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Should I stay or should I go? On the importance of aversive memories and the endogenous cannabinoid system

Memory is not a simple box of souvenirs; it is also, and most importantly, a safety system for organisms. With the help of negative memories, known as aversive memories, we can avoid a threat that we have already confronted. Researchers from Inserm and University of Bordeaux have just discovered that the cannabinoid receptors of the brain control these memories that are crucial for survival. This study is published in Neuron.

When confronted by danger, every individual has to make a crucial choice. This type of simple decision may determine his/her destiny: if the fire alarm goes off, we have learned to heed it and flee, and not to ignore it. In the same way, we avoid food and drinks that might have made us sick in the past.

The body is thus equipped with neurological mechanisms that help it to adjust its behaviour in response to a stimulus. Such is the case with aversive memories, a key survival process, which prepares the body to avoid these potential dangers effectively. These memories are accompanied by physiological responses (fright and flight) that enable one to get away from a dangerous situation.

Although the role of the habenula, a central region of the brain, in this phenomenon has received a great deal of attention in recent years, the same is not true of the endogenous cannabinoid system of the habenular neurons, on which Giovanni Marsicano and his team (particularly Edgar Soria-Gomez) have focused. This system involves the type 1 cannabinoid receptors. These receptors, the activity of which is normally regulated by endocannabinoids the bodys own molecules are the target of the main psychoactive components of cannabis.

The researchers conditioned mice so that they reacted to certain danger signals (sounds or smells). When they exposed them to these signals, mice that were deficient in cannabinoid receptors in the habenula expressed neither the fear nor the repulsion observed in normal mice. Interestingly, this impaired reaction did not apply to neutral or positive memories, which remained unchanged in these mice.

At molecular level, the scientists observed that, although the functioning of the habenula normally involves two molecules (acetylcholine and glutamate), the defect observed in these mice is caused by an imbalance in neurotransmission involving only acetylcholine.

These results demonstrate that the endogenous cannabinoid system in the habenula exclusively controls the expression of aversive memories, without influencing neutral or positive memories, and does so by selectively modulating acetylcholine in the neural circuits involved, explains Giovanni Marsicano, Inserm Research Director.

The control of these particular memories is an integral part of diseases associated with the emotional process, such as depression, anxiety or drug addiction. As a consequence, the endogenous cannabinoid system of the habenula might represent a new therapeutic target in the management of these conditions.

Filed under memory habenula endocannabinoids cannabinoid system acetylcholine neuroscience science

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Stem Cell Research Hints at Evolution of Human Brain

The human cerebral cortex contains 16 billion neurons, wired together into arcane, layered circuits responsible for everything from our ability to walk and talk to our sense of nostalgia and drive to dream of the future. In the course of human evolution, the cortex has expanded as much as 1,000-fold, but how this occurred is still a mystery to scientists.

Now, researchers at UC San Francisco have succeeded in mapping the genetic signature of a unique group of stem cells in the human brain that seem to generate most of the neurons in our massive cerebral cortex.

The new findings, published Sept. 24 in the journal Cell, support the notion that these unusual stem cells may have played an important role in the remarkable evolutionary expansion of the primate brain.

We want to know what it is about our genetic heritage that makes us unique, said Arnold Kriegstein, MD, PhD, professor of developmental and stem cell biology and director of the Eli and Edyth Broad Center of Regeneration Medicine and Stem Cell Research at UCSF. Looking at these early stages in development is the best opportunity to understand our brains evolution.

Building a Brain from the Inside Out

The grand architecture of the human cortex, with its hundreds of distinct cell types, begins as a uniform layer of neural stem cells and builds itself from the inside out during several months of embryonic development.

Until recently, most of what scientists knew about this process came from studies of model organisms such as mice, where nearly all neurons are produced by stem cells called ventricular radial glia (vRGs) that inhabit a fertile layer of tissue deep in the brain called the ventricular zone (VZ). But recent insights suggested that the development of the human cortex might have some additional wrinkles.

In 2010, Kriegsteins lab discovered a new type of neural stem cell in the human brain, which they dubbed outer radial glia (oRGs) because these cells reside farther away from the nurturing ventricles, in an outer layer of the subventricular zone (oSVZ). To the researchers surprise, further investigations revealed that during the peak of cortical development in humans, most of the neuron production was happening in the oSVZ rather than the familiar VZ.

oRG stem cells are extremely rare in mice, but common in primates, and look and behave quite differently from familiar ventricular radial glia. Their discovery immediately made Kriegstein and colleagues wonder whether this unusual group of stem cells could be a key to understanding what allowed primate brains to grow to their immense size and complexity.

