Postnatal development of hippocampal CA2 structure and function during the emergence of social recognition of peers

Abstract

It is now well-established that the hippocampal CA2 region plays an important role in social recognition memory in adult mice. The CA2 is also important for the earliest social memories, including those that mice have for their mothers and littermates, which manifest themselves as a social preference for familiarity over novelty. The role of the CA2 in the development of social memory for recently encountered same-age conspecifics, that is, peers, has not been previously reported. Here, we used a direct social interaction test to characterize the emergence of novelty preference for peers during development and found that at the end of the second postnatal week, pups begin to significantly prefer novel over familiar peers. Using chemogenetic inhibition at this time, we showed that CA2 activity is necessary for the emergence of novelty preference and for the ability to distinguish never encountered from recently encountered peers. In adulthood, the CA2 region is known to integrate a large number of inputs from various sources, many of which participate in social recognition memory, but previous studies have not determined whether these afferents are present at adult levels by the end of the second postnatal week. To explore the development of CA2 inputs, we used immunolabeling and retrograde adenovirus circuit tracing and found that, by the end of the second postnatal week, the CA2 is innervated by many regions, including the dentate gyrus, supramammillary nucleus of the hypothalamus, the lateral entorhinal cortex, and the median raphe nucleus. Using retroviral labeling of postnatally generated granule cells in the dentate gyrus, we found that mossy fiber projections to the CA2 mature faster during development than those generated in adulthood. Together, our findings indicate that the CA2 is partially mature in afferent connectivity by the end of the second postnatal week, connections that likely facilitate the emergence of social recognition memory and preference for novel peers.

Introduction to the special issue on: A new view of hippocampal area CA2

“…Social isolation appears to have effects on its own in CA2 (Bartesaghi & Severi, 2004), as does juvenile stress, which can impact synaptic plasticity in CA2 (to be reported by Sreedharan and colleagues). Also in this Special Issue is a report that CA2 activity is necessary when young mice are learning to recognize peers, and that many of the connections to/from CA2 are developing in this same time frame (Diethorn & Gould, 2023). Given CA2's role in the development of social cognition, it may come as no surprise that CA2 is also impacted in several mouse models for the study of developmental disorders such as Rett Syndrome, 22q11.2 deletion syndrome, and a mouse strain with deficits in social cognition (Carstens et al, 2021; Cope et al, 2022; Piskorowski et al, 2016).…”

Development of the hippocampal CA2 region and the emergence of social recognition

“…Although this projection arises in embryonic development, it undergoes further innervation during the postnatal period of both monkeys and humans (Berger et al., 2001). To date, no studies have investigated the presence of SuM afferents in the CA2 during embryonic life in rodents, but we have shown that this pathway is present by P14 in mouse pups and continues to develop during the late postnatal period (Diethorn & Gould, 2023). The appearance of the SuM to CA2 projection in embryonic development is in part mediated by CA2 MR activation, with conditional receptor deletion resulting in profoundly diminished and sometimes a complete absence of glutamatergic SuM innervation in postnatal life (McCann et al., 2021).…”

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

“…The CA2 has been called a social memory “hub” because it receives and integrates inputs from multiple brain areas (Hitti and Siegelbaum, 2014; Oliva et al, 2020; Diethorn and Gould, 2023), including from granule cells of the dentate gyrus (Kohara et al, 2014), a population known to undergo adult neurogenesis (Song et al, 2012). Adult-born granule cells (abGCs) are important for discriminating between novel and familiar peers (Pereira-Caixeta et al, 2018; Cope et al, 2020), and although these cells are known to project to the CA2 (Llorens-Martin et al, 2015), the function of this circuit remains unexplored.…”