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Neuroscience and the Year of the Snake

Anne Trafton |

In the Chinese calendar, 2013 is the Year of the Snake, and to celebrate we’ve compiled a list of interesting facts about how snakes have contributed to brain research. [Click for English version of graphic.]

Snake venom

Snake venom has been a rich source of reagents for neuroscience research. Venom from the many-banded krait, a species found in Taiwan and Southern China, led to the identification of the first neurotransmitter receptor. In 1963 Chang and Lee at the National Taiwan University isolated a toxin, known as alpha-bungarotoxin, that binds strongly to the receptor for acetylcholine, the main neurotransmitter at neuromuscular synapses. This toxin, used by snakes to paralyze their victims’ muscles, was used by researchers to purify the acetylcholine receptor, and is still widely used today to study the biology of synapses.

Snake venom played central role in the identification of nerve growth factor (NGF) by Stanley Cohen and Rita Levi-Montalcini, who shared the 1986 Nobel Prize for their work. They discovered that the venom of the moccasin snake (a species of pit viper from the Southeastern US) was a rich source of a factor that could induce outgrowth of fibers from cultured neurons. This enabled them to characterize and eventually purify NGF, the first growth factor to be identified and the prototype for a large family of signaling molecules.

Snake venom has also led to several important advances in pain research, an area of great therapeutic interest. A protein complex isolated from the Texas coral snake has recently been shown to activate acid-sensitive ion channels (ASICs) in pain neurons, which is why bites from these snakes are so painful.  A peptide from the venom of a different species (the black mamba of East Africa, among the most venomous of all snakes) blocks the same channels and shows powerful analgesic effects – suggesting a promising new direction for drug development.

There are hundreds of species of venomous snakes, whose venoms contain a rich diversity of substances that have evolved specifically to interfere with the nervous systems of their victims and predators – a diversity that has only begun to be explored.

Snake evolution and behavior

Several families of snakes, including pit vipers, boas and pythons, can hunt at night using infrared (IR) radiation emitted by their warm-blooded prey. This ability arises from pit organs below the eyes, which allow these snakes to locate IR sources, sometimes with great accuracy. The molecular basis of IR detection was recently identified, and found to be an ion channel of the TRP family that is highly sensitive to warmth. The corresponding channel in other species is not strongly temperature-sensitive and is used mainly to detect chemical irritants (in humans, it responds to wasabi and mustard).  During snake evolution the same channel appears to have been co-opted for IR detection on several independent occasions in different snake families.

Another example of the evolutionary flexibility of brain and behavior comes from the tentacled snake of South-East Asia. This species hunts underwater, lying in wait for fish and detecting their location through a combination of vision and vibration. The snake captures a fish by exploiting its startle reflex – by making a feint with its body, the snake induces the fish to make a stereotypical escape response, directly toward the snake’s jaws. The snake can predict the fish’s behavior and makes a lunge to swallow it, all within about 25ms, or 1/40th second [video]. Remarkably a naïve snake, raised in captivity with no prior experience of fish, can do the same. Thus, the snake’s brain has been pre-wired by evolution to perform this behavior without the need for learning.

Snake phobia

Some people have a phobia for snakes, as do some animals, providing a useful model for understanding the neural basis of fear and anxiety. In one study, researchers even scanned volunteer subjects as they confronted a live snake inside the MRI scanner. These phobic responses are at least partly innate; monkeys, for example, will respond fearfully to a snake-like object even if they have never encountered one before. This raises interesting questions about how our brains are pre-wired to recognize specific stimuli, and also provides an opportunity to study how innate and leaned responses interact to control behavior.

These days snakes have more to fear from humans than vice versa, and many species around the world are now endangered. Awareness of their biology and potential for neuroscience discovery may strengthen efforts to conserve these remarkable creatures.

What do snakes have to do with neuroscience?

Anne Trafton |

In the Chinese calendar, 2013 is the Year of the Snake, and to celebrate we’ve compiled a list of interesting facts about how snakes have contributed to brain research. [Click for Chinese version of graphic.]