We wanted to know more about the differences between these two different stem cell populations, said Alex Pollen, PhD, a postdoctoral researcher in Kriegsteins lab and co-lead author of the new study. We predicted oRGs could be a major contributor to the development of the human cortex, but at first we only had circumstantial evidence that these cells even made neurons.

Outsider Stem Cells Make Their Own Niche

In the new research, Pollen and co-first author Tomasz Nowakowski, PhD, also a postdoctoral researcher in the Kriegstein lab, partnered with Fluidigm Corp. to develop a microfluidic approach to map out the transcriptional profile the set of genes that are actively producing RNA of cells collected from the VZ and SVZ during embryonic development.

They identified gene expression profiles typical of different types of neurons, newborn neural progenitors and radial glia, as well as molecular markers differentiating oRGs and vRGs, which allowed the researchers to isolate these cells for further study.

The gene activity profiles also provided several novel insights into the biology of outer radial glia. For example, researchers had previously been puzzled as to how oRG cells could maintain their generative vitality so far away from the nurturing VZ. In the mouse, as cells move away from the ventricles, they lose their ability to differentiate into neurons, Kriegstein explained.

But the new data reveals that oRGs bring a support group with them: The cells express genes for surface markers and molecular signals that enhance their own ability to proliferate, the researchers found.

This is a surprising new feature of their biology, Pollen said. They generate their own stem cell niche.

The researchers used their new molecular insights to isolate oRGs in culture for the first time, and showed that these cells are prolific neuron factories. In contrast to mouse vRGs, which produce 10 to 100 daughter cells during brain development, a single human oRG can produce thousands of daughter neurons, as well as glial cellsnon-neuronal brain cells increasingly recognized as being responsible for a broad array of maintenance functions in the brain.

New Insights into Brain Evolution, Development and Disease

The discovery of human oRGs self-renewing niche and remarkable generative capacity reinforces the idea that these cells may have been responsible for the expansion of the cerebral cortex in our primate ancestors, the researchers said.

The research also presents an opportunity to greatly improve techniques for growing brain circuits in a dish that reflect the true diversity of the human brain, they said. Such techniques have the potential to enhance research into the origins of neurodevelopmental and neuropsychiatric disorders such as microcephaly, lissencephaly, autism and schizophrenia, which are thought to affect cell types not found in the mouse models that are often used to study such diseases.

The findings may even have implications for studying glioblastoma, a common brain cancer whose ability to grow, migrate and hack into the brains blood supply appears to rely on a pattern of gene activity similar to that now identified in these neural stem cells.

The cerebral cortex is so different in humans than in mice, Kriegstein said. If youre interested in how our brains evolved or in diseases of the cerebral cortex, this is a really exciting discovery.

The study represents the first salvo of a larger BRAIN Initiative-funded project in Kriegsteins lab to understand the thousands of different cell types that occupy the developing human brain

At the moment, we simply dont have a good understanding of the brains parts list, Kriegstein said, but studies like this are beginning to give us a real blueprint of how our brains are built.

Filed under stem cells radial glia glial cells cerebral cortex evolution gene expression neuroscience science

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Reproducible neuroscience with real tango Consonant results resonate in the brain

Most neuroscientific studies rely on a single experiment and assume their findings to be reliable. However, the validity of this assumption needs to be tested before accepting the findings as the ground truth. Indeed, the lack of replication studies in addition to the inconsistency of neuroimaging findings severely limits the advancement of knowledge in the field of neuroscience, all of which has recently become a hot topic within the neuroscientific community.

Concerned about this state of affairs, researchers at the Finnish Centre for Interdisciplinary Music Research (CIMR), University of Jyvskyl, in Finland, and from Aarhus University, in Denmark, aimed to replicate previous findings on how the brain processes music using a novel, naturalistic free listening context. Their results, published in Neuroimage, demonstrate that laboratory conditions resembling real-life contexts can yield reliable results, making findings more ecologically valid. The more we can simulate reality in a lab in a reliable way, the more truetolife the findings will be, and this is critical to modelling the way the brain actually understands the world, sums up Doctoral Student Iballa Burunat, the lead author of the study.

The research team employed an identical methodology as in the original study, but using a new group of participants. As in the original study, participants had to just listen to the musical piece Adis Nonino by A. Piazzolla. Researchers assessed how similar the observed brain activity was between the original and the new study. Replicating the experiment allowed the researchers to fine-tune the findings of the previous study, concluding what brain areas are involved in the processing of different musical elements, like tonality, timbre, and rhythm, and how accurately the neural correlates could be replicated for each of these musical elements. For instance, they observed that highlevel musical features, such as tonality and rhythm, were less replicable than lowlevel (timbral) ones. One reason for this may be that the neural processing of highlevel musical features is more sensitive to state and traits of the listeners compared to the processing of lowlevel features, which may hinder the replication of previous findings, says Academy Professor Petri Toiviainen, from the University of Jyvskyl, a co-author of the study.

