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The A–Z of smell
Neuroscience
triggered a chain reaction in which a chemical called cAMP activated the enzyme cAMP-dependent protein kinase A (PKA). PKA in turn modified other proteins, which strengthened the electrical connections between neurons for several minutes.The result was a hypersensitive neural circuit. This is analogous to short-term memory. For long-term memory, some other factor is needed, and in 1990 Kandel and his colleagues found it. Biologists knew that for the hypersensitivity to be ingrained for days, new genes had to be turned on. Kandel’s team discovered that PKA turns on a protein called CREB1 that activates genes.The genes activated by CREB1 then churn out proteins that reshape the nerve endings to build more synapses, making the nerve more likely to trigger action potentials in neighbouring nerves. CREB1 seemed to be the molecular cue for forming long-term memories.When Kandel’s team blocked CREB1, the neurons were only capable of short-term memory. Conversely, if they injected activated CREB1 into neurons, the cells converted experience into long-term memory and grew new synapses with far less stimulation. Soon researchers found that CREB1 was the gatekeeper for long-term memory in other animals. Boosting a CREB1-like molecule in flies gave the insects the equivalent of a photographic memory – they could learn in one training session what normal flies needed ten sessions to learn. Alternatively, mice with a defect in CREB1 were unable to remember their way around a maze for longer than a day. The potential for a drug that could enhance human memory was not lost upon Kandel and his team. In December 1998, they injected mice with rolipram, a drug that increases the activity of PKA and therefore indirectly boosts CREB1.The animals were trained to associate a warning tone with a mild electric shock and to react by freezing. A day later, drug-treated animals froze 62% more often than control animals (Proceedings of the National Academy of Sciences, vol. 95, p. 15020). And last April, Kandel reported that a similar treatment with rolipram helped old mice to remember mazes, doubling the percentage of animals that could learn to find their way to a cosy hiding place and nearly halving their error rate (Proceedings of the National Academy of Sciences, vol. 96, p. 5280). Kandel has since farmed out the research to the New York-based company that he and Columbia University helped found – Memory Pharmaceuticals. Rolipram itself holds only limited promise as a memory drug as it tends to induce vomiting in humans. But Kandel imagines that a drug based on similar principles might be available in 10–15 years. While there are certainly other neuron-shaping molecules waiting to be discovered, they would still not completely explain memory. Consider Kandel’s experience of Leonardo da Vinci’s masterpiece. How does his brain capture this particular experience in his long-term memory? Biologists are beginning to approach this problem by thinking of the brain as a collection of systems. One system might memorize spatial information – where on the wall
KEYSTONE MILLENNIUM MEETING: CONFERENCE REPORT September 2000
the painting hangs – while another records the smells of and sounds of the crowd. But what these systems are and how they interact is still a mystery. One approach to solving it begins with human brain imaging. Suppose, for example, a tiny region of the hippocampus were to light up in a brain scan while a research subject admires a piece of art. One region that could potentially be involved is called CA3. Geneticists could identify genes that are active in the mouse CA3, for example, and try knocking them out to get an idea of the normal function of each gene. But disrupting such genes may affect many more regions of the brain than just CA3. So biologists could then ‘dissect’ the control regions of each gene to find a way to switch it on or off only in CA3 and nowhere else. Using this approach, Kandel’s lab has already disrupted the ability of new synapses to form in CA3 and concluded that it is not involved in spatial memory (Cell, vol. 83, p. 1211). With strategies like this, scientists can systematically map functions to different parts of the brain.Yet even this enormous amount of work might fall short of fully explaining what happens in Kandel’s brain when he pictures the Mona Lisa. There the question of memory overlaps with the mystery of consciousness. Whether science will ever solve consciousness, Kandel refuses to speculate. “Let’s talk again in a few decades,” says the 70-year-old neurobiologist. “Then I’ll be able to tell you whether there are limitations ahead or not.” Philip Cohen
The A–Z of smell A man smells rain and is transported back to a romantic afternoon in Paris.A woman refuses to have lily of the valley in her house because the scent reminds her of a hated teacher. Scientists have yet to discover how an odour can subconsciously dredge up a memory or a thought. Almost nothing is known about how the olfactory system is wired to the emotional and cognitive centres of the brain, or to what extent smell dictates behaviour and mood. Could smell, for instance, have the power to enhance memory or treat mood disorders? These are questions to which Richard Axel of Columbia University, New York, would like to know the answers. To find them, he is building a picture of smell from the ground up – from the genes that control it to the ways in which it influences consciousness. The mammalian olfactory system is remarkable for its ability to recognize a vast array of odours – some 10 000 in all.The human visual system, by comparison, distinguishes only a few hundred hues. In 1991, Axel and his colleague Linda Buck, now at Harvard Medical School in Boston, took the first step towards discovering how the instructions for such a sensitive detection system could be accommodated in an already overcrowded genome.
