Tiny Molecule Could Help Diagnose and Treat Mental Disorders

English

 

According to the World Health Organization, such mood disorders as depression affect some 10% of the world’s population and are associated with a heavy burden of disease. That is why numerous scientists around the world have invested a great deal of effort in understanding these diseases. Yet the molecular and cellular mechanisms that underlie these problems are still only partly understood.

The existing anti-depressants are not good enough: Some 60-70% of patients get no relief from them. For the other 30-40%, that relief is often incomplete, and they must take the drugs for a long period before feeling any effects. In addition, there are many side effects associated with the drugs. New and better drugs are clearly needed, an undertaking that requires, first and foremost, a better understanding of the processes and causes underlying the disorders.
 
 
depression
 
The Weizmann Institute’s Prof. Alon Chen, together with his then PhD student Dr. Orna Issler, investigated the molecular mechanisms of the brain’s serotonin system, which, when misregulated, is involved in depression and anxiety disorders. Chen and his colleagues researched the role of microRNA molecules (small, non-coding RNA molecules that regulate various cellular activities) in the nerve cells that produce serotonin. They succeeded in identifying, for the first time, the unique “fingerprints” of a microRNA molecule that acts on the serotonin-producing nerve cells. Combining bioinformatics methods with experiments, the researchers found a connection between this particular microRNA, (miR135), and two proteins that play a key role in serotonin production and the regulation of its activities. The findings appeared today in Neuron.
 


The scientists noted that in the area of the brain containing the serotonin-producing nerve cells, miR135 levels increased when antidepressant compounds were introduced. Mice that were genetically engineered to produce higher-than-average amounts of the microRNA were more resistant to constant stress: They did not develop any of the behaviors associated with chronic stress, such as anxiety or depression, which would normally appear. In contrast, mice that expressed low levels of miR135 exhibited more of these behaviors; in addition, their response to antidepressants was weaker. In other words, the brain needs the proper miR135 levels – low enough to enable a healthy stress response and high enough to avoid depression or anxiety disorders and to respond to serotonin-boosting antidepressants. When this idea was tested on human blood samples, the researchers found that subjects who suffered from depression had unusually low miR135 levels in their blood. On closer inspection, the scientists discovered that the three genes involved in producing miR135 are located in areas of the genome that are known to be associated with risk factors for bipolar mood disorders.

These findings suggest that miR135 could be a useful therapeutic molecule – both as a blood test for depression and related disorders, and as a target whose levels might be raised in patients. Yeda Research and Development Co. Ltd., the technology transfer arm of the Weizmann Institute, has applied for a patent connected to these findings and recently licensed the rights to miCure Therapeutics to develop a drug and diagnostic method. After completing preclinical trials, the company hopes to begin clinical trials in humans.
 
Prof. Alon Chen is the Head of the Max Planck Society - Weizmann Institute of Science Laboratory for Experimental Neuropsychiatry and Behavioral Neurogenetics.

Prof. Alon Chen’s research is supported by the  Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics; the Perlman Family Foundation, Founded by Louis L. and Anita M. Perlman; the Adelis Foundation; the Irving I Moskowitz Foundation; the European Research Council; and the Ruhman Family Laboratory for Research in the Neurobiology of Stress.
 
depression
Life Sciences
English
  • Alon Chen
  • Anxiety
  • Depression
  • MicroRNA
  • Neurobiology
  • Neurotransmitter

A Break in the Signal

English

Our nerves respond to a range of stimuli

 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The story of the boy who cried “wolf” is more than just a fairy tale. In the story, the more he cried out, the less attention the villagers paid to his cries. That phenomenon, we now know, reflects a deeper biological reality: The nervous system cannot sustain attention at high levels of stimulation. Our sensory systems contain mechanisms for adapting, so that a few seconds after entering a crowded room we can carry on a conversation; we barely pause in our reading when someone turns on a light; and we cease to feel the clothing on our bodies seconds after we get dressed.  

Scientists think that this downward adjustment of the nerves’ responses helps them cope with the gap between the huge physical range of stimuli they must take in and their limited abilities when it comes to processing them. For example, a loud sound can be thousands of times the intensity of a weak one, whereas the nerve cells can vary the rate of their firing only on a scale of hundreds. By adapting to persistent environmental stimuli, the nerve cells are freed to function at their optimal activity range, both when responding to strong stimuli – such as the din of a train – or to much weaker inputs – say, a whisper.

This phenomenon has been demonstrated in the lab, with exposure to a stimulus that repeats periodically. After a short while, the nerve cells adapt and the signals they fire in response to the stimulus gradually diminish in strength. Research in the lab of Prof. Ilan Lampl of the Neurobiology Department, which recently appeared in the Journal of Neuroscience, takes the subject of adaptation one step further. Dr. Keti Cohen-Kashi, a postdoctoral fellow in his group, asked what happens when one interrupts the regular periodicity of the stimulus, even by a little.
 
(l-r) Dr. Keti Cohen-Kashi, Prof. Ilan Lampl and Boaz Mohar
 
She designed an experiment in which the activity of nerve cells in a part of the rats’ brains – the cortex – was monitored as their whiskers were exposed to a periodic stimulus. The repeating stimulus was then stopped and, after a short rest, a single stimulus – identical to those in the previous series – was given again. As expected, the firing of the nerve cells steadily faded – some three- to four-fold – as the periodic stimulus continued. The researchers’ surprise was in the response to the “unexpected” stimulus that followed: About a third of the monitored cells responded with a bang – three times the intensity of their maximal response to the original stimulus.
 
