Chondroitin 4-O-sulfation regulates hippocampal perineuronal nets and social memory.

Glycan alterations are associated with aging, neuropsychiatric, and neurodegenerative diseases, although the contributions of specific glycan structures to emotion and cognitive functions remain largely unknown. Here, we used a combination of chemistry and neurobiology to show that 4-O-sulfated chondroitin sulfate (CS) polysaccharides are critical regulators of perineuronal nets (PNNs) and synapse development in the mouse hippocampus, thereby affecting anxiety and cognitive abilities such as social memory. Brain-specific deletion of CS 4-O-sulfation in mice increased PNN densities in the area CA2 (cornu ammonis 2), leading to imbalanced excitatory-to-inhibitory synaptic ratios, reduced CREB activation, elevated anxiety, and social memory dysfunction. The impairments in PNN densities, CREB activity, and social memory were recapitulated by selective ablation of CS 4-O-sulfation in the CA2 region during adulthood. Notably, enzymatic pruning of the excess PNNs reduced anxiety levels and restored social memory, while chemical manipulation of CS 4-O-sulfation levels reversibly modulated PNN densities surrounding hippocampal neurons and the balance of excitatory and inhibitory synapses. These findings reveal key roles for CS 4-O-sulfation in adult brain plasticity, social memory, and anxiety regulation, and they suggest that targeting CS 4-O-sulfation may represent a strategy to address neuropsychiatric and neurodegenerative diseases associated with social cognitive dysfunction.

Bonobos and chimpanzees remember familiar conspecifics for decades.

Recognition and memory of familiar conspecifics provides the foundation for complex sociality and is vital to navigating an unpredictable social world [Tibbetts and Dale, Trends Ecol. Evol. 22, 529-537 (2007)]. Human social memory incorporates content about interactions and relationships and can last for decades [Sherry and Schacter, Psychol. Rev. 94, 439-454 (1987)]. Long-term social memory likely played a key role throughout human evolution, as our ancestors increasingly built relationships that operated across distant space and time [Malone et al., Int. J. Primatol. 33, 1251-1277 (2012)]. Although individual recognition is widespread among animals and sometimes lasts for years, little is known about social memory in nonhuman apes and the shared evolutionary foundations of human social memory. In a preferential-looking eye-tracking task, we presented chimpanzees and bonobos (N = 26) with side-by-side images of a previous groupmate and a conspecific stranger of the same sex. Apes' attention was biased toward former groupmates, indicating long-term memory for past social partners. The strength of biases toward former groupmates was not impacted by the duration apart, and our results suggest that recognition may persist for at least 26 y beyond separation. We also found significant but weak evidence that, like humans, apes may remember the quality or content of these past relationships: apes' looking biases were stronger for individuals with whom they had more positive histories of social interaction. Long-lasting social memory likely provided key foundations for the evolution of human culture and sociality as they extended across time, space, and group boundaries.

Archaeological evidence for initial migration of Neolithic Proto Sino-Tibetan speakers from Yellow River valley to Tibetan Plateau.

Sino-Tibetan is the second largest language family in the world. Recent linguistic and genetic studies have traced its origin to Neolithic millet farmers in the Yellow River region of China around 8,000 y ago and also suggested that initial divergence among branches of Sino-Tibetan coincided with expansion of the Neolithic Yangshao culture to the west and southwest during the sixth millennium BP. However, archaeological investigations to date have been insufficient to understand the lifeways of these migrant Proto Sino-Tibetan speakers. Here, we present the results of the interdisciplinary research on the material culture and ritual activities related to the initial southwestward migration of Yangshao populations, based on evidence from microfossil remains on ceramics at three sites in Gansu and Sichuan, regional archaeological contexts, and ethnographic accounts of modern Gyalrong Tibetans. The first Yangshao migrants may have integrated with indigenous hunter-gatherers in the NW Sichuan highlands, and adopted broad-spectrum subsistence strategies, consisting of both millet farming and foraging for local wild resources. Meanwhile, the migrants appear to have retained important ritual traditions previously established in their Yellow River homelands. They prepared qu starter with Monascus mold and rice for brewing alcoholic beverages, which may have been consumed in communal drinking festivals associated with the performance of ritual dancing. Such ritual activities, which to some extent have survived in the skorbro-zajiu ceremonies in SW China, may have then played a central role in maintaining and reinforcing cultural identities, social values, and connections with the homelands of the Proto Sino-Tibetan migrants.

