Tag: Neuroscience

How Do Bats Get Street-Smart?

TAU researchers find that baby fruit bats acquire their boldness from their adoptive mothers.

Tel Aviv University researchers conducted the first ever “cross-adoption” behavioral study in bats, whereby pups of urban fruit bats were adopted by rural mothers and vice versa in order to learn whether the relative boldness of city bats is a genetic or acquired trait. Prof. Yovel: “We wanted to find out whether boldness is transferred genetically or learned somehow from the mother. Our findings suggest that this trait is passed on to pups by the mothers that nurse and raise them, even when they are not their biological mothers.” Thus, the bat species’ willingness to take risks is an acquired rather than hereditary trait, passed on in some way from mother to young pup

The study was led by TAU’s Prof. Yossi Yovel, Head of the Sagol School of Neuroscience, member of the School of Zoology at The George S. Wise Faculty of Life Sciences and The Steinhardt Museum of Natural History, and recipient this year of the Blavatnik Young Scientists Award in Israel and the Kadar Family Award for Outstanding Research at TAU. It was conducted by Dr. Lee Harten, Nesim Gonceer, Michal Handel and Orit Dash from Prof. Yovel’s laboratory, in collaboration with Prof. H. Bobby Fokidis from Rollins College in Florida. The paper was published in BMC Biology.

Rural Bats More Risk Adverse

Dr. Harten explains: “While most animals do not live in an urban environment, some species thrive in it. We are trying to understand how they do this. Fruit bats are an excellent example of a species that has adapted well to the human environment of the city. Bat colonies thrive in Tel Aviv and other cities, while other colonies still live in rural areas. Research has shown that city-adapted fruit-bats tend to be bolder and take more risks than those living in the wild. We wanted to examine, under laboratory conditions, whether this trait is genetic or acquired.

In a preliminary experiment the researchers placed food inside a box that required adult bats to land and enter in order to get the food. They found that urban bats solved the problem immediately, while rural bats hesitated and took several hours to learn the trick. Prof. Yovel: “Similar results were observed in past experiments with birds: birds living in the city take more risks than birds of the same species residing in rural areas. Our study was the first to test this issue in bats.”

Bat Boldness: Genetic or Acquired?

The next step was testing whether this boldness is a hereditary trait, or a quality acquired by experience. To this end, the researchers conducted the same experiment with young bat pups, still fed by their mothers, who had never searched for food independently. They found that the urban pups, just like their parents, are bolder and learn faster than their rural counterparts.

Prof. Yovel: “These findings first led us to think that boldness is hereditary – passed on genetically from the urban parents to their pups. However, we know that young pups are still exposed to their mothers after birth. We decided to check whether pups learn from their mothers or are influenced by them in some other way.”

To answer this question, the researchers introduced a cross-adoption method: pups born to urban mothers were raised by rural mothers, and vice versa. They note that this was the first experiment of this type ever conducted in bats, and also the first ‘nature vs. nurture’ study for boldness in urban animals.

Liquid Courage?

Dr. Harten: “We found that the pups behaved like their adoptive mothers, not like their biological mothers. This means that boldness is an acquired rather than hereditary trait, passed on in some way from mother to young pup. We hypothesize that the agent may be some substance in the mother’s milk.” In an additional experiment the researchers discovered that the urban mothers’ milk contains a higher level of the hormone cortisol than the milk of rural mothers. It has not yet been ascertained, however, that this is the agent for the inter-generational transfer of boldness.

Prof. Yovel concludes: “The urban environment presents animals with more challenges and a greater variety of situations. It is therefore plausible that bats and other animals living in the city require more boldness and higher learning skills. In our study we focused on bat pups, examining whether bold behavior is the result of genetics, environment, or some combination between the two. In light of our findings, we hypothesize that the trait is passed on to pups in early stages of development, through some component of their mothers’ milk.” Dr. Harten adds: “We believe that a better understanding of the needs and behaviors of urban animals can help us protect them and adapt urban development to their needs.” 

Featured image: “Baby bat with its adoptive mother (Photo: Yuval Barkai)”

Can Higher Temperatures Accelerate the Rate of Evolution?

TAU researchers use worms to demonstrate that epigenetic inheritance of sexual attractiveness can impact the evolutionary process.

