Cognitive information is encoded in patterns of nervous activity and decoded by molecular listening devices at the synapse. Professor Seth Grant explains how different patterns of neural firing are critical to cognition.

Cognitive information is encoded in patterns of nervous activity and decoded by molecular listening devices at the synapse. Professor Seth Grant explains how different patterns of neural firing are critical to cognition. We are all used to thinking about codes such as Morse codes, and other kinds of codes, which are simply ways of encoding information. I’d like to tell you about the neural code, and this is a very important fact that should underpin all of our studies in the nervous system. It is that information about our environment is all encoded in the electrical patterns of action potentials. Just like Morse code, it’s the patterns of nerve cells firing that encode information. E.D. Adrian: The discovery that information is encoded in patterns of action potentials was made by Professor E.D. Adrian in Cambridge University during the 1920s, and he published this very small book here called The Basis of Sensation in 1928 that describes that. What Adrian’s work tells us is that if we want to understand how sensory information from our environment – whether it be taste, touch, or smell – is decoded or interpreted by the brain and used for laying down processes such as learning memory. And we must understand how patterns of action potentials, or nerve cell-firing, is extracted, and how information is taken out of those patterns, and laid down in biochemical mechanisms. Glutamate release and NMDA: When patterns of action potentials arrive at synapses in the central nervous system, they cause the release of glutamate, the neurotransmitter, from the presynaptic terminal onto receptors at the postsynaptic side. One of the most important receptors is the NMDA receptor (also known as the N-Methyl-D-Asparate receptor), and when that one is activated during the process of learning, it activated the biochemistry of learning. Gutamate activates the NMDA receptor: When the neurotransmitter glutamate activates the NMDA receptor, the NMDA receptor changes its shape. When it does so, it opens up a pore, or a channel, in the middle of the receptor, and what flows through that channel is a calcium ion that is normally found outside a cell, and it races into the inside of the postsynaptic terminal. Binding to kinases: Once inside the postsynaptic terminal, these calcium ions trigger biochemical events. They do so by binding on to proteins, and one of the most important types of proteins that they bind to are called kinases. Phosphorylation: Kinases are enzymes, and these enzymes have a very special and simple role: it is to add a phosphate group onto other proteins. So, when a kinase becomes activated, it adds a phosphate onto other proteins, which are called protein substrates. As a result of adding these phosphate groups, these other proteins are now altered. Kinases regulate receptors in the cell: I’m now going to tell you about the roles of the many different proteins that are found on the postsynaptic side of the synapse. In recent we’ve discovered that there are not just a small number of proteins, that there are actually hundreds of them in this postsynaptic terminal. It is these proteins that are regulated by the kinases, and it is these proteins that do many different jobs in the nerve cell. For example, some of those proteins cause receptors to be added onto the surface of the cell. Kinases regulate proteins that change cell structure: There are other sorts of proteins that change the structure of the nerve cell and the synapse itself. Kinases regulate the formation of new synaptic proteins There are also other proteins that are responsible for making new synaptic proteins. Kinases regulate proteins that control gene expression: As well as proteins at the synapse, the signals from the synapse go all the way back to the synapse and control the gene expression and the synthesis of RNA itself So from this you should understand that all of these proteins on the postsynaptic side of the synapse control many different properties of the nerve cell, and it is these properties that are activated and very carefully regulated during the process of learning and memory. Different patterns of activity turn on different proteins to different extents So patterns of action potentials come to the synapse, they activate the receptor, it turns on kinases, which then regulate dozens if not hundreds of postsynaptic proteins, which then change the properties of the synapse, its shape and gene expression. But not all patterns of activity do the same thing. Under some conditions, a pattern of activity that might occur during some forms of learning might turn on the receptor in a slightly different way to what it might do during a different type of learning. As a result of the receptor being turned on by different patterns of activity in different ways, you would then drive and activate different sets of these postsynaptic proteins in these networks. It is as though different information is coming into this network of proteins, and this network of proteins is decoding these patterns of activity. Low frequency activation pattern Let’s imagine now a low-frequency pattern of neuronal activity, which comes in and activates the receptor and some of these kinases. It might only turn on some proteins that cause receptors to be inserted into the membrane. High frequency activation pattern Another type of pattern activity might be one with a very high frequency, and it might do much more. It might do much more – it might come in and not just activate receptors on the surface. It might also cause genes in the nucleus to be turned on, which would then lay down long-term memories. Different patterns have different effects So now when you look at the picture of the molecular network, you should see that different patterns of activity are being sorted and traveling through that molecular network so as to change different properties of the nerve cell in ways that are physiologically important for those different patterns of activity. Gene mutations impair learning networks across species Many different studies using gene mutations or drugs that interfere with proteins have shown us that when you knock out different proteins in these networks that I’ve described, that you end up with defects in learning. There is certainly true in genetically modified mice and rats. In humans, it has been shown, that mutations that are inherited and that knock out these proteins, also result in learning defects as well as other kinds of mental illnesses. Postsynaptic networks are implicated in human diseases. One of the exciting applications of these molecular networks is to be able to ask, in what way are these networks disturbed in various kinds of human diseases? And so, we construct simple network maps of schizophrenia, autism, mental retardation and other diseases. When you look at these maps, you will discover that some of the genes involved with schizophrenia are in slightly different places on the maps to those involved with autism and other diseases. We think that by looking at this molecular maps, we will be able to find new ways to discover drugs that will ultimately be useful in treating these conditions. Synaptic networks are similar to computer circuits In neuroscience, it has been traditionally thought that all of our mental processes are effectively encoded in those large numbers of nerve cells that make up the complex of circuits our nervous system. But we are now looking at the possibility that these highly complex molecular circuits that occur within the synapses might be essential and important for both processing and storing information. It is as though that all synapses have within them a highly complex molecular computer or molecular computer chip like that found in your personal computer. We think it is likely that the brain processes information, not only at this cellular neuronal circuit level, but also at this microscopic molecular circuitry level as well.

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