When listening to a piece of music, we cant separate its auditory characteristics from its affective, cognitive, and contextual dimensions. It is precisely the integration of all these aspects that gives coherence to our listening experience. This is why taking a more naturalistic approach makes neuroscience more faithful to reality, a goal that a fully controlled setting that uses very simple and artificially created sounds falls short of. The success in replicating these findings should encourage scientists to move towards more reallife paradigms that capture the complexity of the real world.

The neuroscientific community needs to challenge the current scientific model driven by dysfunctional research practices tacitly encouraged by the publish or perish doctrine, which is precisely leading to the low reliability and the high discrepancy of results, states Iballa Burunat. The authors stress that more incentives are needed for replicating experiments, and agree that scientific journals should more often than not welcome replication studies to ensure that published research is robust and reliable.

Filed under brain activity neuroimaging music neuroscience science

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(Image caption: Lateral view of the Paranthropus robustus skull SK 46 from the site of Swartkrans, South Africa showing the 3D virtual reconstruction of the ear and the hearing results for the early hominins. Credit: Rolf Quam)

2-Million-Year-Old Fossils Reveal Hearing Abilities of Early Humans

Research into human fossils dating back to approximately two million years ago reveals that the hearing pattern resembles chimpanzees, but with some slight differences in the direction of humans.

Rolf Quam, assistant professor of anthropology at Binghamton University, led an international research team in reconstructing an aspect of sensory perception in several fossil hominin individuals from the sites of Sterkfontein and Swartkrans in South Africa. The study relied on the use of CT scans and virtual computer reconstructions to study the internal anatomy of the ear. The results suggest that the early hominin species Australopithecus africanus and Paranthropus robustus, both of which lived around 2 million years ago, had hearing abilities similar to a chimpanzee, but with some slight differences in the direction of humans.

Humans are distinct from most other primates, including chimpanzees, in having better hearing across a wider range of frequencies, generally between 1.0-6.0 kHz. Within this same frequency range, which encompasses many of the sounds emitted during spoken language, chimpanzees and most other primates lose sensitivity compared to humans.

We know that the hearing patterns, or audiograms, in chimpanzees and humans are distinct because their hearing abilities have been measured in the laboratory in living subjects, said Quam. So we were interested in finding out when this human-like hearing pattern first emerged during our evolutionary history.

Previously, Quam and colleagues studied the hearing abilities in several fossil hominin individuals from the site of the Sima de los Huesos (Pit of the Bones) in northern Spain. These fossils are about 430,000 years old and are considered to represent ancestors of the later Neandertals. The hearing abilities in the Sima hominins were nearly identical to living humans. In contrast, the much earlier South African specimens had a hearing pattern that was much more similar to a chimpanzee.

In the South African fossils, the region of maximum hearing sensitivity was shifted towards slightly higher frequencies compared with chimpanzees, and the early hominins showed better hearing than either chimpanzees or humans from about 1.0-3.0 kHz. It turns out that this auditory pattern may have been particularly favorable for living on the savanna. In more open environments, sound waves dont travel as far as in the rainforest canopy, so short range communication is favored on the savanna.

We know these species regularly occupied the savanna since their diet included up to 50 percent of resources found in open environments said Quam. The researchers argue that this combination of auditory features may have favored short-range communication in open environments.

That sounds a lot like language. Does this mean these early hominins had language? No, said Quam. Were not arguing that. They certainly could communicate vocally. All primates do, but were not saying they had fully developed human language, which implies a symbolic content.

The emergence of language is one of the most hotly debated questions in paleoanthropology, the branch of anthropology that studies human origins, since the capacity for spoken language is often held to be a defining human feature. There is a general consensus among anthropologists that the small brain size and ape-like cranial anatomy and vocal tract in these early hominins indicates they likely did not have the capacity for language.

We feel our research line does have considerable potential to provide new insights into when the human hearing pattern emerged and, by extension, when we developed language, said Quam.

Ignacio Martinez, a collaborator on the study, said, Were pretty confident about our results and our interpretation. In particular, its very gratifying when several independent lines of evidence converge on a consistent interpretation.

How do these results compare with the discovery of a new hominin species, Homo naledi, announced just two weeks ago from a different site in South Africa?

