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

Abstract

The hippocampus is critical for memory formation. Area CA2 has been shown to contribute to several essential brain functions including social novelty discrimination, sharp-wave ripple initiation and spatial encoding. The supramammillary nucleus (SuM) sends long-range projections to area CA2, is active during novelty exposure, and the SuM-CA2 connection has recently been shown to be important for social novelty discrimination. However, the properties and targets of the SuM input in CA2 are unknown. Using optogenetics, we found that stimulation of SuM axons elicited mixed excitatory and inhibitory responses in area CA2 pyramidal neurons (PNs). We examined the strength of the SuM excitatory input to interneurons in area CA2 and identified parvalbumin-expressing basket cells as responsible for the feedforward inhibitory drive of SuM over area CA2. We demonstrated that inhibition recruited by the SuM input onto area CA2 PNs increased the precision of their action potential firing both in conditions of low and high cholinergic tone. Furthermore, we observed a clear modulation of CA1 activity with SuM stimulation in area CA2 in vivo and in slice, 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.

A direct lateral entorhinal cortex to hippocampal CA2 circuit conveys social information required for social memory

“…However, it has not yet been shown whether the supramammillary inputs differentiate between a novel versus a familiar animal. Moreover, because the supramammillary inputs preferentially excite inhibitory neurons in the CA2 region (Chen et al, 2020;Robert et al, 2020), it is unclear how such an input could enhance CA2 PN firing to social novelty. Finally, as the computation of novelty requires processing of complex sensory information and its comparison with stored representations, such computations are more likely to be performed in higher-order brain regions.…”

A direct lateral entorhinal cortex to hippocampal CA2 circuit conveys social information required for social memory

“…However, it is not yet known whether the supramammillary inputs differentiate between a novel versus a familiar animal. Moreover, because the supramammillary inputs preferentially excite inhibitory neurons in the CA2 region 11,39 , it is unclear how such an input could enhance CA2 PN firing to social novelty. Finally, as the computation of novelty requires processing of complex sensory information and its comparison to stored representations, such computations are likely performed in higher-order brain regions.…”