Neuronal excitability and fear memories - Emily Jones

After last week’s papers on creating and re-activating memories, this week’s topic focused on erasing them. The type of memory of interest for both papers is conditioned fear. What would happen if we deleted the neurons we thought to be largely responsible for encoding the conditioned fear memory in question? Intuitively, we should think that the memory would be deleted too.
Han et al. (2009) approached this question with a rule of thumb we established in one of our first classes. If we wanted to figure out if variable A caused variable B (if specific neurons are really responsible for a memory), then logically, eliminating A should do the same for B. To do this, Han and colleagues zeroed in on CREB, a transcription factor whose increase in lateral amygdala (LA) neurons positively correlated with the neuron’s chance of recruitment into encoding a subsequent auditory fear memory. The team ablated neurons that over expressed CREB using diphtheria toxin (DT), transgenic mice with DT-receptors, and CREB-cre vectors (with appropriate controls). Although the results were straightforward and helped drive home the point that neurons that over expressed CREB, I noticed a discrepancy in their figure 4C. Retraining mice after ablating neurons responsible for the initial fear training show that mice can be re-conditioned to the same auditory fear. However, freezing percentage was not exactly back up to that of Control-cre or Control-cre and CREB-cre in test 1 of figure 4A. Is this reduction in freezing upon retraining due to noise in the data or perhaps due to the removal of neurons initially responsible for the fear memory. Did ablation of those neurons decrease the strength of the fear memory?
In 2015, Yiu and colleagues expanded on the 2009 paper’s findings and examined the mechanism of neurons over-expressing CREB. Why does CREB have this effect on the formation of memories? The results from Yiu et al. (2014) show that preferential neuron recruitment into fear memories are not specific to neurons over-expressing CREB-- it is the heightened excitability induced by CREB that is key to neuron recruitment. Yiu’s team determined this through a variety of tests, each using different ways to increase neuronal excitability, but all impressively yielding similar results. Neurons that were excited immediately before fear conditioning were biased in memory allocation and contributed to enhanced memory formation.
Relatedly, conditioning a mouse to fear is inherently different from a mouse’s instinctual fears. In efforts to improve ecological validity, I wonder if it would be valuable to explore this kind of fear memory erasing paradigm in more instinctual fears (i.e. frightening mice with an aggressor or predator).

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