Memory-Boosting Chemical Is Identified in Mice

Memory improved in mice injected with a small, drug-like molecule discovered by UCSF San Francisco researchers studying how cells respond to biological stress.

The same biochemical pathway the molecule acts on might one day be targeted in humans to improve memory, according to the senior author of the study, Peter Walter, PhD, UCSF professor of biochemistry and biophysics and a Howard Hughes Investigator.

The discovery of the molecule and the results of the subsequent memory tests in mice were published in eLife, an online scientific open-access journal, on May 28, 2013.

In one memory test included in the study, normal mice were able to relocate a submerged platform about three times faster after receiving injections of the potent chemical than mice that received sham injections.

The mice that received the chemical also better remembered cues associated with unpleasant stimuli – the sort of fear conditioning that could help a mouse avoid being preyed upon.

Notably, the findings suggest that despite what would seem to be the importance of having the best biochemical mechanisms to maximize the power of memory, evolution does not seem to have provided them, Walter said.

“It appears that the process of evolution has not optimized memory consolidation; otherwise I don’t think we could have improved upon it the way we did in our study with normal, healthy mice,” Walter said.

The memory-boosting chemical was singled out from among 100,000 chemicals screened at the Small Molecule Discovery Center at UCSF for their potential to perturb a protective biochemical pathway within cells that is activated when cells are unable to keep up with the need to fold proteins into their working forms.

However, UCSF postdoctoral fellow Carmela Sidrauski, PhD, discovered that the chemical acts within the cell beyond the biochemical pathway that activates this unfolded protein response, to more broadly impact what’s known as the integrated stress response. In this response, several biochemical pathways converge on a single molecular lynchpin, a protein called eIF2 alpha.

Scientists have known that in organisms ranging in complexity from yeast to humans different kinds of cellular stress — a backlog of unfolded proteins, DNA-damaging UV light, a shortage of the amino acid building blocks needed to make protein, viral infection, iron deficiency — trigger different enzymes to act downstream to switch off eIF2 alpha.

“Among other things, the inactivation of eIF2 alpha is a brake on memory consolidation,” Walter said, perhaps an evolutionary consequence of a cell or organism becoming better able to adapt in other ways.

Turning off eIF2 alpha dials down production of most proteins, some of which may be needed for memory formation, Walter said. But eIF2 alpha inactivation also ramps up production of a few key proteins that help cells cope with stress.

Study co-author Nahum Sonenberg, PhD, of McGill University previously linked memory and eIF2 alpha in genetic studies of mice, and his lab group also conducted the memory tests for the current study.

The chemical identified by the UCSF researchers is called ISRIB, which stands for integrated stress response inhibitor. ISRIB counters the effects of eIF2 alpha inactivation inside cells, the researchers found.

“ISRIB shows good pharmacokinetic properties [how a drug is absorbed, distributed and eliminated], readily crosses the blood-brain barrier, and exhibits no overt toxicity in mice, which makes it very useful for studies in mice,” Walter said. These properties also indicate that ISRIB might serve as a good starting point for human drug development, according to Walter.

Walter said he is looking for scientists to collaborate with in new studies of cognition and memory in mouse models of neurodegenerative diseases and aging, using ISRIB or related molecules.

In addition, chemicals such as ISRIB could play a role in fighting cancers, which take advantage of stress responses to fuel their own growth, Walter said. Walter already is exploring ways to manipulate the unfolded protein response to inhibit tumor growth, based on his earlier discoveries.

At a more basic level, Walter said, he and other scientists can now use ISRIB to learn more about the role of the unfolded protein response and the integrated stress response in disease and normal physiology.

Scientists create phantom sensations in non-amputees

The sensation of having a physical body is not as self-evident as one might think. Almost everyone who has had an arm or leg amputated experiences a phantom limb: a vivid sensation that the missing limb is still present. A new study by neuroscientists at the Karolinska Institutet in Sweden shows that it is possible to evoke the illusion of having a phantom hand in non-amputated individuals.

In an article in the scientific periodical Journal of Cognitive Neuroscience, the researchers describe a perceptual illusion in which healthy volunteers experience having an invisible hand. The experiment involves the participant sitting at a table with their right arm hidden from their view behind a screen. To evoke the illusion, the scientist touches the right hand of the participant with a small paintbrush while imitating the exact movements with another paintbrush in mid-air within full view of the participant.

