Low doses of psychedelic drug erases conditioned fear in mice

Low doses of a psychedelic drug erased the conditioned fear response in mice, suggesting that the agent may be a treatment for post-traumatic stress disorder and related conditions, a new study by University of South Florida researchers found.

The unexpected finding was made by a USF team studying the effects of the compound psilocybin on the birth of new neurons in the brain and on learning and short-term memory formation. Their study appeared online June 2 in the journal Experimental Brain Research, in advance of print publication.

Psilocybin belongs to a class of compounds that stimulate select serotonin receptors in the brain.  It occurs naturally in certain mushrooms that have been used for thousands of years by non-Western cultures in their religious ceremonies.

While past studies indicate psilocybin may alter perception and thinking and elevate mood, the psychoactive substance rarely causes hallucinations in the sense of seeing or hearing things that are not there, particularly in lower to moderate doses.

There has been recent renewed interest in medicine to explore the potential clinical benefit of psilocybin, MDMA and some other psychedelic drugs through carefully monitored, evidence-based research.

“Researchers want to find out if, at lower doses, these drugs could be safe and effective additions to psychotherapy for treatment-resistant psychiatric disorders or adjunct treatments for certain neurological conditions,” said Juan Sanchez-Ramos, MD, PhD, professor of neurology and Helen Ellis Endowed Chair for Parkinson’s Disease Research at the USF Health Morsani College of Medicine.

Dr. Sanchez-Ramos and his colleagues wondered about psilocybin’s role in the formation of short-term memories, since the agent binds to a serotonin receptor in the hippocampus, a region of the brain that gives rise to new neurons. Lead author for this study was neuroscientist Briony Catlow, a former PhD student in Dr. Sanchez-Ramos’ USF laboratory who has since joined the Lieber Institute for Brain Development, a translational neuroscience research center located in the Johns Hopkins Bioscience Park.

The USF researchers investigated how psilocybin affected the formation of memories in mice using a classical conditioning experiment. They expected that psilocybin might help the mice learn more quickly to associate a neutral stimulus with an unpleasant environmental cue.

To test the hypothesis, they played an auditory tone, followed by a silent pause before delivering a brief shock similar to static electricity. The mice eventually learned to link the tone with the shock and would freeze, a fear response, whenever they heard the sound.

Later in the study, the researchers played the sound without shocking the mice after each silent pause. They assessed how many times it took for the mice to resume their normal movements, without freezing in anticipation of the shock.

Regardless of the doses administered, neither psilocybin nor ketanserin, a serotonin inhibitor, made a difference in how quickly the mice learned the conditioned fear response.  However, mice receiving low doses of psilocybin lost their fearful response to the sound associated with the unpleasant shock significantly more quickly than mice getting either ketanserin or saline (control group). In addition, only low doses of psilocybin tended to increase the growth of neurons in the hippocampus.

“Psilocybin enhanced forgetting of the unpleasant memory associated with the tone,” Dr. Sanchez-Ramos said. “The mice more quickly dissociated the shock from the stimulus that triggered the fear response and resumed their normal behavior.”

The result suggests that psilocybin or similar compounds may be useful in treating post-traumatic stress disorder or related conditions in which environmental cues trigger debilitating behavior like anxiety or addiction, Dr. Sanchez-Ramos said.

These Decapitated Worms Regrow Old Memories Along with New Heads

It’s long been known that many species of worms have the remarkable ability to grow back body and even specific organs when they’ve been cut off. But new research by a pair of scientists from Tufts University has revealed that planarians—small creatures, often called flatworms, that can live in water or on land—are capable of regenerating something even more amazing.

The researchers, Tal Shomrat and Michael Levin, trained flatworms to travel across a rough surface to access food, then removed their heads. Two weeks later, after the heads grew back, the worms somehow regained their tendency to navigate across rough terrain, as the researchers recently documented in the Journal of Experimental Biology.

Interest in flatworm memories dates to the 1950s, when a series of strange experiments by Michigan biologist James McConnell indicated that worms could gain the ability to navigate a maze by being fed the ground-up remains of other flatworms that had been trained to run through the same maze. McConnell speculated that a type of genetic material called “memory RNA” was responsible for this phenomenon, and could be transferred between the organisms.

