author Noa Ofen, Ph.D., assistant professor in WSU’s Institute of Gerontology and Department of Pediatrics, cognitive ability, including the ability to learn and remember new information, dramatically changes between childhood and adulthood. This ability parallels with dramatic changes that occur in the structure and function of the brain during these periods.
In the study, “The Development of Brain Systems Associated with Successful Memory Retrieval of Scenes,” Ofen and her collaborative team tested the development of neural underpinnings of memory from childhood to young adulthood. The team of researchers exposed participants to pictures of scenes and then showed them the same scenes mixed with new ones and asked them to judge whether each picture was presented earlier. Participants made retrieval judgments while researchers collected images of their brains with magnetic resonance imaging (MRI).
Using this method, the researchers were able to see how the brain remembers. “Our results suggest that cortical regions related to attentional or strategic control show the greatest developmental changes for memory retrieval,” said Ofen.
The researchers said that older participants used the cortical regions more than younger participants when correctly retrieving past experiences.
“We were interested to see whether there are changes in the connectivity of regions in the brain that support memory retrieval,” Ofen added. “We found changes in connectivity of memory-related regions. In particular, the developmental change in connectivity between regions was profound even without a developmental change in the recruitment of those regions, suggesting that functional brain connectivity is an important aspect of developmental changes in the brain.”
This study marks the first time that the development of connectivity within memory systems in the brain has been tested, and the results suggest that the brain continues to rearrange connections to achieve adult-like performance during development.
Ofen and her research team plan to continue research in this area, focused on modeling brain network connectivity, and applying these methods to study abnormal brain development.
- Noa Ofen, Xiaoqian J. Chai, Karen D. I. Schuil, Susan Whitfield-Gabrieli, and John D. E. Gabrieli. The Development of Brain Systems Associated with Successful Memory Retrieval of Scenes. The Journal of Neuroscience, 18 July 2012, 32(29):10012-10020 DOI: 10.1523/JNEUROSCI.1082-11.2012
Wayne State University – Office of the Vice President for Research (2012, July 24). Better understanding of memory retrieval between children and adults. ScienceDaily. Retrieved July 26, 2012, from http://www.sciencedaily.com /releases/2012/07/120724115105.htm
ScienceDaily (July 23, 2012) — Neuroscientists have found strong evidence that vivid memory and directly experiencing the real moment can trigger similar brain activation patterns.
The study, led by Baycrest’s Rotman Research Institute (RRI), in collaboration with the University of Texas at Dallas, is one of the most ambitious and complex yet for elucidating the brain’s ability to evoke a memory by reactivating the parts of the brain that were engaged during the original perceptual experience. Researchers found that vivid memory and real perceptual experience share “striking” similarities at the neural level, although they are not “pixel-perfect” brain pattern replications.
The study appears online this month in the Journal of Cognitive Neuroscience, ahead of print publication.
“When we mentally replay an episode we’ve experienced, it can feel like we are transported back in time and re-living that moment again,” said Dr. Brad Buchsbaum, lead investigator and scientist with Baycrest’s RRI. “Our study has confirmed that complex, multi-featured memory involves a partial reinstatement of the whole pattern of brain activity that is evoked during initial perception of the experience. This helps to explain why vivid memory can feel so real.”
But vivid memory rarely fools us into believing we are in the real, external world — and that in itself offers a very powerful clue that the two cognitive operations don’t work exactly the same way in the brain, he explained.
In the study, Dr. Buchsbaum’s team used functional magnetic resonance imaging (fMRI), a powerful brain scanning technology that constructs computerized images of brain areas that are active when a person is performing a specific cognitive task. A group of 20 healthy adults (aged 18 to 36) were scanned while they watched 12 video clips, each nine seconds long, sourced from YouTube.com and Vimeo.com. The clips contained a diversity of content — such as music, faces, human emotion, animals, and outdoor scenery. Participants were instructed to pay close attention to each of the videos (which were repeated 27 times) and informed they would be tested on the content of the videos after the scan.
A subset of nine participants from the original group were then selected to complete intensive and structured memory training over several weeks that required practicing over and over again the mental replaying of videos they had watched from the first session. After the training, this group was scanned again as they mentally replayed each video clip. To trigger their memory for a particular clip, they were trained to associate a particular symbolic cue with each one. Following each mental replay, participants would push a button indicating on a scale of 1 to 4 (1 = poor memory, 4 = excellent memory) how well they thought they had recalled a particular clip.
Dr. Buchsbaum’s team found “clear evidence” that patterns of distributed brain activation during vivid memory mimicked the patterns evoked during sensory perception when the videos were viewed — by a correspondence of 91% after a principal components analysis of all the fMRI imaging data.
The so-called “hot spots,” or largest pattern similarity, occurred in sensory and motor association areas of the cerebral cortex — a region that plays a key role in memory, attention, perceptual awareness, thought, language and consciousness.
Dr. Buchsbaum suggested the imaging analysis used in his study could potentially add to the current battery of memory assessment tools available to clinicians. Brain activation patterns from fMRI data could offer an objective way of quantifying whether a patient’s self-report of their memory as “being good or vivid” is accurate or not.
The study was funded with grants from the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada.
- Bradley R. Buchsbaum, Sabrina Lemire-Rodger, Candice Fang, Hervé Abdi. The Neural Basis of Vivid Memory Is Patterned on Perception. Journal of Cognitive Neuroscience, 2012; : 1 DOI: 10.1162/jocn_a_00253
Baycrest Centre for Geriatric Care (2012, July 23). Why does a vivid memory ‘feel so real?’. ScienceDaily. Retrieved July 25, 2012, from http://www.sciencedaily.com /releases/2012/07/120723134745.htm