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Researchers create artificial link between unrelated memories


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.”

The above story is reprinted from materials provided by MedicalXpress.

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

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New Alzheimer’s treatment fully restores memory function


Of the mice that received the treatment, 75 percent got their memory functions back.

Australian researchers have come up with a non-invasive ultrasound technology that clears the brain of neurotoxic amyloid plaques – structures that are responsible for memory loss and a decline in cognitive function in Alzheimer’s patients.

If a person has Alzheimer’s disease, it’s usually the result of a build-up of two types of lesions – amyloid plaques, and neurofibrillary tangles. Amyloid plaques sit between the neurons and end up as dense clusters of beta-amyloid molecules, a sticky type of protein that clumps together and forms plaques.

Neurofibrillary tangles are found inside the neurons of the brain, and they’re caused by defective tau proteins that clump up into a thick, insoluble mass. This causes tiny filaments called microtubules to get all twisted, which disrupts the transportation of essential materials such as nutrients and organelles along them, just like when you twist up the vacuum cleaner tube.

As we don’t have any kind of vaccine or preventative measure for Alzheimer’s – a disease that affects 343,000 people in Australia, and 50 million worldwide – it’s been a race to figure out how best to treat it, starting with how to clear the build-up of defective beta-amyloid and tau proteins from a patient’s brain. Now a team from the Queensland Brain Institute (QBI) at the University of Queensland have come up with a pretty promising solution for removing the former.

Publishing in Science Translational Medicine, the team describes the technique as using a particular type of ultrasound called a focused therapeutic ultrasound, which non-invasively beams sound waves into the brain tissue. By oscillating super-fast, these sound waves are able to gently open up the blood-brain barrier, which is a layer that protects the brain against bacteria, and stimulate the brain’s microglial cells to activate. Microglila cells are basically waste-removal cells, so they’re able to clear out the toxic beta-amyloid clumps that are responsible for the worst symptoms of Alzheimer’s.

The team reports fully restoring the memory function of 75 percent of the mice they tested it on, with zero damage to the surrounding brain tissue. They found that the treated mice displayed improved performance in three memory tasks – a maze, a test to get them to recognise new objects, and one to get them to remember the places they should avoid.

“We’re extremely excited by this innovation of treating Alzheimer’s without using drug therapeutics,” one of the team, Jürgen Götz, said in a press release. “The word ‘breakthrough’ is often misused, but in this case I think this really does fundamentally change our understanding of how to treat this disease, and I foresee a great future for this approach.”

The team says they’re planning on starting trials with higher animal models, such as sheep, and hope to get their human trials underway in 2017.

You can hear an ABC radio interview with the team here.

The above story is reprinted from materials provided by ScienceAlert.

Team prevents memory problems caused by sleep deprivation

December 13, 2014 Leave a comment

The hippocampus of a mouse in the University of Pennsylvania study glows green where cells have taken up a receptor that triggers a cAMP signalling pathway. After administering the ligand to the receptor, researchers could selectively boost cAMP levels in this region and this cell type only. They found that ‘rescuing’ these cells with a shot of cAMP preventing the memory problems that sleep loss can induce. Credit: University of Pennsylvania

Sleep is a critical period for memory consolidation, and most people don’t get enough. Research has shown that even brief periods of sleep deprivation can lead to deficits in memory formation.

In a new study, published in the Journal of Neuroscience, a team led by scientists from the University of Pennsylvania found that a particular set of cells in a small region of the brain are responsible for memory problems after sleep loss. By selectively increasing levels of a signaling molecule in these cells, the researchers prevented mice from having .

Robbert Havekes was the lead author on the study. He is a research associate in the lab of Ted Abel, the study’s senior author and Brush Family Professor of Biology in Penn’s School of Arts & Sciences. Coauthors from the Abel lab included Jennifer C. Tudor and Sarah L. Ferri. They collaborated with Arnd Baumann of Forschungszentrum Jülich, Germany, and Vibeke M. Bruinenberg and Peter Meerlo of the University of Groningen, The Netherlands.

