Some of the most enduring social connections begin when infants first recognize their caregivers, memories that form the basis of many family relationships. It remains unknown whether these early social memories persist into adulthood in mice and, if so, which brain regions support them. Here we show that mice form memories of their mother within days after birth and that these memories persist into adulthood. Pups display greater interest in the mother than in an unfamiliar dam before weaning, after which this preference reverses. Inhibition of CA2 neurons in the pup temporarily blocks the ability to discriminate between the mother and an unfamiliar dam, whereas doing so in adulthood prevents the formation of short-term memories about conspecifics, as well as social discrimination related to long-term memories of the mother. These results suggest that the CA2 supports memories of the mother during infancy and adulthood with a developmental switch in social preference.

Throughout adulthood, the dentate gyrus continues to produce new granule cells, which integrate into the hippocampal circuitry. New neurons have been linked to several known functions of the hippocampus, including learning and memory, anxiety and stress regulation, and social behavior. We explored whether transgenic reduction of adult-born neurons in mice would impair social memory and the formation of social dominance hierarchies. We utilized a conditional transgenic mouse strain (TK mice) that selectively reduces adult neurogenesis by treatment with the antiviral drug valganciclovir (VGCV). TK mice treated with VGCV were unable to recognize conspecifics as familiar 24 hr after initial exposure. We then explored whether reducing new neurons completely impaired their ability to acquire or retrieve a social memory and found that TK mice treated with VGCV were able to perform at control levels when the time between exposure (acquisition) and re-exposure (retrieval) was brief. We then explored whether adult-born neurons are involved in dominance hierarchy formation by analyzing their home cage behavior as well as their performance in the tube test, a social hierarchy test, and did not find any consistent alterations in behavior between control and TK mice treated with VGCV. These data suggest that adult neurogenesis is essential for social memory maintenance, but not for acquisition nor retrieval over a short time frame, with no effect on social dominance hierarchy. Future work is needed to explore whether the influence of new neurons on social memory is mediated through connections with the CA2, an area involved in social recognition. 3 Significance Statement Adult hippocampal neurogenesis has been implicated in behaviors linked to the hippocampus, including social behavior. We utilized a conditional transgenic mouse line to reduce adult-born neurons and explored social memory and social dominance hierarchy formation. We found that mice with reduced numbers of new neurons were unable to recognize conspecifics as familiar with a long delay after initial exposure but were able to recognize them as familiar with a short delay. We did not observe changes in social dominance as measured by home cage behavior or tube test performance in mice with reduced numbers of new neurons. These data confirm and extend previous reports to show that adult-born neurons are essential for maintenance but not for acquisition or short-term retrieval of social memories, nor for social dominance.

Social memory dysfunction is an especially devastating symptom of many neuropsychiatric disorders, which makes understanding the cellular and molecular processes that contribute to such abnormalities important. Evidence suggests that the hippocampus, particularly the CA2 region, plays an important role in social memory. We sought to identify potential mechanisms of social memory dysfunction in the hippocampus by investigating features of neurons, glia, and the extracellular matrix (ECM) of BTBR mice, an inbred mouse strain with deficient social memory. The CA2 is known to receive inputs from dentate gyrus adult-born granule cells (abGCs), neurons known to participate in social memory, so we examined this cell population and found fewer abGCs, as well as fewer axons from abGCs in the CA2 of BTBR mice compared to controls. We also found that BTBR mice had fewer pyramidal cell dendritic spines, in addition to fewer microglia and astrocytes, in the CA2 compared to controls. Along with diminished neuronal and glial elements, we found atypical perineuronal nets (PNNs), specialized ECM structures that regulate plasticity, in the CA2 of BTBR mice. By diminishing PNNs in the CA2 of BTBR mice to control levels, we observed a partial restoration of social memory. Our findings suggest that the CA2 region of BTBR mice exhibits multiple cellular and extracellular abnormalities and identify atypical PNNs as one mechanism producing social memory dysfunction, although the contribution of reduced abGC afferents, pyramidal cell dendritic spine and glial cell numbers remains unexplored.

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.

20 (848)-445-8945 21 22 42 43 44 45 46 Abstract 47Some mood disorders, such as major depressive disorder, are more prevalent in women 48 than in men. However, historically preclinical studies in rodents have a lower inclusion rate of 49 females than males, possibly due to the fact that behavior can be affected by the estrous cycle. 50Several studies have demonstrated that chronic antidepressant treatment can decrease anxiety-51 like behaviors and increase adult hippocampal neurogenesis in male rodents. However, very few 52 studies have conclusively looked at the effects of antidepressants on behavior and neurogenesis 53 across the estrous cycle in naturally cycling female rodents. Here we analyze the effects of 54 chronic treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine (Prozac) on 55 behavior and adult hippocampal neurogenesis in naturally cycling C57BL/6J females across all 56 four phases of the estrous cycle. Interestingly, we find that the effects of fluoxetine on both 57 behavior and adult hippocampal neurogenesis are driven by mice specifically in the estrus or 58 diestrus phases of the estrous cycle. Taken together our data is the first to illustrate the impact of 59 fluoxetine on brain and behavior across all four stages of the murine estrous cycle. 60 61 Highlights: 62• Chronic fluoxetine reduces anxiety-like behaviors in naturally cycling female mice 63• Chronic fluoxetine increases adult hippocampal neurogenesis in naturally cycling female 64 mice 65• The effects of chronic fluoxetine on behavior and adult hippocampal neurogenesis are 66 driven by the estrus and diestrus phases of the estrous cycle 67 68