It would be really interesting to study the hearing pattern in this new species, said Quam. Stay tuned.

The study was published on Sept. 25 in the journal Science Advances.

Filed under hearing evolution australopithecus paranthropus communication neuroscience science

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Of brains and bones: How hunger neurons control bone mass

In an advance that helps clarify the role of a cluster of neurons in the brain, Yale School of Medicine researchers have found that these neurons not only control hunger and appetite, but also regulate bone mass.

The study is published Sept. 24 online ahead of print in the journal Cell Reports.

We have found that the level of your hunger could determine your bone structure, said one of the senior authors, Tamas L. Horvath, the Jean and David W. Wallace Professor of Comparative Medicine, and professor of neurobiology and obstetrics, gynecology, and reproductive sciences. Horvath is also director of the Yale Program in Integrative Cell Signaling and Neurobiology of Metabolism.

The less hungry you are, the lower your bone density, and surprisingly, the effects of these neurons on bone mass are independent of the effect of the hormone leptin on these same cells.

Horvath and his team focused on agouti-related peptide (AgRP) neurons in the hypothalamus, which control feeding and compulsive behaviors. Using mice that were genetically-engineered so their cells selectively interfere with the AgRP neurons, the team found that these same cells are also involved in determining bone mass.

The team further found that when the AgRP circuits were impaired, this resulted in bone loss and osteopenia in mice the equivalent of osteoporosis in women. But when the team enhanced AgRP neuronal activity in mice, this actually promoted increased bone mass.

Taken together, these observations establish a significant regulatory role for AgRP neurons in skeletal bone metabolism independent of leptins action, said co-senior author Dr. Karl Insogna, professor of medicine, and director of the Yale Bone Center. Based on our findings, it seems that the effect of AgRP neurons on bone metabolism in adults is mediated at least in part by the sympathetic nervous system, but more than one pathway is likely involved.

There are other mechanisms by which the AgRP system can affect bone mass, including actions on the thyroid, adrenal and gonad systems, Insogna added. Further studies are needed to assess the hormonal control of bone metabolism as a pathway modulated by AgRP neurons.

Filed under AgRP neurons hypothalamus leptin neural circuits bone mass neuroscience science

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From brain, to fat, to weight loss

Weight is controlled by the hormone leptin, which acts in the brain to regulate food intake and metabolism. However, it was largely unknown until now, how the brain signals back to the fat tissue to induce fat breakdown. Now, a breakthrough study led by Ana Domingos at Instituto Gulbenkian de Cincia (IGC; Portugal), in collaboration with Jeffrey Friedmans group at Rockefeller University (USA), has shown that fat tissue is innervated and that direct stimulation of neurons in fat is sufficient to induce fat breakdown. These results, published in the latest issue of the prestigious journal Cell, set up the stage for developing novel anti-obesity therapies.

Fat tissue constitutes 20 to 25% of human body weight being an energy storage container, in the form of triglycerides. Twenty years ago Jeffrey Friedman and colleagues identified the hormone leptin, which is produced by fat cells in amounts that are proportional to the amount of fat, and informs the brain about how much fat is available in the body. Leptin functions as an adipostat neuro-endocrine signal that preserves bodys fat mass in a relatively narrow range of variation. Low leptin levels increase appetite and lower basal metabolism, whereas high leptin levels blunt appetite and promote fat breakdown. However, until now it was largely unknown what circuits close the neuroendocrine loop, such that leptin action in the brain signals back to the fat.

Now, the research team led by Ana Domingos, combined a variety of techniques to functionally establish, for the first time, that white fat tissue is innervated. We dissected these nerve fibers from mouse fat, and using molecular markers identified these as sympathetic neurons, explains Ana Domingos. But most remarkable, when we used an ultra sensitive imaging technique, on the intact white fat tissue of a living mouse, we observed that fat cells can be encapsulated by these sympathetic neural terminals.

Next, researchers used genetic engineered mice, whose sympathetic neurons could be activated by blue light, to assess the functional relevance of these fat projecting neurons. Roksana Pirzgalska, a doctorate student in Domingos laboratory and co-first author of the study explains: We used a powerful technique called optogenetics, to locally activate these sympathetic neurons in fat pads of mice, and observed fat breakdown and fat mass reduction. Ana Domingos adds: The local activation of these neurons, leads to the release of norepinephrine, a neurotransmitter, that triggers a cascade of signals in fat cells leading to fat hydrolysis. Without these neurons, leptin is unable to drive fat-breakdown. The conclusions and future directions are clear according to Ana Domingos: This result provides new hopes for treating central leptin resistance, a condition in which the brains of obese people are insensitive to leptin. Senior co-author Jeffrey Friedman adds: These studies add an important new piece to the puzzle that enables leptin to induce fat loss.

