Brain on a Chip” Reveals How the Brain Folds
Being born with a “tabula rasa” – a clean slate – in the case of the brain is something of a curse. Our brains are already wrinkled like walnuts by the time we are born. Babies born without these wrinkles – smooth brain syndrome – suffer from severe developmental deficiencies and their life expectancy is markedly reduced. The gene that causes this syndrome helped Weizmann Institute of Science researchers to probe the physical forces that cause the brain’s wrinkles to form. In their findings, reported in Nature Physics, the researchers describe a method they developed for growing tiny “brains on chips” from human cells that enabled them to track the physical and biological mechanisms underlying the wrinkling process.

Tiny brains grown in the lab from embryonic stem cells –called organoids – were pioneered in the last decade by Profs. Yoshiki Sasai in Japan and Juergen Knoblich in Austria. Prof. Orly Reiner of the Institute’s Molecular Genetics Department says that her lab, along with many others, embraced the idea of growing organoids. But Dr. Eyal Karzbrun, in her lab, had to put a bit of a damper on their enthusiasm: The sizes of the organoids they obtained were far from uniform; with no blood vessels, the insides did not have a steady supply of nutrients and started to die; and the thickness of the tissue got in the way of the optical imaging and microscope tracking.

So Karzbrun developed a new approach to growing organoids – one that would enable the group to follow their growth processes in real time: He limited their growth in the vertical axis. This gave him a “pita”-shaped organoid – round and flat with a thin space in the middle. This shape enabled the group to image the thin tissue as it developed and to supply nutrients to all the cells. And by the second week of the tiny “brain’s” growth and development, wrinkles began to appear and then to deepen. Karzbrun: “This is the first time that folding has been observed in organoids, apparently due to the architecture of our system.”

Wrinkles in time
Karzbrun is a physicist by training, and he naturally turned to physical models for the behavior of elastic materials to understand the formation of the wrinkles. Folds or wrinkles in a surface are the result of mechanical instability – compression forces applied to some part of the material. So for example, if there is uneven expansion in one part of the material, another part might be forced to fold in order to accommodate the pressure. In the organoids, the scientists found such mechanical instability in two places: The cytoskeleton – the internal skeleton – of the cells in the center of the organoid contracted; and the nuclei of the cells near the surface expanded. Or, to think of it another way, the outside of the “pita” grew faster than its inside.

While this achievement was impressive, Reiner was not convinced that the wrinkles in the organoids were really modeling the folds in a developing brain. So the group grew new organoids, this time bearing the same mutations carried by babies with smooth brain syndrome. Reiner had identified this gene – LIS1 – back in 1993, and has investigated its role in the developing brain and in the disease, which affects one in 30,000 births. Among other things, the gene is involved in the migration of nerve cells to the brain during embryonic development, and it also regulates the cytoskeleton and molecular motors in the cell.

The organoids with the mutated gene grew to the same proportions as the others, but they developed few folds and the ones they did develop were very different in shape from the normal wrinkles. Working on the assumption that differences in the physical properties of the cell were responsible for these variations, the group investigated the organoid’s cells with atomic force microscopy, with the help of Dr. Sidney Cohen of the Chemical Research Support Department. By measures of elasticity, the normal cells were about twice as stiff as the mutated ones, which were basically soft. Reiner: “We discovered a significant difference in the physical properties of cells in the two organoids, but we observed difference in their biological properties as well. For example, the nuclei in the centers of the mutant organoids moved more slowly, and we saw significant differences in gene expression.”

Source:
https://wis-wander.weizmann.ac.il/life-sciences/%E2%80%9Cbrain-chip%E2%80%9D-reveals-how-brain-folds

Journal article:
https://www.nature.com/articles/s41567-018-0046-7

Gif: As the organoid develops, the tissue in the outer part folds in a manner similar to those in the developing brain.

#stemcells #brainorganoids #lissencephaly #brainwrinkles #geneexpression #braindevelopment #neuroscience

Brain ageing may begin earlier than expected
Physicists have devised a new method of investigating brain function, opening a new frontier in the diagnoses of neurodegenerative and ageing related diseases.

This new non-invasive technique could potentially be used for any diagnosis based on cardiovascular and metabolic-related diseases of the brain.

