Week 4

I found the first paper concise yet effective in supporting the hypothesis that ablation of CREB-overexpressing neurons in the LA was sufficient for erasing a fear memory. It is unclear to me whether the fear memory in its entirety is erased or if the association between the tone and the sensation of fear is uncoupled but, regardless of the interpretation, selectively removing the memory trace neurons in the LA after fear memory acquisition clearly erases the memory in  either case.

The conclusions from the Yiu et al paper were hard to dispute as they do a thorough job of addressing alternate hypotheses throughout the paper. I was really excited by the Kir2.1, hM3Dq DREADD, and optogenetics experiments in which the experimenters selectively manipulate the excitability of the cell without altering the CREB expression because it decouples the excitability phenotype of CREB overexpression from the many other downstream effects of CREB. This supports the point that CREB overexpression is responsible for the preferential inclusion of neurons in the memory trace. While the CREB overexpression and dominant negative CREB expression experiments make a similar point, they alone do not pinpoint the change in excitability due to CREB expression as the key component in determining which neurons are recruited. The synthetic reactivation of the memory trace experiments using CNO administration after memory formation adds additional validity to the fact that they are truly manipulating the fear memory and not some peripheral aspect of the memory, which is pretty amazing.

After reading these papers, I’m curious about the exact mechanism by which CREB comes to be more expressed in these cells. Is there something even before CREB expression that governs which of these cells will express more CREB, and therefore be preferentially activated/chosen to be part of the memory trace? Although, it is equally possible that there is nothing special about the exact cells that are expressing CREB. Maybe each cell in the LA equally likely to be overexpressing CREB at any given time and the ones that are chosen to be part of the memory trace are the ones that randomly happen to be expressing higher levels of CREB at the exact moment of a fear conditioning trial. I believe this is the interpretation that the authors might go with considering the fact that pre-ablation of the neurons before fear training does not hinder the ability to form the fear memory. But it would be pretty cool if there was something extra special about these neurons, even beyond the CREB expression.