In 2009, a group from Abel’s lab published a study in Nature that identified the cyclic AMP, or cAMP, signaling pathway as playing a role in sleep-loss-associated . Whereas depriving mice of sleep impaired their spatial memory, restoring levels of cAMP in their brain prevented this effect.

“The challenge following this important study,” Abel said, “was to determine if the impact of  was mediated by particular regions of the brain and particular neural circuits. We suspected that the hippocampus, the brain region that mediates spatial navigation and contextual memory, was critical.”

In the current work, they set out to answer these questions. They targeted excitatory neurons because of their importance in transmitting signals in the brain and the fact that their functioning relies on cAMP signaling. The limitation of previous studies was that they lacked a way to increase cAMP in just one area of the brain in a cell-type specific fashion. Havekes, Abel and colleagues devised a way of doing this that they term a “pharmacogenetic” approach, blending genetic modification and drug administration.

They engineered a non-pathogenic virus to harbor the gene encoding the receptor for the protein octopamine, which triggers cAMP pathway activation in fruit flies but is not naturally found in the brains of mice. The researchers injected this virus into the hippocampus of mice so that the excitatory neurons in that region alone would express the octopamine receptor.

“It sounds weird. Why would you put a receptor there that is never going to be activated?” Havekes said. “The trick is, you follow that up by giving mice the ligand of the receptor, which is octopamine, and that will activate the receptors only where they are present.”

The team confirmed that only the excitatory hippocampal neurons expressed the receptor and that they could selectively increase cAMP levels in only these cells by giving the mice a systemic injection of octopamine.

“This way, we could manipulate the cAMP pathways that we previously saw being affected by sleep deprivation but selectively in specific neural circuits in the brain,” Havekes says.

With this pharmacogenetic tool in hand, Havekes, Abel and colleagues began the sleep deprivation tests with the mice expressing the octopamine receptor in their hippocampus. First the researchers trained mice in a spatial memory task. They put them in a box that had three different objects, each in a distinct location.

Then, because previous research had shown that cAMP signaling contributes to hippocampus-dependent  in two time windows—first directly after training and again three to four hours after training—the researchers gave mice in the experimental groups injections of octopamine in both of these windows to boost cAMP levels.

Mice receiving the cAMP boost were divided into two groups: One was left to sleep undisturbed, while the other was sleep-deprived for five hours by gently tapping their cage or rearranging their bedding.

One full day after the initial training, all of the mice were tested again. This time, there was a twist: one of the objects originally in the box had been moved to a new location.

“If the mice had learned and remembered the location of the objects during their training, then they would realize, okay, this is the object that has moved, and they’ll spend more time exploring that particular object,” Havekes explained. “If they didn’t remember well, they would explore all the objects in a random fashion.”

The researchers found that the sleep-deprived mice that received the octopamine injections spent more time exploring the object that had moved, just as mice that had not been sleep deprived did. On the other hand, sleep-deprived  that didn’t express the receptor explored all the objects at random, a sign that they had failed to remember the locations of the objects from their initial training as a result of the brief period of sleep deprivation.

“What we’ve shown is this memory loss due to sleep deprivation is really dependent on misregulation of cAMP signaling in the excitatory neurons of the hippocampus,” Havekes said.

As a next step, the group would like to explore what cAMP is doing to help consolidate memory. They would also like to investigate how other cell types in the brain, such as astrocytes, might be affected. And finally, while this study focused on the impact of a brief period of sleep deprivation, Havekes is curious to know how not getting enough sleep on a daily basis, as is more similar to human experiences, might be affecting .

“Thinking about people who do shift work or doctors who work long hours, if we can tackle the cognitive problems that result from , that would be a great thing,” Havekes said.

“At least in the mouse using these sophisticated tools, we’re able to reverse the negative impact of sleep deprivation on cognition,” Abel said.

Scientists Map Process by Which Brain Cells Form Long-Term Memories

July 2, 2013 2 comments

Scientists at the Gladstone Institutes have deciphered how a protein called Arc regulates the activity of neurons – providing much-needed clues into the brain’s ability to form long-lasting memories.

These findings, reported in Nature Neuroscience, also offer newfound understanding as to what goes on at the molecular level when this process becomes disrupted.

