Posted on behalf of Benjamin Paffhausen:
The authors studied long term sensitization of the withdrawal reflex in Aplysia, which is an example of
long term memory (LTM). Previous findings suggested that activation of protein kinase A (PKA) and extracellular signal regulated kinase (ERK) lead to long term facilitation (LTF), a form of LTM. PKA and ERK are activated by serotonin. PKA and ERK both activate an inducer, CREB1 for example, a transcription factor important for LTF. The interesting part is that these two enzymes with the same trigger and the same target need different amounts of time to reach their peak of activity. While PKA is already back to a basal level 15 minutes after activation by serotonin, ERK reaches the peak of its activity after 45 minutes with an initial delay of 25 minutes after serotonin stimulation. So one trial of stimulation would result in very little overlap between these two necessary components for an effect on the inducer.
Before this study, since 1986, the best training protocol (‘standard protocol’) consisted of giving five times a 5-minute serotonin stimulus with a 20-minute interstimulus interval (ISI). The authors developed a computational model of these enzyme cascades to identify an optimized protocol enhancing the effectiveness of training by maximizing the overlap of activated PKA and ERK. They tested the model
on every protocol that only differed in the ISI in a 5 min resolution and an overall time window of 200 minutes. The result of testing every combinations of ISIs on the model was a sequence of ISIs of 10, 10, 5 and 30 minutes, which was predicted to lead to more than 50 % more inducer. For the protocol which the model predicted (called the ‘enhanced protocol’) the highest overlap of PKA and ERK was tested in vitro against the standard protocol to see if training with that would improve the learning. In neuronal cultures, the activated CREB1 was significantly increased in the enhanced protocol compared to the standard protocol. The magnitude of excitatory postsynaptic potentials after 5 days was greater only in the animals trained with the enhanced protocol. Also the response duration was enhanced, after 1 day in the standard and enhanced protocol, and after 5 days only in the enhanced protocol.
Thus, in what is an exceedingly rare case in biology computational models can predict future results in real biological experiments, in this case enhanced learning and memory.
Zhang, Y., Liu, R., Heberton, G., Smolen, P., Baxter, D., Cleary, L., & Byrne, J. (2011). Computational design of enhanced learning protocols Nature Neuroscience DOI: 10.1038/nn.2990
Tags: Aplysia, CREB, ERK, modelling, PKA, sensitization, serotonin
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Am 15. June 2023 um 22:42 Uhr
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Am 11. August 2023 um 05:03 Uhr
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