Lampl explains that the single, sudden stimulus “breaks” the adaptation. This mechanism may arise from our survival instincts: Adaptation leaves the sensory systems free to pick up on the unfamiliar, sudden surprises in our surroundings while ignoring the familiar background stimuli.
 
Although the research was done on rats, Lampl says that the findings may explain the results of certain experiments done with human volunteers. In one experiment conducted in Italy, the subjects experienced the stimuli on a finger. Like the rats in Lampl’s lab, these subjects received an additional, surprise stimulus, but this one was in a slightly different frequency and was sometimes applied to the corresponding finger of the other hand. The volunteers were then asked to guess whether the additional stimulus was identical to the previous set. It turns out that their answers were more accurate if the second stimulus was given on the same hand. The new study suggests that this is because some of the nerve cells in the brain that are connected to this hand may have had a stronger response to the second stimulus.
 

How is adaptation broken? To further understand the phenomenon, the scientists used a special recording method that enabled them to distinguish between two types of signal sent between cortical cells – one that excites a response and one that inhibits it. They found that it is actually the inhibitory signals that are responsible for the increased strength of the response the second time around. While the signals that excite the response have had a chance to return to their former levels over the rest period, the inhibitory signals, which have also dropped in magnitude with the repeated stimulus, are still only at partial strength. So it was the absence of inhibition that caused a stronger signal in some of the nerve cells.

 

neuron
 

Parallel paths


In an additional study in Lampl’s lab, which appeared in the Journal of Neuroscience, he and his team uncovered some clues to a long-standing question: If adaptation involves a drop in the nerves’ response to a periodic stimulus, how does the brain distinguish between signals that lessen in intensity due to internal adaptation and those that lessen because the signal from the external stimulus falls off (for example a receding train whistle)?

Research student Boaz Mohar used a new technique to insert electrodes deep into the brain – in the rats’ brainstem – to measure the electrical activity of a group of cells involved in the first stage of processing information from the whisker. These experiments showed that when the intensity of the stimulus is higher, the corresponding adaptation is slower and weaker. But then Mohar discovered a second group of cells responding to the stimuli. Surprisingly, in these cells, higher stimulus was tied to stronger and faster adaptation.   

Each group of cells represents the starting point of a different information-processing pathway, both of them leading to the higher levels of the brain, in the cortex. The existence of two, parallel paths for transferring sensory information may help the brain decide, by monitoring how fast the nerves’ responses fade, which of the two kinds of stimulus – adapation or ebbing – is being experienced.

According to Lampl, the mechanism of the first group of cells goes against conventional thinking. It has been supposed that at higher intensities the response of the nerve cells should fall off faster, as they would deplete their reserves more quickly; but the research findings show that this is not always the case. In his present research, Lampl is looking to see if the explanation might lie in interactions between the two pathways, as well as investigating how these pathways are involved in processing more complex, natural stimuli.
 
Prof. Ilan Lampl's research is supported by the  Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics; the Marianne Manoville Beck Laboratory for Research in Neurobiology in Honor of her Parents; the Jeanne and Joseph Nissim Foundation for Life Sciences Research; the Adelis Foundation; the estate of Dorothy Geller; and the estate of Florence and Charles Cuevas.


 
 
Our nerves respond to a range of stimuli
Life Sciences
English
  • Ilan Lampl
  • Nerve cell
  • Neurobiology
  • Sensory nerves
  • Sensory stimulus

New German-Israeli Laboratory Inaugurated at the Weizmann Institute

English

 

(l-r) Prof. Dr. Peter Gruss, President of the Max Planck Society, Prof. Daniel Zajfman, President of the Weizmann Institute with the signed agreement
 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
On Tuesday, March 4, 2014, a cooperation agreement was signed between the Max Planck Society and the Weizmann Institute of Science to inaugurate the Max Planck - Weizmann Laboratory for Experimental Neuropsychiatry and Behavioral Neurogenetics. The agreement was officially signed at the Weizmann Institute by Prof. Dr. Peter Gruss, President of the Max Planck Society, Prof. Daniel Zajfman, President of the Weizmann Institute, Dr. Ludwig Kronthaler, General Secretary of the Max Planck Society and Prof. Haim Garty, Vice President of the Weizmann Institute.

Prof. Alon Chen of the Weizmann Institute of Science will serve as head of the new Lab.
Prof. Alon Chen
 
The Laboratory will be addressing one of the looming issues of this century: the causes of cognitive, emotional, behavioral and neurological disorders. Some 450 million people worldwide suffer from some form of mental illness, and it is becoming increasingly clear that these disorders arise from a complex interplay between genetics and environment. The field of neuropsychiatry attempts to untangle this relationship, to understand the process by which genetic makeup and variations in physical brain structure lead to particular behaviors or mental illness.

Researchers from both institutes will be directly addressing such complex psychiatric disorders as depression, schizophrenia, anxiety and autism, using a wide range of multidisciplinary research methods, from the genomic and biochemical to the clinical. According to the agreement, the Laboratory will support joint research projects between scientists at the two institutes, host joint seminars and symposia, arrange exchanges of visiting scientists and students, and create opportunities for research students to get joint training.   

Prof. Alon Chen’s research is supported by the Nella and Leon Benoziyo Center for Neurological Diseases; the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics; Roberto and Renata Ruhman, Brazil; the Perlman Family Foundation, Founded by Louis L. and Anita M. Perlman; the Adelis Foundation; Marc Besen and the Pratt Foundation; the Irving I Moskowitz Foundation; and the European Research Council.
 