The researchers at Lancaster University (UK) and the Medical University of Gdansk (Poland) deciphered oscillations in the cerebrospinal fluid which lies between the brain and skull.

A device for non-invasive recordings of this translucent fluid was developed by researchers at the Technical University of Gdansk (Poland), and recordings on healthy subjects were made at the Medical University of Gdansk (Poland) and the University of Regina (Canada).

Using methods developed by physicists at Lancaster, it has been shown that the circulation throughout the brain of this fluid is highly fluctuating, and that these fluctuations are slow but interconnected by the rhythms of breathing and the heart rate.

Researchers found that some of these oscillations are linked with blood pressure, but are generally slower, occurring at lower frequencies, which have been shown in previous studies to be related to oscillations in vascular motion and blood oxygenation.

Preliminary results published in Scientific Reports showed evidence of a decline in the coherence between these oscillations in participants over the age of 25, indicating that brain ageing may begin earlier than expected.

Professor Aneta Stefanovska from Lancaster University, who has been studying the physics of biological oscillations for over 20 years, said: “Combining the technique to noninvasively record the fluctuation corresponding to cerebrospinal fluid and our sophisticated methods to analyse oscillations which are not clock-like but rather vary in time around their natural values, we have come to an interesting and non-invasive method that can be used to study ageing and changes due to various neurodegenerative diseases.“

Source:
http://www.lancaster.ac.uk/news/articles/2018/brain-ageing-may-begin-earlier-than-expected/

Journal article:
https://www.nature.com/articles/s41598-018-21038-0

#cerebrospinalfluid #brainage #neurodegenerativediseases #subarachnoidspace #bloodpressure #oscillations #neuroscience

How the brain responds to injustice
Punishing a wrongdoer may be more rewarding to the brain than supporting a victim. That is one suggestion of new research published in JNeurosci, which measured the brain activity of young men while they played a “justice game.”

Study participants played a game in which two players – a “Taker” and a “Partner” – each start out with 200 chips. The Taker can steal up to 100 of the Partner’s chips, and then the Partner can retaliate by spending up to 100 chips to reduce the Taker’s stash by up to 300 chips. Participants played as either a Partner or an Observer, who could either punish the Taker or help the Partner by spending chips to increase the Partner’s stash.

Mirre Stallen and colleagues found that participants were more willing to punish the Taker when they experienced injustice directly as a Partner as opposed to a third-party Observer. The decision to punish was associated with activity in the ventral striatum, a brain region involved in reward processing, and distinguishable from the severity of the punishment.

Before beginning the experiment, all participants were given a nasal spray, with some randomly assigned to receive the hormone oxytocin, which has been suggested to have a role in punishing. Participants in the oxytocin group chose to give more frequent, but less intense, punishments. This finding implicates oxytocin in corrective punishments akin to a “slap on the wrist” to maintain fairness.

Source:
https://www.eurekalert.org/pub_releases/2018-02/sfn-htb021418.php

Journal article:
http://www.jneurosci.org/content/38/12/2944

#oxytocin #neuroimaging #brainactivity #punishment #socialinjustice #neuroscience

Can't get an image out of your head? Your eyes are helping to keep it there
Even though you are not aware of it, your eyes play a role in searing an image into your brain, long after you have stopped looking at it.

Through brain imaging, Baycrest scientists have found evidence that the brain uses eye movements to help people recall vivid moments from the past, paving the way for the development of visual tests that could alert doctors earlier about those at risk for neurodegenerative illnesses.

The study, published in the journal Cerebral Cortex, found that when people create a detailed mental image in their head, not only do their eyes move in the same way as when they first saw the picture, their brains showed a similar pattern of activity.

“There’s a theory that when you remember something, it’s like the brain is putting together a puzzle and reconstructing the experience of that moment from separate parts,” says Dr. Bradley Buchsbaum, senior author on the study, scientist at Baycrest’s Rotman Research Institute (RRI) and psychology professor at the University of Toronto. “The pattern of eye movements is like the blueprint that the brain uses to piece different parts of the memory together so that we experience it as a whole.”

This is the first time a direct connection has been established between a person’s eye movements and patterns of brain activity, which follows up on previous studies linking what we see to how we remember.

