The ability to learn associations between events is critical for survival, but it has not been clear how different pieces of information stored in memory may be linked together by populations of neurons. In a study published April 2nd in Cell Reports, synchronous activation of distinct neuronal ensembles caused mice to artificially associate the memory of a foot shock with the unrelated memory of exploring a safe environment, triggering an increase in fear-related behavior when the mice were re-exposed to the non-threatening environment. The findings suggest that co-activated cell ensembles become wired together to link two distinct memories that were previously stored independently in the brain.
“Memory is the basis of all higher brain functions, including consciousness, and it also plays an important role in psychiatric diseases such as post-traumatic stress disorder,” says senior study author Kaoru Inokuchi of the University of Toyama. “By showing how the brain associates different types of information to generate a qualitatively new memory that leads to enduring changes in behavior, our findings could have important implications for the treatment of these debilitating conditions.”
Recent studies have shown that subpopulations of neurons activated during learning are reactivated during subsequent memory retrieval, and reactivation of a cell ensemble triggers the retrieval of the corresponding memory. Moreover, artificial reactivation of a specific neuronal ensemble corresponding to a pre-stored memory can modify the acquisition of a new memory, thereby generating false or synthetic memories. However, these studies employed a combination of sensory input and artificial stimulation of cell ensembles. Until now, researchers had not linked two distinct memories using completely artificial means.
With that goal in mind, Inokuchi and Noriaki Ohkawa of the University of Toyama used a fear-learning paradigm in mice followed by a technique called optogenetics, which involves genetically modifying specific populations of neurons to express light-sensitive proteins that control neuronal excitability, and then delivering blue light through an optic fiber to activate those cells. In the behavioral paradigm, one group of mice spent six minutes in a cylindrical enclosure while another group explored a cube-shaped enclosure, and 30 minutes later, both groups of mice were placed in the cube-shaped enclosure, where a foot shock was immediately delivered. Two days later, mice that were re-exposed to the cube-shaped enclosure spent more time frozen in fear than mice that were placed back in the cylindrical enclosure.
The researchers then used optogenetics to reactivate the unrelated memories of the safe cylinder-shaped environment and the foot shock. Stimulation of neuronal populations in memory-related brain regions called the hippocampus and amygdala, which were activated during the learning phase, caused mice to spend more time frozen in fear when they were later placed back in the cylindrical enclosure, as compared with stimulation of neurons in either the hippocampus or amygdala, or no stimulation at all.
The findings show that synchronous activation of distinct cell ensembles can generate artificial links between unrelated pieces of information stored in memory, resulting in long-lasting changes in behavior. “By modifying this technique, we will next attempt to artificially dissociate memories that are physiologically connected,” Inokuchi says. “This may contribute to the development of new treatments for psychiatric disorders such as post-traumatic stress disorder, whose main symptoms arise from unnecessary associations between unrelated memories.”
More information: Cell Reports, Ohkawa et al.: “Artificial Association of Pre-Stored Information to Generate a Qualitatively New Memory” www.cell.com/cell-reports/abst… 2211-1247(15)00270-3
The finding could mean recollections are more enduring than expected and disrupt plans for PTSD treatments.
As intangible as they may seem, memories have a firm biological basis. According to textbook neuroscience, they form when neighboring brain cells send chemical communications across the synapses, or junctions, that connect them. Each time a memory is recalled, the connection is reactivated and strengthened. The idea that synapses store memories has dominated neuroscience for more than a century, but a new study by scientists at the University of California, Los Angeles, may fundamentally upend it: instead memories may reside inside brain cells. If supported, the work could have major implications for the treatment of post-traumatic stress disorder (PTSD), a condition marked by painfully vivid and intrusive memories.
More than a decade ago scientists began investigating the drug propranolol for the treatment of PTSD. Propranolol was thought to prevent memories from forming by blocking production of proteins required for long-term storage. Unfortunately, the research quickly hit a snag. Unless administered immediately after the traumatic event, the treatment was ineffective. Lately researchers have been crafting a work-around: evidence suggests that when someone recalls a memory, the reactivated connection is not only strengthened but becomes temporarily susceptible to change, a process called memory reconsolidation. Administering propranolol (and perhaps also therapy, electrical stimulation and certain other drugs) during this window can enable scientists to block reconsolidation, wiping out the synapse on the spot.
