When we form a memory, brain cells need to deliver supplies to strengthen specific neural connections. A new study from MPFI and Weill Cornell Medicine has revealed how two cellular switches, Rab4 and Rab10, direct supplies to where they are needed.

Key Findings

• New tools track cellular supply routes: Scientists created biosensors to measure Rab proteins, cellular switches that direct the delivery of supplies inside cells. Beyond the findings in this paper, these sensors allow observation of the activity along complex supply routes, critical for many cellular functions.
• Rab4 provides a boost in the first minutes: During the strengthening of neuronal connections, Rab4 is activated, rapidly delivering the necessary supplies.
• Rab10 acts a brake: Rab10 shunts supplies away from the neural connection and is turned off for more than 30 minutes to enhance the strengthening of neural connections.
• Broader impacts: As Rab10 gene variants are linked to resilience against Alzheimer’s Disease, these findings are critical to further research into strategies to protect memories in dementia.

When we form a memory, specific, highly active connections between our neurons are strengthened through a process called synaptic potentiation. This strengthening involves structural changes to physically enlarge the connection and make it more responsive to incoming messages. Accomplishing this requires a complex logistical operation within the neuron to quickly and precisely deliver the necessary supplies to remodel the strengthening connection.

Cellular Railroad Switches

A large family of cellular switches, known as Rab proteins, regulates the flow of supplies in cells. Like railroad switches, different Rab proteins direct supplies toward one destination or another. To examine how these cellular switches direct supplies during synaptic potentiation, the researchers developed biosensors to measure the activity of Rab switches and specific supplies needed for strengthening neural connections.

“These biosensors give us a window into how these molecular switches behave in real time, at the level of single spines,” said Dr. Jie Wang, lead author of the study. “By understanding which and how Rab proteins are regulated during synaptic potentiation, we can begin to understand the logistical complexity that is required to strengthen neuronal connections when we form a memory.”

The scientists found that changes in Rab4 and Rab10 switches were both critical during the strengthening of neural connections. However, the two switches worked in opposite directions. When Rab4 was activated, it boosted the strengthening of neural connections, whereas Rab10 activation decreased it.

“Our findings suggest that during synaptic plasticity, we have a local and coordinated logistical operation to rapidly turn on Rab4 to increase the delivery of supplies to the surface of the growing connection and at the same time turn off the Rab10 switch that might be directing supplies away from the surface and toward disposal,” describes MPFI scientific Director and senior author Dr. Ryohei Yasuda.

To directly test this idea, the scientists tracked the delivery of neurotransmitter receptors, a crucial supply for strengthening neural connections. These receptors receive the information sent from connected neurons. The more receptors present, the easier a message is received. The team found that when Rab4 was activated, more receptors were directed to the neural connection. On the other hand, activation of Rab10 directed these receptors away from the connection.

Relevance to Alzheimer’s Resilience

These discoveries reveal the critical role of Rab cellular switches in strengthening connections during memory formation. Because gene variants in Rab10 have also been implicated in providing resilience against Alzheimer’s disease, the work may point toward new strategies for protecting memory in neurodegenerative conditions.

“I am excited about the potential for the tools and findings from this project, particularly for Rab10, to advance studies in Alzheimer’s resilience and Rab10 as a potential as a therapeutic target,” described Dr. Yasuda.  “Beyond that, we have created a library of tools that will help us, and other scientists, study the complex logistical operations essential for all cellular functions.”

Just as rail switches guide freight trains to the right track, more than 60 different Rab proteins direct cellular cargo. The Yasuda lab is sharing these biosensors to provide scientists a way to watch cellular logistics in action.

Publication:

Wang, J., Nishiyama, J., Parra-Bueno, P., Okaz, E., Oz, G., Liu, X., Watabe, T., Suponitsky-Kroyter, I., McGraw, T. E., Szatmari, E. M., & Yasuda, R. (2025). Rab10 inactivation promotes AMPAR trafficking and spine enlargement during long-term potentiation. eLife, 13, RP103879. 10.7554/eLife.10387910.7554/eLife.103879).

This work was supported by grants from Japan Society for the Promotion of Science Overseas Research Fellowship, National Institute of Health, a donation from the Luen Fung Group and the Max Planck Florida Institute for Neuroscience. This content is solely the authors’ responsibility and does not necessarily represent the official views of the funders.

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Summary:

• Birds, unlike humans, can sleep deeply with both halves of their brains (symmetrically) or with one half sleeping lighter than the other (asymmetrically).
• Study of European jackdaws led by an international team of researchers shows that when sleep-deprived, jackdaws were more likely to fall into deep sleep with both brain halves at the expense of keeping one half vigilant – especially early in the night, when the need to recover is greatest.
• Observing how birds navigate the trade-off between vigilance and sleep may help scientists better understand how sleep loss affects brain function more broadly, including in us.

