8 2 Vertebrate Learning Vertebrate animals and mammals in particular seem to display a greater capacity for learning and storing long term memories than most invertebrates perhaps due to the greater complexity and organization of their central nervous systems In order for an animal to remember something it must retain a long term cellular and molecular change Because cells are constantly replaced this also means that these changes must be passed on from cells to daughter cells during mitosis The mechanisms of how experiences cause these changes what the changes are exactly and how they are maintained are active fields of research as there is still a lot that we do not know learning and memory Read the Studies of Learning and Memory in Vertebrates http www ncbi nlm nih gov books NBK28220 section 50 5 from Basic Neurochemistry before proceeding Most of what we do know comes from studies in mammals where a part of the brain called the hippocampus seems to be crucial to forming long term memories A common experimental set up for studying learning and memory in mammals is called the Morris water maze as seen below If rats and mice are put into a pool of water in which they cannot touch the bottom they will swim In the Morris water maze a small shallow pool is filled with an opaque liquid like diluted milk Submerged under the surface is a small platform that the animal could use to stand on and some visual landmark is placed on the edge of the tank to orient the animal If a mouse is put into this pool several times it will learn where the platform is and swim directly to it However a mouse with a damaged hippocampus will not form this memory and will continue to swim until it happens upon the platform just as it did the first time it was in the maze If a mouse s hippocampus is damaged after the training process it performs like normal swimming quickly to the platform Results from experiments like these suggest that the hippocampus is important in forming long term memories but they are stored elsewhere Neurons in the hippocampus called the CA3 and CA1 neurons appear to be responsible for long term memory formation and their molecular and electrical responses to stimulation have been extensively studied The most common cellular model for memory formation involves the neurons in the hippocampus and is called long term potentiation LTP LTP is an activity dependent increase in a response at the level of particular neurons When a particular pre synaptic neuron in the hippocampus is repetitively strongly stimulated eventually the post synaptic neuron will respond by depolarizing more and firing more action potentials This is a cellular model of memory a neural pathway is repetitively activated and this leaves a record in the neurons such that the response remains increased after the repetitive activity ceases LTP occurs in several parts of the mammalian brain but it is most studied in the hippocampus LTP itself seems to decay after 1 2 weeks but recall that it does not seem to be necessary for long term memory storage just formation Consolidation of memories appears to happen in other areas including the neocortex The figure below shows normal activity at a synapse in the hippocampus in response to low intensity stimulation If the same pathway is strongly electrically stimulated this will induce LTP Like most other excitatory synapses in the central nervous system the pre synaptic neuron releases glutamate onto the post synaptic neuron which expresses two ionotropic Glu receptors the AMPA glutamate receptor Glu R and the NMDA Glu R When multiple receptors bind the same ligand under natural conditions they can often be distinguished by the drugs that they bind It has been demonstrated experimentally that these receptors bind the drugs AMPA and NMDA respectively Under resting conditions the NMDA receptor is plugged by an atom of Mg2 When Glu is released pre synaptically it binds both receptors but only the AMPA receptor permits ion flow It allows both Na and K through but the electrochemical gradient for Na is much stronger so the net effect is a small EPSP If the pre synaptic neuron is stimulated at a high frequency a lot of Glu will be released causing more AMPA receptors to open and a greater EPSP in the post synaptic cell This greater positive charge inside will displace the cation Mg2 unblocking the NMDA receptor This channel is also fairly non selective permitting Na K and Ca2 through Recall that there is a huge chemical gradient for Ca2 to enter the cell Thus as Na enters and K exits Ca2 will also enter causing a greater EPSP and greater intracellular Ca2 This will activate a Ca2 dependent enzyme called calcium calmodulin dependent protein kinase II CaMKII as well as protein kinase C PKC which you should remember from long term sensitization in Aplysia These phosphorylate a variety of proteins including positively feeding back onto the AMPA receptor to increase AMPA activity The current AMPA receptors are phosphorylated by CaMKII increasing their sensitivity to Glu also vesicles containing more AMPA receptor are targeted to the membrane inserting more receptors at the synapse and making the cell more responsive PKC activates a signaling pathway that leads to the pre synaptic cell causing it to release more Glu when stimulated Thus strong repetitive activation of this pathway in the hippocampus leads to both long term pre synaptic and post synaptic changes that will cause an increased response when the pathway is stimulated in the future There are actually three steps in the pathway of hippocampal neurons at which LTP can take place repetitive activity results in an increase in post synaptic response but we are focusing only on one LTP can be divided into an early phase and a late phase The cellular mechanisms of early LTP resemble short term sensitization in that they affect proteins and other molecules that are already present Late LTP resembles long term sensitization in that it necessitates synthesis of new proteins and will eventually lead to growth of new axon branches and formation of new synapses By increasing the number of synapses between the CA3 and CA1 neurons activation of CA3 will lead to a greater post synaptic response in CA1 What would happen if LTP accrued in the hippocampus never being reversed Eventually the neurons would reach a saturation point and fail to respond further to increased activity or changes in activity patterns and potentially lose the ability to
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