Thomas Jessell named winner of 2013 Scolnick Prize

The Scolnick Prize is awarded annually by the McGovern Institute to recognize outstanding advances in the field of neuroscience.

“We congratulate Tom Jessell on this award,” says Robert Desimone, director of the McGovern Institute and chair of the selection committee. “He has been a pioneer in transforming developmental neuroscience from a descriptive to a mechanistic and molecular science.”

Jessell received his PhD from Cambridge University, and has held faculty appointments at Harvard Medical School and at Columbia University, where he is now the Claire Tow Professor of Neuroscience. He is also an investigator of the Howard Hughes Medical Institute.

Since moving to Columbia University in 1985, Jessell’s primary interest has been the embryonic development of the nervous system, specifically the spinal cord, which because of its relative simplicity and evolutionary conservation offers an ideal system for understanding general principles of neural development.

Jessell’s work has revealed the molecular mechanisms responsible for establishing the spatial organization of the spinal cord. He showed that the cord is shaped during embryonic development by diffusible signaling molecules known as “morphogens.” Two different classes of molecules are secreted by the most dorsal and ventral parts of the developing cord respectively, forming two opposing concentration gradients in the dorso-ventral axis. The concentrations of these signaling molecules provide “positional information” to embryonic cells, instructing them to differentiate in ways that are appropriate for their specific locations within the cord.

Jessell has also studied the molecular mechanisms by which developing cells respond to positional signals. Spinal motor neurons, for example, are known to cluster into “pools,” groups of neurons that form at stereotypic locations within the ventral spinal cord and which innervate a common target muscle. There are at least 50 different muscles in a vertebrate limb, each of which must be correctly innervated to allow precise control of movement. Jessell has shown that the identities of different motor pools are specified by combinations of transcription factors which are activated in different spatial domains in response to positional cues. These transcriptional “master regulators” work by controlling the expression of downstream genes that determine the distinctive properties of different neurons, including their shapes, their biochemical and electrical properties, and their choice of peripheral and central connections.

The discovery of these genetic mechanisms has made it possible to identify and manipulate the activity of specific classes of neurons with great precision, and Jessell has used this approach to reveal the link between functional circuitry and motor behavior.

In addition to fundamental questions, Jessell’s work has important practical implications for the emerging field of regenerative medicine. There is great interest in stem cells as a renewable source of cells for transplantation therapy, but for this approach to succeed, stem cells must be converted to the desired cell type. Jessell’s work on transcriptional control of neural identity provides a roadmap for such efforts, and he has demonstrated its feasibility in the case of spinal motor neurons, which degenerate in diseases such as amyotrophic lateral sclerosis. In collaboration with his former postdoc Hynek Wichterle, Jessell recently showed that embryonic stem cells can be induced to form a wide variety of motor neuron subtypes, and that when these neurons are transplanted into host embryos they can settle at the correct locations in the spinal cord and form appropriate axonal projections toward their normal targets. The implications of this result go well beyond motor neuron diseases; many disorders of the nervous system affect particular cell types, and the ability to convert stem cells to specific classes of neurons may eventually find wide applications in clinical neuroscience.

In addition to his many research contributions, Jessell also had great influence as a teacher and mentor. He is a coauthor of the classic textbook Principles of Neural Science, now in its fifth edition, and he has trained dozens of students and postdocs, many of whom are now recognized leaders in the field of neural development. Among the most notable is Marc Tessier-Lavigne, now president of Rockefeller University, whose pioneering work on the molecular basis of axon guidance was begun during a postdoctoral fellowship in Jessell’s lab.

The McGovern Institute will award the Scolnick Prize to Dr Jessell on Monday April 1, 2013. At 4.00 pm he will deliver a lecture entitled “Sifting Circuits for Motor Control,” to be followed by a reception, at the McGovern Institute in the Brain and Cognitive Sciences Complex, 43 Vassar Street (building 46, room 3002) in Cambridge. The event is free and open to the public.

Neuroscience and the Year of the Snake

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?

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

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.

Brain Scan Cover Image: Fall 2012

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

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

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

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.