Can environment impact genetic diversity in face of changing conditions, such as higher temperatures (think global warming)? Researchers at Tel Aviv University have discovered that epigenetic inheritance – inheritance which does not involving changes in the DNA sequence – can affect the genetic composition of the population for many generations. The environment can actually impact genetic diversity under certain conditions and the researchers believe that it’s a way for the environment to adjust genetic diversity.

Worms Get It from their Mama’s Mama’s Mama’s… 

Females of the worm species C. elegans produce both egg cells (or “oocytes”) and sperm, and can self-reproduce (hence are considered hermaphrodites). They produce their sperm in a limited amount, only when they are young. At the same time, there are also rare C. elegans males in the population that can provide more sperm to the female worms through mating.

In normal conditions, the female hermaphrodites secrete pheromones to attract males for mating only when they grow old and run out of their own sperm (at this point mating becomes the only way for them to continue and reproduce). Therefore, when the hermaphrodite is young, and still has sperm, she can choose whether to mix her genes by sexually reproducing with a male, or not.

In the new study, exposure to elevated temperatures was found to encourage more hermaphrodites to mate, and this trait was also preserved in the offspring for multiple generations, even though they were raised in comfortable temperatures and did not experience the stress from the increased heat.

The study, which was published today in the journal Development Cell, was led by Prof. Oded Rechavi and Dr. Itai Toker, as well as Dr. Itamar Lev and MD-PhD student Dr. Yael Mor, who did their doctorates under Prof. Rechavi’s supervision at the School of Neurobiology, Biochemistry & Biophysics, George S. Wise Faculty of Life Sciences, and the Sagol School of Neuroscience. The study was conducted in collaboration with the Rockefeller University in New York.

Securing Genetic Diversity

Why did the higher temperatures result in the C. elegans worms becoming more attractive, mating more with males? Dr. Itai Toker explains that “The heat conditions we created disrupted the inheritance of small RNA molecules that control the expression of genes in the sperm, so the worm’s sperm was not able to fertilize the egg with the efficiency that it normally would. The worm sensed that the sperm it produced was partially damaged, and therefore began to secrete the pheromone and attract males at an earlier stage, while it was still young.”

If that wasn’t enough, Dr. Rechavi points out that the really fascinating finding was that the trait of enhanced attractiveness was then passed on for many generations to offspring who did not experience the conditions of higher temperatures. The researchers found that heritable small RNA molecules, not changes in the DNA, transmitted the enhanced attractiveness between generations. Small RNAs control gene expression through a mechanism known as RNA interference or gene silencing – they can destroy mRNA molecules and thus prevent specific genes from functioning in a given time at a given tissue or cell.

Dr. Itai Toker adds that, “In the past, we discovered a mechanism that passes on small RNA molecules to future generations, in parallel and in a different way from the usual DNA-based inheritance mechanism. This enables the transmission of certain traits transgenerationally. By specifically inhibiting the mechanism of small RNA inheritance, we demonstrated that the inheritance of increased attractiveness depends on the transmission of small RNAs that control sperm activity.”

Mating, as opposed to fertilizing themselves, comes at a price for the female, hermaphroditic worms, as it allows them to pass on only half of their genome to the next generation. This “dilution” of the parents’ genetic contribution is a heavy price to pay. The benefit, however, is that it increases genetic diversity. By conducting lab evolution experiments we indeed discovered that it may be a useful adaptive strategy.

The researchers later experimented with evolution: They tracked the offspring of mothers who passed on the trait of attractiveness to males with the help of small RNAs, and allowed them to compete for males, for many generations, against normal offspring from a control group. The researhers observed how the inheritance of sexual attractiveness led to more mating in these competitive conditions, and that as a result the attractive offspring were able to spread their genes in the population more successfully.

 

Prof. Oded Rechavi (photo: Yehonatan Zur Duvdevani)

Environment’s Response to Global Warming?

In general, living things respond to their environment by changing their gene expression, without changing the genes themselves. The understanding that some of the epigenetic information, including information about the parents’ responses to environmental challenges, is encoded in small RNA molecules and can be passed down from generation to generation has revolutionized our understanding of heredity, challenging the dogma that has dominated evolution for a century or more. However, to date researchers have not been able to find a way in which epigenetic inheritance can affect the genetic sequence (DNA) itself.

