Posttraining Ablation of Adult-Generated Neurons Degrades Previously Acquired Memories

Abstract

New neurons are continuously generated in the subgranular zone of the adult hippocampus and, once sufficiently mature, are thought to integrate into hippocampal memory circuits. However, whether they play an essential role in subsequent memory expression is not known. Previous studies have shown that suppression of adult neurogenesis often (but not always) impairs subsequent hippocampusdependent learning (i.e., produces anterograde effects). A major challenge for these studies is that these new neurons represent only a small subpopulation of all dentate granule cells, and so there is large potential for either partial or complete compensation by granule cells generated earlier on during development. A potentially more powerful approach to investigate this question would be to ablate adultgenerated neurons after they have already become part of a memory trace (i.e., retrograde effects). Here we developed a diphtheria toxin-based strategy in mice that allowed us to selectively ablate a population of predominantly mature, adult-generated neurons either before or after learning, without affecting ongoing neurogenesis. Removal of these neurons before learning did not prevent the formation of new contextual fear or water maze memories. In contrast, removal of an equivalent population after learning degraded existing contextual fear and water maze memories, without affecting nonhippocampal memory. Ablation of these adult-generated neurons even 1 month after learning produced equivalent memory degradation in the water maze. These retrograde effects suggest that adultgenerated neurons form a critical and enduring component of hippocampal memory traces.

Zif268 / egr1 gene controls the selection, maturation and functional integration of adult hippocampal newborn neurons by learning

“…Their reduced potential for being activated by glutamatergic inputs would impede their recruitment by training (Fig. S7D), preventing their contribution to long-term spatial memory (44). Our previous studies in zif268-KO mice have shown that zif268 is required for the expression of late-phase hippocampal LTP (25), long-term stability of hippocampal place cell representations (31), and consolidation of several forms of long-term memory (25,28).…”

Functional Differentiation of Adult-Born Neurons along the Septotemporal Axis of the Dentate Gyrus: Figure 1.

“…Adult neurogenesis is required for contextual discrimination, spatial memory, and spatial pattern separation (Clelland et al 2009;Arruda-Carvalho et al 2011;Sahay et al 2011;Denny et al 2012;Nakashiba et al 2012;Niibori et al 2012; see Abrous and Wojtowicz 2015 for in-depth discussion). A role for adultborn neurons in relation to emotion was first proposed with the observation that changes in adult neurogenesis correlate with mood-related manipulations in both negative (Gould et al 1992) and positive directions (Malberg et al 2000;van Praag et al 2002) (especially in the temporal DG).…”

Role of Adult Hippocampal Neurogenesis in Cognition in Physiology and Disease: Pharmacological Targets and Biomarkers

“…Recent studies looking at the effect of post-training ablation (retrograde effects) of newborn neurons and silencing of adult-generated neurons on hippocampal memory further highlight the importance of this neuronal population in formation of memory. Ablation of newborn neurons using a diphtheria toxinbased strategy after learning leads to degradation of existing contextual fear and water maze memories, even when the ablation is induced 1 month after learning (Arruda-Carvalho et al 2011). Along the same line, using an optogenetic approach, it has been shown that silencing newborn neurons affects the retrieval of memory after completion of training.…”