In the study, researchers used a mathematical algorithm to analyze the brain scans and eye movements of 16 young adults between the ages of 20 to 28. Individuals were shown a set of 14 distinct images for a few seconds each. They were asked to remember as many details of the picture as possible so they could visualize it later on. Participants were then cued to mentally visualize the images within an empty rectangular box shown on the screen. Brain imaging and eye-tracking technology simultaneously captured the brain activity and eye movements of the participants as they memorized and remembered the pictures.

The study, led by RRI graduate student Michael Bone, discovered the same pattern of eye movements and brain activation, but compressed, when the picture was memorized and then remembered.

“This is likely because when we recall a memory, it’s a condensed version of the original experience. For example, if a marriage proposal took two minutes, when we picture this memory in our head, we re-experience it in a much shorter timeframe,” says Dr. Buchsbaum. “The eye movements are like a short-hand code that your brain runs through to trigger the memory.”

By looking at the patterns of eye movement and brain activity, researchers were able to identify which image a person was remembering during the task.

As next steps, the study will explore distinguishing whether the eye movements lead the brain to reactivate the memory or vice versa. Having a greater understanding of this causal relationship could inform the creation of a diagnostic tool using the eyes to catch when a person’s memory is headed down an unhealthy path, adds Dr. Buchsbaum.

Source:
https://www.eurekalert.org/pub_releases/2018-02/bcfg-cga021318.php

Journal article:
https://academic.oup.com/cercor/advance-article/doi/10.1093/cercor/bhy014/4836786

#eyemovements #neuroimaging #brainactivity #memory #mentalimagery #neuroscience #research

Love and fear are visible across the brain instead of being restricted to any brain region
In the field of affective neuroscience, rivaling theories debate whether emotional states can be regarded as an activity of only certain brain regions. According to a new doctoral dissertation at Aalto University, an emotional state affects the operation of the entire brain instead of individual emotions being localized only in specific regions in the brain.

‘From the biological point of view, an emotion is a state of the entire brain at a given moment. For example, the brain may interpret certain action models, memories and bodily changes altogether as anger,’ explains Doctoral Candidate Heini Saarimäki.

Different emotional states of the participants were evoked with films, mental imagery or guided imagery based on narratives. After that, a classifier algorithm based on machine learning was trained to connect the specific emotions and the brain data related to them. The classifier algorithm was then tested by giving it new brain data and by measuring how successfully the algorithm recognized the correct emotion solely on the basis of the brain data. The method for measuring brain activity is based on measuring the changes in the blood oxygen content in the brain and it provides information on the activation of the brain with millimeter-accuracy.

The researchers were particularly interested in emotion-specific brain maps, that is, maps on the localization of emotions in various areas across the entire brain. By analyzing the activity of the entire brain, a machine learning algorithm may be able to determine the emotional state in question.

Saarimäki and her colleagues discovered that the brain maps of basic emotions such as anger, happiness, sadness, fear, surprise and disgust were to some extent similar across people. Basic emotions seem to be at least partially biologically determined, whereas social emotions – gratitude, contempt, pride and shame – are to a greater extent built on experience. In social emotions, the differences in brain activity between people are greater than in basic emotions.

Source:
http://www.aalto.fi/en/current/news/2018-02-14/

Journal article:
https://aaltodoc.aalto.fi/handle/123456789/29707

Image: An emotional state mainly activates wide, overlapping neural networks. When comparing groups of emotions, positive emotions activate the anterior prefrontal cortex, negative basic emotions tend to activate the somatomotor and subcortical regions, and negative social emotions activate brain areas that process motor and social information.
Image credit: Heini Saarimäki.

#functionalconnectivity #emotion #neuroimaging #brainactivity #neuroscience

Running helps the brain counteract negative effect of stress
Most people agree that getting a little exercise helps when dealing with stress. A BYU study discovers exercise under stress also helps protect your memory.

The study, published in the journal of Neurobiology of Learning and Memory, finds that running mitigates the negative impacts chronic stress has on the hippocampus, the part of the brain responsible for learning and memory.

“Exercise is a simple and cost-effective way to eliminate the negative impacts on memory of chronic stress,” said study senior author Jeff Edwards, associate professor of physiology and developmental biology at BYU.

Inside the hippocampus, memory formation and recall occur optimally when the synapses or connections between neurons are strengthened over time. That process of synaptic strengthening is called long-term potentiation (LTP). Chronic or prolonged stress weakens the synapses, which decreases LTP and ultimately impacts memory. Edwards’ study found that when exercise co-occurs with stress, LTP levels are not decreased, but remain normal.