“Epigenetics in general, and the inheritance of parental responses facilitated by small RNAs in particular, is a new field that is garnering a lot of attention,” says Dr. Lev. “We have now proven that the environment can change not only the expression of genes, but, indirectly, also genetic heredity, and for many generations.”

“Generally, epigenetic inheritance of small RNA molecules is a transient matter: the organism is exposed to a particular environment, and preserves the epigenetic information for 3-5 generations. In contrast, evolutionary change occurs over hundreds and thousands of generations. We looked for a link between epigenetics and genetics and found that a change in the environment, that is relevant to global warming, induces transgenerational secretion of a pheromone to attract males, and thus affects the evolution of the worms’ genome.”

Dr. Mor adds, “We think that it’s a way for the environment to adjust genetic diversity. After all, evolution requires variability and selection. The classical theory is that the environment can influence selection, but cannot affect variability, which is created randomly as a result of mutations. We found that the environment can actually impact genetic diversity under certain conditions.”

Tel Aviv University Scientists Successfully Reduce Metastatic Spread Following Tumor Removal Surgery

A Study Performed in Colorectal Cancer Patients Found that Implementing a Stress-Inflammatory Response Reducing Treatment During Surgery Could Lead to a Decrease in Metastatic Risk

A research group from Tel Aviv University successfully reduced metastatic spread following tumor removal surgery in colorectal cancer patients. Using a short medication treatment around the time of the surgery, the researchers were able to reduce body stress responses and physiological inflammation during this critical period, thus preventing the development of metastases in the years following the surgery. The study, which was recently published in “Cancer”, was led by Prof. Shamgar Ben-Eliyahu from TAU School of Psychological Sciences and Sagol School of Neuroscience, and Prof. Oded Zmora from Shamir (Assaf Harofeh) Medical Center. During the study, which lasted 3 years, the researchers have monitored 34 patients, who received treatment surrounding a colorectal tumor removal surgery. During the pre- and post-surgical period, the patients were administered two safe and known drugs: Propranolol (Deralin), an anti-anxiety and blood pressure reducing drug, and Etodolac (Etopan), an anti-inflammatory analgesic. The drugs were only administered to the patients for 20 days – starting from 5 days prior to surgery, and until two weeks after – with half of the patients receiving a placebo treatment, as a control group. The results are highly promising: while only 12.5% (2 out of 16) of patients receiving the drugs treatment exhibited metastatic disease, in the control group (which did not receive the treatment) the rate of metastases development was found to be 33% (6 out of 18 patients), which is the known rate for colorectal cancer patients. Prof. Ben-Eliyahu says that he is highly satisfied with these data, but also states that “despite the impressive results, this treatment must be examined again, in a much larger number of patients, in order to test whether it is, in fact, life-saving”. According to Prof. Ben-Eliyahu, the study of molecular markers in the cancerous tissue excised from the patients showed that the treatment with the medications has led to a reduction in the metastatic potential of the tumor and potentially the residual cancer cells. In addition, the drugs triggered some beneficial alterations in infiltrating tumor leukocytes (patients’ white blood cells) number and type – which are also markers indicating a reduced chance of disease recurrence. Prof. Ben-Eliyahu explains: “When the body is in a state of stress, whether physiological (from surgery) or psychological, this causes a release of high amounts of two types of hormones, prostaglandins and catecholamines. These hormones suppress the activity of the immune cells, thus indirectly promoting the development of cancer metastases. In addition, these hormones also directly promote the acquisition of metastatic traits in cancer tissue. Our study shows that inexpensive, accessible medication treatment could be used in order to reduce body stress responses and inflammation associated with surgery, which affects the tumor, significantly reducing the risk of metastases that might be detected months or years after surgery.” Following the success of the initial research, Prof. Ben-Eliyahu and Prof. Zmora encourage Israeli colorectal and pancreatic cancer patients, intended for surgery, to apply for participation in a large-scale clinical study which is now starting across the State in eight different Medical Centers – in order to save lives.

TAU Researchers Find Gene Mechanism Linked to Autism and Alzheimer’s

Experimental drug has potential to treat rare syndromes that impair brain functions.

Researchers at Tel Aviv University, led by Prof. Illana Gozes from the Department of Human Molecular Genetics and Biochemistry at the Sackler Faculty of Medicine and the Sagol School of Neuroscience, have unraveled a mechanism shared by mutations in certain genes which cause autism, schizophrenia, and other conditions. The researchers also found that an experimental drug previously developed in Prof. Gozes’ lab is effective in lab models for these mutations, and believe the encouraging results may lead to effective treatments for a range of rare syndromes that impair brain functions and cause autism, schizophrenia, and neurodegenerative diseases like Alzheimer’s.