Subsequent research into planarian memory RNA exploited the fact that the worms could easily regenerate heads after decapitation. In some studies, the worms’ heads were cut off and then regenerated while they swam in RNA solutions; in others, as the Field of Science blog points out, worms that had already been trained to navigate a maze were tested after they were decapitated and their heads grew back.

Unfortunately, McConnell’s findings were largely discredited—critics pointed to sloppy research methods, and some even charged that planarians had no capacity for long-term memory—and research in this area lay dormant. Recently, though, Shomrat and Levin developed automated systems to train and test the worms, which would enable standardized and rigorous measures of how the organisms acquired and retained memories over time. And though memory RNA is still believed to be a myth, their recent research has confirmed that these worms’ memories do work in astoundingly bizarre ways.

The researchers’ computerized system dealt with the worms, from the species Dugesia japonica, in two groups of 72 each. One group was conditioned to live in a rough-bottomed petri dish, with the other in a smooth-bottomed one, for ten days. Both dishes were stocked with ample worm food (small pieces of beef liver), so each group was conditioned to learn that their particular surface meant “food is nearby.”

Next, each group was separately put into a rough-bottomed petri dish with food located only in one quadrant, along with a bright blue LED. Flatworms typically avoid light, so spending time in that quadrant meant that their expectation of food nearby trumped their aversion to light.

As a result of their conditioning, the worms who’d lived in rough containers were much quicker to flock to the lit quadrant. The researchers had the automated system’s video cameras track how long it took for the worms to spend three straight minutes under the lights, and those reared in the rough dishes took an average of six minutes to pass this number, compared to about seven and a half minutes for the other group. This difference showed that the former group had been conditioned to associate rough surfaces with food, and explored these surfaces more readily.

Afterward, all worms were fully decapitated (every bit of brain was removed) and left alone to regrow their heads over the course of the next two weeks. When they were put back in the chamber with the rough surface, the group that had previously lived in the rough dishes—that is, their previous heads had lived in the rough dishes—were still willing to venture into the lit quadrant of the rough dish and spend an extended period of time there more than a minute faster than the other group.

Incredible as it seems, some lingering memories of the rough-surface conditioning seem to have lived on in the bodies of these worms, even after their heads were chopped off. The biological explanation for this is unclear, as The Verge blog notes. Previous research confirmed that the worms’ behavior is controlled by their brains, but it’s possible that some of their memories may have been stored in their bodies, or that the training given to their initial heads somehow modified other parts of their nervous systems, which then altered how their new brains grew.

There’s also another sort of explanation. The researchers speculate that epigenetics—changes to an organism’s DNA structure that alter the expression of genes—could play a role, perhaps encoding the memory (“rough floors = food”) permanently in the worms’s DNA.

In that case, this strange experiment would provide yet another surprising outcome. There may not be such a thing as “memory RNA” per se, but in speculating on the role of genetic material in the retention of these worms’ memories, McConnell may have been on the right track after all.

Visualizing a memory trace

Whole brain imaging of zebrafish reveals neuronal networks involved in retrieving long-term memories during decision making

In mammals, a neural pathway called the cortico-basal ganglia circuit is thought to play an important role in the choice of behaviors. However, where and how behavioral programs are written, stored and read out as a memory within this circuit remains unclear. A research team led by Hitoshi Okamoto and Tazu Aoki of the RIKEN Brain Science Institute has for the first time visualized in zebrafish the neuronal activity associated with the retrieval of long-term memories during decision making.

The team performed experiments on genetically engineered zebrafish expressing a fluorescent protein that changes its intensity when it binds to calcium ions in neurons and thereby acts as an indicator of neuronal activity. “Neurons in the fish cortical region form a neural circuit similar to the mammalian cortico-basal ganglia circuit,” says Okamoto.

The fish were trained on an avoidance task by placing individual fish into a two-compartment tank and shining a red light for several seconds into the compartment containing the fish. If the fish did not move into the other compartment in response to the light, it was ‘punished’ with a mild electric shock. After several repetitions, the fish learned to avoid the shock by switching compartments as soon as the light came on. 