Led by Gladstone senior investigator Steve Finkbeiner, MD, PhD, this research delved deep into the inner workings of synapses. Synapses are the highly specialized junctions that process and transmit information between neurons. Most of the synapses our brain will ever have are formed during early brain development, but throughout our lifetimes these synapses can be made, broken and strengthened. Synapses that are more active become stronger, a process that is essential for forming new memories.

However, this process is also dangerous, as it can overstimulate the neurons and lead to epileptic seizures. It must therefore be kept in check.

The researchers’ experiments revealed that Arc acted as a master regulator of the entire homeostatic scaling process. During memory formation, certain genes must be switched on and off at very specific times in order to generate proteins that help neurons lay down new memories. The image is an arc immunohistochemical staining of a rat dentate gyrus. This is used for illustrative purposes and is not connected to the research.

Neuroscientists recently discovered one important mechanism that the brain uses to maintain this important balance: a process called “homeostatic scaling.” Homeostatic scaling allows individual neurons to strengthen the new synaptic connections they’ve made to form memories, while at the same time protecting the neurons from becoming overly excited. Exactly how the neurons pull this off has eluded researchers, but they suspected that the Arc protein played a key role.

“Scientists knew that Arc was involved in long-term memory, because mice lacking the Arc protein could learn new tasks, but failed to remember them the next day,” said Finkbeiner, who is also a professor of neurology and physiology at UC San Francisco, with which Gladstone is affiliated. “Because initial observations showed Arc accumulating at the synapses during learning, researchers thought that Arc’s presence at these synapses was driving the formation of long-lasting memories.”

But Finkbeiner and his team thought there was something else in play.

The Role of Arc in Homeostatic Scaling

In laboratory experiments, first in animal models and then in greater detail in the petri dish, the researchers tracked Arc’s movements. And what they found was surprising.

“When individual neurons are stimulated during learning, Arc begins to accumulate at the synapses – but what we discovered was that soon after, the majority of Arc gets shuttled into the nucleus,” said Erica Korb, PhD, the paper’s lead author who completed her graduate work at Gladstone and UCSF.

“A closer look revealed three regions within the Arc protein itself that direct its movements: one exports Arc from the nucleus, a second transports it into the nucleus, and a third keeps it there,” she said. “The presence of this complex and tightly regulated system is strong evidence that this process is biologically important.”

In fact, the team’s experiments revealed that Arc acted as a master regulator of the entire homeostatic scaling process. During memory formation, certain genes must be switched on and off at very specific times in order to generate proteins that help neurons lay down new memories. From inside the nucleus, the authors found that it was Arc that directed this process required for homeostatic scaling to occur. This strengthened the synaptic connections without overstimulating them – thus translating learning into long-term memories.

Implications for a Variety of Neurological Diseases

“This discovery is important not only because it solves a long-standing mystery on the role of Arc in long-term memory formation, but also gives new insight into the homeostatic scaling process itself – disruptions in which have already been implicated in a whole host of neurological diseases,” said Finkbeiner. “For example, scientists recently discovered that Arc is depleted in the hippocampus, the brain’s memory center, in Alzheimer’s disease patients. It’s possible that disruptions to the homeostatic scaling process may contribute to the learning and memory deficits seen in Alzheimer’s.”

Dysfunctions in Arc production and transport may also be a vital player in autism. For example, the genetic disorder Fragile X syndrome – a common cause of both mental retardation and autism, directly affects the production of Arc in neurons.

“In the future,” added Dr. Korb, “we hope further research into Arc’s role in human health and disease can provide even deeper insight into these and other disorders, and also lay the groundwork for new therapeutic strategies to fight them.”

Journal reference: Abstract for “Arc in the nucleus regulates PML-dependent GluA1 transcription and homeostatic plasticity” by Erica Korb, Carol L Wilkinson, Ryan N Delgado, Kathryn L Lovero and Steven Finkbeiner in Nature Neuroscience. Published online June 9 2013 doi:10.1038/nn.3429

The above story is reprinted from materials provided by UCSF press release.

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.

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The above story is reprinted from materials provided by ScientificAmerican magazine.