Recognizing the opponent: The consolidation of long-term social memory in zebrafish males.

Recognizing and remembering another individual in a social context could be beneficial for individual fitness. Especially in agonistic encounters, remembering an opponent and the previous fight could allow for avoiding new conflicts. Considering this, we hypothesized that this type of social interaction forms a long-term recognition memory lasting several days. It has been shown that a second encounter 24 h later between the same pair of zebrafish males is resolved with lower levels of aggression. Here, we evaluated if this behavioral change could last for longer intervals and a putative mechanism associated with memory storage: the recruitment of NMDA receptors. We found that if a pair of zebrafish males fight and fight again 48 or 72 h later, they resolve the second encounter with lower levels of aggression. However, if opponents were exposed to MK-801 (NMDA receptor antagonist) immediately after the first encounter, they solved the second one with the same levels of aggression: that is, no reduction in aggressive behaviors was observed. These amnesic effect suggest the formation of a long-term social memory related to recognizing a particular opponent and/or the outcome and features of a previous fight.

Let's call! Using the phone to increase vaccine acceptance.

In the context of the COVID-19 pandemic, we develop and test experimentally three phone-based interventions to increase vaccine acceptance in Mozambique. The first endorses the vaccine with a simple positive message. The second adds the activation of social memory on the country's success in eradicating wild polio with vaccination campaigns. The third further adds a structured interaction with the participant to develop a critical view toward misleading information and minimize the sharing of fake news. We find that combining the endorsement with the stimulation of social memory and the structured interaction increases vaccine acceptance and trust in institutions.

E3 Ubiquitin Ligase Uhrf2 Knockout Reveals a Critical Role in Social Behavior and Synaptic Plasticity in the Hippocampus.

The hippocampal formation, particularly the CA2 subregion, is critical for social memory formation and memory processing, relying on synaptic plasticity-a fundamental mechanism by which synapses strengthen. Given the role of the ubiquitin-proteasome system (UPS) in various nervous system processes, including learning and memory, we were particularly interested in exploring the involvement of RING-type ubiquitin E3 ligases, such as UHRF2 (NIRF), in social behavior and synaptic plasticity. Our results revealed altered social behavior in mice with systemic Uhrf2 knockout, including changes in nest building, tube dominance, and the three-chamber social novelty test. In Uhrf2 knockout mice, the entorhinal cortex-CA2 circuit showed significant reductions in synaptic plasticity during paired-pulse facilitation and long-term potentiation, while the inability to evoke synaptic plasticity in the Schaffer-collateral CA2 synapses remained unaffected. These changes in synaptic plasticity correlated with significant changes in gene expression including genes related to vesicle trafficking and transcriptional regulation. The effects of Uhrf2 knockout on synaptic plasticity and the observed gene expression changes highlight UHRF2 as a regulator of learning and memory processes at both the cellular and systemic levels. Targeting E3 ubiquitin ligases, such as UHRF2, may hold therapeutic potential for memory-related disorders, warranting further investigation.

Effects of social context manipulation on dorsal and ventral hippocampal neuronal responses.

The hippocampus is critical for contextual memory and has recently been implicated in various kinds of social memory. Traditionally, studies of hippocampal context coding have manipulated elements of the background environment, such as the shape and color of the apparatus. These manipulations produce large shifts in the spatial firing patterns, a phenomenon known as remapping. These findings suggest that the hippocampus encodes and differentiates contexts by generating unique spatial firing patterns for each environment a subject encounters. However, we do not know whether the hippocampus encodes social contexts defined by the presence of particular conspecifics. We examined this by exposing rats to a series of manipulations of the social context, including the presence of familiar male, unfamiliar male and female conspecifics, in order to determine whether remapping is a plausible mechanism for encoding socially-defined contexts. Because the dorsal and ventral regions of the hippocampus are thought to play different roles in spatial and social cognition, we recorded neurons in both regions. Surprisingly, we found little evidence of remapping in response to manipulation of the social context in either the dorsal or ventral hippocampus, although we saw typical remapping in response to changing the background color. This result suggests that remapping is not the primary mechanism for encoding different social contexts. However, we found that a subset of hippocampal neurons fired selectively near the cages that contained the conspecifics, and these responses were most prevalent in the ventral hippocampus. We also found a striking increase in the spatial information content of ventral hippocampal firing patterns. These results indicate that the ventral hippocampus is sensitive to changes in the social context and neurons that respond selectively near the conspecific cages could play an important, if not fully understood role in encoding the conjunction of conspecifics, their location and the environment.

