CREB regulates spine density of lateral amygdala neurons: implications for memory allocation

Derya Sargin,Gemma Higgs,Sheena A Josselyn,Jin-Hee Han,Valentina Mercaldo,Paul W Frankland,Adelaide P Yiu

doi:10.3389/fnbeh.2013.00209

Abstract

Neurons may compete against one another for integration into a memory trace. Specifically, neurons in the lateral nucleus of the amygdala with relatively higher levels of cAMP Responsive Element Binding Protein (CREB) seem to be preferentially allocated to a fear memory trace, while neurons with relatively decreased CREB function seem to be excluded from a fear memory trace. CREB is a ubiquitous transcription factor that modulates many diverse cellular processes, raising the question as to which of these CREB-mediated processes underlie memory allocation. CREB is implicated in modulating dendritic spine number and morphology. As dendritic spines are intimately involved in memory formation, we investigated whether manipulations of CREB function alter spine number or morphology of neurons at the time of fear conditioning. We used viral vectors to manipulate CREB function in the lateral amygdala (LA) principal neurons in mice maintained in their homecages. At the time that fear conditioning normally occurs, we observed that neurons with high levels of CREB had more dendritic spines, while neurons with low CREB function had relatively fewer spines compared to control neurons. These results suggest that the modulation of spine density provides a potential mechanism for preferential allocation of a subset of neurons to the memory trace.

Highlights

The cAMP Responsive Element Binding Protein (CREB) is an activity regulated transcription factor that modulates the transcription of genes with cAMP responsive elements (CRE) located in their promoter regions
We first confirmed the effects of manipulating CREB function in a small portion (∼8–10%) of lateral amygdala (LA) neurons on the formation of tone fear memory by microinjecting herpes simplex viral (HSV) vectors encoding GFP, CREB or dominant-negative CREB (CREBS133A) into the LA of adult mice 3 d before fear conditioning
Consistent with our earlier findings (Han et al, 2007, 2009) and those of other research groups (Zhou et al, 2009; Rexach et al, 2012), increasing CREB levels in a small portion of LA neurons enhanced tone fear memory, while disrupting CREB function by microinjecting CREBS133A vector had no effect on fear memory (Figures 1C,D)

Summary

Introduction

The cAMP Responsive Element Binding Protein (CREB) is an activity regulated transcription factor that modulates the transcription of genes with cAMP responsive elements (CRE) located in their promoter regions. Post-training ablation (Han et al, 2009) or silencing (Zhou et al, 2009) of neurons overexpressing CREB disrupted subsequent expression of the fear memory, confirming the importance of these neurons. Together, these data suggest that neurons with high levels of CREB at the time of training are preferentially allocated to the memory trace because they somehow outcompete their neighbors (Won and Silva, 2008)

Methods

Results

Conclusion