 
(l-r) Prof. Dr. Peter Gruss, President of the Max Planck Society, Prof. Daniel Zajfman, President of the Weizmann Institute with the signed agreement
Life Sciences
English
  • Alon Chen
  • Anxiety
  • Autism
  • Daniel Zajfman
  • Depression
  • Max Planck Society
  • Neurobiology
  • Schizophrenia

Writ Large – and Small

English
 
 
Writ Large – and Small

When you jot notes on a pad, you move different sets of muscles than when you write in large letters on a blackboard. Yet your handwritten a on the pad is formed with the same unique curves as the a on the blackboard. How does our brain encode the complex motions of writing? Does it employ a single set of instructions for both notepads and boards – or multiple ones? This question has been debated in neurobiology circles for a while; but a team of Weizmann Institute scientists that included both mathematicians and neurobiologists has now provided a surprising answer. Their results appeared recently in Neuron.


One of those scientists is research student Naama Kadmon Harpaz, whose work spans both mathematics and neurobiology. She began her graduate studies in the Neurobiology Department and is now in the Computer Science and Applied Mathematics Department  working in the group of Prof. Tamar Flash. Also participating in the study was neurobiologist Dr. Ilan Dinstein, a former postdoctoral fellow in Prof. Rafi Malach’s lab who is now on the faculty of Ben-Gurion University of the Negev.
 
To conduct their study, Kadmon Harpaz, Dinstein and Flash asked volunteers to trace out three letters, in both large and small versions, on a concealed touch screen. While the volunteers were writing, their brains were being scanned in the Institute’s functional magnetic resonance (fMRI) apparatus to capture the brain activation underlying the physical act. In addition, the team analyzed the movements themselves: the geometrical and temporal features of the writing and its kinematics (paths and speeds).

When the results were added together and analyzed, the findings were conclusive: Certain areas in the brain encode the act of writing both small and large letters in a highly similar way. In mathematical terms, the code is “scale invariant” – that is, the pattern of activation looks very similar for large and for small, fast and slow. A one-size-fits-all code meshes with earlier research which had suggested that, even though the muscles used are different, the basic kinematics of the movement when writing large or small are the same.
 
 
Top: Movement traces from single trials of three representative subjects. Orange and blue are small and large letters, respectively. Bottom: Mean movement traces after performing the Procrustes transformation (small mean is scaled to the size of the large mean) revealing a similarity in the path shape across scales

 
 
 
 

Simplified control

 
 
(l-r) Prof. Tamar Flash and Naama Kadmon
 

 

The fMRI results highlighted two areas of the brain that exhibited this “scale-invariant” encoding: One, called the anterior intraparietal sulcus (aIPS), is known to be important for such functions as hand-eye coordination and the planning of movement; the other, the primary motor cortex (M1), is thought to be the executor of the hand’s action. In the hierarchy of the brain, aIPS is said to be “upstream” – that is, it deals with more abstract information. Thus one might expect this brain area to encode symbols in a scale-invariant manner. But the scientists were surprised to find that the downstream area, M1 – thought to be a source of purely instantaneous neural commands for the more mechanical aspects of movement that are sent to the spinal cord and from there to the muscles – also encodes the ensuing action with scale invariance.
 
The researchers think that the encompassing scale invariance they identified acts to simplify the “control problem” and increases the efficiency of neural computation.  

Prof. Flash: “Concerning the generation of movement, the brain is thought to function from the top down, from abstract representation to physical output; yet we found this abstract coding in a supposedly downstream area. We think, on the one hand, that the brain is more of a network and less of a strictly top-down hierarchy than previously thought and, on the other hand, that our brain extends its abstract coding patterns to our seemingly concrete actions in the world around us.”
 
 
This experiment, say the researchers, is among the first to use fMRI to investigate motor control in humans. Most fMRI research looks at the brain’s reaction to such input as photos or video clips, while research into output – e.g., motor control – most often involves electrodes recording the activity of single or multiple neurons in non-human primates. By using fMRI to examine motor control in human subjects, says Dinstein, “we were able to see many areas in the brain at once. We could observe what each was doing in relation to the other.” 
 
According to Flash, these findings may have relevance for a number of areas of scientific research. For example, the insight they provide into the workings of the brain could be applied to robotics and bio-robotics to improve efficiency and enable a wide range of complex movements. In addition, they may aid in understanding those movement disorders that originate in the brain, among them Parkinson’s disease. They may also lead to a better understanding of the “motor memory” we use daily without a conscious thought. Further questions to be answered include: At what stage does learning to write enable a scale-invariant activity? How does such motor learning take place in the brain?    

Prof.Tamar Flash is the incumbent of the Dr. Hymie Moross Professorial Chair.
 
Life Sciences
English
  • Computer Science and Applied Mathematics
  • Neural code
  • Neurobiology
  • Rafael Malach
  • Scaling
  • Tamar Flash
  • fMRI

Taking Flight

English

bat in flight

 
 
 
 
When Dr. Michael Yartsev first got in touch with his soon-to-be mentor Dr. Nachum Ulanovsky, it was because he wanted to inquire about Ulanovsky’s own former PhD adviser, as he was thinking of applying for a PhD position in that adviser’s lab. But when Ulanovsky, a neurobiologist who was then finishing up his postdoc in the US, started talking about his own research and his plans for setting up a lab at the Weizmann Institute, says Yartsev: “I thought ‘this research program is risky, extremely innovative and exciting – which is exactly what I am looking for.’ That is how I became Nachum’s first student.”
Dr. Michael Yartsev
 
Yartsev, who grew up in Beersheba, completed his BSc and MSc in biomedical engineering at Ben-Gurion University of the Negev. There, he worked on recording the activity of single neurons in the cerebellum of awake, behaviorally active cats. By the time he completed his degrees, he says, he had fallen in love with neuroscience and was looking around for an exciting place to do his PhD. He decided to join Ulanovsky’s group even before the latter returned to Israel. “It just felt so right,” he says.

