Collateral Projections Innervate the Mammillary Bodies and Retrosplenial Cortex: A New Category of Hippocampal Cells

Abstract

To understand the hippocampus it is necessary to understand the subiculum. Unlike other hippocampal subfields, the subiculum projects to almost all distal hippocampal targets, highlighting its critical importance for external networks. The present studies, in male rats and mice, reveal a new category of dorsal subiculum neurons that innervate both the mammillary bodies and the retrosplenial cortex. These bifurcating neurons comprise almost half of the hippocampal cells that project to retrosplenial cortex. The termination of these numerous collateral projections was visualized within the medial mammillary nucleus and the granular retrosplenial cortex (area 29). These collateral projections included subiculum efferents that cross to the contralateral mammillary bodies. Within the granular retrosplenial cortex, the collateral projections form a particularly dense plexus in deep layer II and layer III. This retrosplenial termination site co-localized with markers for VGluT2 and neurotensin. While efferents from the hippocampal CA fields standardly collateralize, subiculum projections often have only one target site. Consequently, the many collateral projections involving the retrosplenial cortex and the mammillary bodies present a relatively unusual pattern for the subiculum, which presumably relates to how both targets have complementary roles in spatial processing. Furthermore, along with the anterior thalamic nuclei, the mammillary bodies and retrosplenial cortex are key members of a memory circuit, which is usually described as both starting and finishing in the hippocampus. The present findings reveal how the hippocampus simultaneously engages different parts of this circuit, so forcing an important revision of this network.

Significance Statement The hippocampus has both cortical and subcortical connections that are critical for spatial learning in rodents and episodic memory in humans. Chief among these connections are the dense hippocampal inputs to the retrosplenial cortex and mammillary bodies, both of which originate in the subiculum. The present experiments reveal that in rodents approximately half of these retrosplenial projections have collaterals that also innervate the mammillary bodies. Consequently, these two areas share common hippocampal information, despite playing different roles in cognition. These same collateral projections contradict longstanding ideas about extended, serial hippocampal networks for memory. As these networks are affected from the earliest stages of Alzheimer’s disease, when memory disorders first appear, there is added significance in understanding their precise connectivity.