"We discovered that most participants, within less than a minute, transfer the sensation of touch to the region of empty space where they see the paintbrush move, and experience an invisible hand in that position", says Arvid Guterstam, lead author of the study. "Previous research has shown that non-bodily objects, such as a block of wood, cannot be experienced as ones own hand, so we were extremely surprised to find that the brain can accept an invisible hand as part of the body."

The study comprises eleven experiments that explore in detail the illusory experience and include 234 volunteers. To demonstrate that the illusion actually worked, the researchers would make a stabbing motion with a knife towards the empty space ‘occupied’ by the invisible hand and measure the participant’s sweat response to the perceived threat. They found that the participants stress responses were elevated while experiencing the illusion but absent when the illusion was broken.

In another experiment, the volunteers were asked to close their eyes and quickly point with their left hand to their right hand (or to where they perceived it to be). After having experienced the illusion for a while, they would point to the location of the invisible hand rather than to their real hand.

The researchers also measured the brain activity of the participants using functional magnetic resonance imaging (fMRI). Perceiving the invisible hand illusion led to increased activity in the same parts of the brain that are normally active when individuals see their real hand being touched or when participants experience a prosthetic hand as their own.

"Taken together, our results show that the sight of a physical hand is remarkably unimportant to the brain for creating the experience of one’s physical self," says Arvid Guterstam.

The researchers hope that the results of their study will offer insight into future research on phantom pain in amputees.

"This illusion suggests that the experience of phantom limbs is not unique to amputated individuals, but can easily be created in non-amputees," says the principal investigator, Dr Henrik Ehrsson, Docent at the Department of Neuroscience. "These results add to our understanding of how phantom sensations are produced by the brain, which can contribute to future research on alleviating phantom pain in amputees."

Bullying by childhood peers leaves a trace that can change the expression of a gene linked to mood

A recent study by a researcher at the Centre for Studies on Human Stress (CSHS) at the Hôpital Louis-H. Lafontaine and professor at the Université de Montréal suggests that bullying by peers changes the structure surrounding a gene involved in regulating mood, making victims more vulnerable to mental health problems as they age. The study published in the journal Psychological Medicine seeks to better understand the mechanisms that explain how difficult experiences disrupt our response to stressful situations. “Many people think that our genes are immutable; however this study suggests that environment, even the social environment, can affect their functioning. This is particularly the case for victimization experiences in childhood, which change not only our stress response but also the functioning of genes involved in mood regulation,” says Isabelle Ouellet-Morin, lead author of the study.

A previous study by Ouellet-Morin, conducted at the Institute of Psychiatry in London (UK), showed that bullied children secrete less cortisol—the stress hormone—but had more problems with social interaction and aggressive behaviour. The present study indicates that the reduction of cortisol, which occurs around the age of 12, is preceded two years earlier by a change in the structure surrounding a gene (SERT) that regulates serotonin, a neurotransmitter involved in mood regulation and depression.

To achieve these results, 28 pairs of identical twins with a mean age of 10 years were analyzed separately according to their experiences of bullying by peers: one twin had been bullied at school while the other had not. “Since they were identical twins living in the same conditions, changes in the chemical structure surrounding the gene cannot be explained by genetics or family environment. Our results suggest that victimization experiences are the source of these changes,” says Ouellet-Morin. According to the author, it would now be worthwhile to evaluate the possibility of reversing these psychological effects, in particular, through interventions at school and support for victims.

(Image: mentalhealthsupport.co.uk)

Postpartum women less stressed by threats unrelated to the baby

Following the birth of a child, new mothers may have an altered perception of stresses around them, showing less interest in threats unrelated to the baby. This change to the neuroendocrine circuitry could help the mothers adapt to the additional stress often accompanying newborns, say researchers from Indiana University’s Kinsey Institute and the University of Zurich.

When viewing disturbing images during the study, postpartum women reported less distress and demonstrated less activity in their amygdala, the part of the brain that controls emotional response, than nulliparous, or childless, women, according to functional magnetic resonance imaging.

When the childless women were administered a nasal spray containing the hormone oxytocin, however, their brain images looked more similar to the postpartum women, and they also reported less subjective stress when viewing the images.

"Our findings extend previous work showing a lower stress response with motherhood that likely enhances her ability to cope with this dramatic new role," said lead author Heather Rupp, director of psychology and neuroscience at Brain Surgery Worldwide Inc. and a research fellow at The Kinsey Institute for Research in Sex, Gender and Reproduction.

The study, “Amygdala response to negative images in postpartum verses nulliparous women and intranasal oxytocin,” was published in the online journal Social Cognitive and Affective Neuroscience.