© 2000 Elsevier Science Ltd. All rights reserved
“Let’s talk again in a few decades, then I’ll be able to tell you whether there are limitations ahead or not.” Eric Kandel
15
Neuroscience
…Scientists have yet to discover how an odour can subconsciously dredge up a memory or a thought. Almost nothing is known about how the olfactory system is wired to the emotional and cognitive centres of the brain, or to what extent smell dictates behaviour and mood…
16
When smelly molecules waft over a patch of skin at the top of the nasal cavity called the olfactory epithelium, they bind to receptors on the end processes of neurons embedded there.That triggers an electrical impulse which travels along the neurons’ axons to the olfactory bulb at the front of the brain. Buck and Axel isolated the family of genes that code for all of the receptor proteins in the mammalian olfactory epithelium. They found about 1000 genes – some 1% of the full mammalian complement. Since then, Axel’s group, along with others, has been unravelling how those 1000 receptors recognize 10 000 odours. Every neuron has only one type of receptor, and every receptor responds to a single section of an odourous molecule. The unique identity of an odour is represented by the combination of receptors it activates.This information then ‘lights up’ a different spatial map within the olfactory bulb, which is read by the higher, conscious centres of the brain. Information from the eyes, ears and touch sensors also generate spatial maps. These are like maps in the A-to-Z sense, because the location of a stimulus in the environment is plotted at a particular position in the brain. But it’s not like that with smell. “The information contained in the olfactory map is of a very different kind,” says Axel. Although neurons are arranged more or less randomly in the olfactory epithelium, all those that carry a particular type of receptor have axons running to the same pair of nodes, or glomeruli, in the olfactory bulb. The pattern of glomeruli that light up in response to a particular odour does not relate at all to the odour’s position in the environment, but define its chemical composition. The big question is: how does the brain extract the right information from the map? The mechanism by which those higher centres know to equate a given pattern of glomerular activity with newly mown hay, say, rather than rotten eggs, continues to elude researchers. Axel is approaching the problem from different angles. First, he wants to see how disturbing the map affects perception. To do that, he needs to know how the map develops in the first place and what guides the axons of newborn neurons to their predetermined destinations. By swapping the DNA sequence encoding one receptor for a different one, his group has already succeeded in diverting neurons to different glomeruli in the bulb, thereby altering the developing map. The receptor itself clearly plays a part in directing the immature neuron, he says. But that isn’t the whole story. It is likely to be one component in a more complex guidance process, he says, “one that is dependent on experience of smell and the resulting activity of neurons”. A second approach exploits the fact that across all members of a species, neurons converging on the olfactory bulb obey the same rules. That is, the same receptor types hook up with the same glomeruli. But every species has its own characteristic odour map, and those maps hold valuable clues as to how olfaction evolved in different lineages.