To learn this, Edwards carried out experiments with mice. One group of mice used running wheels over a 4-week period (averaging 5 km ran per day) while another set of mice was left sedentary. Half of each group was then exposed to stress-inducing situations, such as walking on an elevated platform or swimming in cold water. One hour after stress induction researchers carried out electrophysiology experiments on the animals’ brains to measure the LTP.

Stressed mice who had exercised had significantly greater LTP than the stressed mice who did not run. Edwards and his colleagues also found that stressed mice who exercised performed just as well as non-stressed mice who exercised on a maze-running experiment testing their memory. Additionally, Edwards found exercising mice made significantly fewer memory errors in the maze than the sedentary mice.

The findings reveal exercise is a viable method to protect learning and memory mechanisms from the negative cognitive impacts of chronic stress on the brain.

Source:
https://news.byu.edu/news/running-helps-brain-counteract-negative-effect-stress-study-finds

Journal article (under paywall):
https://www.sciencedirect.com/science/article/pii/S1074742718300042

#hippocampus #running #chronicstress #LTP #learning #memory #neuroscience

Autism, schizophrenia, bipolar disorder share molecular traits
Most medical disorders have well-defined physical characteristics seen in tissues, organs and bodily fluids. Psychiatric disorders, in contrast, are not defined by such pathology, but rather by behavior.

A UCLA-led study, published in Science, has found that autism, schizophrenia and bipolar disorder share some physical characteristics — and important differences — at the molecular level, specifically, patterns of gene expression in the brain. Gene expression is the process by which instructions in DNA are converted into a product, such as a protein.

“These findings provide a molecular, pathological signature of these disorders, which is a large step forward,” said senior author Daniel Geschwind, a distinguished professor of neurology, psychiatry and human genetics and director of the UCLA Center for Autism Research and Treatment. “The major challenge now is to understand how these changes arose.”

Researchers know that certain variations in genetic material put people at risk for psychiatric disorders, but DNA alone doesn’t tell the whole story. Every cell in the body contains the same DNA; RNA molecules, on the other hand, play a role in gene expression in different parts of the body, by “reading” the instructions contained within DNA.

Geschwind and the study’s lead author, Michael Gandal, reasoned that taking a close look at the RNA in human brain tissue would provide a molecular profile of these psychiatric disorders. Gandal is an assistant professor of psychiatry and biobehavioral sciences at UCLA.

Researchers analyzed the RNA in 700 tissue samples from the brains of deceased subjects who had autism, schizophrenia, bipolar disorder, major depressive disorder or alcohol abuse disorder, comparing them to samples from brains without psychiatric disorders.

The molecular pathology showed significant overlap between distinct disorders, such as autism and schizophrenia, but also specificity, with major depression showing molecular changes not seen in the other disorders.

“We show that these molecular changes in the brain are connected to underlying genetic causes, but we don’t yet understand the mechanisms by which these genetic factors would lead to these changes,” Geschwind said. “So, although now we have some understanding of causes, and this new work shows the consequences, we now have to understand the mechanisms by which this comes about, so as to develop the ability to change these outcomes.”

Source:
http://newsroom.ucla.edu/releases/autism-schizophrenia-bipolar-disorder-share-molecular-traits-study-finds

Journal article:
http://science.sciencemag.org/content/359/6376/693

#autism #schizophrenia #bipolardisorder #geneexpression #neuroscience

What are memories made of? Study sheds light on key protein
Ask a nonscientist what memories are made of and you’ll likely conjure images of childhood birthday parties or wedding days. Charles Hoeffer thinks about proteins.

For five years, the assistant professor of integrative physiology at CU Boulder has been working to better understand a protein called AKT, which is ubiquitous in brain tissue and instrumental in enabling the brain to adapt to new experiences and lay down new memories.

Until now, scientists have known very little about what it does in the brain.

But in a new paper funded by the National Institutes of Health, Hoeffer and his co-authors spell it out for the first time, showing that AKT comes in three distinct varieties residing in different kinds of brain cells and affecting brain health in very distinct ways.

The discovery could lead to new, more targeted treatments for everything from glioblastoma—the brain cancer Sen. John McCain has—to Alzheimer’s disease and schizophrenia.