Snake venom

Snake venom has been a rich source of reagents for neuroscience research. Venom from the many-banded krait, a species found in Taiwan and Southern China, led to the identification of the first neurotransmitter receptor. In 1963 Chang and Lee at the National Taiwan University isolated a toxin, known as alpha-bungarotoxin, that binds strongly to the receptor for acetylcholine, the main neurotransmitter at neuromuscular synapses. This toxin, used by snakes to paralyze their victims’ muscles, was used by researchers to purify the acetylcholine receptor, and is still widely used today to study the biology of synapses.

Snake venom played central role in the identification of nerve growth factor (NGF) by Stanley Cohen and Rita Levi-Montalcini, who shared the 1986 Nobel Prize for their work. They discovered that the venom of the moccasin snake (a species of pit viper from the Southeastern US) was a rich source of a factor that could induce outgrowth of fibers from cultured neurons. This enabled them to characterize and eventually purify NGF, the first growth factor to be identified and the prototype for a large family of signaling molecules.

Snake venom has also led to several important advances in pain research, an area of great therapeutic interest. A protein complex isolated from the Texas coral snake has recently been shown to activate acid-sensitive ion channels (ASICs) in pain neurons, which is why bites from these snakes are so painful.  A peptide from the venom of a different species (the black mamba of East Africa, among the most venomous of all snakes) blocks the same channels and shows powerful analgesic effects – suggesting a promising new direction for drug development.

There are hundreds of species of venomous snakes, whose venoms contain a rich diversity of substances that have evolved specifically to interfere with the nervous systems of their victims and predators – a diversity that has only begun to be explored.

Snake evolution and behavior

Several families of snakes, including pit vipers, boas and pythons, can hunt at night using infrared (IR) radiation emitted by their warm-blooded prey. This ability arises from pit organs below the eyes, which allow these snakes to locate IR sources, sometimes with great accuracy. The molecular basis of IR detection was recently identified, and found to be an ion channel of the TRP family that is highly sensitive to warmth. The corresponding channel in other species is not strongly temperature-sensitive and is used mainly to detect chemical irritants (in humans it responds to wasabi and mustard).  During snake evolution the same channel appears to have been co-opted for IR detection on several independent occasions in different snake families.

Another example of the evolutionary flexibility of brain and behavior comes from the tentacled snake of South-East Asia. This species hunts underwater, lying in wait for fish and detecting their location through a combination of vision and vibration. The snake captures a fish by exploiting its startle reflex – by making a feint with its body, the snake induces the fish to make a stereotypical escape response, directly toward the snake’s jaws. The snake can predict the fish’s behavior and makes a lunge to swallow it, all within about 25ms, or 1/40th second [video]. Remarkably a naïve snake, raised in captivity with no prior experience of fish, can do the same. Thus, the snake’s brain has been pre-wired by evolution to perform this behavior without the need for learning.

Snake phobia

Some people have a phobia for snakes, as do some animals, providing a useful model for understanding the neural basis of fear and anxiety. In one study, researchers even scanned volunteer subjects as they confronted a live snake inside the MRI scanner. These phobic responses are at least partly innate; monkeys, for example, will respond fearfully to a snake-like object even if they have never encountered one before. This raises interesting questions about how our brains are pre-wired to recognize specific stimuli, and also provides an opportunity to study how innate and leaned responses interact to control behavior.

These days snakes have more to fear from humans than vice versa, and many species around the world are now endangered. Awareness of their biology and potential for neuroscience discovery may strengthen efforts to conserve these remarkable creatures.

Gloria Choi joins the McGovern Institute

Anne Trafton |

We are pleased to announce the appointment of Gloria Choi as a new McGovern Investigator, starting in summer 2013. She will also be an assistant professor in the MIT Department of Brain and Cognitive Sciences. Choi’s research addresses the mechanisms by which the brain learns to recognize olfactory stimuli and to associate them with appropriate behavioral responses.