The possibility of purging recollections caught the eye of David Glanzman, a neurobiologist at U.C.L.A., who set out to study the process in Aplysia, a sluglike mollusk commonly used in neuroscience research. Glanzman and his team zapped Aplysia with mild electric shocks, creating a memory of the event expressed as new synapses in the brain. The scientists then transferred neurons from the mollusk into a petri dish and chemically triggered the memory of the shocks in them, quickly followed by a dose of propranolol.
Initially the drug appeared to confirm earlier research by wiping out the synaptic connection. But when cells were exposed to a reminder of the shocks, the memory came back at full strength within 48 hours. “It was totally reinstated,” Glanzman says. “That implies to me that the memory wasn’t stored in the synapse.” The results were recently published in the online open-access journal eLife.
If memory is not located in the synapse, then where is it? When the neuroscientists took a closer look at the brain cells, they found that even when the synapse was erased, molecular and chemical changes persisted after the initial firing within the cell itself. The engram, or memory trace, could be preserved by these permanent changes. Alternatively, it could be encoded in modifications to the cell’s DNA that alter how particular genes are expressed. Glanzman and others favor this reasoning.
Eric R. Kandel, a neuroscientist at Columbia University and recipient of the 2000 Nobel Prize in Physiology or Medicine for his work on memory, cautions that the study’s results were observed in the first 48 hours after treatment, a time when consolidation is still sensitive.
Though preliminary, the results suggest that for people with PTSD, pill popping will most likely not eliminate painful memories. “If you had asked me two years ago if you could treat PTSD with medication blockade, I would have said yes, but now I don’t think so,” Glanzman says. On the bright side, he adds, the idea that memories persist deep within brain cells offers new hope for another disorder tied to memory: Alzheimer’s.
Grad student Chi Lu and colleagues demonstrate a highly flexible polymer probe for triggering spinal-cord neurons with light and simultaneously recording their activity.
MIT researchers have demonstrated a highly flexible neural probe made entirely of polymers that can both optically stimulate and record neural activity in a mouse spinal cord — a step toward developing prosthetic devices that can restore functionality to damaged nerves.
“Our goal was to create a tool that would enable neuroscientists and physicians to investigate spinal-cord function on both cellular and systems levels with minimal impact on the tissue integrity,” notes Polina Anikeeva, the AMAX Assistant Professor in Materials Science and Engineering and a senior author of the paper published Nov. 7 in Advanced Functional Materials.
Department of Materials Science and Engineering graduate student Chi (Alice) Lu, who designed and implanted the probe, is the lead author of the study. Co-authors include Ulrich Froriep of the Simons Center for the Social Brain; Ryan Koppes of the Research Laboratory of Electronics; Andres Canales and Jennifer Selvidge of the Department of Materials Science and Engineering; and Vittorio Caggiano and Emilio Bizzi of the McGovern Institute for Brain Research. Professor Yoel Fink provided access to the fiber-drawing tower.
Although optogenetics, a method that makes mammalian nerve cells sensitive to light via genetic modification, has been applied extensively in investigation of brain function over the past decade, spinal-cord research has lagged. Earlier this year Caggiano and Bizzi have demonstrated inhibition of motor functions using optogenetics, and now the collaboration between the two groups yielded a device suitable for spinal optical excitation of muscle activity, while giving the researchers an electrical readout.
“Working in a spinal cord is significantly more difficult than in the brain because it experiences more movements. The radius of the mouse spinal cord is about 1 millimeter, and it is very soft, so it took some time to figure out how to design a device that would perform the stimulation and recording without damaging that tissue,” Lu explains.
The fiber was drawn from a template nearly 1.5 inches thick to its final diameter comparable to that of a human hair. It is flexible enough to be tied in a knot. The probe consists of a transparent polycarbonate optical core; parallel conductive polyethylene electrodes for recording neuronal electrical activity; and cyclic olefin copolymer acting both as electrical insulation and optical cladding. The flexible probe maintains its optical and electrical functions when bent by up to 270 degrees at very small radii of curvature (e.g. 500 µm), albeit with somewhat diminished light-carrying capacity at those conditions. The device still performed well after repeated bending and straightening, holding up under stresses expected from normal body movements, the report shows. MIT has filed a patent on the device platform.