“AKT is a central protein that has been implicated in a bevy of neurological diseases yet we know amazingly little about it,” Hoeffer said. “Our paper is the first to comprehensively examine what its different forms are doing in the brain and where.”

Discovered in the 1970s and known best as an “oncogene” (one that, when mutated, can promote cancer), AKT has more recently been identified as a key player in promoting “synaptic plasticity,” the brain’s ability to strengthen cellular connections in response to experience.

“Let’s say you see a great white shark and you are scared and your brain wants to form a memory of what’s going on. You have to make new proteins to encode that memory,” he said. AKT is one of the first proteins to come online, a central switch that turns on the memory factory.

But not all AKTs are created equal.

For the study, Hoeffer’s team silenced the three different isoforms, or varieties, of AKT in mice and observed their brain activity.

They made a number of key discoveries:

AKT2 is found exclusively in astroglia, the supportive, star-shaped cells in the brain and spinal cord that are often impacted in brain cancer and brain injury.

“That is a really important finding,” said co-author Josien Levenga, who worked on the project as a postdoctoral researcher at CU Boulder. “If you could develop a drug that targeted only AKT2 without impacting other forms, it might be more effective in treating certain issues with fewer side-effects.”

The researchers also found that AKT1 is ubiquitous in neurons and appears to be the most important form in promoting the strengthening of synapses in response to experience, aka memory formation. (This finding is in line with previous research showing that mutations in AKT1 boost risk of schizophrenia and other brain disorders associated with a flaw in the way a patient perceives or remembers experiences.)

AKT3 appears to play a key role in brain growth, with mice whose AKT3 gene is silenced showing smaller brain size.

“Before this, there was an assumption that they all did basically the same thing in the same cells in the same way. Now we know better,” Hoeffer said.

He notes that pan-AKT inhibitors have already been developed for cancer treatment, but he envisions a day when drugs could be developed to target more specific versions of the protein (AKT1 enhancers for Alzheimer’s and schizophrenia, AKT2 inhibitors for cancer), leaving the others forms untouched, preventing side-effects.

More animal research is underway to determine what happens to behavior when different forms of the protein go awry.

“Isoform specific treatments hold great promise for the design of targeted therapies to treat neurological diseases with much greater efficacy and accuracy than those utilizing a one-size-fits-all approach,” the authors conclude. “This study is an important step in that direction.”

Source:
https://www.colorado.edu/today/2018/01/24/what-are-memories-made-study-sheds-light-key-protein

Paper:
https://cdn.elifesciences.org/articles/30640/elife-30640-v2.pdf

#memory #hippocampus #synapticplasticity #AKT #oncogene #memoryfomation #neuroscience

Miles Davis is not Mozart: The brains of jazz and classical pianists work differently
A musician’s brain is different to that of a non-musician. Making music requires a complex interplay of various abilities which are also reflected in more strongly developed brain structures. Scientists at the Max Planck Institute for Human Cognitive and Brain Sciences (MPI CBS) in Leipzig have recently discovered that these capabilities are embedded in a much more finely-tuned way than previously assumed—and even differ depending on the style of the music: They observed that the brain activity of jazz pianists differs from those of classical pianists, even when playing the same piece of music. This could give insight into the processes which generally take place while making music and which are specific for certain styles.

Keith Jarret, world-famous jazz pianist, once answered in an interview when asked if he would ever be interested in doing a concert where he would play both jazz and classical music: “No, that’s hilarious. […] It’s like a chosen practically impossible thing […] It’s [because of] the circuitry. Your system demands different circuitry for either of those two things.“ Where non-specialists tend to think that it should not be too challenging for a professional musician to switch between styles of music, such as jazz and classical, it is actually not as easy as one would assume, even for people with decades of experience.

Scientists at the Max Planck Institute for Human Cognitive and Brain Sciences (MPI CBS) in Leipzig demonstrated that there could be a neuroscientific explanation for this phenomenon: They observed that while playing the piano, different processes occur in jazz and classical pianists’ brains, even when performing the same piece.

“The reason could be due to the different demands these two styles pose on the musicians—be it to skillfully interpret a classical piece or to creatively improvise in jazz. Thereby, different procedures may have established in their brains while playing the piano which makes switching between the styles more difficult”, says Daniela Sammler, neuroscientist at MPI CBS and leader of the current study about the different brain activities in jazz and classical pianists.

