Neuroscience

Retrieval of developmental social memories requires activation of the adult-born granule cell-CA2 circuit in mice

Blake J. Laham
Isha R. Gore
Casey J. Brown
Elizabeth Gould author has email address

Princeton Neuroscience Institute, Princeton University, Princeton NJ 08544

https://doi.org/10.7554/eLife.90600.1

Open access
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Figures and data

Adult-born neurons support retrieval of the earliest social memories.
a-aiii, Dentate gyrus granule cells, both mature (ZnT3+) and adult-born (3R-Tau+), send robust projections to CA2. b, Schematic showing injection of cre-dependent AAV (mCherry) targeting CA2 in PV-cre transgenic mice. c,d, abGC projections in close proximity to cell bodies and dendrites of CA2 PCP4+ pyramidal cells and mCherry+ PV+ interneurons. e,f, abGC fibers (3R-Tau+) in the CA2 are more abundant near the soma and dendrites of PV+ interneurons (mCherry+) than near the soma and dendrites of pyramidal cells (PCP4+). g, Timeline for behavioral experiment. h, Schematic demonstrating direct social interaction assay used at three experimental time points. i, Ablation of abGCs abolishes ability to retrieve memory of the mother (Drug x Genotype: p = 0.0074; vGCV+: p = 0.0021). After removing vGCV from rodent chow and allowing adult neurogenesis to recovery over the course of six weeks, animals regain the ability to retrieve the memory of the mother (p > 0.999). j-kii, Hippocampal adult neurogenesis at three different drug time points. VGCV administration produces a dramatic loss of l, abGCs (3R-Tau+ cells) in DG (p < 0.0001) and n, 3R-Tau+ fibers in CA2 stratum lucidum (p = 0.0036). Six weeks after removing vGCV from the rodent chow, DG abGC number, m, undergoes a 70% recovery (p = 0.0062), and, o, 3R-Tau+ fibers present in CA2 stratum lucidum undergo a complete recovery (p = 0.8389).^*p < 0.05, bars represent mean + SEM. Scale bars = 200 μm for a-aiii and j-kii; 20 μm for c,d. ns = not significant.

Inhibiting 4-6-week-old abGC projections to CA2 prevents retrieval of the earliest social memories.
a, Schematic of breeding to produce Nestin-cre:Gi double transgenic offspring. b, Timeline outlining tamoxifen administration, cannula implantation, and behavioral testing. c, Schematic demonstrating direct social interaction testing. d-dii, histology depicting 4-6-week-old Gi-DREADD+ abGCs in the DG. e, Inhibiting 4-6-week-old abGC projections to CA2 with CNO prevents retrieval of the memory of the mother (Genotype x Drug: p = 0.0487; Nestin-cre:Gi Veh-CNO: p = 0.0057). f, Inhibiting 10-12-week-old abGC projections to CA2 does not influence retrieval of the earliest social memories (Genotype x Drug: p = 0.2008). g, Schematic for experiment assessing abGC contributions to social memory consolidation. Systemic inhibition of abGCs during memory consolidation has no significant effect on social memory (Genotype x Drug: p = 0.2730). ^*p < 0.05, bars represent mean + SEM. Scale bars = 200 μm. ns = not significant.

