CREB Giveth & Genetic Manipulation Taketh Away: The Story of Auditory Fear Memory in the Amygala

The idea that CREB levels can designate which neurons are recruited to the auditory fear memory trace is introduced in the 2009 Han et. al. paper. However, CREB plays a vast variety of roles within the cell, so the reason for this is unclear. It is the 2014 Yiu et. a. paper that finally gives an indication as to which role of CREB is important to this particular function. As it turns out, neuron excitability is the key.

After reading the first paper, I will admit that I had some burning questions left. For example- what role was CREB playing in this process? (thank you Yiu et. al) What happens if you knock out or knock down CREB function? Would it make it impossible for an auditory fear memory to be encoded at all? Is CREB necessary for this memory encoding process? Could this even be answered without making the affected neurons completely dysfunctional? Furthermore, could you allow the memory to be encoded, and temporarily erase it by simply inhibiting the CREB-cre cells instead of killing them all together? Could the memory be rescued by re-activating the same CREB-cre cells later on? After reading the second paper, I still wondered if there are other proteins in the cell that could play the same role in increasing neuronal excitability. Is CREB still necessary or simply some factor to increase excitability? Is CREB directly involved with the voltage dependent potassium channels examined in this paper, or are they independent mechanisms of excitability?

Something I have noticed in both of these papers is that the only measure of fear behavior is freezing. While freezing has been traditionally measured, it does not appear to be the only fear behavior displayed by some animals. An escape-like darting behavior has also been observed which would make it seem as though those animals were not freezing at all. Although the data in these papers seemed convincing, this is an important consideration to make when freezing is the only measurement used for fear behavior.

My final thoughts on these papers concerns the human disorder of post-traumatic stress disorder (PTSD). Although these methods are obviously not meant as a clinical treatment for humans, it may be interesting to consider what factors would create such an extremely strong fear memory to be encoded. The papers note that the size of the memory trace does not differ in size with the strength of the memory (ie. less neurons in the trace do not cause a weaker memory)- so what does cause a much stronger memory encoding? Is it possible that people who are susceptible to PTSD have a naturally higher level of CREB? Alternatively, are their amygdala neurons naturally more excitable? These are interesting questions to think about as field moves towards answering more questions about the human correlates of the brain regions and processes observed in mice.