As most people who have pulled an all-nighter will agree, lost sleep can leave us feeling foggy and far from our best. In some ways, birds respond similarly, often sleeping longer and more deeply after sleep loss. But unlike humans, birds can sleep with one eye open, keeping one half of the brain somewhat alert while the other sleeps deeply. This balance between vigilance and deep sleep helps them stay aware of danger while still getting some much-needed shut-eye. However, a new study of European jackdaws shows that this strategy has its limits: when sleep-deprived, these clever, social birds were more likely to fall into deep sleep in both brain halves – even at the cost of losing vigilance. The findings offer new insight into sleep and the consequences of going without it.

Keeping an eye out

Sleep is essential across the animal kingdom, but there is wide variation in how it happens. When humans sleep, our brains cycle through stages, alternating between rapid eye movement (REM) sleep and non-REM sleep roughly every 90 minutes. Birds go through these same stages, but typically in much shorter bursts – and their sleep patterns are far more flexible than ours. One weapon in their sleep armory is the ability to sleep with one eye open during non-REM sleep, a state known as asymmetric sleep. This is characterized by light sleep in the brain half connected to the open eye and deep sleep in the brain half connected to the closed eye. It allows birds, such as ducks, to keep one side of the brain more alert while the other enters a deeper state of sleep.

Non-REM sleep is thought to play a key role in memory consolidation and clearing waste from the brain. However, recharging one brain hemisphere with one eye open takes longer than resting both sides together in deep, symmetrical sleep. Scientists are still uncovering when, how, and why birds rely on this nap-time balancing act.

The new study of European jackdaws, led by researchers at the Max Planck Institute for Biological Intelligence and the Groningen Institute for Evolutionary Life Sciences, reveals a trade-off between getting sleep and staying alert. The findings, which tracked sleep patterns across several brain regions in nine jackdaws, are published today in Current Biology.

Previous studies have shown how birds and some other animals use adaptable, vigilant sleep strategies to stay alert in challenging situations – from great frigatebirds sleeping asymmetrically mid-flight, to mallard ducks keeping one eye open when vulnerable on the outer edge of their group, to northern fur seals sleeping asymmetrically when in the water. Even humans – who do not sleep with one eye open – tend to sleep more lightly with the left half of the brain on the first night in a new environment. This new research reveals where such strategies fall short: sleep-deprived jackdaws spent more time in deep, symmetrical sleep, while asymmetric sleep became less common – especially early in the night, when the need to recover is greatest.

“Sleep is a dangerous part of life for many animals, as it leaves them exposed to all kinds of risks,” says Niels Rattenborg, group leader at the Max Planck Institute for Biological Intelligence. “Some birds can function surprisingly well on far less sleep than we can, but even that strategy appears to have its limits. We have found that when they’re tired, jackdaws are more likely to sleep deeply – even if that means becoming more vulnerable. Observing how birds navigate the trade-off between vigilance and sleep may help us better understand sleep in general.”

Tracking tiredness

To investigate how European jackdaws recover from sleep loss – and how they switch between symmetric and asymmetric sleep – researchers studied nine birds using electroencephalograms (EEGs), which measure the activity of millions of neurons across the brain.

The researchers found that some brain areas slept more deeply than others, which may suggest that regions used more during wakefulness need deeper sleep. For example, not all parts of the jackdaws’ brains responded to sleep loss in the same way. Regions involved in vision and decision-making showed stronger signals after sleep deprivation, while others, like the memory-related hippocampus, were less affected.

“Our findings reveal that even the highly flexible sleep strategies used by jackdaws have limits,” says Peter Meerlo, a group leader at the Groningen Institute for Evolutionary Life Sciences. “That tells us something fundamental about sleep: it’s not just a passive state, but a behavior shaped by both evolution and environmental demands. The study offers a fresh perspective on how animals balance the need for sleep with the risk of predation or other threats – and could help us better understand how sleep loss affects brain function more broadly, including in humans.”

Sjoerd J. van Hasselt*, Dolores Martinez-Gonzalez*, Gert-Jan Mekenkamp, Alexei L. Vyssotski, Simon Verhulst, Gabriël J. L. Beckers, Niels C. Rattenborg$, Peter Meerlo$
*, $ These authors contributed equally.
Sleep pressure causes birds to trade asymmetric sleep for symmetric sleep. Current Biology, online 31 March, 2025 Link

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Researchers from the Max Planck Institute of Psychiatry asked themselves which genetic variants might be involved in the response to stress. Using a new methodology, they were able to test over 3600 specific variants in parallel to determine which were functional. This pioneering study on the molecular level of stress found that the genetic variants that modulate sensitivity to the consequences of stress have an effect on the risk of psychiatric disorders.