So far, the Columbia team has studied the system in insects, fish and mammals. “The logic is the same in all of them, in the sense that the brain reads a spatial map,” says Axel. But in each case the evolutionary process has picked out a different section of the genome to code for the receptor proteins. Last March, Axel’s team identified a handful of odour receptor genes in the fruit fly Drosophila (Cell, vol. 96, pp. 725–736).The fly’s mating activity is powerfully affected by certain odours, and by tinkering with its genes Axel hopes to relate patterns of neural activity to its reproductive behaviour. One spin-off might be the development of new insecticides. He says that by blocking the appropriate receptors, it should be possible to put crop-eating pests off reproduction. In mammals, however, the reproductive side of scent is complicated by the existence of a second olfactory system, which evolved separately from the main one. This is the vomeronasal organ, a pair of sacs located behind the nostrils. This ‘sexual nose’ relays information via a separate pathway to the amygdala and hypothalamus – the brain’s emotional centres – bypassing the higher, cognitive regions. It is involved in the nonconscious perception of smell, and detects the sexual signals called pheromones and triggers innate behaviours such as mating. When Axel and Buck identified the genes that code for receptors in the main olfactory epithelium, they also stumbled on a smaller, distinct family of genes that code for receptors in the vomeronasal organ. Last year, Axel and Catherine Dulac of Harvard University found that this system is wired differently from the main one. That may reflect the simpler and more stereotypical function of the vomeronasal organ, says Axel. It only has to recognize a small number of pheromones, each of which triggers an automatic, preprogrammed response. Controversy still rages over whether the human sexual nose influences our behaviour. When it comes to physical attraction, nobody knows to what extent we are at the mercy of invisible airborne molecules. For Axel, however, the answer is part of a broader and more tantalizing mystery: how does an odorant binding to a receptor elicit a particular thought? Laura Spinney
Use your head In Richard Andersen’s lab in Pasadena, a monkey is learning to manipulate an animated arm on a computer screen. But it is not pressing keys or moving a mouse. This monkey is being taught to control the arm by brainpower alone. The experiment is in its infancy. At the moment the researchers are learning how to read the monkey’s intentions by recording neural signals from electrodes implanted in its brain. But the hope is that by converting those signals into computer commands, the monkey will one day be able to control the virtual limb without so much as twitching an eyebrow.
KEYSTONE MILLENNIUM MEETING: CONFERENCE REPORT September 2000
© 2000 Elsevier Science Ltd. All rights reserved
triggered a chain reaction in which a chemical called cAMP activated the enzyme cAMP-dependent protein kinase A (PKA). PKA in turn modified other proteins, which strengthened the electrical connections between neurons for several minutes.The result was a hypersensitive neural circuit. This is analogous to short-term memory. For long-term memory, some other factor is needed, and in 1990 Kandel and his colleagues found it. Biologists knew that for the hypersensitivity to be ingrained for days, new genes had to be turned on. Kandel’s team discovered that PKA turns on a protein called CREB1 that activates genes.The genes activated by CREB1 then churn out proteins that reshape the nerve endings to build more synapses, making the nerve more likely to trigger action potentials in neighbouring nerves. CREB1 seemed to be the molecular cue for forming long-term memories.When Kandel’s team blocked CREB1, the neurons were only capable of short-term memory. Conversely, if they injected activated CREB1 into neurons, the cells converted experience into long-term memory and grew new synapses with far less stimulation. Soon researchers found that CREB1 was the gatekeeper for long-term memory in other animals. Boosting a CREB1-like molecule in flies gave the insects the equivalent of a photographic memory – they could learn in one training session what normal flies needed ten sessions to learn. Alternatively, mice with a defect in CREB1 were unable to remember their