“Some cases of autism are caused by mutations in various genes,” explains Gozes. “Today, we know of more than 100 genetic syndromes associated with autism, 10 of which are considered relatively common (though still extremely rare). In our lab, we focus mainly on one of these, the ADNP syndrome. The ADNP syndrome is caused by mutations in the ADNP gene, which disrupt the function of the ADNP protein, leading to structural defects in the skeleton of neurons in the brain. In the current study, we identified a specific mechanism that causes this damage in mutations in two different genes: ADNP and SHANK3 – a gene associated with autism and schizophrenia. According to estimates, these two mutations are responsible for thousands of cases of autism around the world.”

To start with, the researchers obtained cells from patients with ADNP syndrome. They discovered that when the ADNP protein is defective, neurons with faulty skeletons (microtubules) are formed, impairing brain functions. They also found, however, that ADNP mutations take different forms, some of which cause less damage.

Gozes explains that in some mutations, a section added to the protein protects it and reduces the damage by connecting to a control site of the neuron’s skeletal system and that this same control site is found on SHANK3 – a much studied protein, with mutations that are associated with autism and schizophrenia. “We concluded that the ability to bond with SHANK3 and other similar proteins provides some protection against the mutation’s damaging effects,” she says.

At the next stage of the study, the researchers found additional sites on the ADNP protein that can bond with SHANK3 and similar proteins. One of these sites is located on NAP, a section of ADNP which was developed into an experimental drug, called Davunetide, by Prof. Gozes’ lab.

Moreover, the researchers demonstrated that extended treatment with Davunetide significantly improved the behavior of lab animals with autism caused by SHANK3.

“In previous studies we showed that Davunetide is effective for treating ADNP syndrome models. The new study has led us to believe that it may also be effective in the case of Phelan McDermid syndrome, caused by a mutation in SHANK3, as well as other syndromes that cause autism through the same mechanism,” explains Gozes.

Participants in the study: Dr. Yanina Ivashko-Pachima, Maram Ganaiem, Inbar Ben-Horin-Hazak, Alexandra Lobyntseva, Naomi Bellaiche, Inbar Fischer, Gilad Levy, Dr. Shlomo Sragovich, Dr. Gidon Karmon, and Dr. Eliezer Giladi from the Sackler Faculty of Medicine and Sagol School of Neuroscience at TAU, Dr. Boaz Barak from The School of Psychological Sciences, Gershon H. Gordon Faculty of Social Sciences and the Sagol School of Neuroscience at TAU, and Dr. Shula Shazman from the Department of Mathematics and Computer Science at the Open University. The paper was published in the scientific journal Molecular Psychiatry.

Pure Escapism

The new Escape Room Project provides a creative way of making learning more fun

University exams are not the easiest time for students. The pressure leads to thoughts of escape – to anywhere except the test itself. TAU has now taken the concept of “escape” one step further through the Escape Room Project, a physical space that provides a hands-on and alternative way of learning complex course material.  

Escape rooms have become increasingly popular over the last decade. Groups sign up to be locked in a room and are timed on how fast they can solve puzzles, usually following a story line, that will allow them to “escape” the room and complete the game. This interactive format and team based problem-solving is exactly what appealed to TAU educators who are always searching for creative ways of making learning more fun.

The Project is run by Minducate, a collaboration between the Sagol School of Neuroscience and TAU Online— Innovative Learning Center. Last year the Project piloted three escape rooms based on four academic courses with some 250 students and staff taking part.  

From the mad hatter to the disappearing cat

This year the Project is operating an escape room called ChemX, which is based on a course in life sciences, as well as another called “Alice In Wonderland“ for courses in neurobiology, neurophysiology and neuro-anatomy.  

The escape rooms follow two fundamental design principles: they are content-rich and they pose a highly challenging riddle to the students. The game takes advantage of the whole space in the room to create a range of stimuli that work on both the mind and the senses. Student teams move from clue to clue by applying their course knowledge and when they finish – escape the room. They are then also better prepared to take the course exam.   