The interaction of genes and the environment is critical in modulating the risk of developing psychiatric disorders. This has been known for many years. Stress is one of the most relevant environmental factors. But why are some people able to deal well with stress and stressful life events, while others go on to develop psychiatric disorders? That is a question on everyone’s mind. Scientists from the MPI of Psychiatry (MPI) approached this question on a molecular level. They used new molecular genetic and statistical techniques to look at many genetic variants simultaneously, in order to understand how they affect cells in their reaction to stress.

Led by postdoc, and the study’s first author, Signe Penner-Goeke, the team at the MPI used statistical methods that allowed them to better understand how these variants work in the brain and even allowed them to predict causal effects. The scientists modeled stress using dexamethasone, a synthetic molecule that mimics the effect of the stress hormone cortisol. Using cells that are known to be highly reactive to stress, they identified over 500 regions that responded to stress as well as 79 variants that affected gene expression only when treated with dexamethasone. Findings showed that some of the variants had an effect on the risk of developing psychiatric disorders: “We found a number of variants associated with psychiatric disorders,” states Penner-Goeke.

Stress tests

Researchers at MPI then sought to identify how the combination of variants modulated risk. In an experiment where they stressed individuals in a stress task, findings showed that a higher number of variants were associated with an increase in cortisol. This difference was not seen before the stress task, meaning these variants were only relevant in stressful situations. Another test indicated that individuals with more risk variants had a more intense reaction when startled. These individuals also showed an increased amplitude of being startled with repeated exposures.

This is the first study explaining the molecular level of stress: The genetic variants that modulate the physiological response to stress are involved in the risk of psychiatric disorders. “Genetics have an effect on the sensitivity to the consequences of stress. This molecular mechanism could explain why stressful life events correlate more or less with psychiatric disorders,” MPI´s director Elisabeth Binder summarizes. These findings are essential for predicting which individuals may have a higher risk for developing psychiatric disorders in response to stress, which could be harnessed to better prevent and treat psychiatric disorders.

Signe Penner-Goeke et al: High-throughput screening of glucocorticoid-induced enhancer activity reveals mechanisms of stress-related psychiatric disorders PNAS, 2023 Link

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The mineral calcium is a crucial building block of countless body functions. For many processes, calcium flows selectively from the cells’ surroundings into them. However, the behavior of calcium concentrations in the important extracellular area has hardly been studied so far due to a lack of methods. Now, after years of development, a team led by Oliver Griesbeck of the Max Planck Institute for Biological Intelligence is providing sensors that close this gap.

***

Calcium is important for bones, teeth and muscles. Yet, calcium also plays a crucial role in the nervous system: If, for example, an impulse is to be passed on from one nerve cell to the next, voltage-dependent calcium channels open and the mineral compound flows into the nerve cell from the nearby environment. In response to this increase in calcium, the cell releases so-called neurotransmitter molecules that can activate a downstream neuron. In this way, a message can be transmitted from one cell to the next.

What calcium does inside a cell has been quite well investigated. The calcium occurrence outside the cells, on the other hand, was mostly noted as “present” and then largely ignored. This was not least due to the fact that – especially in the brain – the interstitial spaces between cells are often very narrow, widely branched, and sometimes partially divided into individual subspaces. Together with the fact that there were hardly any suitable tools for detecting calcium outside cells, detailed investigations were almost impossible.

“For a comprehensive understanding of calcium functions in the body, it is important to be able to study the interplay of calcium deposits both inside and outside cells directly in the tissue. We therefore developed genetically encoded biosensors that can be used to measure calcium in the often difficult-to-access intercellular spaces,” relates Oliver Griesbeck, head of a research group at the Max Planck Institute for Biological Intelligence.

What sounds almost simple when told by Oliver Griesbeck is the result of years of work. Time and again, he and his colleagues had to optimize the newly developed sensors to meet all the requirements. After all, the sensors not only have to work reliably at the much higher calcium concentrations outside cells; they also have to be sensitive enough to indicate a change in concentration here with a large fluorescence change. This is exactly what the team has now achieved with the new GreenT-EC biosensors.

The newly developed GreenT-EC biomolecules are produced by a genetically modified organism itself. If the molecules are transported to the extracellular space, the sensors fluoresce bright green due to the high calcium concentration in this environment. A change in concentration here is then indicated by measurable changes in fluorescence.

