Adult-born granule cells modulate CA2 network activity during retrieval of developmental memories of the mother.

Adult-born granule cells (abGCs) project to the CA2 region of the hippocampus, but it remains unknown how this circuit affects behavioral function. Here, we show that abGC input to the CA2 of adult mice is involved in the retrieval of remote developmental memories of the mother. Ablation of abGCs impaired the ability to discriminate between a caregiving mother and a novel mother, and this ability returned after abGCs were regenerated. Chemogenetic inhibition of projections from abGCs to the CA2 also temporarily prevented the retrieval of remote mother memories. These findings were observed when abGCs were inhibited at 4-6 weeks old, but not when they were inhibited at 10-12 weeks old. We also found that abGCs are necessary for differentiating features of CA2 network activity, including theta-gamma coupling and sharp wave ripples, in response to novel versus familiar social stimuli. Taken together, these findings suggest that abGCs are necessary for neuronal oscillations associated with discriminating between social stimuli, thus enabling retrieval of remote developmental memories of the mother by their adult offspring.

Activation of the CA2-ventral CA1 pathway reverses social discrimination dysfunction in Shank3B knockout mice.

Mutation or deletion of the SHANK3 gene, which encodes a synaptic scaffolding protein, is linked to autism spectrum disorder and Phelan-McDermid syndrome, conditions associated with social memory impairments. Shank3B knockout mice also exhibit social memory deficits. The CA2 region of the hippocampus integrates numerous inputs and sends a major output to the ventral CA1 (vCA1). Despite finding few differences in excitatory afferents to the CA2 in Shank3B knockout mice, we found that activation of CA2 neurons as well as the CA2-vCA1 pathway restored social recognition function to wildtype levels. vCA1 neuronal oscillations have been linked to social memory, but we observed no differences in these measures between wildtype and Shank3B knockout mice. However, activation of the CA2 enhanced vCA1 theta power in Shank3B knockout mice, concurrent with behavioral improvements. These findings suggest that stimulating adult circuitry in a mouse model with neurodevelopmental impairments can invoke latent social memory function.

The estrous cycle modulates early-life adversity effects on mouse avoidance behavior through progesterone signaling.

Early-life adversity (ELA) increases the likelihood of neuropsychiatric diagnoses, which are more prevalent in women than men. Since changes in reproductive hormone levels can also increase the probability of anxiety disorders in women, we examined the effects of ELA on adult female mice across the estrous cycle. We found that during diestrus, when progesterone levels are relatively high, ELA mice exhibit increased avoidance behavior and increased theta oscillation power in the ventral hippocampus (vHIP). We also found that diestrus ELA mice had higher levels of progesterone and lower levels of allopregnanolone, a neurosteroid metabolite of progesterone, in the vHIP compared with control-reared mice. Progesterone receptor antagonism normalized avoidance behavior in ELA mice, while treatment with a negative allosteric modulator of allopregnanolone promoted avoidance behavior in control mice. These results suggest that altered vHIP progesterone and allopregnanolone signaling during diestrus increases avoidance behavior in ELA mice.

Puberty enables oestradiol-induced progesterone synthesis in female mouse hypothalamic astrocytes.

The development of oestrogen positive feedback is a hallmark of female puberty. Both oestrogen and progesterone signalling are required for the functioning of this neuroendocrine feedback loop but the physiological changes that underlie the emergence of positive feedback remain unknown. Only after puberty does oestradiol (E2) facilitate progesterone synthesis in the rat female hypothalamus (neuroP), an event critical for positive feedback and the LH surge. We hypothesize that prior to puberty, these astrocytes have low levels of membrane oestrogen receptor alpha (ERα), which is needed for facilitation of neuroP synthesis. Thus, we hypothesized that prepubertal astrocytes are unable to respond to E2 with increased neuroP synthesis due a lack of membrane ERα. To test this, hypothalamic tissues and enriched primary hypothalamic astrocyte cultures were acquired from prepubertal (postnatal week 3) and post-pubertal (week 8) female mice. E2-facilitated neuroP was measured in the hypothalamus pre- and post-puberty, and hypothalamic astrocyte responses were measured after treatment with E2. Prior to puberty, E2-facilitated neuroP synthesis did not occur in the hypothalamus, and mERα expression was low in hypothalamic astrocytes, but E2-facilitated neuroP synthesis in the rostral hypothalamus and mERα expression increased post-puberty. The increase in mERα expression in hypothalamic astrocytes corresponded with a post-pubertal increase in caveolin-1 protein, PKA phosphorylation, and a more rapid [Ca2+ ]i flux in response to E2. Together, results from the present study indicate that E2-facilitated neuroP synthesis occurs in the rostral hypothalamus, develops during puberty, and corresponds to a post-pubertal increase in mERα levels in hypothalamic astrocytes.

Atypical perineuronal nets in the CA2 region interfere with social memory in a mouse model of social dysfunction.

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.

Newborn mice form lasting CA2-dependent memories of their mothers.

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.

How Stress Influences the Dynamic Plasticity of the Brain's Extracellular Matrix.

Diffuse and structured extracellular matrix (ECM) comprise ∼20% of the brain's volume and play important roles in development and adult plasticity. Perineuronal nets (PNNs), specialized ECM structures that surround certain types of neurons in the brain, emerge during the postnatal period, making their development and maintenance potentially sensitive to experience. Recent studies have shown that stress affects diffuse ECM as well as PNNs, and that such effects are dependent on life stage and brain region. Given that the ECM participates in synaptic plasticity, the generation of neuronal oscillations, and synchronous firing across brain regions, all of which have been linked to cognition and emotional regulation, ECM components may be candidate therapeutic targets for stress-induced neuropsychiatric disease. This review considers the influence of stress over diffuse and structured ECM during postnatal life with a focus on functional outcomes and the potential for translational relevance.