Alteration of hippocampal CA2 plasticity and social memory in adult rats impacted by juvenile stress.

The hippocampal CA2 region has received greater attention in recent years due to its fundamental role in social memory and hippocampus-dependent memory processing. Unlike entorhinal cortical inputs, the Schaffer collateral inputs to CA2 do not support activity-dependent long-term potentiation (LTP), which serves as the basis for long-term memories. This LTP-resistant zone also expresses genes that restrict plasticity. With the aim of exploring social interaction and sociability in rats that were subjected to juvenile stress, we addressed questions about how the neural circuitry is altered and its effects on social behavior. Although there was induction of LTP in both Schaffer collateral and entorhinal cortical pathways in juvenile-stressed rats, LTP declined in both pathways after 2-3 h. Moreover, exogenous bath application of substance P, a neuropeptide that resulted in slow onset long-lasting potentiation in control animals while it failed to induce LTP in juvenile-stressed rats. Our study reveals that juvenile-stressed rats show behavioral and cellular abnormalities with a long-lasting impact in adulthood.

Relations between parental metacognitive talk and children's early metacognition and memory.

After decades of research suggesting that metacognition-that is, processes whereby people monitor and regulate their cognitive performance-did not emerge and is not related to children's performance until late childhood, recent studies have provided evidence that even preverbal infants can access their internal states. The existence of this basic metacognition raises the question of the variables influencing its development at such a young age and whether such early skills could predict successful cognitive performance. The current study had two main goals: (a) exploring the relation between parental metacognitive style and children's early metacognition and (b) determining whether these early metacognitive skills can predict children's memory performance. To this end, 2.5- to 4.5-year-old children (N = 72) and their parents were recruited. To assess parental metacognitive style, parent-child dyads were invited to participate in a 15-min session during which they played memory games. The parents' speech during this session was later coded for metacognitive content. Children's memory was assessed using cued recall and recognition tests. During one of these recognition tests, participants had the opportunity to ask for a cue to help them decide whether their response was correct (i.e., metacognitive measure). Results revealed that parental metacognitive style predicted both children's metacognitive accuracy and memory performance. Interestingly, a mediation effect of children's metacognitive skills on the relation between parental style and memory performance was found. These findings suggest that environmental factors such as parental metacognitive style are related to children's early metacognition, which in turn is linked to children's memory development.

Age-Dependent Behavioral and Synaptic Dysfunction Impairment Are Improved with Long-Term Andrographolide Administration in Long-Lived Female Degus (Octodon degus).

In Octodon degus, the aging process is not equivalent between sexes and worsens for females. To determine the beginning of detrimental features in females and the ways in which to improve them, we compared adult females (36 months old) and aged females (72 months old) treated with Andrographolide (ANDRO), the primary ingredient in Andrographis paniculata. Our behavioral data demonstrated that age does not affect recognition memory and preference for novel experiences, but ANDRO increases these at both ages. Sociability was also not affected by age; however, social recognition and long-term memory were lower in the aged females than adults but were restored with ANDRO. The synaptic physiology data from brain slices showed that adults have more basal synaptic efficiency than aged degus; however, ANDRO reduced basal activity in adults, while it increased long-term potentiation (LTP). Instead, ANDRO increased the basal synaptic activity and LTP in aged females. Age-dependent changes were also observed in synaptic proteins, where aged females have higher synaptotagmin (SYT) and lower postsynaptic density protein-95 (PSD95) levels than adults. ANDRO increased the N-methyl D-aspartate receptor subtype 2B (NR2B) at both ages and the PSD95 and Homer1 only in the aged. Thus, females exposed to long-term ANDRO administration show improved complex behaviors related to age-detrimental effects, modulating mechanisms of synaptic transmission, and proteins.