“It was quite impressive when we were finally able to really observe the dynamics of calcium concentrations outside cells,” recalls Oliver Griesbeck. The team has already tested the new sensors in various animal species, where they worked reliably. “Now we hope that the sensors will be used in a wide variety of studies, providing answers to the many unanswered questions about the movement of calcium in the body.”

Ariel A. Valiente-Gabioud, Inés Garteizgogeascoa Suñer, Agata Idziak, Arne Fabritius, Jérome Basquin, Julie Angibaud, U. Valentin Nägerl, Sumeet Pal Singh, Oliver Griesbeck; Fluorescent Sensors for Imaging of Interstitial Calcium; Nature Communications, online 5. Oct. 2023. Link.

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A new computer program allows scientists to observe the behavior of multiple animals simultaneously and over extended periods, while automatically analyzing their motion. What may seem obvious marks a significant milestone, and paves the way for robust and accessible standardization and evaluation of such complex observations.

Imagine a researcher in the 19th century wearing a pith helmet, observing animals in their natural habitat. Or envision Konrad Lorenz, a veteran of the Max Planck Society, in the 1970s closely following his gray geese near Lake Starnberg – the beginning of behavioral research involved observing and recording what one sees. The next step took place in the laboratory, where standardized environments were created to establish comparability. Researchers gained invaluable insights, but there were always limitations: the environment and test setup, the number of animals, and the duration of the observations did not correspond to the complexity of certain natural behaviors, either individual or social. Moreover, observing animal behavior aims not only to better understand how specific species react to given stimuli, but also to help researchers better define mental disorders in humans in order to provide improved and individualized treatment.

A few years ago, scientists achieved a breakthrough using the open-source toolbox DeepLabCut. They were not only able to track the center point of individual animals in simple environments but also automatically detect the complex body posture of multiple animals in real-world environments. This paved the way for the development of new tools capable of extracting information from these data, as capturing posture is not the same as analyzing the underlying behaviors.

Linking movement to behavior

Two research groups at the Max Planck Institute of Psychiatry took on this task. The teams led by Mathias V. Schmidt and Bertram Müller-Myhsok developed a Python package called DeepOF, which links the position of individual body markers over time with behavioral patterns. This allows them to analyze the behavior of animals, in their case mice, in a semi-natural environment in detail over any desired timeframe. Two different approaches are used. In a supervised analysis pipeline, behaviors are predefined based on body postures over time, and the obtained data can be directly read and analyzed. “Even more exciting is the unsupervised analysis pipeline”, enthuses statistician Müller-Myhsok. “Our program searches for similar behavioral episodes and classifies them”, biologist Mathias Schmidt adds: “This approach opens up entirely new dimensions, enabling hypothesis-free automated investigation of complex social behavior and yielding highly interesting results”.

This type of tool opens up new possibilities and brings behavioral biology, in terms of complexity, to a level comparable to molecular or functional biological analysis methods. “In the future we can now better combine our results with other measurement dimensions, such as EEG recordings, neural activity data, or biosensor data”, reports biologist Joeri Bordes. Lucas Miranda, the author of the DeepOF program, is enthusiastic about “open science” because “our program is freely available to researchers around the world, our code is of course open, and anyone is welcome to contribute to the project”.

The scientific journal Nature Communications has given the program an independent seal of approval by publishing the teams’ study. Moreover, thorough code and functionality reviews were assessed by the Journal of Open Source Software (JOSS).

The program also represents an improvement for animal welfare, as the animals are subjected to fewer experiments. Ultimately, the detailed analysis of behavior through this new dimension represents a significant step towards better translating the data regarding the exploration of human diseases and their treatment.

Joeri Bordes, Lucas Miranda, Maya Reinhardt, Sowmya Narayan, Jakob Hartmann, Emily L. Newman, Lea Maria Brix, Lotte van Doeselaar, Clara Engelhardt, Larissa Dillmann, Shiladitya Mitra, Kerry J. Ressler, Benno Pütz, Felix Agakov, Bertram Müller-Myhsok & Mathias V. Schmidt. Automatically annotated motion tracking identifies a distinct social behavioral profile following chronic social defeat stress, Nature Communications, July 18, 2023. Link.

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Recognizing motion requires an enormous amount of computing power from the brain. A new study from Alexander Borst’s department at the Max Planck Institute for Biological Intelligence shows how the fly brain masters this task: By performing a neuronal computation on three network levels, it distributes the workload over several steps. This is the first time that researchers have deciphered a neuronal network in which one cell type performs the same computation at all network levels. This approach helps fruit flies to reliably recognize different motion patterns – the prerequisite for staying on track.

***

Fruit flies are masters at detecting motion, and they have to be: even the slightest gust of wind can throw such a small fly off its flight path. To stay on course, flies orient themselves to the optical flow. These are motion patterns that appear on a fly’s retina as it moves. Depending on its direction of motion, the patterns differ and tell the fly whether it is moving straight ahead or has turned around a certain axis.

