Plumes in the sleeping avian brain

When we drift into deep slow-wave sleep (SWS), waves of neuronal activity wash across our neocortex. Birds also engage in SWS, but they lack this particular brain structure. Researchers from the Max Planck Institute for Ornithology in Seewiesen, Germany together with colleagues from the Netherlands and Australia have gained deeper insight into the sleeping avian brain. They found complex 3D plumes of brain activity propagating through the brain that clearly differed from the two-dimensional activity found in mammals. These findings show that the layered neuronal organization of the neocortex is not required for waves to propagate, and raise the intriguing possibility that the 3D plumes of activity perform computations not found in mammals.

Mammals, including humans, depend upon the processing power of the neocortex to solve complex cognitive tasks. This part of the brain also plays an important role in sleep. During SWS, slow neuronal oscillations propagate across the neocortex as a traveling wave, much like sports fans performing the wave in a stadium. It is thought that this wave might be involved in coordinating the processing of information in distant brain regions. Birds have mammalian-like cognitive abilities, but yet different neuronal organization. They lack the elegant layered arrangement of neurons characteristic of the neocortex. Instead, homologous neurons are packaged in unlayered, seemingly poorly structured nuclear masses of neurons.

Researchers from the Max Planck Institute for Ornithology in Seewiesen together with colleagues from the Netherlands and Australia now investigated in female zebra finches how brain activity changed over space and time during sleep. “When we first looked at the recordings, it appeared that the slow waves were occurring simultaneously in all recording sites. However, when we visualized the data as a movie and slowed it down, a fascinating picture emerged!” says Gabriël Beckers from Utrecht University, who developed the high-resolution recording method at the Max Planck Institute for Ornithology in Seewiesen. The waves were moving across the two-dimensional recording array as rapidly changing arcs of activity. Rotating the orientation of the array by 90 degrees revealed similar patterns, and thereby established the 3D nature of the plumes propagating through the brain. The researchers found similar patterns in distant brain regions involved in processing different types of information, suggesting that this type of activity is a general feature of the sleeping avian brain.

In addition to revealing how neurons in the avian brain behave during sleep, this research also adds to our understanding of the sleeping neocortex. “Our findings demonstrate that the traveling nature of slow waves is not dependent upon the layered organization of neurons found in the neocortex, and is unlikely to be involved in functions unique to this pattern of neuronal organization,” says Niels Rattenborg, head of the Avian Sleep Group in Seewiesen. “In this respect, research on birds refines our understanding of what is and is not special about the neocortex.” Finally, the researchers wonder whether the 3D geometry of wave propagation in the avian brain reflects computational properties not found in the neocortex. While this idea is clearly speculative, the authors note that during the course of evolution, birds replaced the three-layered cortex present in their reptilian ancestors with nuclear brain structures. “Presumably, there are benefits to the seemingly disorganized, nuclear arrangement of neurons in the avian brain that we are far from understanding. Whether this relates to what we have observed in the sleeping bird brain is a wide open question,” says Rattenborg.

Brain development provides insights into adolescent depression

Lead research Professor Nick Allen from the Melbourne School of Psychological Sciences said, “It is well known that the brain continues to change and remodel itself during adolescence as part of healthy development.”

“In this study, we found that the pattern of development (such as changes in brain structure between ages twelve to sixteen) in several key brain regions differed between depressed and non-depressed adolescents,” Professor Allen said.

The brain regions involved include areas associated with the experience and regulation of emotion, as well as areas associated with learning and memory. 



“The findings are an important breakthrough for exploring possible causes of depression in adolescence. They also suggest that both prevention and treatment for depression (even for early signs and symptoms of depression) in adolescence is essential, especially targeting those in the early years of adolescence aged twelve to sixteen,” he said.

“We also observed some differences between males and females. For males, less growth in an area of the brain involved in processing threat and other unexpected events that is a critical part of the brain’s fear circuitry, was associated with depression. On the other hand, for females, greater growth of this area was found to be associated with depression.” 



“This is important information because depression becomes much more common amongst girls during adolescence, and these findings tell us about some of the neurobiological factors that might play a role in this gender difference,” he said.

Professor Allen says adolescence is a period during the lifespan where risk for developing depression dramatically increases.

The study examined eighty-six adolescents (41 female) with no history of depressive disorders before age 12 by using a Magnetic Resonance Imaging (MRI) scanner, which allowed researchers to measure the volume of particular brain regions of interest. 

