How Do We Learn and Remember?

The mechanisms of learning and memory are at the essence of how the brain works

One of the most fascinating and mysterious properties of the brain is its capacity to learn, or its ability to change in response to experience and to retain that knowledge throughout an organism’s lifetime. The ability to learn and to establish new memories is fundamental to our very existence; we rely on memory to engage in effective actions, to understand the words we read, to recognize the objects we see, to decode the auditory signals representing speech, and even to provide us with a personal identity and sense of self. Memory plays such as important and ubiquitous role that it is often taken for granted—the only time most people pay attention to their memory is when it fails, as too often happens through brain injury or disease.

Identifying the complex processes underlying learning, memory and brain plasticity is critical for understanding how the brain works, and remains one of the fundamental challenges facing the brain sciences. Although much has been learned about the neural basis of learning and memory over the years, it is becoming increasingly clear that further advances and insights can only be achieved through an interdisciplinary approach to the problem. Brown’s Brain Science Program (BSP) researchers are accomplishing this goal by examining the wide variety of phenomena associated with learning and memory at all levels of complexity, ranging from molecules, synapses, cells, neuronal ensembles, and neural systems, to the behavior of whole animals.

Molecular and Synaptic Mechanisms of Memory

Synapses are the connections between nerve cells, and they are also the major site of information exchange and storage in the brain. We now know that synapses can alter their effectiveness based on their activity, and that this phenomenon, known as synaptic plasticity, may be the fundamental basis of learning and memory. Researchers at Brown, including Professors Barry Connors, Anna Dunaevsky and Justin Fallon, are interested in how synapses are formed and maintained, and how they are modified by experience to store new information. In one major area of research these scientists are asking how ephemeral episodes of neural activity are transformed into long-lasting changes in synaptic strength. To persist, synaptic modifications require the synthesis of new proteins, many of which arise by the translation of mRNAs at synapses. Since synapses are far away from the cell body—where the mRNAs are made—the neuron must have means for sequestering the message at these remote locations and triggering their translation in response to synaptic activity. Professor Fallon and his students, for example, have discovered a novel molecular mechanism, called cytoplasmic polyadenylation, for the regulation of such local translation and are working to understand how this system functions in learning and memory. They are also studying whether this mechanism plays a role in the pathogenesis of Fragile X Syndrome, the most common form of inherited mental retardation. Finally, they are also investigating the molecular basis of synapse formation and elimination using the highly tractable nerve-muscle synapse.

Neural Systems of Memory

Researchers at Brown have long been interested in the intersection between brain functions and behavior, including understanding the neural basis of memory. Much of this research has focused on the structures composing a medial temporal lobe system that has been found to play a critical role in declarative memory functions in both rodents and primates, including humans. This research utilizes multidisciplinary approaches including neuroanatomical and neuronal recording studies. For example, by removing a brain structure in animal models, researchers are characterizing the ensuing defects in learning or memory, and thereby learn more about the region's functions. Such a study can then be advanced by recording neuronal activity in the intact structure in a behaving animal, to examine this area as animals learn new tasks. Professors Mayank Mehta and Rebecca Burwell study how new environments are learned in the hippocampus—a gateway for transforming sensations and thoughts into long-term memories. An understanding of the neural and cognitive substrates underlying memory and learning can be also be acquired through the investigation of memory and language disorders in humans, as Professors Sheila Blumstein, Katherine Demuth, William Heindel do in their labs. More recently, it has become possible to follow these same processes in humans using fMRI methods. This technique makes it possible to image not only the detailed structure of the living human brain, but to visualize changes in the brain’s blood flow that is a marker for brain activity. Professor Jerome Sanes uses this method to explore brain mechanisms that underlie motor skill learning. MRI, electrophysiological (i.e., EEG) and behavioral methods are also used by Professors Michael Tarr, Sheila Blumstein, and William Heindel to investigate the neural substrates underlying perceptual and semantic memory. The Brain Science Program’s MRI Research Facility has state-of-the-art MRI machines that will be expanding to include even more advanced imaging methods within the University’s new Life Sciences Building. The information gained by these studies should contribute to our understanding human memory and cognition, and may hold implications for persons with various memory disorders.

Computational and Mathematical Models of Memory

One of the distinguishing features of the Brain Sciences Program at Brown University is the unusually close and frequent interaction of brain theorists with bench experimentalists. Although the utility of theoretical arguments is well established in the physical sciences, with a few notable exceptions, the blending of theory and experiment in neuroscience has been challenging. Researchers at Brown have been at the forefront of developing theoretical models that have proved invaluable in elucidating the connections between molecular and cellular events mediating learning and memory. One of these projects, for example, that developed from a collaboration of Nobel Laureate Leon Cooper and Applied Mathematics/Neuroscience Professor Elie Bienenstock has led to a theory of synaptic plasticity (the BCM theory),which applied to a simple model of the visual cortex and the visual environment, explains how experience shapes the development of the visual system and determines its ultimate wiring pattern. The BCM theory has also sparked considerable experimental studies to show how synapses know when to increase or decrease their strength. The theoretical work on learning and memory has served to provide a deeper understanding of the physiology underlying learning and memory. Work in the laboratories of Professors James Anderson and Harel Shouval are examining the theoretical foundations of learning using simulations and models that incorporate artificial intelligence and statistics to develop adaptive machines that can take advantage of observations and examples in order to solve a variety of tasks that are achieved easily by human nervous systems, but poorly by computers.

The combined efforts of theoretical and experimental researchers in the Brain Science Program provide a unique approach to both understanding the nature of human learning and memory and the biological mechanisms that allow us to learn and remember.