Alexander Borst’s department studies motion vision in the fly brain at the level of small circuits. Here, ‘motion opponency’ plays a crucial role. Certain neurons are activated by motion in one direction and inhibited by motion in the opposite direction. In 2015, the researchers made a scientific breakthrough when they discovered so-called LPi cells as the cellular basis for this phenomenon.

Since then, the neuronal network of motion vision can be divided into three levels. As the first direction-selective cells, T4/T5 cells (first level) analyze a small image section. They forward their information to LPi cells (second level) and output cells (third level). LPi cells inhibit output cells that respond to opposite directions and are thus responsible for their motion opponency. This prevents output cells from being activated by non-specific signals. Output cells collect the signals from many T4/T5 cells and thus receive information about a larger image area. If their computations indicate that the fly is off course, a course correction is initiated.

By chance, the researchers now gained even more insights into this network. When Georg Ammer, first author of the study, tested new electrophysiology equipment, he chose LPi cells as ‘test objects’ and was suddenly confronted with completely unexpected measurement results. To get to the bottom of this observation, the neurobiologist and his colleagues combined various experimental methods, including voltage-sensitive dyes and the analysis of connectome data sets. They found that LPi cells exert their inhibitory function at all network levels. They inhibit not only output cells with opposite preferential directions, but also T4/T5 cells and other LPi cells. “We were very surprised by this result,” Georg Ammer reports. “Up to that point, we didn’t know any network in which the same neuronal computation is performed at each level and even by the same cell type.”

To the scientists, LPi cells seemed rather inconspicuous at first. Within the network, they contribute only about 5-10% of all synapses. However, electrophysiology experiments showed that these inhibitory synapses are very effective: They are about ten- to 20-fold stronger than activating synapses, so despite being outnumbered, they can cause similar voltage changes.

But why is the same computation done in three different places and not just once at the end? The researchers were able to explain this approach, which at first sounds rather cumbersome, with computer models. As the network filters out local noise already at the first two levels, it protects output cells from being overloaded with unimportant information and keeps them responsive to relevant information. This allows output cells to distinguish motion patterns with high sensitivity, even under difficult conditions.

Inhibition between two oppositely tuned channels, as in motion opponency, is a universal principle of neuronal networks. “It could well be that in other species and different brain regions the same computation is distributed across multiple levels and that this principle has great functional importance there as well,” Alexander Borst explains. Dividing difficult tasks into smaller bites is thus not only a helpful strategy in our everyday lives – neurons also benefit from this approach.

Georg Ammer, Etienne Serbe-Kamp, Alex S. Mauss, Florian G. Richter, Sandra Fendl, Alexander Borst; Multilevel visual motion opponency in Drosophila; Nature Neuroscience, online October, 2nd 2023. Link

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Animals possess specialized networks of neurons in the brain that receive signals about the outside world from the retina and respond by initiating appropriate behavior. Researchers at the Max Planck Institute for Biological Intelligence studied a genetic mutation in zebrafish that eliminates all connections between retina and brain throughout development. The team found that in these ‘deep-blind’ fish the brain circuits are fully functional, as direct brain stimulation with optogenetics can drive normal visual behavior. This shows that the assembly of the brain in zebrafish requires little, if any, visual experience.

***

Zebrafish, just like humans, rely heavily on vision: large parts of the brain are dedicated to processing visual information, and vision is crucial for the animal to find food and navigate its environment. Just like human babies, young zebrafish also learn from experience: They prefer familiar food and memorize where they found it. Underlying this process is the formation of new connections between brain cells and the refinement of old ones.

“When we study brain development, we broadly distinguish between innate and experience-dependent processes,” explains Herwig Baier, director at the Max Planck Institute for Biological Intelligence. “The assembly of neuronal circuits, for example in visual brain areas, is classically considered an experience-dependent process: the neuronal networks are thought to be shaped by visual inputs and neuronal activity.” But what happens if the visual information is never there in the first place?

To address this question, researchers have investigated how animals like fish or mice develop when they grow up in the dark. In this case, the brain is deprived of visual experience – but the eyes still send many signals to the brain. The retina normally converts patterns of photons that hit the back of the eye to patterns of electrical impulses, which are then transmitted to the brain by specialized cells with long axons called retinal ganglion cells. Retinal ganglion cells are the gatekeepers for the visual input that reaches the brain. Their activity pattern contains all the information that animals have about their visual surroundings. But this is not the only way in which the eye can talk to the brain.