Ulanovsky works with bats, both in his lab in the Neurobiology Department and in the wild. His lab contains a darkened, soundproofed “bat cave” equipped with visible-range and infrared cameras and microphones that enable him and his team to investigate the bats’ highly developed spatial navigational abilities. The Egyptian fruit bats they work with, says Yartsev, “are extremely intelligent animals and, once they get used to you, they are also pretty friendly...at least most of them.” The key to working with these animals, he found, is to respect the fact that each individual bat has its own unique personality; acknowledging this is the key to getting their cooperation.
 
 
Yartsev’s research focused on two specialized classes of cells in the mammalian brain: the place-cells in the hippocampus and grid-cells in the entorhinal cortex. These cells are widely believed to be pivotal for spatial memory and navigation – whether in humans, rodents or any other mammals. While much of this research is done with rats, bats gave Ulanovsky’s group a unique advantage: They enabled the researchers to examine problems similar to those that rodent researchers have been grappling with for a long time, but from a completely different perspective – one that has turned out to be very useful. For example, questions such as the neural mechanisms of 3-D navigation have proved impossible to address using standard animal models.

In their first set of experiments with the bats (published in Nature in 2011), Yartsev and Ulanovsky investigated how the grid cells create a map-like network in the brain. In the process they disproved the most widely accepted class of computational models of grid cells – models that were based solely on rodent experiments. In a second set of experiments (published in Science in 2013), they used tiny, wireless devices to measure the activity of individual neurons in the bats’ brains as they flew around an artificial tree in the lab. Using this innovative technology, the researchers were able, for the first time, to observe how the place cells in the bats’ brains perceive three-dimensional, volumetric space and to answer the question: Do they relate equally to all three axes of space? (The answer is yes, each cell appears to be almost equally sensitive to all the three spatial axes in the room.)  
 
Dr. Nachum Ulanovsky
 
In addition to the scientific papers, Yartsev wrote an essay describing their work with bats for studying the neural basis of the mammalian spatial representation system. That essay, which appeared in Science, made him the 2013 grand prize winner for the prestigious Eppendorf and Science Prize for Neurobiology. He also recently received the Donald B. Lindsley Prize in Behavioral Neuroscience from the Society of Neuroscience. Yartsev is the first Israeli student to receive these prestigious prizes.

Admitting to enjoying the recognition his work has received, Yartsev emphasizes that for him the real prize has been the experience and knowledge he gained in the process: “It has truly been an honor and a privilege being Nachum’s first student, and I envy all of those who will be his students in the years to come. Being part of this lab has truly been a wonderful experience.”

At present, Yartsev is a CV Starr Fellow at Princeton University, where he is conducting postdoctoral research in the lab of Prof. Carlos Brody. There he is investigating the neural basis of decision making, including how the brain rapidly routes information to guide choices and how new information is integrated into the process. Along the way he is acquiring new techniques for studying the brain, among them optogenetics – a method for controlling neural circuits with light.

In the future, he intends to return to researching bats. “I plan to use these incredible animals to study how information available in the environment around us guides our actions, choices and decisions,” he says.

Yartsev is married to Liza and they have a five-year-old son, Ariel. They enjoy traveling together, and especially relish new places and new experiences.


 
 
 
(l-r) Drs. Michael Yartsev and Nachum Ulanovsky
Life Sciences
English
  • Bats
  • Brain research
  • Nachum Ulanovsky
  • Neurobiology
  • Neuron
  • Optogenetics

Past Brain Activation Revealed in Scans

English

What if experts could dig into the brain, like archaeologists, and uncover the history of past experiences? This ability might reveal what makes each of us a unique individual, and it could enable the objective diagnosis of a wide range of neuropsychological diseases. New research at the Weizmann Institute hints that such a scenario is within the realm of possibility: It shows that spontaneous waves of neuronal activity in the brain bear the imprints of earlier events for at least 24 hours after the experience has taken place.


The new research stems from earlier findings in the lab of Prof. Rafi Malach of the Institute’s Neurobiology Department and others that the brain never rests, even when its owner is resting. When a person is resting with closed eyes – that is, no visual stimulus is entering the brain – the normal bursts of nerve cell activity associated with incoming information are replaced by ultra-slow patterns of neuronal activity. Such spontaneous or “resting” waves travel in a highly organized and reproducible manner through the brain’s outer layer – the cortex – and the patterns they create are complex, yet periodic and symmetrical. 
 
The day after effect of brain activation: The brain image at the back presents spontaneous (resting state) patterns before an fMRI-based neurofeedback training session. The front brain image presents spontaneous (resting state) patterns a day after the training session, illustrating the long-term trace of the training
 
Like hieroglyphics, it seemed that these patterns might have some meaning, and research student Tal Harmelech, under the guidance of Malach and Dr. Son Preminger, set out to uncover their significance. Their idea was that the patterns of resting brain waves may constitute “archives” for earlier experiences. As we add new experiences, the activation of our brain’s networks lead to long-term changes in the links between brain cells, a facility referred to as plasticity. As our experiences become embedded in these connections, they create “expectations” that come into play before we perform any type of mental task, enabling us to anticipate the result. The researchers hypothesized that information about earlier experiences would thus be incorporated into the links between networks of nerve cells in the cortex, and these would show up in the brain’s spontaneously emerging wave patterns.