One crucial distinction between the two groups of musicians is the way in which they plan movements while playing the piano. Regardless of the style, pianists, in principle, first have to know what they are going to play—meaning the keys they have to press—and, subsequently, how to play—meaning the fingers they should use. It is the weighting of both planning steps which is influenced by the genre of the music.

According to this, classical pianists focus their playing on the second step, the „How“. For them it is about playing pieces perfectly regarding their technique and adding personal expression. Therefore, the choice of fingering is crucial. Jazz pianists, on the other hand, concentrate on the “What”. They are always prepared to improvise and adapt their playing to create unexpected harmonies.

“Indeed, in the jazz pianists we found neural evidence for this flexibility in planning harmonies when playing the piano”, states Roberta Bianco, first author of the study. “When we asked them to play a harmonically unexpected chord within a standard chord progression, their brains started to replan the actions faster than classical pianists. Accordingly, they were better able to react and continue their performance.“ Interestingly, the classical pianists performed better than the others when it came to following unusual fingering. In these cases their brains showed stronger awareness of the fingering, and consequently they made fewer errors while imitating the chord sequence.

The scientists investigated these relations in 30 professional pianists; half of them were specialized in jazz for at least two years, the other half were classically trained. All pianists got to see a hand on a screen which played a sequence of chords on a piano scattered with mistakes in harmonies and fingering. The professional pianists had to imitate this hand and react accordingly to the irregularities while their brain signals were registered with EEG (Electroencephalography) sensors on the head. To ensure that there were no other disturbing signals, for instance acoustic sound, the whole experiment was carried out in silence using a muted piano.

“Through this study, we unraveled how precisely the brain adapts to the demands of our surrounding environment”, says Sammler. It also makes clear that it is not sufficient to just focus on one genre of music if we want to fully understand what happens in the brain when we perform music—as it was done so far by just investigating Western classical music. “To obtain a bigger picture, we have to search for the smallest common denominator of several genres”, Sammler explains. “Similar to research in language: To recognize the universal mechanisms of processing language we also cannot limit our research to German”.

Source:
http://www.cbs.mpg.de/brains-of-jazz-and-classical-pianists-work-differently

Journal article:
https://www.sciencedirect.com/science/article/pii/S1053811917310820?via%3Dihub

#neuroscience #music #brainoscillations #actionplanning #EEG #brainactivity

Researchers Discover Key Link Between Mitochondria and Cocaine Addiction
For years, scientists have known that mitochondria—the power source of cells—play a role in brain disorders such as depression, bipolar disorder, anxiety and stress responses. But recently scientists at the University of Maryland School of Medicine (UMSOM) have identified significant mitochondrial changes in brain cells that take place in cocaine addiction, and they have been able to block them.

In mice exposed repeatedly to cocaine, UMSOM researchers were able to identify an increase in a molecule that plays a role in mitochondria division (or fission) in a reward region of the brain. Researchers were able to block this change by using a special chemical, Mdivi-1. The researchers also blocked responses to cocaine by genetically manipulating the fission molecule within the mitochondria of brain cells, according to research published in Neuron.

“We are actually showing a new role for mitochondria in cocaine-induced behavior, and it’s important for us to further investigate that role,” said Mary Kay Lobo, PhD, Associate Professor of Anatomy and Neurobiology.

The researchers initially studied the mitochondria in cocaine-exposed mice and determined that mitochondria fission increased in the major reward region of the brain. To confirm this same change in humans, researchers were able to identify similar changes in the mitochondrial fission molecule in tissue collected from post mortem individuals who were cocaine dependents.

Dr. Lobo said that this latest research could help UMSOM researchers better understand changes in brain cells and mitochondria from other addictive disorders. “We are interested to see if there are mitochondrial changes when animals are taking opiates. That is definitely a future direction for the lab,” she said.

Journal article:
https://www.cell.com/neuron/abstract/S0896-6273(17)31090-5

Source:
http://www.medschool.umaryland.edu/news/2018/University-of-Maryland-School-of-Medicine-Researchers-Discover-Key-Link-Between-Mitochondria-and-Cocaine-Addiction.html

#mitochondria #cocaineaddiction #nucleusaccumbens #drp1 #Mdivi-1 #neuroscience