Computational model of a positive BDNF feedback loop in hippocampal neurons following inhibitory avoidance training

Abstract

Inhibitory avoidance (IA) training in rodents initiates a molecular cascade within hippocampal neurons. This cascade contributes to the transition of short- to long-term memory (i.e., consolidation). Here, a differential equation-based model was developed to describe a positive feedback loop within this molecular cascade. The feedback loop begins with an IA-induced release of brain-derived neurotrophic factor (BDNF), which in turn leads to rapid phosphorylation of the cAMP response element-binding protein (pCREB), and a subsequent increase in the level of the β isoform of the CCAAT/enhancer binding protein (C/EBPβ). Increased levels of C/EBPβ lead to increased bdnf expression. Simulations predicted that an empirically observed delay in the BDNF-pCREB-C/EBPβ feedback loop has a profound effect on the dynamics of consolidation. The model also predicted that at least two independent self-sustaining signaling pathways downstream from the BDNF-pCREB-C/EBPβ feedback loop contribute to consolidation. Currently, the nature of these downstream pathways is unknown.