Much recent work has been devoted to the question of how the binding of odorant molecules to their receptors in the olfactory epithelium leads to the perception of odors. In other sensory modalities such as vision, touch or hearing, the primary sensory cortex shows a topographical organization in which stimulus features are systematically mapped on the cortical surface. In the piriform cortex, however, no such order has been found; while individual inputs to the cortex are tuned to specific odorants, their projections within the piriform cortex appears topographically random. Consistent with this, olfactory stimuli typically activate sparse ensembles of piriform cells, with no obvious spatial pattern. Yet somehow the brain must learn to recognize these apparently arbitrary spatial patterns of activity and to endow them with behavioral significance.

Choi uses the power of rodent molecular genetics to study how this happens. Using the optogenetic molecule Channelrhodopsin2, she has been able to activate sparse arbitrarily-chosen populations of neurons within the piriform cortex using direct light stimulation. She has shown that animals can learn to recognize and distinguish these artificial “smell-like” cues, which can be flexibly associated with either rewarding or aversive stimuli to drive the appropriate behavioral responses.

In her own lab at MIT, Choi plans to dissect the brain circuits underlying this behavior, to understand how sensory representations in piriform cortex can drive downstream targets to generate learned behavioral responses. She also plans to extend her approach to study social behavior, which in rodents is strongly affected by olfactory cues. One important modulator of social behavior is the hormone oxytocin, and Choi plans to study how oxytocin may control the mechanisms by which animals learn to attribute social significance to olfactory stimuli.

Olfactory learning also provides an opportunity to study more general questions about how the brain learns to categorize sensory stimuli and to associate them with complex rule-based behaviors. Such cognitive processes have been linked to the prefrontal cortex in humans and other species, and olfactory behavior in mice may offer a new and genetically tractable system for exploring these issues.

Choi received her bachelor’s degree from University of California, Berkeley, and her Ph.D. from Caltech, where she studied with David Anderson. She is currently a postdoctoral research scientist in the laboratory of Richard Axel at Columbia University.

Editing the genome with high precision

Anne Trafton |

Researchers at MIT, the Broad Institute and Rockefeller University have developed a new technique for precisely altering the genomes of living cells by adding or deleting genes. The researchers say the technology could offer an easy-to-use, less-expensive way to engineer organisms that produce biofuels; to design animal models to study human disease; and to develop new therapies, among other potential applications.

To create their new genome-editing technique, the researchers modified a set of bacterial proteins that normally defend against viral invaders. Using this system, scientists can alter several genome sites simultaneously and can achieve much greater control over where new genes are inserted, says Feng Zhang, an assistant professor of brain and cognitive sciences at MIT and leader of the research team.

“Anything that requires engineering of an organism to put in new genes or to modify what’s in the genome will be able to benefit from this,” says Zhang, who is a core member of the Broad Institute and MIT’s McGovern Institute for Brain Research.

Zhang and his colleagues describe the new technique in the Jan. 3 online edition of Science. Lead authors of the paper are graduate students Le Cong and Ann Ran.

Early efforts

The first genetically altered mice were created in the 1980s by adding small pieces of DNA to mouse embryonic cells. This method is now widely used to create transgenic mice for the study of human disease, but, because it inserts DNA randomly in the genome, researchers can target the newly delivered genes to replace existing ones.

In recent years, scientists have sought more precise ways to edit the genome. One such method, known as homologous recombination, involves delivering a piece of DNA that includes the gene of interest flanked by sequences that match the genome region where the gene is to be inserted. However, this technique’s success rate is very low because the natural recombination process is rare in normal cells.

More recently, biologists discovered that they could improve the efficiency of this process by adding enzymes called nucleases, which can cut DNA. Zinc fingers are commonly used to deliver the nuclease to a specific location, but zinc finger arrays can target every possible sequence of DNA, limiting their usefulness. Furthermore, assembling the proteins is a labor-intensive and expensive process.