In the experiment, the researchers had volunteers undertake a training exercise that would strongly activate a well-defined network of nerve cells in the frontal lobes. While undergoing scans of their brain activity in the Institute’s functional magnetic resonance imaging (fMRI) scanner, the subjects were asked to imagine a situation in which they had to make rapid decisions. The subjects received auditory feedback in real time, based on the information obtained directly from their frontal lobe, which indicated the level of neuronal activity in the trained network. This “neurofeedback” strategy proved highly successful in activating the frontal network – a part of the brain that is notoriously difficult to activate under controlled conditions.

To test whether the connections created in the brain during this exercise would leave their traces in the patterns formed by the resting brain waves, the researchers performed fMRI scans on the resting subjects before the exercise, immediately afterward, and 24 hours later. Their findings, which appeared in the Journal of Neuroscience, showed that the activation of the specific areas in the cortex did indeed remodel the resting brain wave patterns. Surprisingly, the new patterns not only remained the next day, they were significantly strengthened. These observations fit in with the classic learning principles proposed by Donald Hebb in the mid-20th century, in which the co-activation of two linked nerve cells leads to long term strengthening of their link, while activity that is not coordinated weakens this link. The fMRI images of the resting brain waves showed that brain areas that were activated together during the training sessions exhibited an increase in their functional link a day after the training, while those areas that were deactivated by the training showed a weakened functional connectivity.  

This research suggests a number of future possibilities for exploring the brain. For example, spontaneously emerging brain patterns could be used as a “mapping tool” for unearthing cognitive events from an individual’s recent past. Or, on a wider scale, each person’s unique spontaneously emerging activity patterns might eventually reveal a sort of personal profile – highlighting each individual’s abilities, shortcomings, biases, learning skills, etc. “Today, we are discovering more and more of the common principles of brain activity, but we have not been able to account for the differences between individuals,” says Malach. “In the future, spontaneous brain patterns could be the key to obtaining unbiased individual profiles.” Such profiles could be especially useful in diagnosing or learning the brain pathologies associated with a wide array of cognitive disabilities.   
 
Prof. Rafi Malach’s research is supported by the Nella and Leon Benoziyo Center for Neurosciences; the Nella and Leon Benoziyo Center for Neurological Diseases; the Carl and Micaela Einhorn-Dominic Brain Research Institute; the Norman and Helen Asher Center for Human Brain Imaging; the Murray H. and Meyer Grodetsky Center for Research of Higher Brain Functions; the Kahn Family Research Center for Systems Biology of the Human Cell; the Friends of Dr. Lou Siminovitch; the Adelis Foundation; and the Mike and Valeria Rosenbloom through the Mike Rosenbloom Foundation. Prof. Malach is the recipient of the Helen and Martin Kimmel Award for Innovative Investigation; and he is the incumbent of the Barbara and Morris L. Levinson Professorial Chair in Brain Research.
 
The day after effect of brain activation: The brain image at the back presents spontaneous (resting state) patterns before an fMRI-based neurofeedback training session. The front brain image presents spontaneous (resting state) patterns a day after the training session, illustrating the long-term trace of the training
Life Sciences
English
  • Brain research
  • Nerve network
  • Neurobiology
  • Rafael Malach
  • fMRI

New Angle on Perception

English

 

How does the brain form a detailed, updated, accurate image of the world? The simple answer is that the sensory organs send electrical impulses though their nerve cells, which ultimately conduct those signals to the various “information-processing” centers in the brain. Recent research at the Weizmann Institute introduces a new wrinkle in that picture, however, showing that the information processing may begin in the sensory organs themselves, before the first neuron ever receives the incoming data.


This research, led by Prof. Ehud Ahissar of the Neurobiology Department, focused on a unique sensory organ: the whisker hair of a rat. Crucial to a rat’s sense of touch, each follicle at the base of a whisker hair contains around 2,000 receptors for sending information to the underlying nerve cells, which relay it on to the brain. As sensory organs go, whiskers are ideal for observation: They are, basically, long, thin, elastic rods that bend as they encounter an object.
 
whisking infographic
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In the experiments, objects were placed in various positions near the rats’ heads. In the first series of trials, the rats were anesthetized and their whisker hairs activated by the electrical stimulation of their motor nerves. This gave the researchers precise control over the whiskers’ movements. The entire experiment was filmed on a high-speed camera, which enabled the scientists to precisely measure the changes in a whisker hair as it came into contact with the object. They identified four variables: global bending over the entire hair, the amount of bending at the base, the angle of the hair in relation to the rat’s head and the extent of angular movement that is blocked by the contact (angle absorption).
 
(l-r) David Deutsch, Dr. Knarik Bagdasarian and Prof. Ehud Ahissar
 
The research team – which included Dr. Knarik Bagdasarian, then research students Drs. Marcin Szwed, Per Magne Knutsen, Maciej Pietr and Erez Simony, and research student David Deutsch – discovered that just knowing the figures for each pair of angular and bending variables was sufficient to pinpoint exactly where the object was in relation to the rat’s head. The closer it was to the head, the greater the bending at the base and angle absorption, and the smaller the global bending and angle protraction. The combinations of bending and angular variables also revealed the angle of the object in relation to the nose-tail axis of the rat’s head. These two pieces of information – distance and angle – identified the object’s precise location. The scientists then observed the process in alert rats that were allowed to move their whiskers naturally; they found that the same relationships held true.