The researchers conducted experiments with their neural probe in genetically-altered mice that express the light-sensitive protein channelrhodopsin 2 (ChR2) labeled with yellow fluorescent protein. The ChR2 makes neurons in the mice respond to blue light. These mice, developed by Professor Guoping Feng and colleagues at the McGovern Institute for Brain Research, provide a convenient model system for optoelectronic neural prosthetics. “When pulses of blue light are delivered to the spinal cord, we can directly observe neuronal response by getting an electrical recording,” explains Lu, who entered the third year of her doctoral program this fall.
“Laser pulses … delivered through the [polycarbonate] core of the fiber probe robustly evoked neural activity in the spinal cord, as recorded with the … electrodes integrated within the same device,” the researchers report.
The fiber was inserted into the proximal lumbar section of the spinal cord in mice, and light delivered through it triggered activity in one of the calf muscles, the gastrocnemius muscle. The results in the optically-sensitive mice were validated by comparison with results in wild type mice, which showed no response to the optical trigger. A toe pinch showed the device could still record mechanically stimulated neuronal activity in the wild-type mice. The researchers monitored muscle activity through electromyographical (EMG) recording, while the conductive polyethylene electrodes in the new device recorded neuronal activity in the spinal cord.
The MIT researchers’ combination in a single system of both recording activity from neurons and stimulating neurons with light is new, says Ravi V. Bellamkonda, the Wallace H. Coulter Professor and Department Chair of Biomedical Engineering at Georgia Institute of Technology and the Emory School of Medicine. “In principle, one would like to use ‘closed-loop’ systems, i.e., you detect a neurological event — like the brain wanting to move a limb — and then stimulate to affect that function when the natural link between them is severed due to an injury like spinal cord damage,” he explains.
“This is excellent engineering combining electrical and optical engineering for an important biological application — modulation of neural function in a closed-loop way. I am eager to see this technology being used in a biologically significant ways in the future,” Bellamkonda says.
The work was funded in part by grants from the National Science Foundation through the Center for Sensorimotor Neural Engineering and Center for Materials Science and Engineering; the McGovern Institute for Brain Research Neurotechnology Program; and the Simons Foundation.
Source: MIT press release
Image Source: The image is credited to the Chi (Alice) Lu and Polina Anikeeva and is adapted from the MIT press release
Original Research: Abstract for “Polymer Fiber Probes Enable Optical Control of Spinal Cord and Muscle Function In Vivo” by Chi Lu, Ulrich P. Froriep, Ryan A. Koppes, Andres Canales, Vittorio Caggiano, Jennifer Selvidge, Emilio Bizzi and Polina Anikeeva in Advanced Functional Materials. Published online August 26 2014 doi:10.1002/adfm.201401266
How does short-term memory work in relation to long-term memory? Are short-term daily memories somehow transferred to long-term storage while we sleep?
Alison Preston, an assistant professor at the University of Texas at Austin’s Center for Learning and Memory, recalls and offers an answer for this question.
A short-term memory’s conversion to long-term memory requires the passage of time, which allows it to become resistant to interference from competing stimuli or disrupting factors such as injury or disease. This time-dependent process of stabilization, whereby our experiences achieve a permanent record in our memory, is referred to as “consolidation.”
Memory consolidation can occur at many organizational levels in the brain. Cellular and molecular changes typically take place within the first minutes or hours of learning and result in structural and functional changes to neurons (nerve cells) or sets of neurons. Systems-level consolidation, involving the reorganization of brain networks that handle the processing of individual memories, may then happen, but on a much slower time frame that can take several days or years.
Memory does not refer to a single aspect of our experience but rather encompasses a myriad of learned information, such as knowing the identity of the 16th president of the United States, what we had for dinner last Tuesday or how to drive a car. The processes and brain regions involved in consolidation may vary depending on the particular characteristics of the memory to be formed.
Let’s consider the consolidation process that affects the category of declarative memory—that of general facts and specific events. This type of memory relies on the function of a brain region called the hippocampus and other surrounding medial temporal lobe structures. At the cellular level, memory is expressed as changes to the structure and function of neurons. For example, new synapses—the connections between cells through which they exchange information—can form to allow for communication between new networks of cells. Alternately, existing synapses can be strengthened to allow for increased sensitivity in the communication between two neurons.
Consolidating such synaptic changes requires the synthesis of new RNA and proteins in the hippocampus, which transform temporary alterations in synaptic transmission into persistent modifications of synaptic architecture. For example, blocking protein synthesis in the brains of mice does not affect the short-term memory or recall of newly learned spatial environments in hippocampal neurons. Inhibiting protein synthesis, however, does abolish the formation of new long-term representations of space in hippocampal neurons, thus impairing the consolidation of spatial memories.