way around a maze for longer than a day. The potential for a drug that could enhance human memory was not lost upon Kandel and his team. In December 1998, they injected mice with rolipram, a drug that increases the activity of PKA and therefore indirectly boosts CREB1.The animals were trained to associate a warning tone with a mild electric shock and to react by freezing. A day later, drug-treated animals froze 62% more often than control animals (Proceedings of the National Academy of Sciences, vol. 95, p. 15020). And last April, Kandel reported that a similar treatment with rolipram helped old mice to remember mazes, doubling the percentage of animals that could learn to find their way to a cosy hiding place and nearly halving their error rate (Proceedings of the National Academy of Sciences, vol. 96, p. 5280). Kandel has since farmed out the research to the New York-based company that he and Columbia University helped found – Memory Pharmaceuticals. Rolipram itself holds only limited promise as a memory drug as it tends to induce vomiting in humans. But Kandel imagines that a drug based on similar principles might be available in 10–15 years. While there are certainly other neuron-shaping molecules waiting to be discovered, they would still not completely explain memory. Consider Kandel’s experience of Leonardo da Vinci’s masterpiece. How does his brain capture this particular experience in his long-term memory? Biologists are beginning to approach this problem by thinking of the brain as a collection of systems. One system might memorize spatial information – where on the wall
KEYSTONE MILLENNIUM MEETING: CONFERENCE REPORT September 2000
the painting hangs – while another records the smells of and sounds of the crowd. But what these systems are and how they interact is still a mystery. One approach to solving it begins with human brain imaging. Suppose, for example, a tiny region of the hippocampus were to light up in a brain scan while a research subject admires a piece of art. One region that could potentially be involved is called CA3. Geneticists could identify genes that are active in the mouse CA3, for example, and try knocking them out to get an idea of the normal function of each gene. But disrupting such genes may affect many more regions of the brain than just CA3. So biologists could then ‘dissect’ the control regions of each gene to find a way to switch it on or off only in CA3 and nowhere else. Using this approach, Kandel’s lab has already disrupted the ability of new synapses to form in CA3 and concluded that it is not involved in spatial memory (Cell, vol. 83, p. 1211). With strategies like this, scientists can systematically map functions to different parts of the brain.Yet even this enormous amount of work might fall short of fully explaining what happens in Kandel’s brain when he pictures the Mona Lisa. There the question of memory overlaps with the mystery of consciousness. Whether science will ever solve consciousness, Kandel refuses to speculate. “Let’s talk again in a few decades,” says the 70-year-old neurobiologist. “Then I’ll be able to tell you whether there are limitations ahead or not.” Philip Cohen
The A–Z of smell A man smells rain and is transported back to a romantic afternoon in Paris.A woman refuses to have lily of the valley in her house because the scent reminds her of a hated teacher. Scientists have yet to discover how an odour can subconsciously dredge up a memory or a thought. Almost nothing is known about how the olfactory system is wired to the emotional and cognitive centres of the brain, or to what extent smell dictates behaviour and mood. Could smell, for instance, have the power to enhance memory or treat mood disorders? These are questions to which Richard Axel of Columbia University, New York, would like to know the answers. To find them, he is building a picture of smell from the ground up – from the genes that control it to the ways in which it influences consciousness. The mammalian olfactory system is remarkable for its ability to recognize a vast array of odours – some 10 000 in all.The human visual system, by comparison, distinguishes only a few hundred hues. In 1991, Axel and his colleague Linda Buck, now at Harvard Medical School in Boston, took the first step towards discovering how the instructions for such a sensitive detection system could be accommodated in an already overcrowded genome.
