02/10/12 Mark Good -

Neuroscience of Learning & Memory Habituation & Sensitisation

Memories are stored and encoded in the medial temporal lobe region Well focus on the work of Eric Kandel o We question which sort of neural wiring supports memory; plasticity in a neural chain (e.g. reflex circuit; input output via synapse) or plasticity in a superordinate chain? The brain is made up of a series of superordinate chain circuits where a simple circuit (e.g. reflex) is interfaced with a superordinate circuit. Superordinate circuits have 3 levels o Input circuit affects superordinate circuit o Input circuit affects output circuit o Superordinate circuit affects output circuit o Kandel focussed on this Hebb focussed on a third type; plasticity in a cell assembly (input goes via neural networks to output) o We can use many superordinate circuits to build neural networks for very complicated things e.g., learning a language o Cells that fire together, wire together When cells are firing at the same time, a process occurs whereby coincident activity occurs such that a network of neurons become activated as a function of being coactive during the learning experience

Changes that might occur at the synapse to support learning an memory - After learning you get an increase in amount of NT (neurotransmitter) released o E.g. memory of Mark; if after the lecture we feel scared of Mark (which we didnt have before) then the presynaptic terminal might release more neurotransmitter - After learning the post synaptic terminal gets bigger; there are more receptors on the post-synaptic neuron so its more sensitive to same amount of NT a bigger reaction - Or, you might get both of the above; more NT and more NTr - They all lead to a bigger response Superordinate Circuit Involving an Interneuron - The above involved a simple monosynaptic circuit; now were talking about if there was an input from a different neuron modulating activity of the presynaptic neuron; i.e. there is a 2nd input o After learning there might be increased activity from the second input that increases NT release from the Pre-S neuron (pre-synaptic) In 1970s Eric Kandel worked sea slug called Aplysia Californica; it has a very simple brain which consisted of 8 ganglia. He focused on the 9th, abdominal ganglia. If you tap a snails eye enough times it will no longer withdraw it = Habituation; Aplysia has a similar reaction where is sucks water in and forces water over its gill to extract oxygen, and then the waste water is forced out of the back. If you touch Aplysia then the gill withdraws into the body. Sensitisation is an enhancement, rather than reduction of a response. Kandel touched the siphon of the slug and electrocuted it at the same time, such that in future whenever the siphon was touched there was an exaggerated response. You can stick electrodes into the cells of the abdominal ganglia (the cells have a massive diameter in the Aplysia); Kandel dissected out the circuit in the abdominal ganglia that mediates the gill response. Siphon is attached to sensory neuron which has presynaptic connections with dendrites of motor neuron which attaches to gill. This is a simple monosynaptic connection; upon stimulation of the syphon the gill will withdraw - There is also a superordinate circuit carrying information from the skin; they make connections with facilitating interneurons, which connect with the Pre-S side of the synapse in the simple circuit. Kandel recorded activity in the sensory and motor neuron during the process of habituation by poking it. He saw that the sensory neuron still fires but the motor neuron shows no response in habituation. Either the motor neuron is dead (which is probably unlikely because that same motor neuron mediates breathing in Aplysia,
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which did not stop) or there is a modification in the synapse (more likely). The change therefore is in the pre or post synaptic element. Habituation can be a STM (seconds or mins) and can become a LTM

Kandel posed that the change is due to a decrease in the release of NT from the sensory neuron; he said that as a consequence of habituation, the Ca2 signal that comes in the Pre-S terminal is reduced and therefore less NT vesicles dock and release at the front of the membrane. Short-term habituation: Reduction in NT release - Proved by Quantal analysis (this supported Kandels hypothesis) - We dont know why the calcium signal declines Long term habituation: Change in synapse structure - The number of connection is actually pruned back; e.g. if at the beginning there were 3 presynaptic connections to the motor neuron then after time there might just be one These changes are specific to the pathway/circuit undergoing (habituation) training Sensitisation The strong shock to the tail leads to an increase in the size of the withdrawal response when you touch any part of the body You can get short and long term forms We see that the sensory neuron AP is the same but the motor neuron response is bigger The facilitating interneuron from the tail gets activated during the shock and releases 5HT and splashes the presynaptic terminal of the sensory neuron with it o Normally 5HT causes the release of cAMP-dependant PKA which shuts down potassium channels (which are responsible for returning a membrane back to its resting state); thus lengthening the activity of the AP on the Pre S terminal Ca2+ are open for longer More activity from synaptic vesicles bigger response from motor neuron This process is called spike broadening (i.e. AP is lengthened) This explains short term sensitisation Long term sensitisation results in morphological changes in the circuit in the opposite direction to habituation; the size of the active zones increases and there are more synaptic vesicles in the active zone