Participants underwent an MRI scan first at age twelve and again at age sixteen, when rates of depression were beginning to increase. 

Researchers also conducted detailed interviews with each of the participants at four different time points between age twelve and age eighteen. Thirty participants experienced a first episode of a depressive disorder during the follow-up period.

These findings have recently been published in the American Journal of Psychiatry.

Yeast model reveals Alzheimer’s drug candidate and its mechanism of action

Using a yeast model of Alzheimer’s disease (AD), Whitehead Institute researchers have identified a drug that reduces levels of the toxic protein fragment amyloid-β (Aβ) and prevents at least some of the cellular damage caused when Ab accumulates in the brains of AD patients.

“We can use this yeast model to find small molecules that will address the underlying cellular pathologies of Alzheimer’s, an age-related disease whose burden will become even more significant as our population grows older,” says Kent Matlack, a former staff scientist in Whitehead Member Susan Lindquist’s lab. “We need a no-holds-barred approach to find effective compounds, and we need information about their mechanism of action quickly. Our work demonstrates that using a yeast model of Ab toxicity is a valid way to do this.”

The U.S. National Institute on Aging estimates that 5.1 million Americans may have AD, the most common form of dementia, which progressively robs patients of their memories, thinking, and reasoning skills. Research focused on the disease has been hampered by the affected cells’ location in the brain, where they cannot be studied until after an AD patient’s death. To explore the cellular processes compromised by AD, researchers in Lindquist’s lab created a yeast model, first described in the journal Science in 2011, that mimics in vivo the accumulation of Aβ that occurs in the human disease.

In the current research, which is described in this week’s issue of the journal Proceedings of the National Academy of Sciences (PNAS), a team of scientists in Lindquist’s lab used the yeast model to screen approximately 140,000 compounds to identify those capable of rescuing the cells from Aβ toxicity. One of the more promising classes of compounds has previously shown efficacy in animal models of AD and is about to complete a second phase II trial for AD. The mechanism by which the best-studied member of this class, clioquinol, targets Ab within the cell – where a large portion of it is produced in neurons – was unclear.  

“Our work in the yeast model shows that clioquinol decreases the amount of Aβ in the cells by 90%,” says Daniel Tardiff, a scientist in Lindquist’s lab. “That’s a strong decrease, and it’s dose-dependent. I’ve tested a lot of compounds before, and I’ve never seen anything as dramatic.”

Clioquinol chelates copper, meaning that it selectively binds the metal. In many AD patients, Aβ aggregates have higher concentrations of copper and other metals than normal, healthy brain tissue. Biochemical experiments also show that copper makes Aβ more toxic.

With clioquinol’s chelation capabilities in mind, Tardiff and Matlack, co-authors of the PNAS paper, tested clioquinol’s effect on Aβ-expressing cells in the presence of copper. The drug dramatically increased the degradation of Aβ in a copper-dependent manner, and even restored the cellular protein-trafficking process known as endocytosis, which is disrupted in both the yeast model and in AD-affected neurons.

“The clioquinol probably has a slightly higher affinity for copper than Aβ does, but it is not a strong enough chelator to strip the cell’s normal metalloproteins of the copper they need,” says Matlack. “From what we’ve seen in the yeast model, we think the drug pulls the copper away from Aβ. That would alter Aβ’s structure and likely make it more susceptible to degradation, thus shortening its half-life in the cell.”

The results from clioquinol in yeast and the clinical potential of closely related compounds are promising. While these compounds are not yet ready to serve as AD drugs in the clinic, the identification of an AD-relevant compound and cellular pathology – along with the Lindquist lab’s previous identification of human AD risk alleles that reduce Ab toxicity in yeast – suggests that this discovery platform will continue to yield information and lead to more compounds with equal or greater effectiveness, some of which will hopefully make a difference in human disease.

“It is important to remember that this class of compounds was shown to work in mouse models and in a limited human trial,” says Lindqust, who is also a professor of biology at MIT and an investigator of the Howard Hughes Medical Institute. “We have validated the yeast model and shown that we can find such compounds at a speed that was inconceivable before—indeed we found some compounds that look even more effective.”

Research reveals first glimpse of a brain circuit that helps experience to shape perception

Odors have a way of connecting us with moments buried deep in our past. Maybe it is a whiff of your grandmother’s perfume that transports you back decades. With that single breath, you are suddenly in her living room, listening as the adults banter about politics. The experiences that we accumulate throughout life build expectations that are associated with different scents. These expectations are known to influence how the brain uses and stores sensory information. But researchers have long wondered how the process works in reverse: how do our memories shape the way sensory information is collected?