Filed under leptin fat tissue weight loss neurons lipolysis neuroscience science

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Liquid crystals are familiar to most of us as the somewhat humdrum stuff used to make computer displays and TVs. Even for scientists, it has not been easy to find other uses.

(Image caption: These magnified images show how untreated liquid crystals (top) respond to the human islet amyloid peptide (lower right), which forms aggregates and is involved in diabetes; and rat islet amyloid (lower left), which does not aggregate. The actual width of these panels is 280 microns, approximately the diameter of several human hairs lying side by side. Credit: Courtesy of Advanced Functional Materials, Sadati and others)

Now a group of researchers at the University of Chicagos Institute for Molecular Engineering is putting liquid crystals to work in a completely unexpected realm: as detectors for the protein fibers implicated in the development of neuro-degenerative diseases such as Alzheimers. Their novel approach promises an easier, less costly way to detect these fibers and to do so at a much earlier stage of their formation than has been possible beforethe stage when they are thought to be the most toxic.

It is extremely important to develop techniques that allow us to detect the formation of these so-called amyloid fibrils when theyre first starting to grow, said Juan de Pablo, whose group did the new work. We have developed a system that allows us to detect them in a simple and inexpensive manner. And the sensitivity appears to be extremely high.

Amyloid fibrils are protein aggregates that are associated with the development of neuro-degenerative diseases, including Huntingtons, Parkinsons, Alzheimers and mad cow disease, as well as in Type 2 diabetes, where they damage the pancreatic islets. Scientists would like to be able to study their formation both for therapeutic reasons and so they can test the effect of new drugs on inhibiting their growth. But the fibrils that are believed to be most harmful are too tiny to be seen using an optical microscope. So scientists have relied on elaborate and expensive fluorescence- or neutron scattering-based techniques to study them.

A different approach

The de Pablo group took a completely different approach. They exploited the way a liquid crystal responds to a disturbance on its surface. The scientists made a film of a liquid crystal molecule called 5CB, which de Pablo calls the fruit fly of liquid crystal research because it is so well studied. Then they applied chemicals to the 5CB film that caused the molecules to align in such a way as to block the passage of light. Floating on top of the film was a membrane made of molecules resembling those found in the membranes of biological cells. And on top of that was water, into which the scientists injected the molecules that spontaneously form the toxic aggregates.

As aggregates grow on the membrane, they imprint their shape into the liquid crystal underneath, said de Pablo, the Liew Family Professor in Molecular Engineering. The liquid crystal molecules that are at the interface become distorted: they adopt a different orientation, so that light can now go through.

This disturbance on the membranethe imprint of the protein fibersis transmitted down through the liquid crystal film, in effect amplifying it.

The fibers might be tens of nanometers in diameter and a hundred nanometers long, far smaller than a red blood cell. But the disturbance they create is magnified by the liquid crystal so that it is large enough to be seen in polarized light with a simple optical microscope.

Microscopic bright spots

Seen through the microscope, the aggregates appear as tiny bright spots in a sea of black: bright where the liquid crystal has been disturbed to let light pass. The liquid crystal is actually reporting whats happening to the aggregates at the interface, de Pablo said. And these bright spots become bigger and adopt the shape of the actual fibers that the protein is forming. Except youre not seeing the fibers, youre seeing the liquid crystals response to the fibers.

The work of de Pablos team was published online Sept. 9, 2015, by the journal Advanced Functional Materials. Co-authoring the article were IME scientists Monirosadat Sadati, Julio Armas-Perez, Jose Martinez-Gonzalez, and Juan Hernandez-Ortiz, as well as Aslin Izmitli-Apik and Nicholas Abbott of the University of Wisconsin at Madison.

They relied crucially on theoretical molecular models, both to help guide them through the real system and to help them understand what they were seeing. They are now developing sensors for the amyloid fibrils that may allow experimenters to use droplets of liquid crystals in emulsion rather than the flat surfaces used in the proof-of-concept experiments.

That, said de Pablo, would be a lot easier for people to use. He envisions scientists eventually being able to test small samples of blood or other body fluid using the new detectors, or for drug researchers to put the amyloid proteins in water, inject their drug, and study how the drug influences the growth of the aggregates over time.

For research in Type 2 diabetes, or Alzheimers or Parkinsons, having this simple platform to perform these tests at a fraction of the cost of whats required for fluorescence or neutron scattering would be very useful.

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