These results, which were published in Nature Neuroscience, imply that we may need to update the way we describe the process of perception. Today, we know that perception is both an active process and a cyclical one. For example, movement leads to interaction with an object (e.g., a finger alights on a tabletop), and receptors in the organ (finger) activate sensory nerves. These cells conduct information (finger is touching a surface) to the brain. Processing this information leads to the initiation of further movement (sliding the finger across the table’s surface to feel its texture). But, according to the present study, the morphology – physical form and structure – of the sensing organ are an integral part of the cycle, and they enter it at an early stage. In fact, morphological information – bending and angle in the case of the whiskers – appear to be processed mechanically in the follicle before being sent as electrical signals to nerve cells in the brain.

Although the experiment was conducted on rat whiskers, Ahissar believes that this absorption and processing of information arising from the physical properties of the organ may be relevant to other senses and other animals, including humans. Our sense of touch, for instance, is dependent on movement: how much pressure we exert, whether we move our fingers over an object quickly or slowly, and the morphology of our fingertips – all determine which receptors are activated and what signals will be sent to our brain. Even sight, which is still often misconstrued as a passive sense, depends on movement. When we look at faces, for instance, our focus jumps from feature to feature – eyes, nose, mouth – in a sort of visual “touching.” The properties of our eye movements, combined with the morphology of our eyeball, cornea, retina and other parts of the eye determine how accurately we perceive the world through our sense of sight. In other words, the divide between sensing and perception – the first thought to be a function of our external sensory organs, the second the result of processing the data from those sensory organs in the brain – may not be as clear cut as we thought.
 
Prof. Ehud Ahissar's research is supported by the Murray H. and Meyer Grodetsky Center for Research of Higher Brain Functions; the Jeanne and Joseph Nissim Foundation for Life Sciences Research' the Kahn Family Research Center for Systems Biology of the Human Cell; Lord David Alliance, CBE; the Berlin Family Foundation; Jack and Lenore Lowenthal, Brooklyn, NY; Research in Memory of Irving Bieber, M.D. and Toby Bieber, M.D.; the Harris Foundation for Brain Research; and the Joseph D. Shane Fund for Neurosciences. Prof. Ahissar is the incumbent of the Helen Diller Family Professorial Chair in Neurobiology.


 
 
Rats' whiskers
Life Sciences
English
  • Ehud Ahissar
  • Neurobiology
  • Perception
  • Sensory nerves
  • Whiskers

How to Prune a Nerve Cell

English
 
 
 
Sensory axons induced to prune by trophic withdrawal in vitro: While wild-type axons degenerate (left), axons that lack KIF2A remain intact
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Like a sprouting thicket, the cells of the developing nervous system extend long, thin branches called axons into all parts of the growing body. This thicket, at second glance, turns out to be a well-tended garden: As development progresses, quite a few extraneous nerve cells are weeded out and many of the axons are pruned back. This gardening activity remodels the nervous system even as it continues to spread and grow. It is the key to a well-functioning nervous system, and there is some evidence that certain neurological disorders, for instance autism, may be tied to imperfect remodeling.

Dr. Avraham Yaron and research student Maya Maor-Nof of the Weizmann Institute’s Biological Chemistry Department recently revealed a central player in the process of axon pruning. This is crucial, says Yaron: “Before we can understand the mechanisms involved in health or disease, we must be able to identify the various players involved. Until now, we have had very little idea of who or what these players are.”  

Pruning of axons takes place from the inside out: Long structural elements, called microtubules, that run down their length are first disassembled. Microtubules are both backbone and transport system: various payloads, including signaling molecules and other materials, are conveyed up and down the rail-like microtubule system. The researchers wanted to know what mechanism controls the breakdown of microtubule structures during axon pruning. Working with sensory nerve cells grown in culture, they used a process of elimination to identify the one – called KIF2A – that carries out the job. Interestingly enough, KIF2A is a member of the family of motor proteins that travel up and down the microtubules and transport various cargos.

To understand the role KIF2A plays in nervous system development and axonal pruning, the Weizmann researchers obtained knockout mice from scientists from the University of Tokyo, Japan, that were missing KIF2A. In the KIF2A-deficient mice, the axons grew normally but the pruning process was impeded as the microtubules and the axons remained intact.
 
Dr. Avraham Yaron
This confirmed that KIF2A is the crucial factor – one which must be present for pruning to occur. The KIF2A knockout mice were distinguished by the fact that their skin – a main destination for developing sensory nerve axons – was inundated with numerous nerve endings.   

How does the process work? The research findings suggest that KIF2A is controlled by molecules called neurotrophins that play the role of head gardener. Neurotrophins are found in the nerve’s target tissues (the skin, for example, in the case of the sensory nerve cells in the experiments), where they guide the growth of axons in the right direction and help them to survive. But neurotrophin numbers tend to be limited, and the axons end up competing for their signals. When an axon does not obtain a neurotrophin signal, its KIF2A, which is normally present in an inactive form, will become activated and the pruning procedure will be initiated.

This creates a process, according to Yaron, that at first appears to be somewhat random but is in reality quite orderly. Not only are the numbers of axons carefully regulated – leading to optimum configurations of nerve cells – but the pruning also proceeds step by step in a preset, genetically determined order. If the first step – microtubule disassembly – does not take place, the rest of the pruning process cannot follow.

