Andrographolide increases adult hippocampal neurogenesis and prolongs contextual fear memory

Adult neurogenesis in the brain enhances memory retention, particularly under conditions of compromised hippocampal function. However, it is unclear whether changing neurogenesis levels would affect the longevity of a physiological memory trace.

Here, we hypothesized that the mechanisms of potentially pro-neurogenic treatments and the nature of the memory trace are determinant factors in defining whether memories persist.

We subjected adult male C57Bl/6 mice to behavioral procedures that evoke fear memories, which naturally fade within 10 days. We then examined whether increasing adult neurogenesis could prevent the natural decay of these memories. We investigated the hippocampus's dependence on these memories using context, sound, or smell as the conditioned stimuli. Memantine (MEM), andrographolide (ANDRO), and an enriched environment (EE) were used to investigate their effects on neurogenesis and memory retention.

EE and ANDRO increased neurogenesis in the dentate gyrus of the hippocampus (DG). Interestingly, neither treatment altered the progenitor cell population in the DG of Nestin-GFP mice. To gain further insight into the effects of ANDRO and MEM, we recorded the oscillations in DG local field potentials (LFP) immediately and 7 days after the pharmacological treatments. Acute administration of MEM increased slow gamma power in DG, while ANDRO had the opposite effect. Finally, we tested whether treatments would extend the fear conditioning memory. ANDRO and EE increased fear memory, but only for contextual fear conditioning (CFC).

Our study shows that different methods allegedly used to increase adult neurogenesis have varying effects on DG neurophysiology. Moreover, it suggests that memories reliant on the hippocampus, such as CFC, may be more prone to alterations in adult neurogenesis than memories less dependent on this brain region, such as auditory and olfactory conditioned fear memories.