The researchers then examined the neuronal activity of the fish under the microscope in response to exposure to red light. One day after the learning task, the fish showed specific activity in a discrete region of the telencephalon, which corresponds to the cerebral cortex in mammals, when presented with the red light. However, just 30 minutes after the learning task no activity was observed in this part of the brain. The results suggest that this telencephalonic area encodes the long-term memory for the learned avoidance behavior. Confirming this, removing this part of the telencephalon abolished the long-term memory but did not affect learning or short-term storage of the memory. 

In humans, the ability to choose the correct behavioral programs in response to environmental changes is indispensable for everyday life, and the ability to do so is thought to be impaired in various psychiatric conditions such as depression and schizophrenia. 

“Combining the neural imaging technique with genetics, we will be able to investigate how neurons in the cortico-basal ganglia circuit choose the most suitable behavior in any given situation,” says Okamoto. “Our findings open the way to investigate and understand how these symptoms appear in human psychiatric disorders.”

Choline intake improves memory and attention-holding capacity

An experimental study in rats has shown that consuming choline, a vitamin B group nutrient found in foodstuffs like eggs and chicken or beef liver, soy and wheat germ, helps improve long-term memory and attention-holding capacity. The study, conducted by scientists at the University of Granada (Spain) Simón Bolívar University, (Venezuela) and the University of York (United Kingdom), has revealed that choline is directly involved in attention and memory processes and helps modulate them.

Researchers studied the effects of dietary supplements of choline in rats in two experiments aimed at analysing the influence of vitamin B intake on memory and attention processes during gestation and in adult specimens.

In the first experiment, scientists administered choline to rats during the third term of gestation in order to determine the effect of prenatal choline on the memory processes of their offspring. Three groups of pregnant rats were fed choline-rich, standard or choline-deficient diets. When their offspring had reached adult age, a sample of 30 was selected: 10 were female offspring of dams fed a choline-supplement, 10 had followed a choline-deficient diet and the other 10, a standard diet, acting as a control group.

Long-term memory

This sample of adult offspring underwent an experiment to measure their memory retention: 24 hours after being shown an object all the offspring (whether in the choline-supplement group or not) remembered it and it was familiar to them However, after 48 hours, the rats of dams fed a prenatal choline-rich diet recognized the object better than those in the standard diet group, while the choline-deficient group could not recognize it. Thus, the scientists concluded that prenatal choline intake improves long-term memory in the resulting offspring once they reach adulthood.

In the second experiment, the researchers measured changes in attention that occurred in adult rats fed a choline supplement for 12 weeks, versus those with no choline intake. They found that the rats which had ingested choline maintained better attention that the others when presented with a familiar stimulus. The control group, fed a standard diet, showed the normal learning delay when this familiar stimulus acquired a new meaning. However, the choline-rich intake rats showed a fall in attention to the familiar stimulus, rapidly learning its new meaning.

The study has been undertaken by University of Granada Department of Experimental Psychology researchers Isabel De Brugada-Sauras and Hayarelis Moreno-Gudiño (also on the research staff of Simón Bolívar University together with Diamela Carias); Milagros Gallo-Torre, researcher in the University of Granada Department of Psychobiology and Director of the “Federico Olóriz” University Research Institute for Neuroscience; and Geoffrey Hall, of the Department of Psychology of the University of York. Their study has recently given rise to publications in Nutritional Neuroscience and Behavioural Brain Research.

Daydreaming simulated by computer model

Scientists have created a virtual model of the brain that daydreams like humans do.

Researchers created the computer model based on the dynamics of brain cells and the many connections those cells make with their neighbors and with cells in other brain regions. They hope the model will help them understand why certain portions of the brain work together when a person daydreams or is mentally idle. This, in turn, may one day help doctors better diagnose and treat brain injuries.

“We can give our model lesions like those we see in stroke or brain cancer, disabling groups of virtual cells to see how brain function is affected,” said senior author Maurizio Corbetta, MD, the Norman J. Stupp Professor of Neurology at Washington University School of Medicine in St. Louis. “We can also test ways to push the patterns of activity back to normal.”

The study is now available online in The Journal of Neuroscience.

The model was developed and tested by scientists at Washington University School of Medicine in St. Louis, Universitat Pompeu Fabra in Barcelona, Spain, and several other European universities including ETH Zurich, Switzerland; University of Oxford, United Kingdom; Institute of Advanced Biomedical Technologies, Chieti, Italy; and University of Lausanne, Switzerland.