© 2000 Elsevier Science Ltd. All rights reserved
“Let’s talk again in a few decades, then I’ll be able to tell you whether there are limitations ahead or not.” Eric Kandel
15
Neuroscience
…Scientists have yet to discover how an odour can subconsciously dredge up a memory or a thought. Almost nothing is known about how the olfactory system is wired to the emotional and cognitive centres of the brain, or to what extent smell dictates behaviour and mood…
16
When smelly molecules waft over a patch of skin at the top of the nasal cavity called the olfactory epithelium, they bind to receptors on the end processes of neurons embedded there.That triggers an electrical impulse which travels along the neurons’ axons to the olfactory bulb at the front of the brain. Buck and Axel isolated the family of genes that code for all of the receptor proteins in the mammalian olfactory epithelium. They found about 1000 genes – some 1% of the full mammalian complement. Since then, Axel’s group, along with others, has been unravelling how those 1000 receptors recognize 10 000 odours. Every neuron has only one type of receptor, and every receptor responds to a single section of an odourous molecule. The unique identity of an odour is represented by the combination of receptors it activates.This information then ‘lights up’ a different spatial map within the olfactory bulb, which is read by the higher, conscious centres of the brain. Information from the eyes, ears and touch sensors also generate spatial maps. These are like maps in the A-to-Z sense, because the location of a stimulus in the environment is plotted at a particular position in the brain. But it’s not like that with smell. “The information contained in the olfactory map is of a very different kind,” says Axel. Although neurons are arranged more or less randomly in the olfactory epithelium, all those that carry a particular type of receptor have axons running to the same pair of nodes, or glomeruli, in the olfactory bulb. The pattern of glomeruli that light up in response to a particular odour does not relate at all to the odour’s position in the environment, but define its chemical composition. The big question is: how does the brain extract the right information from the map? The mechanism by which those higher centres know to equate a given pattern of glomerular activity with newly mown hay, say, rather than rotten eggs, continues to elude researchers. Axel is approaching the problem from different angles. First, he wants to see how disturbing the map affects perception. To do that, he needs to know how the map develops in the first place and what guides the axons of newborn neurons to their predetermined destinations. By swapping the DNA sequence encoding one receptor for a different one, his group has already succeeded in diverting neurons to different glomeruli in the bulb, thereby altering the developing map. The receptor itself clearly plays a part in directing the immature neuron, he says. But that isn’t the whole story. It is likely to be one component in a more complex guidance process, he says, “one that is dependent on experience of smell and the resulting activity of neurons”. A second approach exploits the fact that across all members of a species, neurons converging on the olfactory bulb obey the same rules. That is, the same receptor types hook up with the same glomeruli. But every species has its own characteristic odour map, and those maps hold valuable clues as to how olfaction evolved in different lineages.
So far, the Columbia team has studied the system in insects, fish and mammals. “The logic is the same in all of them, in the sense that the brain reads a spatial map,” says Axel. But in each case the evolutionary process has picked out a different section of the genome to code for the receptor proteins. Last March, Axel’s team identified a handful of odour receptor genes in the fruit fly Drosophila (Cell, vol. 96, pp. 725–736).The fly’s mating activity is powerfully affected by certain odours, and by tinkering with its genes Axel hopes to relate patterns of neural activity to its reproductive behaviour. One spin-off might be the development of new insecticides. He says that by blocking the appropriate receptors, it should be possible to put crop-eating pests off reproduction. In mammals, however, the reproductive side of scent is complicated by the existence of a second olfactory system, which evolved separately from the main one. This is the vomeronasal organ, a pair of sacs located behind the nostrils. This ‘sexual nose’ relays information via a separate pathway to the amygdala and hypothalamus – the brain’s emotional centres – bypassing the higher, cognitive regions. It is involved in the nonconscious perception of smell, and detects the sexual signals called pheromones and triggers innate behaviours such as mating. When Axel and Buck identified the genes that code for receptors in the main olfactory epithelium, they also stumbled on a smaller, distinct family of genes that code for receptors in the vomeronasal organ. Last year, Axel and Catherine Dulac of Harvard University found that this system is wired differently from the main one. That may reflect the simpler and more stereotypical function of the vomeronasal organ, says Axel. It only has to recognize a small number of pheromones, each of which triggers an automatic, preprogrammed response. Controversy still rages over whether the human sexual nose influences our behaviour. When it comes to physical attraction, nobody knows to what extent we are at the mercy of invisible airborne molecules. For Axel, however, the answer is part of a broader and more tantalizing mystery: how does an odorant binding to a receptor elicit a particular thought? Laura Spinney
Use your head In Richard Andersen’s lab in Pasadena, a monkey is learning to manipulate an animated arm on a computer screen. But it is not pressing keys or moving a mouse. This monkey is being taught to control the arm by brainpower alone. The experiment is in its infancy. At the moment the researchers are learning how to read the monkey’s intentions by recording neural signals from electrodes implanted in its brain. But the hope is that by converting those signals into computer commands, the monkey will one day be able to control the virtual limb without so much as twitching an eyebrow.
KEYSTONE MILLENNIUM MEETING: CONFERENCE REPORT September 2000
© 2000 Elsevier Science Ltd. All rights reserved