Computational Model of a Positive BDNF Feedback Loop in Hippocampal Neurons Following Inhibitory Avoidance Training

Learn Mem. 2016 Nov 15;23(12):714-722. doi: 10.1101/lm.042044.116. Print 2016 Dec.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Avoidance Learning / drug effects
  • Avoidance Learning / physiology*
  • Brain-Derived Neurotrophic Factor / metabolism*
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Computer Simulation*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Feedback, Physiological / drug effects
  • Feedback, Physiological / physiology*
  • Gene Expression / drug effects
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Models, Neurological*
  • Neurons / drug effects
  • Neurons / metabolism
  • Phosphorylation
  • Protein Synthesis Inhibitors / pharmacology
  • RNA, Messenger / metabolism
  • Rats
  • Signal Transduction / drug effects
  • Time Factors

Substances

  • Brain-Derived Neurotrophic Factor
  • CCAAT-Enhancer-Binding Protein-beta
  • Cebpb protein, rat
  • Cyclic AMP Response Element-Binding Protein
  • Protein Synthesis Inhibitors
  • RNA, Messenger