Scientists first recognized in the late 1990s and early 2000s that the brain stays busy even when it’s not engaged in mental tasks. Researchers have identified several “resting state” brain networks, which are groups of different brain regions that have activity levels that rise and fall in sync when the brain is at rest. They have also linked disruptions in  networks associated with brain injury and disease to cognitive problems in memory, attention, movement and speech.

The new model was developed to help scientists learn how the brain’s anatomical structure contributes to the creation and maintenance of resting state networks. The researchers began with a process for simulating small groups of neurons, including factors that decrease or increase the likelihood that a group of cells will send a signal.

“In a way, we treated small regions of the brain like cognitive units: not as individual cells but as groups of cells,” said Gustavo Deco, PhD, professor and head of the Computational Neuroscience Group in Barcelona. “The activity of these cognitive units sends out excitatory signals to the other units through anatomical connections. This makes the connected units more or less likely to synchronize their signals.”

Based on data from brain scans, researchers assembled 66 cognitive units in each hemisphere, and interconnected them in anatomical patterns similar to the connections present in the brain.

Scientists set up the model so that the individual units went through the signaling process at random low frequencies that had previously been observed in brain cells in culture and in recordings of resting brain activity.

Next, researchers let the model run, slowly changing the coupling, or the strength of the connections between units. At a specific coupling value, the interconnections between units sending impulses soon began to create coordinated patterns of activity.

“Even though we started the cognitive units with random low activity levels, the connections allowed the units to synchronize,” Deco said. “The spatial pattern of synchronization that we eventually observed approximates very well—about 70 percent—to the patterns we see in scans of resting human brains.”

Using the model to simulate 20 minutes of human brain activity took a cluster of powerful computers 26 hours. But researchers were able to simplify the mathematics to make it possible to run the model on a typical computer. 

“This simpler whole brain model allows us to test a number of different hypotheses on how the structural connections generate dynamics of brain function at rest and during tasks, and how brain damage affects brain dynamics and cognitive function,” Corbetta said.

University experts spot early signs of Alzheimer’s

Early signs of Alzheimer’s disease can be detected years before diagnosis, according to researchers at Birmingham City University.

The study found that sufferers of a specific type of cognitive impairment have an increased loss of cells in certain parts of the brain, which can be vital in detecting which patients will progress to a diagnosis of Alzheimer’s.

A team of researchers from Birmingham City University (UK), in association with colleagues from Lanzhou University (China) and the Alzheimer’s Disease Neuroimaging Initiative, conducted a brain scan analysis over two years, of patients suffering from amnestic mild cognitive impairment (aMCI) – a condition involving the diminishing of cognitive abilities, from which 80% of patients progress to a diagnosis of Alzheimer’s.

Scans showed that the loss of grey matter in the left hemisphere of the brain was particularly widespread and degenerative for those patients at high risk of developing Alzheimer’s, compared with those with no active neurological disorders.

This region of the brain has been associated with language, decision making, expressing personality, executing movement, planning complex cognitive behaviour and moderating social behaviour. 

One of the researchers involved in the study, Professor Mike Jackson, from Birmingham City University, said: “Continuous loss of cells within the regions of the brain highlighted in this study should act as alarm bells for doctors, as they may indicate that the patient is on course to developing Alzheimer’s.”

The brains parahippocampal gyrus, a region which is known to be related to memory encoding and retrieval, was highlighted as an area that should be looked at carefully when examining brain scans to detect early signs of the disease.

Treating Alzheimer’s early is thought to be vital to prevent damage to memory and thinking. Although treatments are available to temporarily ease symptoms, there has been little in the way of success in slowing down the cognitive decline in patients with mild to moderate Alzheimer’s, which has been partly put down to the late timing of the diagnosis.

Experts at Birmingham City University hope that this study will aid other researchers to find an effective clinical treatment to delay the conversion to Alzheimer’s.

Researchers Identify “Switch” for Long-term Memory

Calcium signal in neuronal cell nuclei initiates the formation of lasting memories

Neurobiologists at Heidelberg University have identified calcium in the cell nucleus to be a cellular “switch” responsible for the formation of long-term memory. Using the fruit fly “Drosophila melanogaster” as a model, the team led by Prof. Dr. Christoph Schuster and Prof. Dr. Hilmar Bading investigates how the brain learns. The researchers wanted to know which signals in the brain were responsible for building long-term memory and for forming the special proteins involved. The results of the research were published in the journal “Science Signaling”.