During development, the retinal ganglion cells also generate their own neuronal activity. Sometimes, waves of electrical activity sweep across the retina’s entire surface, reach the central brain areas, and fine-tune the synaptic connections. In addition, the axons of retinal ganglion cells secrete molecular factors that are received by cells in the central brain and induce developmental changes. All these signals could potentially shape the circuitry of the brain. However, previous studies only looked at the effects of these factors in isolation and analyzed, for instance, how blindness affects brain development.

“To really understand how brain development depends on stimulation from the eyes, one needs to look at what happens when retinal ganglion cells are taken out of the equation,” says Shachar Sherman, lead author of a new study that investigated just this. To do so, the former graduate student in Herwig Baier’s department and his colleagues studied a zebrafish mutant known as lakritz. These mutants have a genetic defect that prevents retinal ganglion cells from forming. Importantly, the defects are restricted to the eye. If it weren’t for their dark color – “Lakritz” is the German word for licorice – one wouldn’t be able to tell the difference between mutants and their wildtype siblings.

Herwig Baier explains: “The lakritz mutant is not just blind; it is deep-blind. Its brain is entirely disconnected from the visual world and any retina-derived signals. This unique situation opened up the possibility to study the influence of retinal ganglion cells on brain development and behavior in a systematic and comprehensive fashion.”

The researchers raised young lakritz zebrafish and compared their brain development to zebrafish without the genetic defect. A virtual cell atlas of the zebrafish brain, developed in the department, helped to identify individual cells and to track their development. “To our surprise, we didn’t see much of a difference,” says Shachar Sherman. “In lakritz, all types of neuronal cells formed at the right place and numbers, only the speed of differentiation was slightly off.”

 

When zebrafish detect prey, their eyes send the information via retinal ganglion cells (black) to specialized brain networks. These networks activate muscles that move the zebrafish tail, causing the animal to turn towards the prey. In the lakritz mutant (bottom), retinal ganglion cells are missing. However, using laser light (blue arrow) and a zebrafish with genetically modified cells*, the researchers could activate the visual networks in the brain, which then elicited the same tail movements. The experiment confirmed that functional cell networks develop in the visual brain areas of young zebrafish even without any connections to the eyes.
* Marked here with a light green circle and labeled ChR2 for the expression of a protein called channelrhodopsin-2.
© Max Planck Institute for Biological Intelligence / Herwig Baier, Julia Kuhl

Given that the brains of lakritz zebrafish developed relatively normally, the researchers wanted to know if the fish are still able to perform behaviors usually triggered by vision. They looked at two such behaviors: orientation towards prey and so-called optokinetic eye movements, which are normally used to stabilize an image of the outside world.

“Since lakritz cannot see, they normally will never perform these behaviors, but the brain circuits might still be there waiting to act,” says Shachar Sherman. To test this, the team used optogenetics to directly activate the brain neurons that would normally become active when needed. Optogenetics is a technique that allows neuroscientists to introduce ‘light switches’ into the neurons of living brains. This way they can remotely control neuronal activity, provided they find ways to stimulate the neurons from the outside with light, a task made easy in zebrafish due to their small size and transparency. “Strikingly, lakritz reacted to the artificial stimuli as if they had actually seen a prey object,” recalls Shachar Sherman. “This shows us that the brain circuits required for these actions develop and function properly even when there is no input from the eyes at all.”

Taken together, the latest research from the Baier department shows that brain development is hardwired to a greater extent than previously thought. “Shachar’s work shows that a complex part of the vertebrate brain, with many dozens of cell types, can develop just fine without sensory inputs,” says Herwig Baier. “This highlights the power of genetically programmed algorithms in building the brain. If this works in zebrafish, why not also in larger animals?”

Future studies will tell how strongly the development of sensory systems across the animal kingdom depends on input from the outside; the eyes and visual brain areas are just one example. The more we know about these processes, the closer we will get to answering the philosophical question of ‘what’s nature and what’s nurture?’ – or, in other words, how much of our brain wiring is innate and how much of it depends on our biography. For now, at least in the zebrafish visual system, nature appears to be the winner.

Shachar Sherman, Irene Arnold-Ammer, Martin W. Schneider, Koichi Kawakami, Herwig BaierRetina-derived signals control pace of neurogenesis in visual brain areas but not circuit assembly Nature Communications, online 27 September 2023. Link

***

CONTACT:

Prof. Dr. Herwig Baier
Director
Max Planck Institute for Biological Intelligence
Martinsried
herwig.baier@bi.mpg.de

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Nightingales match the pitch of their whistle songs to those of their rivals in real time

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Dreams have been considered a hallmark of human sleep for a long time. The latest findings, however, suggest that when pigeons sleep, they might experience visions of flight. Researchers at Ruhr University Bochum and at the Max Planck Institute for Biological Intelligence studied brain activation patterns in sleeping pigeons, using functional magnetic resonance imaging. The study revealed that, similar to mammals, most of the brain is highly active during REM sleep. However, this wake-like state might come at a cost of reduced waste removal from the brain. The researchers published their findings in the journal Nature Communications on 5 June 2023.