Previous research in Yaron’s group, conducted together with Dr. Eli Arama of the Molecular Genetics Department, investigated another type of machinery that regulates nervous system remodeling –  the apoptotic (cell suicide) system . Taken together, this research is beginning to fill in the details of how the nervous system’s “garden” grows: exuberant growth and development alongside judicious thinning, weeding and pruning. Once researchers understand where the balance between them lies and how that balance is achieved, they can begin to understand diseases that arise out of an imbalance, says Yaron. There are some indications, for instance, that autistic brains may suffer from too little pruning – leading to an excess of nerve connections. Yaron thinks that a faulty KIF2A mechanism may play a role in the disorder.
 
Prof. Avraham Yaron's research is supported by the Nella and Leon Benoziyo Center for Neurosciences; the Wolfson Family Charitable Trust; the Koshland Family; the Rowland and Sylvia Schaefer Family Foundation; the Irving Harris Foundation; the estate of Lola Asseof; the estate of Nathan Baltor; and the Joseph D. Shane Fund for Neurosciences.
 
Sensory axons induced to prune by trophic withdrawal in vitro
Life Sciences
English
  • Autism
  • Avraham Yaron
  • Axon
  • Biological Chemistry
  • Brain research
  • Eli Arama
  • Nervous system

Neural Activity in Bats Measured In Flight

English

 

Animals navigate and orient themselves to survive – to find food and shelter or avoid predators, for example. Research conducted by Dr. Nachum Ulanovsky and research student Michael Yartsev of the Weizmann Institute’s Neurobiology Department, published today in Science, reveals for the first time how three-dimensional, volumetric, space is perceived in mammalian brains. The research was conducted using a unique, miniaturized neural-telemetry system developed especially for this task, which enabled the measurement of single brain cells during flight.

The question of how animals orient themselves in space has been extensively studied, but until now experiments were only conducted in two-dimensional settings. These have found, for instance, that orientation relies on “place cells” – neurons located in the hippocampus, a part of the brain involved in memory, especially spatial memory. Each place cell is responsible for a spatial area, and it sends an electrical signal when the animal is located in that area. Together, the place cells produce full representations of whole spatial environments. Unlike the laboratory experiments, however, the navigation of many animals in the real world, including humans, is carried out in three dimensions. But attempts to expand the scope of experiments from two to three dimensions had encountered difficulties.

One of the more famous efforts in this area was conducted by the University of Arizona and NASA, in which they launched rats into space (aboard a space shuttle). However, although the rats moved around in zero gravity, they ran along a set of straight, one-dimensional lines. Other experiments with three-dimensional projections onto two-dimensional surfaces did not manage to produce volumetric data, either. The conclusion was that in order to understand movement in three-dimensional, volumetric space, it is necessary to allow animals to move through all three dimensions – that is, to research animals in flight.

Ulanovsky chose to study the Egyptian fruit bat, a very common bat species in Israel. Because these are relatively large, the researchers were able to attach the wireless measuring system in a manner that did not restrict the bats’ movements.  Developing this sophisticated measuring system was a several-year effort. Ulanovsky, in cooperation with a US commercial company, created a wireless, lightweight (12 g, about 7% of the weight of the bat) device containing electrodes that measure the activity of individual neurons in the bat’s brain.
 
in the bat cave
 
 
 
The next challenge the scientists faced was adapting the behavior of their bats to the needs of the experiment. Bats naturally fly toward their destination – for example, a fruit tree – in a straight line. In other words, their normal flight patterns are one-dimensional, while the experiment required their flights to fill a three-dimensional space.

The solution was to be found in a previous study in Ulanovsky’s group, which tracked wild fruit bats using miniature GPS devices. One of the discoveries was that when bats arrive at a fruit tree, they fly around it, utilizing the full volume of space surrounding the tree. To simulate this behavior in the laboratory – an artificial cave equipped with an array of bat-monitoring devices – the team installed an artificial “tree” made of metal bars and cups filled with fruit.

Measuring the activity of hippocampus neurons in the bats’ brains revealed that the representation of three-dimensional space is similar to that in two dimensions: Each place cell is responsible for identifying a particular spatial area in the “cave” and sends an electrical signal when the bat is located in that area. Together, the population of place cells provides full coverage of the cave – left and right, up and down.

A closer examination of the areas for which individual place cells are responsible provided an answer to a highly-debated question: Does the brain perceive the three dimensions of space as “equal,” that is, does it sense the height axis in the same way as that of length or width? The findings suggest that each place cell responds to a spherical volume of space, i.e., the perception of all three dimensions is uniform. The researchers note that for those non-flying animals that essentially move in flat space, the different axes might not be perceived at the same resolution. It may be that such animals are naturally more sensitive to changes along the length and width axes than that of height. This question is of particular interest when it comes to humans because on the one hand, humans evolved from apes that moved in three-dimensional space when swinging from branch to branch, but on the other hand, modern, ground-dwelling humans generally navigate in two-dimensional space.

The findings provide new insights into some basic functions of the brain: navigation, spatial memory and spatial perception. To a large extent, this is due to the development of innovative technology that allowed the first glimpse into the brain of a flying animal. Ulanovsky believes that this trend, in which research is becoming more “natural,” is the future wave of neuroscience.
 
