PT  - JOURNAL ARTICLE
AU  - Aijing Gao
AU  - Frances Xia
AU  - Axel Guskjolen
AU  - Adam I. Ramsaran
AU  - Adam Santoro
AU  - Sheena A. Josselyn
AU  - Paul W. Frankland
TI  - Elevation of hippocampal neurogenesis induces a temporally-graded pattern of forgetting of contextual fear memories
AID  - 10.1523/JNEUROSCI.3126-17.2018
DP  - 2018 Feb 16
TA  - The Journal of Neuroscience
PG  - 3126-17
4099  - http://www.jneurosci.org/content/early/2018/02/16/JNEUROSCI.3126-17.2018.short
4100  - http://www.jneurosci.org/content/early/2018/02/16/JNEUROSCI.3126-17.2018.full
AB  - Throughout life neurons are continuously generated in the subgranular zone of the hippocampus. The subsequent integration of newly-generated neurons alters patterns of dentate gyrus input and output connectivity, potentially rendering memories already stored in those circuits harder to access. Consistent with this prediction, we previously showed that increasing hippocampal neurogenesis after training induces forgetting of hippocampus-dependent memories, including contextual fear memory. However, the brain regions supporting contextual fear memories change with time, and this time-dependent memory reorganization might regulate the sensitivity of contextual fear memories to fluctuations in hippocampal neurogenesis. By virally expressing the inhibitory DREADD hM4Di we first confirmed that chemogenetic inhibition of dorsal hippocampal neurons impairs retrieval of recent (day-old) but not remote (month-old) contextual fear memories in male mice. We then contrasted the effects of increasing hippocampal neurogenesis at recent vs remote time points after contextual fear conditioning in male and female mice. Increasing hippocampal neurogenesis immediately following training reduced conditioned freezing when mice were replaced in the context one month later. In contrast, when hippocampal neurogenesis was increased time points remote to training, conditioned freezing levels were unaltered when mice were subsequently tested. These temporally-graded forgetting effects were observed using both environmental and genetic interventions to increase hippocampal neurogenesis. Our experiments identify memory age as a boundary condition for neurogenesis-mediated forgetting and suggest that as contextual fear memories mature they become less sensitive to changes in hippocampal neurogenesis levels because they no longer depend on the hippocampus for their expression.Significance statement: New neurons are generated in the hippocampus throughout life. As they integrate into the hippocampus they remodel neural circuitry, potentially making information stored in those circuits harder to access. Consistent with this, increasing hippocampal neurogenesis after learning induces forgetting of the learnt information. The current study in mice asks whether these forgetting effects depend on the age of the memory. We found that post-training increases in hippocampal neurogenesis only impacted recently-acquired, and not remotely-acquired, hippocampal memories. These experiments identify memory age as a boundary condition for neurogenesis-mediated forgetting, and suggest remote memories are less sensitive to changes in hippocampal neurogenesis levels because they no longer depend critically on the hippocampus for their expression.