Guy Teichman, a PhD student at the Sagol School, describes the ChemX room narrative: “A crazy professor created a poison for which he has no antidote. His poor students, now ‘poisoned,’ must quickly find one.”

Guy stresses that the escape room is built to address complex issues that students had problems with during their studies. “In the escape room, abstract concepts become tangible, providing an additional level of understanding of the material,” he says.

The Head of the Project, Dr. Limor Radoszkowicz of Minducate, says that the project has been extremely popular with students and that registration for the slots filled up almost immediately upon opening. She stresses that the escape rooms were designed jointly by academic staff and students.

Outstanding Navigators, both Night and Day

Researchers find that bats navigate well, also during the day, thanks to their unique sensory integration.

It is time to bust a myth about bats – bats actually see well during the day and they know how to navigate the space during daylight hours. A new Tel Aviv University study has found that fruit bats use their biological sonar during the day, even though their vision is excellent and would ostensibly eliminate the need for the bats to emit calls to the environment and use their echoes to locate objects (echolocation). The researchers believe that due to the high accuracy of the bats’ bio-sonar system in estimating how far objects are, echolocation offers an additional tool – on top of vision – to help ensure that the bats are navigating as effectively as possible. This is similar to a person crossing the street using their sense of hearing as well as sight to make sure the road is clear.

Enjoying the Tel Aviv Sun

The study was conducted under the supervision of Prof. Yossi Yovel, head of Tel Aviv University’s Sagol School of Neuroscience and a researcher at the School of Zoology in The George S. Wise Faculty of Life Sciences and the Steinhardt Museum of Natural History. The study was led by Ph.D. student Ofri Eitan in cooperation with Dr. Maya Weinberg, Dr. Sasha Danilovich, and Reut Assa, all from Tel Aviv University, and Yuval Barkai, an urban nature photographer. The study will be published in the journal Current Biology.

The researchers explain that in general, bats are active mainly at night, and echolocation is the tool they use to navigate their way in the dark. They also say, however, that in recent years a growing phenomenon has been witnessed in Israel, particularly in Tel Aviv but also in other cities, in which Egyptian fruit bats roam around even during the day. In the current study, the researchers sought to examine what happens when the bats are active during the day, and whether they are aided by their unique bio-sonar even in conditions of good visibility.

For the first time, the researchers studied the activity and sensory behavior of the fruit bat during the day. The research was conducted with the help of photography and audio recordings of the bats’ activities throughout the day, in three different situations: in the morning, as they went out to explore in Tel Aviv; later in the day, when they visited Tel Aviv’s sycamore trees; and while they were drinking water from an artificial pool. In each of these situations, the bats used echolocation.

Daytime Integration of Senses

Ofri Eitan explains: “We compared the bats’ landings and flights between the trees, and found that prior to landing, the bats increased the sounds they emitted in order to use the echoes to help estimate the distance to the ground. In addition, we found that even in the pools of water, bats increased the rate of their calls before coming into contact with the water and reduced it (and sometimes even ceased the calls completely) after ascending from the water to fly to an open area. On the other hand, there were cases in which the bats emerged from the pool and had a wall placed in front of them, and once again returned to the use of echolocation. So, all our results show that the fruit bats make functional use of echolocation.”

Prof. Yossi Yuval concludes: “Our results are unequivocal and show that fruit bats make frequent use of echolocation even during the day when visibility is good. We hypothesize that this is due to the fact that echolocation helps the bats to measure the distances of objects in the environment more accurately, and that their brains combine the visual information along with the auditory information. This study shows how important integration between different senses is, just as we humans integrate visual and auditory information when we cross a street, for example.”

Why Do Bats Fly Into Walls?

A sensory misperception – like people bumping into a glass wall

Why do bats fly into walls, even though they can hear them? Researchers at Tel Aviv University conducted an experiment in which they released dozens of bats in a corridor blocked by objects of different sizes, made of different materials. To their surprise, the researchers discovered that the bats collided with large sponge walls (that produce a weak echo) as if they did not exist. The bats’ behavior suggested that they did this even though they had detected the wall with their sonar system, indicating that the collision did not result from a sensory limitation, but rather from an acoustic misperception. The researchers hypothesize that the unnatural combination of a large object (wall) and a weak echo disrupts the bats’ sensory perception and causes them to ignore the obstacle (much like people who bump into transparent walls).