The team from the Interdisciplinary Center for Neurosciences (IZN) measured nuclear calcium levels with a fluorescent protein in the association and learning centres of the insect’s brain to investigate any changes that might occur during the learning process. Their work on the fruit fly revealed brief surges in calcium levels in the cell nuclei of certain neurons during learning. It was this calcium signal that researchers identified as the trigger of a genetic programme that controls the production of “memory proteins”. If this nuclear calcium switch is blocked, the flies are unable to form long-term memory.

Prof. Schuster explains that insects and mammals separated evolutionary paths approximately 600 million years ago. In spite of this sizable gap, certain vitally important processes such as memory formation use similar cellular mechanisms in humans, mice and flies, as the researchers’ experiments were able to prove. “These commonalities indicate that the formation of long-term memory is an ancient phenomenon already present in the shared ancestors of insects and vertebrates. Both species probably use similar cellular mechanisms for forming long-term memory, including the nuclear calcium switch”, Schuster continues.

The IZN researchers assume that similar switches based on nuclear calcium signals may have applications in other areas – presumably whenever organisms need to adapt to new conditions over the long term. “Pain memory, for example, or certain protective and survival functions of neurons use this nuclear calcium switch, too”, says Prof. Bading. This cellular switch may no longer work as well in the elderly, which Bading believes may explain the decline in memory typically observed in old age. Thus, the discoveries by the Heidelberg neurobiologists open up new perspectives for the treatment of age- and illness-related changes in brain functions.

To Preserve Memory Into Old Age, Keep Your Brain Active!

A new study from Rush University Medical Center in Chicago claims reading and writing may preserve memory into old age. By keeping your brain active, says study author Robert S. Wilson, PhD, you’re able to slow the rate at which your memory decreases in later years.

This is not the first time researchers have arrived at such a conclusion, of course. Previous studies have also found keeping the brain active by reading, writing, completing crossword puzzles and more can essentially exercise the brain and keep it limber far into old age. One study also concluded that keeping television consumption to a minimal amount may also boost brain power over the years. Wilson’s study was recently published in the journal Neurology.

“Our study suggests that exercising your brain by taking part in activities such as these across a person’s lifetime, from childhood through old age, is important for brain health in old age,” said Wilson in a statement.

For his study, Wilson gathered nearly 300 people around the age of 80. He then gave them tests which were designed to measure both their memory and cognition each year until they passed away at an average age of 89. The same participants also answered questions about their past, such as whether they read books, did any writing, or engaged in any other mentally stimulating activities. The volunteers answered these questions for every part of their life, from childhood to adolescence, middle age and beyond.

When the participants passed away, their brains were then examined at an autopsy as Wilson’s team looked for physical evidence of dementia, such as lesions in the brain, tangles or plaques. After examining the brains of these volunteers and compiling the data from the questionnaires, Wilson’s team found those who had kept their minds active throughout their lives had a slower rate of memory decline than those who did not often participate in mentally challenging activities. Based on the amount of plaques and tangles in the brains, keeping your brain active is responsible for a 15 percent differential in memory decline.

The study also found the rate of memory decline was reduced by 32 percent in people who kept their brains active late in life. Those who were not mentally active had it much worse; their memories declined 48 percent faster than their actively reading and writing peers.

“Based on this, we shouldn’t underestimate the effects of everyday activities, such as reading and writing, on our children, ourselves and our parents or grandparents,” said Wilson.

And this news is hardly surprising. Doctors, teachers and parents have been admonishing children to turn off the television and pick up a book for years. There is no shortage of studies to back up their claims. A 2009 study, for example, found people who keep their brains active saw a 30 to 50 percent decrease in risk of developing memory loss. This study, conducted by doctors at the Mayo Clinic in Rochester, Minnesota observed people between the ages of 70 and 89 with and without diagnosed memory loss.

Those who were likely to read magazines or engage in other social activities were 40 percent less likely to develop memory loss than homebodies who did not read. Furthermore, those who spent less than seven hours a day watching television were 50 percent less likely to develop memory loss than those who planted themselves in front of the tube for long stretches of time.