Isolation driven changes in Iba1-positive microglial morphology are associated with social recognition memory in adults and adolescents.

Microglia are critical for regulation of neuronal circuits that mature from adolescence to adulthood. The morphological complexity and process length of microglia can indicate different activation states. These states are sensitive to a variety of environmental and stress conditions. Microglia are sensitive to many factors that also regulate social behavior, and in turn, microglial manipulations can impact social function. Brief social isolation is one factor that can lead to robust social changes. Here, we explored the role of microglia in the effects of brief social isolation on social recognition memory. Using morphological measures of Iba1 to index microglial intensity, complexity, and process length, we identified different effects of brief isolation on microglial complexity in the basal region of the amygdala between adults and adolescents alongside overall increases in intensity of Iba1 in several cortical brain regions. Short-term social recognition memory is sensitive to the amount of social engagement, and provides an opportunity to test if social engagement produced by brief isolation enhances social learning in a manner that relies on microglia. We found that brief isolation facilitated social interaction across ages but had opposing effects on short-term social recognition. Isolation increased novel partner investigation in adolescents, which is consistent with better social recognition, but increased familiar partner investigation in adults. Depletion of microglia with PLX3397 prevented these effects of brief isolation in adolescents, and reduced them in adults. These results suggest that distinct changes in microglial function driven by the social environment may differentially contribute to subsequent social recognition memory during development.

The serial reproduction of an urban myth: revisiting Bartlett's schema theory.

Frederic Bartlett's schema theory is still widely misunderstood as claiming that remembering is inevitably unreliable. However, according to the logic of his schema theory, remembering should, in relation to certain kinds of material, be relatively reliable. In this study we examined whether a "well-worn" urban myth (the Vanishing Hitchhiker) could be exempt from the fate of other material used in Bartlett's own research on serial reproduction. Supporting Bartlett's ideas, we found that recall of the Hitchhiker story was better (if not perfect) over a series of five reproductions than recall of the classic War of the Ghosts. Recall was also better for a strict (as opposed to a lenient) audience, in line with another prediction from Bartlett's social theory of remembering. Notwithstanding this, we conclude with some critical remarks on the serial reproduction method as an approach to cultural memory.

Parvalbumin interneuron in the ventral hippocampus functions as a discriminator in social memory.

The ability to identify strange conspecifics in societies is supported by social memory, which is vital for gregarious animals and humans. The function of hippocampal principal neurons in social memory has been extensively investigated; however, the nonprincipal neuronal mechanism underlying social memory remains unclear. Here, we first observed parallel changes in the ability for social recognition and the number of parvalbumin interneurons (PVIs) in the ventral CA1 (vCA1) after social isolation. Then, using tetanus toxin-mediated neuronal lesion and optogenetic stimulation approaches, we revealed that vCA1-PVIs specifically engaged in the retrieval stage of social memory. Finally, through the in vivo Ca2+ imaging technique, we demonstrated that vCA1-PVIs exhibited higher activities when subjected mice approached a novel mouse than to a familiar one. These results highlight the crucial role of vCA1-PVIs for distinguishing novel conspecifics from other individuals and contribute to our understanding of the neuropathology of mental diseases with social memory deficits.

Hippocampal Deletion of CB1 Receptor Impairs Social Memory and Leads to Age-Related Changes in the Hippocampus of Adult Mice.

Endocannabinoid system activity declines with age in the hippocampus, along with the density of the cannabinoid receptor type-1 (CB1). This process might contribute to brain ageing, as previous studies showed that the constitutive deletion of the CB1 receptor in mice leads to early onset of memory deficits and histological signs of ageing in the hippocampus including enhanced pro-inflammatory glial activity and reduced neurogenesis. Here we asked whether the CB1 receptor exerts its activity locally, directly influencing hippocampal ageing or indirectly, accelerating systemic ageing. Thus, we deleted the CB1 receptor site-specifically in the hippocampus of 2-month-old CB1flox/flox mice using stereotaxic injections of rAAV-Cre-Venus viruses and assessed their social recognition memory four months later. Mice with hippocampus-specific deletion of the CB1 receptor displayed a memory impairment, similarly as observed in constitutive knockouts at the same age. We next analysed neuroinflammatory changes in the hippocampus, neuronal density and cell proliferation. Site-specific mutant mice had enhanced glial cell activity, up-regulated levels of TNFα in the hippocampus and decreased cell proliferation, specifically in the subgranular zone of the dentate gyrus. Our data indicate that a local activity of the CB1 receptor in the hippocampus is required to maintain neurogenesis and to prevent neuroinflammation and cognitive decline.