The study was led by Dr. Sasha Danilovich then a PhD student in the lab of Prof. Yossi Yovel, Head of the Sagol School for Neuroscience and faculty member at the School of Zoology at the George S. Wise Faculty of Life Sciences. Other participants included Dr. Arian Bonman and students Gal Shalev and Aya Goldstein of the Sensory Perception and Cognition Laboratory at the School of Zoology and the Sagol School of Neuroscience. The paper was published in PNAS.

At the next stage of the experiment, the researchers methodically changed the features of the echoing objects along the corridor in terms of size, texture and echo intensity. They concluded that the bats’ acoustic perception depends on a coherent, typical correlation of the dimensions with objects in nature. For example: large object- strong echo; small object – weak echo.

“Bats excel in acoustic perception. They are able to detect objects as tiny as mosquitoes, using sound waves,” explains Prof. Yovel. “Using echolocation they can calculate the 3-dimensional location of both small and large objects, perceiving their shape, size and texture. To this end a bat’s brain processes various acoustic dimensions from the echoes returning from the object (such as frequency, spectrum and intensity). This perception is based on several senses that combine many different dimensions, such as color and shape.”

In addition, the researchers at TAU discovered that bats are not born with this ability. Repeating the experiment with young bats they found that they do not fly into walls.  The study also found that adult bats can quickly learn the new correlations among the dimensions.

“By presenting the bats with objects whose acoustic dimensions are not coherent, we were able to mislead them, creating a misconception that caused them to repeatedly try to fly through a wall, even though they had identified it with their sonar. The experiment gives us a peek into how the world is perceived by these creatures, whose senses are so unique and different from ours,” says Sasha Danilovich.

Human body parts ‘on-a-chip’ could revolutionize drug testing

A new system will drastically shorten the time it takes to develop safe and effective medication

The U.S. Food and Drug Administration (FDA) approves only 13.8% of all tested drugs, and these numbers are even lower in “orphan” diseases that affect relatively few people. Part of the problem lies in the imperfect nature of preclinical drug testing that aims to exclude toxic effects and predetermine concentrations and administration routes before drug candidates can be tested on people. How new drugs move within the human body and are affected by it, and how drugs affect the body itself, cannot be predicted accurately enough in animal and standard in vitro studies. “To solve this massive preclinical bottleneck problem, we need to become much more effective at setting the stage for drugs that are truly promising and rule out others that for various reasons are likely to fail in people,” explains Prof. Donald Ingber, M.D., Ph.D., founding director of Harvard University’s Wyss Institute for Biologically Inspired Engineering, co-author of two new studies on the subject published in Nature Biomedical Engineering. Co-led by Dr. Ben Maoz of Tel Aviv University’s Department of Biomedical Engineering and Sagol School of Neuroscience and over 50 colleagues, a team of scientists at TAU and Harvard have now devised a functioning comprehensive multi-Organ-on-a-Chip (Organ Chip) platform that enables effective in-vitro-to-in-vivo translation (IVIVT) of human drug pharmacology.

Testing on humans, without humans

“We hope that this platform will enable us to bridge the gap on current limitations in drug development by providing a practical, reliable, relevant system for testing drugs for human use,” says Dr. Maoz, co-first author of both studies and former Technology Development Fellow at the Wyss Institute on the teams of Prof. Ingber and Prof. Kevin Kit Parker, Ph.D., the latter of whom is also a leading author of both studies. In the first of two studies, the scientists developed the “Interrogator,” a robotic liquid transfer device to link individual “Organ Chips” in a way that mimics the flow of blood between organs in the human body. Organ Chips are microfluidic devices composed of a clear flexible polymer the size of a computer memory stick that contains two parallel running hollow channels separated by a porous membrane and independently perfused with cell type-specific media. While one of the channels, the parenchymal channel, is lined with cells from a specific human organ or functional organ structure, the other one is lined with vascular endothelial cells presenting a blood vessel. The membrane allows the two compartments to communicate with each other and to exchange molecules like cytokines and growth factors, as well as drugs and drug products generated by organ-specific metabolic activities. The team then applied their Interrogator automated linking platform and a new computational model they developed to three linked organs to test two drugs: nicotine and cisplatin.