In work published today in Nature Neuroscience, scientists from Cold Spring Harbor Laboratory (CSHL) demonstrate for the first time a way to observe this process in awake animals. The team, led by Assistant Professor Stephen Shea, was able to measure the activity of a group of inhibitory neurons that links the odor-sensing area of the brain with brain areas responsible for thought and cognition. This connection provides feedback so that memories and experiences can alter the way smells are interpreted. 

The inhibitory neurons that forget the link are known as granule cells. They are found in the core of the olfactory bulb, the area of the mouse brain responsible for receiving odor information from the nose. Granule cells in the olfactory bulb receive inputs from areas deep within the brain involved in memory formation and cognition. Despite their importance, it has been almost impossible to collect information about how granule cells function. They are extremely small and, in the past, scientists have only been able to measure their activity in anesthetized animals. But the animal must be awake and conscious in order to for experiences to alter sensory interpretation. Shea worked with lead authors on the study, Brittany Cazakoff, graduate student in CSHL’s Watson School of Biological Sciences, and Billy Lau, Ph.D., a postdoctoral fellow. They engineered a system to observe granule cells for the first time in awake animals. 

Granule cells relay the information they receive from neurons involved in memory and cognition back to the olfactory bulb. There, the granule cells inhibit the neurons that receive sensory inputs. In this way, “the granule cells provide a way for the brain to ‘talk’ to the sensory information as it comes in,” explains Shea. “You can think of these cells as conduits which allow experiences to shape incoming data.”

Why might an animal want to inhibit or block out specific parts of a stimulus, like an odor? Every scent is made up of hundreds of different chemicals, and “granule cells might help animals to emphasize the important components of complex mixtures,” says Shea. For example, an animal might have learned through experience to associate a particular scent, such as a predator’s urine, with danger. But each encounter with the smell is likely to be different. Maybe it is mixed with the smell of pine on one occasion and seawater on another. Granule cells provide the brain with an opportunity to filter away the less important odors and to focus sensory neurons only on the salient part of the stimulus. 

Now that it is possible to measure the activity of granule cells in awake animals, Shea and his team are eager to look at how sensory information changes when the expectations and memories associated with an odor change. “The interplay between a stimulus and our expectations is truly the merger of ourselves with the world. It exciting to see just how the brain mediates that interaction,” says Shea.

A sparse memory is a precise memory

Particular smells can be incredibly evocative and bring back very clear, vivid memories.

Maybe you find the smell of freshly baked apple pie is forever associated with warm memories of grandma’s kitchen. Perhaps cut grass means long school holidays and endless football kickabouts. Or maybe catching the scent of certain medicines sees you revisit a bout of childhood illness.

What’s remarkable about the power of these ‘associative memories’ – connecting sensory information and past experiences – is just how precise they are. How do we and other animals attach distinct memories to the millions of possible smells we encounter?

There’s a clear advantage in doing so: accurately discriminating smells indicating dangers while making no mistakes in following those that are advantageous. But it’s a huge information processing challenge.

Researchers at Oxford University’s Centre for Neural Circuits and Behaviour have discovered that a key to forming distinct associative memories lies in how information from the senses is encoded in the brain.

Their study in fruit flies for the first time gives experimental confirmation of a theory put forward in the 1960s which suggested sensory information is encoded ‘sparsely’ in the brain.

The idea is that we have a huge population of nerve cells in many of our higher brain centres. But only a very few neurons fire in response to any particular sensation – be it smell, sound or vision. This would allow the brain to discriminate accurately between even very similar smells and sensations.

'This “sparse” coding means that neurons that respond to one odour don't overlap much with neurons that respond to other odours, which makes it easier for the brain to tell odours apart even if they are very similar,' explains Dr Andrew Lin, the lead author of the study published in Nature Neuroscience.

While previous studies have indicated that sensory information is encoded sparsely in the brain, there’s been no evidence that this arrangement is beneficial to storing distinct memories and acting on them.

'Sparse coding has been observed in the brains of other organisms, and there are compelling theoretical arguments for its importance,' says Professor Gero Miesenböck, in whose laboratory the research was performed. 'But until now it hasn’t been possible experimentally to link sparse coding with behaviour.'

In their new work, the researchers demonstrated that if they interfered with the sparse coding in fruit flies – if they ‘de-sparsened’ odour representations in the neurons that store associative memories – the flies lost the ability to form distinct memories for similar smells.