***

During sleep, our brain undergoes a complex set of processes to ensure we wake up feeling refreshed. In humans, the different phases of sleep, rapid eye movement (REM) and non-REM sleep, are associated with distinct changes in physiology, brain activity, and cognition. For instance, during REM sleep, our brain is very active and we experience our most vivid, bizarre, and emotional dreams. During non-REM sleep, the brain is metabolically less active and clears out waste products by flushing cerebral spinal fluid through the brain’s ventricles – the interconnected chambers that surround the structures of the brain – and then through the brain. This process supposedly helps the body to remove harmful protein deposits from the brain, like those associated with the development of Alzheimer’s disease.

What happens in a pigeon’s brain during sleep?

The question of whether similar processes also take place in birds has remained unresolved until now. “The last common evolutionary ancestor of birds and mammals dates back about 315 million years, to the early days of land vertebrates,” says Professor Onur Güntürkün, head of the Biopsychology Department at Ruhr University Bochum. “Yet the sleep patterns in birds are remarkably similar to those in mammals, including both REM and non-REM phases.”

To find out what exactly happens when birds sleep, the researchers used infrared video cameras and functional magnetic resonance imaging (fMRI) to observe and record the sleeping and wakeful states of 15 pigeons specially trained to sleep under these experimental conditions.

The video recordings shed light on the sleep phases in the birds. “We were able to observe whether one or both eyes were open or closed and to track eye movements and changes in pupil size through the pigeons’ transparent eyelids during sleep,” explains Mehdi Behroozi from the Bochum team. Simultaneously, the fMRI recordings provided information about brain activation and the flow of cerebral spinal fluid in the ventricles.

Dreams of flying

“During REM sleep, we observed strong activity in brain regions responsible for visual processing, including in those areas that analyze the movement of a pigeon’s surroundings during flight,” says Mehdi Behroozi. The team also noticed activity in the areas that process signals from the body, especially from the wings. “Based on these observations, we think that birds, just like humans, dream during REM sleep, and might be experiencing flight in their dreams,” adds Mehdi Behroozi.

Additionally, the scientists noticed activation of a particular brain area known as the amygdala during these phases. “This suggests that if birds experience something similar to our human dreams, pigeons’ dreams might include emotions as well,” says Gianina Ungurean from the Avian Sleep Group at the Max Planck Institute for Biological Intelligence. This hypothesis is supported by the fact that the birds’ pupils contract rapidly during REM sleep, like they do during courtship or aggressive behaviors while awake, as recently demonstrated by Gianina Ungurean and colleagues.

Washing out the day’s dust

Like in humans, the flow of cerebral spinal fluid through ventricles increases during non-REM sleep in pigeons. However, the team discovered for the first time, in any animal, that the flow diminished dramatically during REM sleep.

“We think that the increased flood of blood into the brain during REM sleep, which supports the elevated brain activity, might block the cerebral spinal fluid from moving from the ventricles into the brain,” explains Niels Rattenborg, head of the Avian Sleep Group. “This suggests that REM sleep and its functions might come at the expense of waste removal from the brain.”

However, the scientists are also entertaining the possibility that REM sleep contributes to waste removal in unexpected ways. “At the onset of REM sleep, the influx of blood increases vessel diameter. This might force cerebral spinal fluid that entered the space surrounding the vessels during non-REM sleep to flow into the brain tissue, and enhance the outflow of fluids carrying waste products,” says Gianina Ungurean.

The researchers speculate that the process of cleaning the brain during sleep may be especially crucial for birds. Since their brains have a higher density of neurons in comparison to mammals, the removal of waste products may require more efficient – or more frequent – flushing cycles. As birds experience more and shorter REM phases during sleep than mammals, the associated frequent surge of blood might help to keep their densely packed brains free of harmful waste products.

Tell us about your dreams!

In the future, the team plans to explore REM sleep’s potential role in waste removal. In addition, they are thinking about ways to learn about the content of a pigeon’s dream. “We hope to train birds to report if and what they just saw upon awakening from REM sleep. That would be an essential step towards establishing whether they dream,” explains Gianina Ungurean.

But even without a detailed dream analysis, the new findings already help us to better understand the role of sleep in birds as well as in humans. They highlight the importance of sleep in maintaining a healthy brain and preventing cognitive decline – and they also imply that dreaming has a very long history.

