What can cellular neuroscientists learn about the human brain from studying a marine snail? Much more than one might suspect.
"On a cell biological level, the mechanisms of learning and memory are identical, as far as we can tell," said David Glanzman, a UCLA professor of physiological science and neurobiology, whose research has strengthened the view that the human brain and that of a snail named Aplysia are surprisingly similar. "Human brains have many more neurons than the Aplysia's, but it doesn't look like there is any difference on a molecular or synaptic level.
"When this animal learns," Glanzman said, "many changes take place in its nervous system. I want to understand what causes these changes for certain forms of learning; I want to understand everything there is to understand. This knowledge will inform us about the kinds of changes that take place in our brains when we learn."
Glanzman's quest for this knowledge will be helped by his selection in November as one of eight scientists awarded the prestigious Senator Jacob Javits Award in the Neurosciences, which provides up to seven years of research funding from the National Institute of Neurological Disorders and Stroke (NINDS). The Jacob Javits Award is presented to investigators who have "demonstrated exceptional scientific excellence and productivity in research areas supported by the NINDS and who are expected to conduct cutting-edge research over the next seven years."
Glanzman's research may lead to such human applications as developing interventions for people with memory-related disorders and reducing age-related memory loss.
Glanzman, who has been conducting research on the marine snail for 20 years, said, "As far as I can tell, everything that my colleagues and I have found in the Aplysia has turned out to be relevant to nervous systems in mammals. The original goal of Eric Kandel, who founded this field and who won the 2000 Nobel Prize, was to use the marine snail to understand human learning. I expect there to be valuable lessons from the Aplysia for age-related memory loss in humans."
The marine snail, which is substantially larger than its garden-variety counterpart, has approximately 20,000 neurons in its central nervous system; humans have approximately one trillion. Glanzman has a good understanding of the functions of approximately 1,000 of the neurons. The marine snail is native to California, living in tidal waters off the coast.
With funding from the Jacob Javits Award, Glanzman's laboratory will study topics including the role of protein synthesis in long-term memory. In both the Aplysia and mammals, learning that is spaced over several hours induces long-term memory and turns on specific genes in neurons, causing proteins to be synthesized that have important functions in long-term memory. Glanzman's team is identifying important genes and proteins, and their functions in learning and memory.
What does the marine snail learn?
"The marine snail has to process information about its environment, and it has to make associations between different stimuli, just as we do," Glanzman said. "It is capable of learning when an environment is safe and when it is not, and of understanding the danger posed by a predator."
Glanzman, whose appointments are in both the UCLA College and UCLA's David Geffen School of Medicine, is especially interested in the role of protein synthesis in long-term memory.
"Long-term memory involves gene transcription and protein synthesis," he said. "Our laboratory has evidence that for long-term memory, protein synthesis may occur at an earlier stage in memory formation than was thought before. Then the questions are: What proteins are being synthesized, where are they being synthesized and what are they doing once they're synthesized? We will use the Jacob Javitz Award to try to answer these questions."
One answer to what is synthesized may be critically important receptors called AMPA glutamate receptors, which mediate most synaptic transmission in the brain. Glanzman is studying the role of AMPA receptors in learning.
In addition, Glanzman plans to start studying a vertebrate: the zebra fish. It has many more neurons than the marine snail, including some that are large and mediate rapid reflexes.
"If you try to pick up a goldfish, it seems to swim away from you quickly," Glanzman said. "What really happens is the fish has an extremely rapid escape response — a reflex that causes the fish to bend its body in a 'C' shape, and then pushes it away from you, and then the fish swims away. That startle reflex is the first response, and that startle reflex is mediated by large neurons known as Mauthner neurons. There is evidence that the zebra fish possesses primitive forms of learning, and more sophisticated forms of learning that the marine snail does not show."
As a Stanford graduate student, Glanzman began studying cognitive psychology and psycholinguistics, but "kept getting more and more reductionistic in my thinking. I wanted to understand how the brain actually works. In the Aplysia, one understands what the physiological and behavioral functions of individual neurons are. You can look at a neuron in the Aplysia and say, 'That's a motor neuron,' 'That's a sensory neuron.' We know that the activity of those neurons has a significant role in behavior. When looking at a change in a synaptic connection between a pair of neurons in the Aplysia nervous system, we know, for some of the neurons, what effect that will have on behavior."
In earlier research, Glanzman's team identified a cellular mechanism in the Aplysia that plays an important role in learning and memory. A protein called the NMDA receptor enhances the strength of synaptic connections in the nervous system, and plays a vital role in memory and in certain kinds of learning in the mammalian brain as well. Glanzman's team demonstrated, in research published in 1994, that strengthening of synaptic connections due to activation of NMDA receptors (N-methyl D-aspartate) is critical for learning in the marine snail.
Glanzman's research is funded by the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke. Reacting to his selection for a Jacob Javits Award in the Neurosciences, he said, "I'm very honored."
Higher invertebrates learn in complex ways, said Glanzman, who noted that bees learn to associate colors with nectar, and marine snails learn to identify food, and to flee from predators.
"Our work implies that the brain mechanisms for forming these kinds of associations might be extremely similar in snails and higher organisms. People may think invertebrates are not very sophisticated, but we don't appreciate just how complicated their nervous systems are, and how complex their behaviors are. We don't fully understand even very simple kinds of learning in these animals."
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