Liver on a chip

“The modularity of our approach and availability of multiple validated Organ Chips for a variety of tissues for other human Body-on-Chip approaches now allows us to develop strategies to make realistic predictions about the pharmacology of drugs much more broadly,” says Prof. Ingber. “Its future use could greatly increase the success rates of Phase I clinical trials.” The researchers accurately modeled the oral uptake of nicotine and intravenous uptake of cisplatin, a common chemotherapy medication, and their first passage through relevant organs with highly quantitative predictions of human pharmacokinetic and pharmacodynamic parameters. “The resulting calculated maximum nicotine concentrations, the time needed for nicotine to reach the different tissue compartments, and the clearance rates in the Liver Chips in our in vitro-based in silico model mirrored closely what had been measured in patients,” concludes Dr. Maoz. The multidisciplinary research project is the culmination of a Defense Advanced Research Projects Agency (DARPA) project at the Wyss Institute. Several authors on both studies, including Prof. Ingber, are employees and hold equity in Emulate, Inc., a company that was spun out of the Wyss Institute to commercially develop Organ Chip technology.

New sleep method strengthens brain’s ability to retain memories

Process that uses smell can strengthen memories stored in one side of the brain, say TAU researchers.

A new joint study by Tel Aviv University and Weizmann Institute of Science researchers has yielded an innovative method for bolstering memory processes in the brain during sleep.

The method relies on a memory-evoking scent administered to one nostril. It helps researchers understand how sleep aids memory, and in the future could possibly help to restore memory capabilities following brain injuries, or help treat people with post-traumatic stress disorder (PTSD) for whom memory often serves as a trigger.

The new study was led by Ella Bar, a PhD student at TAU and the Weizmann Institute of Science. Other principal investigators include Prof. Yuval Nir of TAU’s Sackler Faculty of Medicine and Sagol School of Neuroscience, as well as Profs. Yadin Dudai, Noam Sobel and Rony Paz, all of Weizmann’s Department of Neurobiology.

Turning dreams into memories

“We know that a memory consolidation process takes place in the brain during sleep,” Bar explains. “For long-term memory storage, information gradually transitions from the hippocampus — a brain region that serves as a temporary buffer for new memories — to the neocortex. But how this transition happens remains an unsolved mystery.”

“By triggering consolidation processes in only one side of the brain during sleep, we were able to compare the activity between the hemispheres and isolate the specific activity that corresponds to memory reactivation,” Prof. Nir adds. Bar says, “Beyond promoting basic scientific understanding, we hope that in the future this method may also have clinical applications. For instance, post-traumatic patients show higher activity in the right hemisphere when recalling a trauma, possibly related to its emotional content.

“The technique we developed could potentially influence this aspect of the memory during sleep and decrease the emotional stress that accompanies recall of the traumatic memory. Additionally, this method could be further developed to assist in rehabilitation therapy after one-sided brain damage due to stroke.”

The connection between scent and sleep

The researchers began from the knowledge that memories associated with locations on the left side of a person are mostly stored in the right brain hemisphere and vice versa. While exposed to the scent of a rose, research participants were asked to remember the location of words presented on either the left or right side of a computer screen. Participants were then tested on their memory of the word locations, then proceeded to nap at the lab. As the participants were napping, the scent of roses was administered again, but this time to only one nostril.

With this “one-sided” odor delivery, the researchers were able to reactivate and boost specific memories that were stored in a specific brain hemisphere. The team also recorded electrical brain activity during sleep with EEG. The results showed that the “one-sided” rose scent delivery led to different sleep waves in the two hemispheres. The hemisphere that received the scent revealed better electrical signatures of memory consolidation during sleep. Finally, in the most crucial test of all, subjects were asked after waking up to undergo a second memory test about the words they had been exposed to before falling asleep.

“The memory of the subjects was significantly better for words presented on the side affected by smell than the memory for words presented on the other side,” Bar says.

“Our findings emphasize that the memory consolidation process can be amplified by external cues such as scents,” she concludes. “By using the special organization of the olfactory pathways, memories can be manipulated in a local manner on one side of the brain. Our finding demonstrates that memory consolidation likely involves a nocturnal ‘dialogue’ between the hippocampus and specific regions in the cerebral cortex.”