Posted 11/03









				How Do We Learn and Remember? The mechanisms of learning and memory are at the essence of how the brain works One of the most fascinating and mysterious properties of the brain is its capacity to learn, or its ability to change in response to experience and to retain that knowledge throughout an organism’s lifetime. The ability to learn and to establish new memories is fundamental to our very existence; we rely on memory to engage in effective actions, to understand the words we read, to recognize the objects we see, to decode the auditory signals representing speech, and even to provide us with a personal identity and sense of self. Memory plays such as important and ubiquitous role that it is often taken for granted—the only time most people pay attention to their memory is when it fails, as too often happens through brain injury or disease. Identifying the complex processes underlying learning, memory and brain plasticity is critical for understanding how the brain works, and remains one of the fundamental challenges facing the brain sciences. Although much has been learned about the neural basis of learning and memory over the years, it is becoming increasingly clear that further advances and insights can only be achieved through an interdisciplinary approach to the problem. Brown’s Brain Science Program (BSP) researchers are accomplishing this goal by examining the wide variety of phenomena associated with learning and memory at all levels of complexity, ranging from molecules, synapses, cells, neuronal ensembles, and neural systems, to the behavior of whole animals. Molecular and Synaptic Mechanisms of Memory Synapses are the connections between nerve cells, and they are also the major site of information exchange and storage in the brain. We now know that synapses can alter their effectiveness based on their activity, and that this phenomenon, known as synaptic plasticity, may be the fundamental basis of learning and memory. Researchers at Brown, including Professors Barry Connors, Anna Dunaevsky and Justin Fallon, are interested in how synapses are formed and maintained, and how they are modified by experience to store new information. In one major area of research these scientists are asking how ephemeral episodes of neural activity are transformed into long-lasting changes in synaptic strength. To persist, synaptic modifications require the synthesis of new proteins, many of which arise by the translation of mRNAs at synapses. Since synapses are far away from the cell body—where the mRNAs are made—the neuron must have means for sequestering the message at these remote locations and triggering their translation in response to synaptic activity. Professor Fallon and his students, for example, have discovered a novel molecular mechanism, called cytoplasmic polyadenylation, for the regulation of such local translation and are working to understand how this system functions in learning and memory. They are also studying whether this mechanism plays a role in the pathogenesis of Fragile X Syndrome, the most common form of inherited mental retardation. Finally, they are also investigating the molecular basis of synapse formation and elimination using the highly tractable nerve-muscle synapse. Neural Systems of Memory Researchers at Brown have long been interested in the intersection between brain functions and behavior, including understanding the neural basis of memory. Much of this research has focused on the structures composing a medial temporal lobe system that has been found to play a critical role in declarative memory functions in both rodents and primates, including humans. This research utilizes multidisciplinary approaches including neuroanatomical and neuronal recording studies. For example, by removing a brain structure in animal models, researchers are characterizing the ensuing defects in learning or memory, and thereby learn more about the region's functions. Such a study can then be advanced by recording neuronal activity in the intact structure in a behaving animal, to examine this area as animals learn new tasks. Professors Mayank Mehta and Rebecca Burwell study how new environments are learned in the hippocampus—a gateway for transforming sensations and thoughts into long-term memories. An understanding of the neural and cognitive substrates underlying memory and learning can be also be acquired through the investigation of memory and language disorders in humans, as Professors Sheila Blumstein, Katherine Demuth, William Heindel do in their labs. More recently, it has become possible to follow these same processes in humans using fMRI methods. This technique makes it possible to image not only the detailed structure of the living human brain, but to visualize changes in the brain’s blood flow that is a marker for brain activity. Professor Jerome Sanes uses this method to explore brain mechanisms that underlie motor skill learning. MRI, electrophysiological (i.e., EEG) and behavioral methods are also used by Professors Michael Tarr, Sheila Blumstein, and William Heindel to investigate the neural substrates underlying perceptual and semantic memory. The Brain Science Program’s MRI Research Facility has state-of-the-art MRI machines that will be expanding to include even more advanced imaging methods within the University’s new Life Sciences Building. The information gained by these studies should contribute to our understanding human memory and cognition, and may hold implications for persons with various memory disorders. Computational and Mathematical Models of Memory One of the distinguishing features of the Brain Sciences Program at Brown University is the unusually close and frequent interaction of brain theorists with bench experimentalists. Although the utility of theoretical arguments is well established in the physical sciences, with a few notable exceptions, the blending of theory and experiment in neuroscience has been challenging. Researchers at Brown have been at the forefront of developing theoretical models that have proved invaluable in elucidating the connections between molecular and cellular events mediating learning and memory. One of these projects, for example, that developed from a collaboration of Nobel Laureate Leon Cooper and Applied Mathematics/Neuroscience Professor Elie Bienenstock has led to a theory of synaptic plasticity (the BCM theory),which applied to a simple model of the visual cortex and the visual environment, explains how experience shapes the development of the visual system and determines its ultimate wiring pattern. The BCM theory has also sparked considerable experimental studies to show how synapses know when to increase or decrease their strength. The theoretical work on learning and memory has served to provide a deeper understanding of the physiology underlying learning and memory. Work in the laboratories of Professors James Anderson and Harel Shouval are examining the theoretical foundations of learning using simulations and models that incorporate artificial intelligence and statistics to develop adaptive machines that can take advantage of observations and examples in order to solve a variety of tasks that are achieved easily by human nervous systems, but poorly by computers. The combined efforts of theoretical and experimental researchers in the Brain Science Program provide a unique approach to both understanding the nature of human learning and memory and the biological mechanisms that allow us to learn and remember. Posted 11/03