Over time, the brain systems that support individual, declarative memories also change as a result of systems-level consolidation processes. Initially, the hippocampus works in concert with sensory processing regions distributed in the neocortex (the outermost layer of the brain) to form the new memories. Within the neocortex, representations of the elements that constitute an event in our life are distributed across multiple brain regions according to their content. For example, visual information is processed by primary visual cortex in the occipital lobe at the rear of the brain, while auditory information is processed by primary auditory cortex located in the temporal lobes, which lie on the side of the brain.
When a memory is initially formed, the hippocampus rapidly associates this distributed information into a single memory, thus acting as an index to representations in the sensory processing regions. As time passes, cellular and molecular changes allow for the strengthening of direct connections between neocortical regions, enabling the memory of an event to be accessed independently of the hippocampus. Damage to the hippocampus by injury or neurodegenerative disorder (Alzheimer’s disease, for instance) produces anterograde amnesia—the inability to form new declarative memories—because the hippocampus is no longer able to connect mnemonic information distributed in the neocortex before the data has been consolidated. Interestingly, such a disruption does not impair memory for facts and events that have already been consolidated. Thus, an amnesiac with hippocampal damage would not be able to learn the names of current presidential candidates but would be able to recall the identity 16th US president (Abraham Lincoln, of course!).
The role of sleep in memory consolidation is an ancient question dating back to the Roman rhetorician Quintilian in the first century A.D. Much research in the past decade has been dedicated to better understanding the interaction between sleep and memory. Yet little is understood.
At the molecular level, gene expression responsible for protein synthesis is increased during sleep in rats exposed to enriched environments, suggesting memory consolidation processes are enhanced, or may essentially rely, on sleep. Further, patterns of activity observed in rats during spatial learning are replayed in hippocampal neurons during subsequent sleep, further suggesting that learning may continue in sleep.
In humans, recent studies have demonstrated the benefits of sleep on declarative memory performance, thus giving a neurological basis to the old adage, “sleep on it.” A night of sleep reportedly enhances memory for associations between word pairs. Similar overnight improvements on virtual navigation tasks have been observed, which correlate with hippocampal activation during sleep. Sleep deprivation, on the other hand, is known to produce deficits in hippocampal activation during declarative memory formation, resulting in poor subsequent retention. Thus, the absence of prior sleep compromises our capacity for committing new experiences to memory. These initial findings suggest an important, if not essential, role for sleep in the consolidation of newly formed memories.
Swedish researchers at Uppsala University have, together with Brazilian collaborators, discovered a new group of nerve cells that regulate processes of learning and memory. These cells act as gatekeepers and carry a receptor for nicotine, which can help explain our ability to remember and sort information.
The discovery of the gatekeeper cells, which are part of a memory network together with several other nerve cells in the hippocampus, reveal new fundamental knowledge about learning and memory. The study is published today in Nature Neuroscience.
The hippocampus is an area of the brain that is important for consolidation of information into memories and helps us to learn new things. The newly discovered gatekeeper nerve cells, also called OLM-alpha2 cells, provide an explanation to how the flow of information is controlled in the hippocampus. Read more…
Simply activating a tiny number of neurons can conjure an entire memory.
Our fond or fearful memories — that first kiss or a bump in the night — leave memory traces that we may conjure up in the remembrance of things past, complete with time, place and all the sensations of the experience. Neuroscientists call these traces memory engrams.
But are engrams conceptual, or are they a physical network of neurons in the brain? In a new MIT study, researchers used optogenetics to show that memories really do reside in very specific brain cells, and that simply activating a tiny fraction of brain cells can recall an entire memory — explaining, for example, how Marcel Proust could recapitulate his childhood from the aroma of a once-beloved madeleine cookie.
“We demonstrate that behavior based on high-level cognition, such as the expression of a specific memory, can be generated in a mammal by highly specific physical activation of a specific small subpopulation of brain cells, in this case by light,” says Susumu Tonegawa, the Picower Professor of Biology and Neuroscience at MIT and lead author of the study reported online today in the journal Nature. “This is the rigorously designed 21st-century test of Canadian neurosurgeon Wilder Penfield’s early-1900s accidental observation suggesting that mind is based on matter.” Read more…
Science is bringing some understanding of the heritability, prevalence, and inner workings of one of the most devastating diseases.(left) A PET scan’s bright areas reveal the concentration of amyloid beta, a protein that forms a plaque in Alzheimer’s patients. The scan compares the brains of a healthy patient (left) and a patient suffering from Alzheimer’s (right). Image: Alzheimer’s Disease Education and Referral Center, NIH
This has been a big week in Alzheimer’s news as scientists put together a clearer picture than ever before of how the disease affects the brain. Three recently published studies have detected the disease with new technologies, hinted at its prevalence, and described at last how it makes its lethal progress through the brain.