Adult-born neurons influence CA2 network activity associated with developmental social memory retrieval.
a, Timeline of experiment demonstrating tamoxifen injection schedule and electrode implantation in CA2. b, Histology demonstrating accuracy of electrode placement. c, Schematic of electrophysiological recordings during baseline and social trials. d, Inhibiting 4-6-week-old abGCs with CNO prevents characteristic SWR production patterns present during encoding vs retrieval of social memories (Genotype x Drug: p < 0.0001; Nestin-cre:Gi CNO Novel-Mother: p < 0.0101). e, CA2 SWR frequency is increased during social interactions, regardless of stimulus identity (Stimulus: p < 0.0001). Inhibiting 4-6-week-old abGCs reduces f baseline (Genotype x Drug: p = 0.0622; Nestin-cre:Gi Veh-CNO: p = 0.0308) and g social trial SWR production (Genotype x Drug: p < 0.0001; Nestin-cre:Gi Veh-CNO p = 0.0018), and increases SWR peak amplitude during h baseline (Genotype x Drug: p = 0.0147; Veh-CNO: p = 0.0133) and i social interaction trials (Genotype x Drug: p = 0.0559; Nestin-cre:Gi Veh-CNO: p < 0.0001). j,k, Graphs demonstrating mid gamma amplitude modulation across theta phases in Nestin-cre:Gi mice. l, Inhibiting 4-6-week-old abGCs abolishes the increase in theta-mid gamma PAC present during retrieving the memory of the mother (Genotype x Drug: p = 0.0329; Nestin-cre:Gi Veh-CNO: p = 0.0219). m, Inhibiting 10-12-week-old abGCs has no influence on characteristic SWR production patterns present during encoding vs retrieval of social memories (Genotype x Drug: p = 0.2781). n, CA2 SWR frequency is increased during social interactions, regardless of stimulus familiarity (Stimulus: p < 0.0001). Inhibiting 10-12-week-old abGCs has no influence on o baseline (Genotype x Drug: p = 0.4612) or p social trial SWR production (Genotype x Drug: p = 0.5702), and no influence on SWR peak amplitude during q baseline (Genotype x Drug: p = 0.8125) and r social interaction trials (Genotype x Drug: p = 0.7635). s,t, Graphs demonstrating mid gamma amplitude modulation across theta phases in Nestin-cre:Gi mice. u, Inhibiting 10-12-week-old abGCs has no influence on theta-mid gamma PAC while retrieving the memory of the mother (Genotype x Drug: p = 0.6153). ^*p < 0.05, bars represent mean + SEM. Scale bars = 200 μm. ns = not significant.

VGCV or CNO administration does not alter locomotion during social interaction.
a, GFAP-TK mice display normal locomotion during social interaction after six weeks of VGCV administration (Genotype x Drug: p = 0.8154). CNO administration has no effect on locomotion during b baseline (Genotype x Drug: p = 0.7019) or c social stimulus trials (Genotype x Drug: p = 0.1171) in Nestin-cre and Nestin-cre:Gi mice. Bars represent mean + SEM. ns = not significant.

4-6-week-old abGCs influence multiple features of CA2 SWRs.
a, Schematic of electrophysiological recordings during baseline and social trials during the 4-6-week-old abGC timepoint. b, Silencing 4-6-week-old abGCs reduces average CA2 SWR integral (Genotype x Drug: p = 0.0004; Nestin-cre:Gi Veh-CNO: p = 0.0099). c, Silencing 4-6-week-old abGCs reduces average CA2 SWR duration (Genotype x Drug: p < 0.0001; Nestin-cre:Gi Veh-CNO: p < 0.0001; Drug: p < 0.0001). d, Silencing 10-12-week-old abGCs reduces has no effect on average CA2 SWR integral but a significant interaction is observed (Genotype x Drug: p = 0.0469; Nestin-cre:Gi Veh-CNO: p = 0.7457). e, Silencing 10-12-week-old abGCs does not reduce average CA2 SWR duration but a significant interaction is observed (Genotype x Drug: p = 0.00389; Nestin-cre:Gi Veh-CNO: p = 0.1439). ^*p < 0.05, bars represent mean + SEM. ns = not significant.^*p < 0.05, bars represent mean + SEM. ns = not significant.

Nonsocial stimuli suppress CA2 SWR frequency.
a, Schematic of electrophysiological recordings during baseline and exposure to nonsocial object (plastic toy animal) trials during the 4-6-week-old abGC timepoint. b, Nonsocial stimuli slightly inhibit CA2 SWR frequency (Stimulus: p = 0.0095). c, Silencing 4-6-week-old abGCs has no influence on CA2 SWR frequency during object exposure (Genotype x Drug: p = 0.3806), d average integral (Genotype x Drug: p = 0.2027), and f peak z-score (Genotype x Drug: p = 0.987). e, Silencing 4-6-week-old abGCs reduces average SWR duration during object trials (Genotype x Drug: p = 0.00585; Nestin-cre:Gi Veh-CNO: p = 0.0094). ^*p < 0.05, bars represent mean + SEM. ns = not significant.

4-6-week-old abGCs do not influence theta and gamma power during social interaction.
a,ai,c,ci,e,ei, Normalized power spectra graphs (Social stimulus/baseline). b, Silencing 4-6-week-old abGCs has no influence on theta power (Genotype x Drug: p = 0.6387). d, Silencing 4-6-week-old abGCs has no influence on low gamma power (Genotype x Drug: p = 0.3868). f, Silencing 4-6-week-old abGCs has no influence on mid gamma power (Genotype x Drug: p = 0.5478). Bars represent mean +/- SEM for a,ai,c,ci,e,ei; + SEM for b,d,e. ns = not significant.

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