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.
Scientists have built a light-weight wearable boot-like exoskeleton which reduces the energy needed for walking.
Researchers say the exoskeleton gives a 7% gain without chemical or electrical energy.
According to research published in the journal Nature, the energy saving is relatively modest but represents a considerable improvement on past designs.
Engineers have been trying to create machines since at least the 1890s to make walking easier but it is only recently that any attempt has met with success.
Steven Collins of the Department of Mechanical Engineering at Carnegie Mellon University and colleagues say the device acts in parallel with the user’s calf muscles, off-loading muscle force and reducing the energy consumed in contractions.
The device uses a mechanical clutch to hold a spring as it is stretched and relaxed by ankle movements when the foot is on the ground, helping to fulfil one function of the calf muscles and Achilles tendon.
People take about 10,000 steps a day or hundreds of millions of steps in a lifetime.
“While strong natural pressures have already shaped human locomotion, improvements in efficiency are still possible,” the study says. “Much remains to be learned about this seemingly simple behaviour.”
Watch the exoskeleton in action:
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.
In the first evidence of a natural intervention triggering stem cell-based regeneration of an organ or system, a study in the June 5 issue of the Cell Press journal Cell Stem Cell shows that cycles of prolonged fasting not only protect against immune system damage — a major side effect of chemotherapy — but also induce immune system regeneration, shifting stem cells from a dormant state to a state of self-renewal.
In both mice and a Phase 1 human clinical trial, long periods of not eating significantly lowered white blood cell counts. In mice, fasting cycles then “flipped a regenerative switch”: changing the signaling pathways for hematopoietic stem cells, which are responsible for the generation of blood and immune systems, the research showed.
The study has major implications for healthier aging, in which immune system decline contributes to increased susceptibility to disease as we age. By outlining how prolonged fasting cycles — periods of no food for two to four days at a time over the course of six months — kill older and damaged immune cells and generate new ones, the research also has implications for chemotherapy tolerance and for those with a wide range of immune system deficiencies, including autoimmunity disorders.
“We could not predict that prolonged fasting would have such a remarkable effect in promoting stem cell-based regeneration of the hematopoietic system,” said corresponding author Valter Longo, the Edna M. Jones Professor of Gerontology and the Biological Sciences at the USC Davis School of Gerontology, and director of the USC Longevity Institute.
“When you starve, the system tries to save energy, and one of the things it can do to save energy is to recycle a lot of the immune cells that are not needed, especially those that may be damaged,” Longo said. “What we started noticing in both our human work and animal work is that the white blood cell count goes down with prolonged fasting. Then when you re-feed, the blood cells come back. So we started thinking, well, where does it come from?”
Prolonged fasting forces the body to use stores of glucose, fat and ketones, but also breaks down a significant portion of white blood cells. Longo likens the effect to lightening a plane of excess cargo.
During each cycle of fasting, this depletion of white blood cells induces changes that trigger stem cell-based regeneration of new immune system cells. In particular, prolonged fasting reduced the enzyme PKA, an effect previously discovered by the Longo team to extend longevity in simple organisms and which has been linked in other research to the regulation of stem cell self-renewal and pluripotency — that is, the potential for one cell to develop into many different cell types. Prolonged fasting also lowered levels of IGF-1, a growth-factor hormone that Longo and others have linked to aging, tumor progression and cancer risk.
“PKA is the key gene that needs to shut down in order for these stem cells to switch into regenerative mode. It gives the ‘okay’ for stem cells to go ahead and begin proliferating and rebuild the entire system,” explained Longo, noting the potential of clinical applications that mimic the effects of prolonged fasting to rejuvenate the immune system. “And the good news is that the body got rid of the parts of the system that might be damaged or old, the inefficient parts, during the fasting. Now, if you start with a system heavily damaged by chemotherapy or aging, fasting cycles can generate, literally, a new immune system.”
Prolonged fasting also protected against toxicity in a pilot clinical trial in which a small group of patients fasted for a 72-hour period prior to chemotherapy, extending Longo’s influential past research: “While chemotherapy saves lives, it causes significant collateral damage to the immune system. The results of this study suggest that fasting may mitigate some of the harmful effects of chemotherapy,” said co-author Tanya Dorff, assistant professor of clinical medicine at the USC Norris Comprehensive Cancer Center and Hospital. “More clinical studies are needed, and any such dietary intervention should be undertaken only under the guidance of a physician.”
“We are investigating the possibility that these effects are applicable to many different systems and organs, not just the immune system,” said Longo, whose lab is in the process of conducting further research on controlled dietary interventions and stem cell regeneration in both animal and clinical studies.
- Chia-Wei Cheng, Gregor B. Adams, Laura Perin, Min Wei, Xiaoying Zhou, Ben S. Lam, Stefano Da Sacco, Mario Mirisola, David I. Quinn, Tanya B. Dorff, John J. Kopchick, Valter D. Longo. Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-Cell-Based Regeneration and Reverse Immunosuppression. Cell Stem Cell, 2014; 14 (6): 810 DOI:1016/j.stem.2014.04.014
Surgeons in Cambridgeshire have performed the first heart transplant in Europe using a non-beating heart.
Donor hearts are usually from people who are brain-stem dead, but whose hearts are still beating. In this case, the organ came from a donor after their heart and lungs had stopped functioning, so-called circulatory death. Papworth hospital says the technique could increase the number of hearts available by at least 25%. The recipient Huseyin Ulucan, 60, from London, had a heart attack in 2008. He said: “Before the surgery, I could barely walk and I got out of breath very easily, I really had no quality of life.” He said he was “delighted” with the improvement in health since the transplant. “Now I’m feeling stronger every day, and I walked into the hospital this morning without any problem,” he said.
There have been 171 heart transplant in the past 12 months in the UK. But demand exceeds supply, and some patients have to wait up to three years for a suitable organ. Many patients die before an organ becomes available. Non-beating-heart donors provide kidneys, livers and other organs, but until now it has not been possible to use the heart because of concerns it would suffer damage. The new procedure involved re-starting the heart in the donor five minutes after death and perfusing it and other vital organs with blood and nutrients at body temperature. The lead transplant surgeon, Stephen Large, said: “We had the heart beating for about 50 minutes, and by monitoring its function were able to tell that it was in very good condition.”
The organ was then removed and transferred to a heart-in-a-box machine, where it was kept nourished and beating for a further three hours before the transplant surgery at Papworth. The organ care system is also used for maintaining lung, liver and kidneys outside the body. The standard method for transporting hearts and other organs for transplant is to pack them in ice, but some organs can be damaged by this process. The Papworth team said that restoring the heartbeat after death and keeping the organ nourished had helped reduce damage in the heart muscle. Last year surgeons in Australia performed the world’s first transplant using a non-beating heart, also using the heart-in-a-box technology.
TransMedics, the US company that makes the organ care machine, said each unit cost £150,000 plus £25,000 per patient transplanted. Papworth and Harefield hospitals are the only two heart transplant units in the UK who use the device. Prof James Neuberger, associate medical director for organ donation and transplantation at NHS Blood and Transplant, said: “Sadly, there is a shortage of organs for transplant across the UK and patients die in need of an organ. “We hope Papworth’s work and similar work being developed elsewhere will result in more hearts being donated and more patients benefiting from a transplant in the future. “We are immensely grateful to the donor’s family, and we hope they are taking great comfort in knowing that their relative’s organs have saved lives and have also made an important contribution to heart transplantation in the UK.”