Cholinergic transmission from the basal forebrain modulates social memory in male mice.

Disruptions in social behaviour are prevalent in many neuropsychiatric disorders such as schizophrenia, bipolar disorder and autism spectrum disorders. However, the underlying neurochemical regulation of social behaviour is still not well understood. The central cholinergic system has been proposed to contribute to the regulation of social behaviour. For instance, decreased global levels of acetylcholine release in the brain leads to decreased social interaction and an impairment of social memory in mice. Nonetheless, it has been difficult to ascertain the specific brain areas where cholinergic signalling influences social preference and social memory. In this study, we investigated the impact of different forebrain cholinergic regions on social behaviour by examining mouse lines that differ in their regional expression level of the vesicular acetylcholine transporter-the protein that regulates acetylcholine secretion. We found that when cholinergic signalling is highly disrupted in the striatum, hippocampus, cortex and amygdala mice have intact social preference but are impaired in social memory, as they cannot remember a familiar conspecific nor recognize a novel one. A similar pattern emerges when acetylcholine release is disrupted mainly in the striatum, cortex, and amygdala; however, the ability to recognize novel conspecifics is retained. In contrast, cholinergic signalling of the striatum and amygdala does not appear to significantly contribute to the modulation of social memory and social preference. Furthermore, we demonstrated that increasing global cholinergic tone does not increase social behaviours. Together, these data suggest that cholinergic transmission from the hippocampus and cortex are important for regulating social memory.

Functional Convergence of Motor and Social Processes in Lobule IV/V of the Mouse Cerebellum.

Topographic organization of the cerebellum is largely segregated into the anterior and posterior lobes that represent its "motor" and "non-motor" functions, respectively. Although patients with damage to the anterior cerebellum often exhibit motor deficits, it remains unclear whether and how such an injury affects cognitive and social behaviors. To address this, we perturbed the activity of major anterior lobule IV/V in mice by either neurotoxic lesion or chemogenetic excitation of Purkinje cells in the cerebellar cortex. We found that both of the manipulations impaired motor coordination, but not general locomotion or anxiety-related behavior. The lesioned animals showed memory deficits in object recognition and social-associative recognition tests, which were confounded by a lack of exploration. Chemogenetic excitation of Purkinje cells disrupted the animals' social approach in a less-preferred context and social memory, without affecting their overall exploration and object-based memory. In a free social interaction test, the two groups exhibited less interaction with a stranger conspecific. Subsequent c-Fos imaging indicated that decreased neuronal activities in the medial prefrontal cortex, hippocampal dentate gyrus, parahippocampal cortices, and basolateral amygdala, as well as disorganized modular structures of the brain networks might underlie the reduced social interaction. These findings suggest that the anterior cerebellum plays an intricate role in processing motor, cognitive, and social functions.

Diverse sensory cues for individual recognition.

To be social, the ability to recognize and discriminate conspecific individuals is indispensable in social animals, including primates, rodents, birds, fish, and social insects which live in societies or groups. Recent studies using molecular biology, genetics, in vivo and in vitro physiology, and behavioral neuroscientific approaches have provided detailed insights into how animals process and recognize the information of individuals. Here, we review the most distinct sensory modalities for individual recognition in animals, namely, olfaction and vision. In the case of rodents, two polymorphic gene complexes have been identified in their urine as the key and essential pheromonal components for individual recognition: the major histocompatibility complex (MHC) and the major urinary protein (MUP). Animals flexibly utilize MHC and/or MUP, which are detected by the main olfactory epithelium (MOE) and/or the vomeronasal organ (VNO) for various types of social recognition, such as strain recognition, kin recognition, and individual recognition. In contrast, primates, including humans, primarily use facial appearance to identify others. Face recognition in humans and other animals is naturally unique from genetic, cognitive, developmental, and functional points of view. Importantly note that nurture effects during growth phase such as social experience and environment can also shape and tune this special cognitive ability, in order to distinguish subtle differences between individuals. In this review, we address such unique nature and nurture mechanisms for individual recognition.