Global first at TAU: MRI scan of the brains of 130 species of mammals, including humans, indicates equal connectivity in all of them

The research reveales a universal Law: Conservation of Brain Connectivity

Researchers at Tel Aviv University, led by Prof. Yaniv Assaf of the School of Neurobiology, Biochemistry and Biophysics and the Sagol School of Neuroscience and Prof. Yossi Yovel of the School of Zoology, the Sagol School of Neuroscience, and the Steinhardt Museum of Natural History, conducted a pioneering study – first of its kind in the world: advanced diffusion MRI scans of the brains of mammals representing about 130 species, designed to investigate brain connectivity. The intriguing results, contradicting widespread conjectures, revealed that brain connectivity levels are equal in all mammals, including humans. Prof. Assaf: “We discovered that brain connectivity (namely the efficiency of information transfer through the neural network) does not depend on either the size or structure of any specific brain. In other words, the brains of all mammals – from tiny mice through humans to large bulls and dolphins – exhibit equal connectivity, and information travels with the same efficiency within them. We also found that the brain preserves this balance via a special compensation mechanism: when connectivity between the hemispheres is high, connectivity within each hemisphere is relatively low, and vice versa.” Participants included researchers from the Kimron Veterinary Institute in Beit Dagan, the Blavatnik School of Computer Science at TAU and the Technion’s Faculty of Medicine. The paper was published in Nature Neuroscience in June 2020. Prof. Assaf explains: “Brain connectivity is a central feature, critical to the functioning of the brain. Many scientists have assumed that connectivity in the human brain is significantly higher compared to other animals, as a possible explanation for the superior functioning of the ‘human animal’.” On the other hand, according to Prof. Yovel, “We know that key features are conserved throughout the evolutionary process. Thus, for example, all mammals gave four limbs. In this project we wished to explore the possibility that brain connectivity may be a key feature of this kind – maintained in all mammals regardless of their size or brain structure. To this end we used advanced research tools.”   Intelligent mammals

Size doesn’t count

The project began with advanced diffusion MRI scans of the brains of about 130 mammals – each representing a different species (It must be noted that all brains were removed from dead animals, and no animals were put down for the purposes of this study). The brains, obtained from the Kimron Veterinary Institute, represented a very wide range of mammals – from tiny bats weighing 10 grams to dolphins whose weight can reach hundreds of kilograms. Since the brains of about 100 of these mammals had never been MRI-scanned before, the project generated a novel and globally unique database. The brains of 32 living humans were also scanned in the same way. The unique technology, which detects the white matter in the brain, enabled the researchers to reconstruct the neural network: the neurons and their axons (nerve fibers) through which information is transferred, and the synapses (junctions) where they meet. The next challenge was comparing the scans of different types of animals, whose brains vary greatly in size and/or structure.  For this purpose the researchers employed tools from Network Theory, a branch of mathematics that allowed them to create and apply a uniform gage of brain conductivity: the number of synopses a message must cross to get from one location to another in the neural network. Prof. Assaf explains: “A mammal’s brain consists of two hemispheres connected to each other by a set of neural fibers (axons) that transfer information. For every brain we scanned we measured four connectivity gages: connectivity in each hemisphere (intrahemispheric connections), connectivity between the two hemispheres (interhemispheric) and overall connectivity. We discovered that overall brain connectivity remains the same for all mammals, large or small, including humans. In other words: information travels from one location to another through the same number of synopses. It must be clarified, however, that different brains use different strategies to preserve this equal measure of overall connectivity: some exhibit strong interhemispheric connectivity and weaker connectivity within the hemispheres, while others display the opposite.” Prof. Yovel describes another interesting discovery: “We found that variations in connectivity compensation characterize not only different species but also different individuals within the same species. In other words, the brains of some rats, bats or humans exhibit higher interhemispheric connectivity at the expense of connectivity within the hemispheres, and the other way around – compared to others of the same species. It would be fascinating to hypothesize how different types of brain connectivity may affect various cognitive functions or human capabilities such as sports, music or math. Such questions will be addressed in our future research.”

A New universal law

Prof. Assaf concludes: “Our study revealed a universal Law: Conservation of Brain Connectivity. This Law denotes that the efficiency of information transfer in the brain’s neural network is equal in all mammals, including humans. We also discovered a compensation mechanism which balances the connectivity in every mammalian brain. This mechanism ensures that high connectivity in a specific area of the brain, possibly manifested through some special talent (e.g. sports or music) is always countered by relatively low connectivity in another part of the brain. In future projects we will investigate how the brain compensates for the enhanced connectivity associated with specific capabilities and learning processes.”
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