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
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.
Why is it that we seem to think better when we walk or exercise?
Justin Rhodes, an associate professor of psychology at the University of Illinois at Urbana-Champaign, responds:
After being cooped up inside all day, your afternoon stroll may leave you feeling clearheaded. This sensation is not just in your mind. A growing body of evidence suggests we think and learn better when we walk or do another form of exercise. The reason for this phenomenon, however, is not completely understood.
Part of the reason exercise enhances cognition has to do with blood flow. Research shows that when we exercise, blood pressure and blood flow increase everywhere in the body, including the brain. More blood means more energy and oxygen, which makes our brain perform better.
Another explanation for why working up a sweat enhances our mental capacity is that the hippocampus, a part of the brain critical for learning and memory, is highly active during exercise. When the neurons in this structure rev up, research shows that our cognitive function improves. For instance, studies in mice have revealed that running enhances spatial learning. Other recent work indicates that aerobic exercise can actually reverse hippocampal shrinkage, which occurs naturally with age, and consequently boost memory in older adults. Yet another study found that students who exercise perform better on tests than their less athletic peers.
The big question of why we evolved to get a mental boost from a trip to the gym, however, remains unanswered. When our ancestors worked up a sweat, they were probably fleeing a predator or chasing their next meal. During such emergencies, extra blood flow to the brain could have helped them react quickly and cleverly to an impending threat or kill prey that was critical to their survival.
So if you are having a mental block, go for a jog or hike. The exercise might help pull you out of your funk.
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…
The Who asked “who are you?” but Dartmouth neurobiologist Jeffrey Taube asks “where are you?” and “where are you going?” Taube is not asking philosophical or theological questions. Rather, he is investigating nerve cells in the brain that function in establishing one’s location and direction.
Taube, a professor in the Department of Psychological and Brain Sciences, is using microelectrodes to record the activity of cells in a rat’s brain that make possible spatial navigation—how the rat gets from one place to another—from “here” to “there.” But before embarking to go “there,” you must first define “here.”
“Knowing what direction you are facing, where you are, and how to navigate are really fundamental to your survival,” says Taube. “For any animal that is preyed upon, you’d better know where your hole in the ground is and how you are going to get there quickly. And you also need to know direction and location to find food resources, water resources, and the like.”
Not only is this information fundamental to your survival, but knowing your spatial orientation at a given moment is important in other ways, as well. Taube points out that it is a sense or skill that you tend to take for granted, which you subconsciously keep track of. “It only comes to your attention when something goes wrong, like when you look for your car at the end of the day and you can’t find it in the parking lot,” says Taube. Read more…
Scripps Research Institute Team Wrests Partial Control of a Memory
The work advances understanding of how memories form and offers new insight into disorders such as schizophrenia and post traumatic stress disorder.
Scripps Research Institute scientists and their colleagues have successfully harnessed neurons in mouse brains, allowing them to at least partially control a specific memory. Though just an initial step, the researchers hope such work will eventually lead to better understanding of how memories form in the brain, and possibly even to ways to weaken harmful thoughts for those with conditions such as schizophrenia and post traumatic stress disorder.
The results are reported in the March 23, 2012 issue of the journal Science.
Researchers have known for decades that stimulating various regions of the brain can trigger behaviors and even memories. But understanding the way these brain functions develop and occur normally—effectively how we become who we are—has been a much more complex goal.
“The question we’re ultimately interested in is: How does the activity of the brain represent the world?” said Scripps Research neuroscientist Mark Mayford, who led the new study. “Understanding all this will help us understand what goes wrong in situations where you have inappropriate perceptions. It can also tell us where the brain changes with learning.”
On-Off Switches and a Hybrid Memory
As a first step toward that end, the team set out to manipulate specific memories by inserting two genes into mice. One gene produces receptors that researchers can chemically trigger to activate a neuron. They tied this gene to a natural gene that turns on only in active neurons, such as those involved in a particular memory as it forms, or as the memory is recalled. In other words, this technique allows the researchers to install on-off switches on only the neurons involved in the formation of specific memories.
For the study’s main experiment, the team triggered the “on” switch in neurons active as mice were learning about a new environment, Box A, with distinct colors, smells and textures.
Next the team placed the mice in a second distinct environment—Box B—after giving them the chemical that would turn on the neurons associated with the memory for Box A. The researchers found the mice behaved as if they were forming a sort of hybrid memory that was part Box A and part Box B. The chemical switch needed to be turned on while the mice were in Box B for them to demonstrate signs of recognition. Alone neither being in Box B nor the chemical switch was effective in producing memory recall.
“We know from studies in both animals and humans that memories are not formed in isolation but are built up over years incorporating previously learned information,” Mayford said. “This study suggests that one way the brain performs this feat is to use the activity pattern of nerve cells from old memories and merge this with the activity produced during a new learning session.”
Future Manipulation of the Past
The team is now making progress toward more precise control that will allow the scientists to turn one memory on and off at will so effectively that a mouse will in fact perceive itself to be in Box A when it’s in Box B.
Once the processes are better understood, Mayford has ideas about how researchers might eventually target the perception process through drug treatment to deal with certain mental diseases such as schizophrenia and post traumatic stress disorder. With such problems, patients’ brains are producing false perceptions or disabling fears. But drug treatments might target the neurons involved when a patient thinks about such fear, to turn off the neurons involved and interfere with the disruptive thought patterns.
Notes about this memory research article
In addition to Mayford, other authors of the paper, “Generation of a Synthetic Memory Trace,” are Aleena Garner, Sang Youl Hwang, and Karsten Baumgaertel from Scripps Research, David Rowland and Cliff Kentros from the University of Oregon, Eugene, and Bryan Roth from the University of North Carolina (UNC), Chapel Hill.
This work is supported by the National Institute of Mental Health, the National Institute on Drug Abuse, the California Institute for Regenerative Medicine, and the Michael Hooker Distinguished Chair in Pharmacology at UNC.
Original Research: Abstract for “Generation of a Synthetic Memory Trace” by Aleena R. Garner, David C. Rowland, Sang Youl Hwang, Karsten Baumgaertel, Bryan L. Roth, Cliff Kentros & Mark Mayford in Science