Complexes known as transcription activator-like effector nucleases (TALENs) can also cut the genome in specific locations, but these complexes can also be expensive and difficult to assemble.

Precise targeting

The new system is much more user-friendly, Zhang says. Making use of naturally occurring bacterial protein-RNA systems that recognize and snip viral DNA, the researchers can create DNA-editing complexes that include a nuclease called Cas9 bound to short RNA sequences. These sequences are designed to target specific locations in the genome; when they encounter a match, Cas9 cuts the DNA.

This approach can be used either to disrupt the function of a gene or to replace it with a new one. To replace the gene, the researchers must also add a DNA template for the new gene, which would be copied into the genome after the DNA is cut.

Each of the RNA segments can target a different sequence. “That’s the beauty of this. You can easily program a nuclease to target one or more positions in the genome,” Zhang says.

The method is also very precise — if there is a single base-pair difference between the RNA targeting sequence and the genome sequence, Cas9 is not activated. This is not the case for zinc fingers or TALENs. The new system also appears to be more efficient than TALEN, and much less expensive.

The new system “is a significant advancement in the field of genome editing and, in its first iteration, already appears comparable in efficiency to what zinc finger nucleases and TALENs have to offer,” says Aron Geurts, an associate professor of physiology at the Medical College of Wisconsin. “Deciphering the ever-increasing data emerging on genetic variation as it relates to human health and disease will require this type of scalable and precise genome editing in model systems.”

The research team has deposited the necessary genetic components with a nonprofit called Addgene, making the components widely available to other researchers who want to use the system. The researchers have also created a website with tips and tools for using this new technique.

Engineering new therapies

Among other possible applications, this system could be used to design new therapies for diseases such as Huntington’s disease, which appears to be caused by a single abnormal gene. Clinical trials that use zinc finger nucleases to disable genes are now under way, and the new technology could offer a more efficient alternative.

The system might also be useful for treating HIV by removing patients’ lymphocytes and mutating the CCR5 receptor, through which the virus enters cells. After being put back in the patient, such cells would resist infection.

This approach could also make it easier to study human disease by inducing specific mutations in human stem cells. “Using this genome editing system, you can very systematically put in individual mutations and differentiate the stem cells into neurons or cardiomyocytes and see how the mutations alter the biology of the cells,” Zhang says.

In the Science study, the researchers tested the system in cells grown in the lab, but they plan to apply the new technology to study brain function and diseases.

The research was funded by the National Institute of Mental Health; the W.M. Keck Foundation; the McKnight Foundation; the Bill & Melinda Gates Foundation; the Damon Runyon Cancer Research Foundation; the Searle Scholars Program; and philanthropic support from MIT alumni Mike Boylan and Bob Metcalfe, as well as the newscaster Jane Pauley.

Brain Scan Cover Image: Fall 2012

Anne Trafton |

Neurons in the brain of a transgenic mouse engineered to express a protein that emits light when neurons become active. Image: Qian Chen, Guoping Feng

Satra Ghosh: Social Engineer

Anne Trafton |

Satra Ghosh is a research scientist in John Gabrieli’s lab at the McGovern Institute for Brain Research at MIT. In this video, Satra talks about his research on mild traumatic brain injury in U.S. soldiers.

[Stock footage/music: U.S. Department of Defense, Satra Ghosh, shockwave-sound.com]

McGovern Institute Magic Mug

Anne Trafton |

Our researchers and staff are an amazing bunch of individuals. To thank them for their efforts this past year, we gave them “magic mugs” — they’re quite a hit.

Video Profile: Feng Zhang

Anne Trafton |

Feng Zhang, a member of the McGovern Institute for Brain Research at MIT, is designing new molecular tools for manipulating the living brain. As a student, he played a major role in the development of optogenetics, a technology by which the brain’s electrical activity can be controlled with light-sensitive proteins. He is now working to extend this molecular engineering approach to other aspects of brain function such as gene expression, and to develop new approaches to understanding and eventually treating brain diseases.