The flies are normally able to discriminate between two very similar odours, learning to avoid one and head for the other. This is controlled by the neurons that store associative memories, called Kenyon cells. There’s a separate nerve cell that acts as a control system to dampen down the activity the Kenyon cells, preventing too many of them from firing for any particular odour.

Dr Lin and colleagues showed that if this single nerve cell is blocked, the odour coding in Kenyon cells becomes less sparse and less able to discriminate between smells. The flies end up attaching the same memory to similar, yet different, odours.

Sparse coding does turn out to be important for sensory memories and our ability to act on them. Although the research was carried out in fruit flies, the scientists say sparse coding is likely to play a similar role in human memory.

Although sparse coding in the brain would seem to require much greater numbers of nerve cells, that cost appears to be worth it in being able to form distinct associative memories and act on them – thankfully. A life of experiences and memories is so much more full as a result.

Researchers reveal the dual role of brain glycogen

In 2007, in an article published in Nature Neuroscience, scientists at the Institute for Research in Biomedicine (IRB Barcelona) headed by Joan Guinovart, an authority on glycogen metabolism, suggested that in Lafora Disease (LD), a rare and fatal neurodegenerative condition that affects adolescents, neurons die as a result of the accumulation of glycogen—chains of glucose. They went on to propose that this accumulation is the root cause of this disease.

The breakthrough of this paper was two-sided: first, the researchers established a possible cause of LD and therefore were able to point to a plausible therapeutic target, and second, they discovered that neurons have the capacity to store glycogen—an observation that had never been made—and that this accumulation was toxic.

Other reports defended a different theory and upheld that the glycogen deposits were not cause by the neurodegeneration but were a consequence of another, more important, cell imbalance, such as a down deregulation of autophagy—the cell recycling and cleaning programme. In several articles, Guinovart’s “Metabolic engineering and diabetes therapy” group has recently brought to light evidence of the toxicity of glycogen deposits for LD patients, and has now provided irrefutable data.

In an article published at the beginning of February in Human Molecular Genetics, with the research associate Jordi Duran as first author, the scientists show that in LD the accumulation of glycogen directly causes neuronal death and triggers cell imbalances such a decrease in autophagy and synaptic failure. All these alterations lead to the symptoms of LD, such as epilepsy.

Glycogen, a Trojan horse for neurons?

There was still a greater mystery to be solved. Was glycogen synthase truly a Trojan horse for neurons, as apparently established in the article in Nature Neuroscience? That is to say, was the accumulation of glycogen always fatal for cells, thus explaining why their glycogen synthesis machinery is silenced? The inevitable question was then why these cells had such machinery.

In another paper published in Journal of Cerebral Blood Flow & Metabolism, part of the Nature Group, the researchers provided the first evidence that neurons constantly store glycogen but in a different way: accumulating small amounts and using it as quickly as it becomes available. In this regard, the scientists set up new, more sensitive, analytical techniques to confirm that the machinery responsible for glycogen synthesis and degradation existed. In summary, they showed that, in small amounts, glycogen is beneficial for neurons.

“For example, while the liver accumulates glycogen in large amounts and releases it slowly to maintain blood sugar levels, above all when we sleep, neurons synthesize and degrade small amounts of this polysaccharide continuously. They do not use it as an energy store but as a rapid and small, but constant, source of energy,” explains Guinovart, also senior professor at the University of Barcelona (UB).

To observe the action of glycogen, the scientists forced cultured mouse neurons to survive under oxygen depletion. They demonstrated that the first cells to die were those in which the capacity to synthesise glycogen had been removed. The same experiments were performed in collaboration with Marco Milán’s “Development and growth control” group in the in vivo model of the fruit fly Drosophila melanogaster. These tests led to the same conclusions.

The researchers postulated that glycogen is a lifeguard under oxygen depletion, a condition that leads the brains to shut down and that often occurs at birth and in cerebral infarctions in adults, which leads to severe consequences, such a cerebral paralysis.

“It is the first function of glycogen that we have discovered in neurons, but we still have to identify its function in normal conditions and establish how the mechanism works,” says Jordi Duran. Postdoctoral researcher Isabel Saez is the first author of the article out today, which involved the collaboration of ICREA Research Professor Marco Milán’s lab.

The beneficial and toxic roles of brain glycogen are currently the focus of main research lines conducted by Joan Guinovart’s lab.