Granule cells in the infrapyramidal blade of the dentate gyrus are activated during paradoxical (REM) sleep hypersomnia but not during wakefulness: a study using TRAP mice

Study Objectives Determine whether in the hippocampus and the supramammillary nucleus (SuM) the same neurons are reactivated when mice are exposed one week apart to two periods of wakefulness (W-W), paradoxical sleep rebound (PSR-PSR) or a period of W followed by a period of PSR (W-PSR) Methods We combined the innovative TRAP2 mice method in which neurons expressing cFos permanently express tdTomato after tamoxifen injection with cFos immunohistochemistry. Results We found out that a large number of tdTomato+ and cFos+ cells are localized in the dentate gyrus (DG) after PSR and W while CA1 and CA3 contained both types of neurons only after W. The number of cFos+ cells in the infrapyramidal but not the suprapyramidal blade of the DG was positively correlated with the amount of PS. In addition, we did not find double-labeled cells in the DG whatever the group of mice. In contrast, a high percentage of CA1 neurons were double-labeled in W-W mice. Finally, in the supramammillary nucleus, a large number of cells were double-labeled in W-W, PSR-PSR but not in W-PSR mice. Conclusions Altogether, our results are the first to show that different neurons are activated during W and PS in the supramammillary nucleus and the hippocampus. Further, we showed for the first time that granule cells of the infrapyramidal blade of the DG are activated during PS but not during W. Further experiments are now needed to determine whether these granule cells belong to memory engrams inducing memory reactivation during PS.

Local circuit allowing hypothalamic control of hippocampal area CA2 activity and consequences for CA1

The hippocampus is critical for memory formation. The hypothalamic supramammillary nucleus (SuM) sends long-range projections to hippocampal area CA2. While the SuM-CA2 connection is critical for social memory, how this input acts on the local circuit is unknown. Using mice, we found that SuM axon stimulation elicited mixed excitatory and inhibitory responses in area CA2 pyramidal neurons (PNs). Parvalbumin-expressing basket cells were largely responsible for the feedforward inhibitory drive of SuM over area CA2. Inhibition recruited by the SuM input onto CA2 PNs increased the precision of action potential firing both in conditions of low and high cholinergic tone. Furthermore, SuM stimulation in area CA2 modulated CA1 activity, indicating that synchronized CA2 output drives a pulsed inhibition in area CA1. Hence, the network revealed here lays basis for understanding how SuM activity directly acts on the local hippocampal circuit to allow social memory encoding.

Local circuit allowing hypothalamic control of hippocampal area CA2 activity and consequences for CA1

The hippocampus is critical for memory formation. The hypothalamic supramammillary nucleus (SuM) sends long-range projections to hippocampal area CA2. While the SuM-CA2 connection is critical for social memory, how this input acts on the local circuit is unknown. We found that SuM axon stimulation elicited mixed excitatory and inhibitory responses in area CA2 pyramidal neurons (PNs). We found that parvalbumin-expressing basket cells as responsible for the feedforward inhibitory drive of SuM over area CA2. Inhibition recruited by the SuM input onto CA2 PNs increased the precision of action potential firing both in conditions of low and high cholinergic tone. Furthermore, SuM stimulation in area CA2 modulates CA1 activity, indicating that synchronized CA2 output drives a pulsed inhibition in area CA1. Hence, the network revealed here lays basis for understanding how SuM activity directly acts on the local hippocampal circuit to allow social memory encoding.

Supramammillary nucleus synchronizes with dentate gyrus to regulate spatial memory retrieval through glutamate release

The supramammillary nucleus (SuM) provides substantial innervation to the dentate gyrus (DG). It remains unknown how the SuM and DG coordinate their activities at the circuit level to regulate spatial memory. Additionally, SuM co-releases GABA and glutamate to the DG, but the relative role of GABA versus glutamate in regulating spatial memory remains unknown. Here we report that SuM-DG Ca2+ activities are highly correlated during spatial memory retrieval as compared to the moderate correlation during memory encoding when mice are performing a location discrimination task. Supporting this evidence, we demonstrate that the activity of SuM neurons or SuM-DG projections is required for spatial memory retrieval. Furthermore, we show that SuM glutamate transmission is necessary for both spatial memory retrieval and highly-correlated SuM-DG activities during spatial memory retrieval. Our studies identify a long-range SuM-DG circuit linking two highly correlated subcortical regions to regulate spatial memory retrieval through SuM glutamate release.