Endocrine stress responsivity and social memory in 3xTg-AD female and male mice: A tale of two experiments.

Stress confers risk for the development and progression of Alzheimer's disease (AD). Relative to men, women are disproportionately more likely to be diagnosed with this neurodegenerative disease. We hypothesized that sex differences in endocrine stress responsiveness may be a factor in this statistic. To test this hypothesis, we assessed basal and stress-induced corticosterone, social recognition, and coat state deterioration (surrogate for depression-like behavior) in male and female 3xTg-AD mice. Prior to reported amyloid plaque deposition, 3xTg females (4 months), but not 3xTg males, had heightened corticosterone responses to restraint exposure. Subsequently, only 3xTg females (6 months) displayed deficits in social memory concomitant with prominent ß-amyloid (Aß) immunostaining. These data suggest that elevated corticosterone stress responses may precede cognitive impairments in genetically vulnerable females. 3xTg mice of both sexes exhibited coat state deterioration relative to same-sex controls. Corticolimbic glucocorticoid receptor (GR) dysfunction is associated with glucocorticoid hypersecretion and cognitive impairment. Our findings indicate sex- and brain-region specific effects of genotype on hippocampal and amygdala GR protein expression. Because olfactory deficits may impede social recognition, in Experiment 2, we assessed olfaction and found no differences between genotypes. Notably, in this cohort, heightened corticosterone stress responses in 3xTg females was not accompanied by social memory deficits or coat state deterioration. However, coat state deterioration was consistent in 3xTg males. We report consistent heightened stress-induced corticosterone levels and Aß pathology in female 3xTg-AD mice. However, the behavioral findings illuminate unknown inconsistencies in certain phenotypes in this AD mouse model.

Retrieval-induced forgetting in a social context: Do the same mechanisms underlie forgetting in speakers and listeners?

Selectively retrieving details from memory can result in forgetting related information, a finding known as retrieval-induced forgetting (RIF). The effect has mostly been examined in individuals, but RIF can also be socially transmitted and arise in listeners who are exposed to a speaker's selective memory retrieval. Whether within-individual RIF (WI-RIF) in speakers and socially shared RIF (SS-RIF) in listeners arise on the basis of the same cognitive mechanisms is unclear, however. In four experiments, we assessed both WI-RIF and SS-RIF while varying final test format to examine the potential involvement of output interference, strength-based blocking, and inhibition. WI-RIF and, to a similar degree, SS-RIF were observed on cued-recall tests with and without controlled output order at test, indicating that output interference cannot account for the observed forgetting. In contrast, SS-RIF was reduced relative to WI-RIF on tests of item recognition. These findings are consistent with the view that inhibition and blocking contribute to both WI-RIF and SS-RIF, but that the contribution of inhibition is reduced in listeners relative to speakers.

Effects of collaboration on the qualities of autobiographical recall in strangers, friends, and siblings: both remembering partner and communication processes matter.

Recalling autobiographical memories with others can influence the quality of recall, but little is known about how features of the group influence memory outcomes. In two studies, we examined how the products and processes of autobiographical recall depend on individual vs. collaborative remembering and the relationship between group members. In both studies, dyads of strangers, friends, and siblings recalled autobiographical events individually (elicitation), then either collaboratively or individually (recall). Study 1 involved typing memory narratives; Study 2 involved recalling aloud. We examined shifts in vividness, emotionality, and pronoun use within memory narratives produced by different relationship types. In Study 2, we also coded collaborative dyads' "collaborative processes" or communication processes. In Study 1, all relationships showed decreased positive emotion and I-pronouns and increased negative emotion within collaboratively-produced memory narratives. In Study 2, all relationships showed increased vividness, reduced emotionality and positive and negative emotion, and increased I- and we-pronouns within collaboratively-produced memory narratives. However, strangers used collaborative processes differently from friends and siblings. Some collaborative processes were associated with memory qualities. Across studies, collaboration influenced memory quality more than did relationship type, but relationship type influenced dyads' recall dynamics. These findings indicate the complexity of social influences on memory.