The existence of two forms of Alzheimer’s—early- and late-onset—has long baffled scientists. Of the estimated five million Americans who suffer from Alzheimer’s, only a few thousand are diagnosed with an early-onset form of the affliction, which affects people before the age of 65. This rare early-onset form is thought to be hereditary and scientists have associated multiple genetic mutations contributing to its occurrence. Late-onset Alzheimer’s, although more common, has been the bigger mystery. One variant of the APOE gene-—sometimes known as the Alzheimer’s gene—is linked to the late-onset disease. But the APOE gene, unlike dominant early-onset genes, does not determine whether a person will ultimately have dementia.
Now there’s evidence that late-onset Alzheimer’s has a genetic basis similar to that of early-onset Alzheimer’s. By sequencing select genes associated with the latter, along with frontotemporal dementia, researchers at Washington University in Saint Louis and other institutions found that patients with late-onset Alzheimer’s carry some of the same genetic mutations as those with the early-onset form. The evidence, published on Wednesday in PLoS ONE, bolsters the argument that the forms of Alzheimer’s that appear at different life stages should be classified as the same disease. As to why the disease appears earlier in some cases, the scientists speculated that those patients diagnosed relatively early in life carry more genetic risk factors for the disease.
This study’s use of rapid genetic sequencing, the authors noted, may provide a model for more precise identification of dementias. Within the study, the researchers identified patients who may have been misdiagnosed as having Alzheimer’s; the genes of these patients suggested that they had another type of dementia. Given the heritable component, patients with a family history could be screened to detect and diagnose Alzheimer’s early.
Other genetic research unveiled in the past week or so has shed light on the biological processes that underlie how Alzheimer’s affects the brain. Certain mutations may lead to an increased production of a protein called amyloid beta in the region of the brain that creates memory. This excess amyloid beta, naturally secreted by brain cells, then becomes a complex called an oligomer. These oligomers may interrupt the signals transmitted between neurons. As in other neurodegenerative diseases like Parkinson’s or Huntington’s, the spread of oligomers appears to be driving the disease process.
Oligomer-linked diseases are relatively common, in part because oligomers can also play an essential biological role in the brain. A recent investigation using fruit flies reveals that the presence of a specific oligomer is actually required for the flies to form long-term memories.
In an early stage of Alzheimer’s, the naturally secreted amyloid beta protein builds up as oligomers in the brain, which then go on to form larger aggregates called plaques. Later in the disease, another aberrant form of a protein called tau starts to build up, in the entorhinal cortex. Normally, tau helps provide structure crucial to neuron functioning. The buildup of tau, however, causes the protein to tangle and eventually kill brain cells. What was unknown until recently, however, was how the tau protein spreads through different brain regions.
Two studies—one to be published in Neuron and the other published in PLoS ONE on Wednesday—have answered this question using brain samples from mice genetically engineered to express tau as it occurs in the human brain. Using a staining technique to highlight tau’s distribution in the brain, they compared samples from mice of different ages to analyze how tau moved through brain cells over time. They found the protein spread from neuron to neighboring neuron, traveling along synapses.
Understanding how this protein moves may allow scientists to stop tau in its tracks. “This opens up a whole new world of biology,” says Columbia University’s Karen Duff, an author on the study published in PLoS ONE. Tau is implicated in 30 different forms of dementia. In addition, the movement of tau may be similar to the spread of oligomers associated with Parkinson’s and Huntington’s. Nonetheless, we are still a long way from a therapeutic solution and stopping tau, which comes at a relatively late stage of Alzheimer’s, might be a very limited therapy.
As the world’s population continues to age, Alzheimer’s becomes a threat to more of us with every passing day. Although we may not yet have new treatments from this work, the take-away on these findings is clear: If we really are going to win the war, or even a battle, against Alzheimer’s, we need basic research that can delve into the complex biology that contorts proteins and kills brain cells to find treatments for this disease.