Role of long-range CA3 connectivity in linking spatial and aversive information

Abstract

The CA3 region of the hippocampus is an auto-associative network that is thought to enable rapid associations between spatial locations and non-spatial information. As such, it is important for retention and retrieval of contextual memories. These abilities are believed to be supported by the high degree of local interconnectivity between individual CA3 pyramidal cells via axon collaterals. This interconnectivity is also interhemispheric, with numerous dorsal CA3 pyramidal cell axons crossing the commissure and forming synapses in the contralateral CA3 and CA1 areas. In addition, CA3 pyramidal neurons also elaborate dense long-range projections that connect hippocampal areas longitudinally along the septotemporal axis. Individual axon collaterals may extend for up to 75% of the entire septotemporal axis. The role of these longitudinal axons in conveying information within the CA3 system is not well understood. The differential anatomical connectivity of ventral and dorsal hip- pocampus to cortical and sub-cortical areas suggests that the dorsal hippocampus is implicated preferentially in processing spatial information, while the ventral hip- pocampus is strongly recruited during processing of emotionally salient memories. This view, which is supported by genetic and behavioral studies, raises the question of whether the longitudinal CA3 projections are involved when animals associate spatial information with aversive or reward information.<br /> We addressed these questions by directly imaging from CA3 pyramidal cell axons projecting from ventral to dorsal hippocampus using dual color two-photon calcium imaging in awake behaving head-fixed mice. We compared these data to measurements from CA3 axons within the dorsal CA3 system (commissurally projecting CA3 axons). The task required the mice to learn the location of an aversive stimulus on a 150 cm linear track. Activity in the two axonal systems was examined in separate batches of mice while the animals encoded the space, learnt the aversive stimulus lo- cation and retrieved its memory. Importantly, we were able to track axons across multiple days of experiments to determine how their representations change during learning.<br /> We observed that –- as previously suggested – the dorsal CA3 commissural axons showed a more precise representation of the space compared to the longitudinal, ventral-to-dorsal axonal system. During spatial aversive learning, spatial representa- tions changed in the ventral-to-dorsal axons, with an over-representation of the lin- ear track segment preceding the aversive stimulus present during memory formation and maintenance. This over-representation was due to a precise sequence of spatially selective stabilization and de novo formation of place axons. In contrast, dorsal CA3 commissural axons did not show a significant deformation of spatial maps. How- ever, in this axon system, de novo formation of place axons was significantly increased in the memory maintenance phase. We show this increase to be spatially selective. Thus, ventral CA3 exhibits a defined sequence of changes in spatial coding through- out learning that precedes changes in dorsal CA3. This is consistent with a model in which the ventral to dorsal CA3 projection is relevant in the integration of aversive information into dorsal hippocampal spatial maps