Gianina Ungurean*, Mehdi Behroozi*, Leonard Böger, Xavier Helluy, Paul-Antoine Libourel, Onur Güntürkün, Niels C. Rattenborg. Wide-spread brain activation and reduced CSF flow during avian REM sleep. Nature Communications, online 5 June 2023. Link
* These authors contributed equally to this work

CONTACT:

Niels Rattenborg
Research Group Leader
Max Planck Institute for Biological Intelligence
Seewiesen
Email: niels.rattenborg@bi.mpg.de

The post When pigeons dream first appeared on Max Planck Neuroscience.

An orchestra of complex neuronal networks performs a symphonic masterpiece called vision – an exciting field for neurobiologists like Alexander Borst, director at the Max Planck Institute for Biological Intelligence. In his department’s latest study, the scientists found a microcircuit which inverts excitatory to inhibitory signals and is thus able to transform a single type of neuronal input for multiple purposes. The discovery of this microcircuit is an important puzzle piece for the better understanding of the visual process of the fruit flies Drosophila and ultimately of vision itself.

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Vision is one of the most important senses in humans. Accordingly, a large part of the brain is dedicated to processing visual information. In order to compute visual information quickly and accurately, a multitude of neuronal networks must perform a complex interplay – which fruit flies can help us to understand. Surprisingly, besides the obvious differences between the eyes of humans and fruit flies, many parallels can be found in the way how their brains process visual information. Since the visual system of flies is very efficient but significantly less complex than ours, it’s not surprising that this is one of the best understood neuronal networks in neuroscience.

In the flies’ visual system, a cascade of cells is responsible to transform light information into direction-specific signals. T4 cells, for example, respond to moving bright edges (ON-pathway), while T5 cells only respond to moving dark edges (OFF-pathway). Both, T4 and T5 cells have four subtypes that are tuned to the four cardinal directions (front-to-back, back-to-front, upwards and downwards). This means that each neuron only reacts to a specific direction of visual motion, their so-called preferred direction, while showing little reaction when stimulated by a moving edge in other directions (= null direction).

The mechanism to calculate direction selectivity in the ON-pathway has recently been deciphered by the department, leaving the exact implementation in the OFF-pathway yet to be understood. To this end, the scientists from Alexander Borst’s department developed a unique combination of calcium imaging with thermogenetic, optogenetic, and pharmacologic techniques to investigate the neuronal network underlying the OFF-pathway of Drosophila.

They found that several input neurons activate T5 cells when a signal moving in T5’s preferred direction is received. By suppressing or activating these input neurons, the scientists tested their role on how T5 cells compute direction. Taking together all the experiments, the team was able to confirm that the input neurons influence and shape the tuning of the T5 cells’ preferred direction.

In addition to activating input neurons, there are also inhibitory neurons, which reduce the outgoing signals of another cell. This is how all signals from directions other than the preferred direction is suppressed in T4 cells. Surprisingly, there are no such inhibitory neurons for T5 cells. This posed a mystery to the researchers: How does null direction suppression work in T5? In other words, how are these neurons able to react only to signals in their preferred direction without the inhibitory neurons?

The team led by Amalia Braun discovered a microcircuit underlying the T5 null direction suppression: CT1, an unusual large-field neuron, receives and inverses excitatory inputs, which leads to an inhibitory signal needed for null direction suppression. “By using genetic methods to remove single cell types, we could show that the tuning curve of a T5 cell’s direction detection substantially broadened when CT1 is gone. This could also be confirmed by using algorithmic modeling,” explains Amalia Braun. “Thus, while the excitatory neurons influence T5 cells directly for their preferred direction, an excitatory signal taking the detour via a CT1 cell inverting the signal leads to null direction suppression.”

With the discovery of this microcircuit, the department could once again add a new act to the complex symphonic composition of Drosophila’s visual system. “The CT1 microcircuit is a striking example for the multilayered and diverse mechanisms of inhibition and excitation in the brain, and how a neuronal network leverages a single type of signal for multiple purposes”, summarizes last author Matthias Meier.

The identification of this microcircuit, enabling and shaping motion detection, is substantially deepening our understanding of the visual processing of Drosophila – and ultimately of vision itself.

Amalia Braun, Alexander Borst, Matthias Meier. Disynaptic inhibition shapes tuning of OFF motion detectors in Drosophila. Current Biology, online 25 May 2023. Link

CONTACT:
Prof. Dr. Alexander Borst
Director
Max Planck Institute for Biological Intelligence
Martinsried
E-Mail: alexander.borst@bi.mpg.de

The post Fruit fly’s complex symphony of vision first appeared on Max Planck Neuroscience.