I fear that I may be stereotyping myself in some regard, as it seems that every post I’ve made here thus far has concerned some aspect of homeostatic regulation and how such regulation can go awry in instances of obesity. This fear, however, is not the reason why I am changing my tune today. Rather I am blogging about memory because this paper focuses itself on a peptide (IGF-II) that I know quite well from the world of energy balance regulation. Because the peptide is involved in memory, I can broaden my horizons while remaining safely enclosed in my narrow enclave.
The Insulin-like Growth Factors (IGFs) are a family of peptides that, as one might guess, bear a structural resemblance to insulin. Like insulin, the IGFs were initially characterized for their involvement in homeostasis and development. Indeed, IGF-I acts as a growth factor during development, but also during adulthood. IGF-II is a somewhat different story, because while it is important in development, its role in adulthood is not as easy to understand. To be sure it is found in the brain and its existence is essential for normal function, but the details have a long way to go. One thing that is known, however, is that IGF-II is a likely target of the CREB/C/EBP system. Learning and memory are have as their neural correlates a series of structural and functional neurobiological changes, and the CREB/C/EBP system is important in regulating these changes. The question thus becomes: how is the interaction between C/EBP and IGF-II important for the neurobiology of memory?
To begin with, the authors used an inhibitory avoidance task as a simple model of learning. In this model, a rat is given a choice between two different rooms. The rat is initially placed into a ‘safe’ room next door to a different colored ‘shock’ room. Curious beings that they are, rats generally explore the ‘shock’ room, only to be administered a mild electrical shock. Provided the proper operation of learning and memory, a rat should take longer to enter the ‘shock’ room the next time it’s in the apparatus. If the animal doesn’t seem to remember this when tested later, it’s a good sign that something is going wrong with memory.
IGF-II is upregulated in the hippocampus about 20h after this training. C/EBP is upregulated around the same time points. Next they tried blocking C/EBP in the hippocampus immediately after training. It’s already known that doing this blocks the formation of memory in this model (the rat never learns to avoid the bad box), but here they show that this also attenuates the increase in IGF-II expression. Blocking IGF-II in the same way also disrupts memory formation. Interestingly, this is true whether it is blocked early after the test (8h) or much later (24-32h). Eventually, however, blocking IGF-II stops affecting the memory. At 96 or 104h, blocking IGF-II does not affect performance in the (previously learned) task. Perhaps by this time point, the memory had already been stamped in, and whatever role IGF-II played in doing that was finally over with. The authors also showed that injecting IGF-II into the hippocampus improves memory retention, further strengthening the case that it is important in memory.
Finally, the authors looked at how IGF-II interacts with the cellular mechanisms of memory. Long-term potentiation (LTP) refers to a phenomenon whereby the synapses between two connected neurons are strengthened by their coincident activation. Because these synaptic alterations last for quite some time after the initial stimulus has vanished, LTP is an ideal candidate mechanism for memory. Anyhow, IGF-II promotes LTP in the hippocampus. Furthermore, IGF-II increases the expression of GluR1 AMPA receptor subunits, another molecular marker of memory storage.
So what does this all tell us? Well ultimately it’s just another piece of the puzzle. But one wonders what the role of this “endogenous cognitive enhancer” might be in our normal, day-to-day life. Alternately, could this system be exploited therapeutically? Could we use this knowledge in the treatment of disorders such as PTSD, where all too often it is our memory working against us?
Chen DY, Stern SA, Garcia-Osta A, Saunier-Rebori B, Pollonini G, Bambah-Mukku D, Blitzer RD, & Alberini CM (2011). A critical role for IGF-II in memory consolidation and enhancement. Nature, 469 (7331), 491-7 PMID: 21270887