Researchers Discover Link Between Fear and Sound Perception

Anyone who’s ever heard a Beethoven sonata or a Beatles song knows how powerfully sound can affect our emotions. But it can work the other way as well – our emotions can actually affect how we hear and process sound. When certain types of sounds become associated in our brains with strong emotions, hearing similar sounds can evoke those same feelings, even far removed from their original context. It’s a phenomenon commonly seen in combat veterans suffering from posttraumatic stress disorder (PTSD), in whom harrowing memories of the battlefield can be triggered by something as common as the sound of thunder. But the brain mechanisms responsible for creating those troubling associations remain unknown. Now, a pair of researchers from the Perelman School of Medicine at the University of Pennsylvania has discovered how fear can actually increase or decrease the ability to discriminate among sounds depending on context, providing new insight into the distorted perceptions of victims of PTSD. Their study is published in Nature Neuroscience.

“Emotions are closely linked to perception and very often our emotional response really helps us deal with reality,” says senior study author Maria N. Geffen, PhD, assistant professor of Otorhinolaryngology: Head and Neck Surgery and Neuroscience at Penn. “For example, a fear response helps you escape potentially dangerous situations and react quickly. But there are also situations where things can go wrong in the way the fear response develops. That’s what happens in anxiety and also in PTSD — the emotional response to the events is generalized to the point where the fear response starts getting developed to a very broad range of stimuli.”

Geffen and the first author of the study, Mark Aizenberg, PhD, a postdoctoral researcher in her laboratory, used emotional conditioning in mice to investigate how hearing acuity (the ability to distinguish between tones of different frequencies) can change following a traumatic event, known as emotional learning. In these experiments, which are based on classical (Pavlovian) conditioning, animals learn to distinguish between potentially dangerous and safe sounds — called “emotional discrimination learning.” This type of conditioning tends to result in relatively poor learning, but Aizenberg and Geffen designed a series of learning tasks intended to create progressively greater emotional discrimination in the mice, varying the difficulty of the task. What really interested them was how different levels of emotional discrimination would affect hearing acuity – in other words, how emotional responses affect perception and discrimination of sounds. This study established the link between emotions and perception of the world – something that has not been understood before.

The researchers found that, as expected, fine emotional learning tasks produced greater learning specificity than tests in which the tones were farther apart in frequency. As Geffen explains, “The animals presented with sounds that were very far apart generalize the fear that they developed to the danger tone over a whole range of frequencies, whereas the animals presented with the two sounds that were very similar exhibited specialization of their emotional response. Following the fine conditioning task, they figured out that it’s a very narrow range of pitches that are potentially dangerous.”

When pitch discrimination abilities were measured in the animals, the mice with more specific responses displayed much finer auditory acuity than the mice who were frightened by a broader range of frequencies.  “There was a relationship between how much their emotional response generalized and how well they could tell different tones apart,” says Geffen. “In the animals that specialized their emotional response, pitch discrimination actually became sharper. They could discriminate two tones that they previously could not tell apart.”

Another interesting finding of this study is that the effects of emotional learning on hearing perception were mediated by a specific brain region, the auditory cortex. The auditory cortex has been known as an important area responsible for auditory plasticity. Surprisingly, Aizenberg and Geffen found that the auditory cortex did not play a role in emotional learning. Likely, the specificity of emotional learning is controlled by the amygdala and sub-cortical auditory areas. “We know the auditory cortex is involved, we know that the emotional response is important so the amygdala is involved, but how do the amygdala and cortex interact together?” says Geffen. “Our hypothesis is that the amygdala and cortex are modifying subcortical auditory processing areas. The sensory cortex is responsible for the changes in frequency discrimination, but it’s not necessary for developing specialized or generalized emotional responses. So it’s kind of a puzzle.”

Solving that puzzle promises new insight into the causes and possible treatment of PTSD, and the question of why some individuals develop it and others subjected to the same events do not. “We think there’s a strong link between mechanisms that control emotional learning, including fear generalization, and the brain mechanisms responsible for PTSD, where generalization of fear is abnormal,” Geffen notes. Future research will focus on defining and studying that link.