Dr. Nachum Ulanovsky’s research is supported by the Rowland and Sylvia Schaefer Family Foundation; the Mike Rosenbloom Foundation; the Irving B. Harris Foundation; the Angel Faivovich Foundation for Ecological Research; the estate of Fannie Sherr; Mr. and Mrs. Steven Harowitz, San Francisco, CA; and the European Research Council.

 
Image: Dr. Yossi Yovel in the lab of Dr. Nachum Ulanovsky, Weizmann Institute of Science
Life Sciences
English
  • Bats
  • Brain
  • Nachum Ulanovsky
  • Perception

The Secret of the Smile

English

we all smile

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At a very young age, babies learn to smile back. Soon after, they realize that if they themselves initiate the smiling, they will get a smile in return. As adults, too, we automatically correlate our own facial expressions with those of others: Being greeted with a scowl by someone at whom we have smiled feels completely different from a scowl prompted by our own hostile stare. In other words, the ability to identify the facial expressions of all participants, including ourselves, is crucial for interpreting complex social situations. In people with autism, this ability is obviously missing. Yet despite a large body of research into brain mechanisms dealing with the facial representation of emotions, virtually no studies have focused on ways by which the brain monitors one’s own behavior.

A study conducted in the laboratory of Dr. Rony Paz of the Weizmann Institute’s Neurobiology Department has for the first time revealed how the brain integrates self-monitoring with observations of others. These findings, reported in the Proceedings of the National Academy of Sciences (PNAS), also open new avenues of research into the faulty processing of emotional and social information, such as that which occurs in people with autism.
 
 
Dr. Rony Paz
 
Research student Uri Livneh, together with Jennifer Resnik and Yosef Shohat, created a unique experimental system in which two monkeys, separated by an opaque shutter, faced one another. Periodically, the shutter turned clear for a few seconds, enabling the monkeys to interact spontaneously, through nonvocal facial expressions, as they do in nature. The scientists identified three major expressions: a positive one, characterized by smacking the lips and contracting the surrounding muscles; a threatening one, characterized mainly by stretching the eyebrows and increasing the eyes’ movements; and a neutral one, observed when the shutter was closed and no interaction took place. In the course of the experiment, the scientists measured the electrical activity of individual neurons in the monkeys’ brains.

The scientists focused on two brain areas involved in processing emotional information and responding to positive and negative facial expressions: the amygdala and a certain portion of the cortex. They found that neurons in both these areas were responsible for two different activities: They both processed information about the individual’s own facial expressions and decoded the expressions of others.

The scientists were able to differentiate the electrical signals involved in the two types of decoding only by conducting extremely precise measurements, at a resolution of a few dozen milliseconds. They revealed that the amygdala actually knows about the smile before it occurs; it receives a neural signal directly from the part of the brain that controls the facial muscles as the smile is being created. This then provides the proper context for interpreting the facial expression of others. Thanks to this close overlap of the neural networks charged with interpreting one’s own and others’ behavior, the amygdala and cortex can quickly receive all the relevant information and create a complete and accurate picture of a social situation.

In follow-up research, the scientists plan to examine whether the same networks are involved in social learning – that is, learning through observing others. For example, if one monkey learns something by classic conditioning, can another monkey learn the same thing just by watching? Does the monkey brain have a neural network for learning by observation? And if so, what can this network teach us about human social learning?

Yet another potential future study concerns neuropsychiatric disorders characterized by defective social communication, as in autism. Autistic people have difficulty creating and interpreting emotional and social situations. Previous research had shown that the neural networks examined in the current study don’t function properly in these people, but appropriate models for studying these networks in depth were not available. “The unique experimental system we have developed can provide a basis for creating a natural model of autism,” says Paz. “The system enables researchers to observe natural and versatile social behavior unique to primates while at the same time analyzing the complex neural networks underlying this behavior.”
 

A connection with animals

Yosef Shohat
 
Yosef Shohat, lab technician and manager of Dr. Rony Paz’s laboratory, is an animal person. As a child, he used to go to the beach after storms to collect wounded seagulls to take care of at home. Birds, dogs, insects – all found shelter on his balcony in Kiryat Haim, much to the displeasure of his mother. At age 25, his dedication to animals led to a tragic incident: Yosef tried to restrain a camel that had gone wild while carrying children on its back, and he was attacked and nearly fatally wounded by the animal. He remained paralyzed for a long time; but following prolonged rehabilitation – and contrary to the prognosis of all the doctors – he regained control of his body. Yosef credits animals with this medical miracle: “I needed the connection to animals to overcome not only the physical difficulties but also my depressed mental state.” In the wake of his injury, he gave up on studies of animal behavior at Oranim College, but not on his connection with four-legged and flying creatures. The injury has also caused him to forget the foreign languages he once knew, English and Arabic (he is now learning them anew), but not his mother tongue, Hebrew, nor the nonverbal language in which he communicates with animals.

Yosef lives in Rehovot with his wife, Stavit, who works in the Hebrew University’s Faculty of Agriculture. They have two sons: Omer, 12, and Segev, 10.
 
Dr. Rony Paz's research is supported by the Sylvia Schaefer Alzheimer's Research Fund; the Ruth and Herman Albert Scholars Program for New Scientists; Pascal and Ilana Mantoux, Israel/ France; Katy and Gary Leff, Calabasas, CA; and the European Research Council. Dr. Paz is the incumbent of the Beracha Foundation Career Development Chair.
 

 

 
 
 
we all smile
Life Sciences
English
  • Amygdala
  • Autism
  • Learning and memory
  • Neuron
  • Rony Paz

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