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Loss of a loved one is a painful event that substantially elevates the risk for physical and mental illness and impaired daily function. Socially monogamous prairie voles are laboratory‐amenable rodents that form life‐long pair bonds and exhibit distress upon partner separation, mirroring phenotypes seen in humans. These attributes make voles an excellent model for studying the biology of loss. In this review, we highlight parallels between humans and prairie voles, focusing on reward system engagement during pair bonding and loss. As yearning is a unique feature that differentiates loss from other negative mental states, we posit a model in which the homeostatic reward mechanisms that help to maintain bonds are disrupted upon loss, resulting in yearning and other negative impacts. Finally, we synthesize studies in humans and voles that delineate the remodeling of reward systems during loss adaptation. The stalling of these processes likely contributes to prolonged grief disorder, a diagnosis recently added to the Diagnostic and Statistical Manual for Psychiatry. [ABSTRACT FROM AUTHOR]

Spiny mice are gregarious animals that prefer to socialize with large groups. A new pioneering study reveals an underlying neural circuit governing this social preference. [ABSTRACT FROM AUTHOR]

In pair bonding animals, coordinated behavior between partners is required for the pair to accomplish shared goals such as raising young. Despite this, experimental designs rarely assess the behavior of both partners within a bonded pair. Thus, we lack an understanding of the interdependent behavioral dynamics between partners that likely facilitate relationship success. To identify intra‐pair behavioral correlates of pair bonding, we used socially monogamous prairie voles (Microtus ochrogaster) and tested both partners using social choice and non‐choice tests at short‐ and long‐term pairing timepoints. Females developed a preference for their partner more rapidly than males, with preference driven by different behaviors in each sex. Further, as bonds matured, intra‐pair behavioral sex differences and organized behavior emerged—females consistently huddled more with their partner than males did regardless of overall intra‐pair affiliation levels. When animals were allowed to freely interact with a partner or a novel vole in sequential free interaction tests, pairs spent more time interacting together than either animal did with a novel vole, consistent with partner preference in the more commonly employed choice test. Total pair interaction in freely moving voles was correlated with female, but not male, behavior. Via a social operant paradigm, we found that pair‐bonded females, but not males, are more motivated to access and huddle with their partner than a novel vole. Together, our data indicate that as pair bonds mature, sex differences and organized behavior emerge within pairs, and that these intra‐pair behavioral changes are likely organized and driven by the female animal. [ABSTRACT FROM AUTHOR]

The rewarding properties of social interactions facilitate relationship formation and maintenance. Prairie voles are one of the few laboratory species that form selective relationships, manifested as "partner preferences" for familiar partners versus strangers. While both sexes exhibit strong partner preferences, this similarity in outward behavior likely results from sex‐specific neurobiological mechanisms. We recently demonstrated that in operant trials, females worked hardest for access to familiar conspecifics of either sex, while males worked equally hard for access to any female, indicating a sex difference in social motivation. As tests were performed with one social target at a time, males might have experienced a ceiling effect, and familiar females might be more relatively rewarding in a choice scenario. Here we performed an operant social choice task in which voles lever‐pressed to gain temporary access to either the chamber containing their mate or one containing a novel opposite‐sex vole. Females worked hardest to access their mate, while males pressed at similar rates for either female. Individual male behavior was heterogeneous, congruent with multiple mating strategies in the wild. Voles exhibited preferences for favorable over unfavorable environments in a non‐social operant task, indicating that lack of social preference does not reflect lack of discrimination. Natural variation in oxytocin receptor genotype at the intronic single nucleotide polymorphism NT213739 was associated with oxytocin receptor density, and predicted individual variation in stranger‐directed aggressive behavior. These findings suggest that convergent preference behavior in male and female voles results from sex‐divergent pathways, particularly in the realm of social motivation. [ABSTRACT FROM AUTHOR]

Abstract Background The arginine vasopressin V1a receptor (V1aR) modulates social cognition and behavior in a wide variety of species. Variation in a repetitive microsatellite element in the 5' flanking region of the V1aR gene (AVPR1A) in rodents has been associated with variation in brain V1aR expression and in social behavior. In humans, the 5' flanking region of AVPR1A contains a tandem duplication of two ~350 bp, microsatellite-containing elements located approximately 3.5 kb upstream of the transcription start site. The first block, referred to as DupA, contains a polymorphic (GT)25 microsatellite; the second block, DupB, has a complex (CT)4-(TT)-(CT)8-(GT)24 polymorphic motif, known as RS3. Polymorphisms in RS3 have been associated with variation in sociobehavioral traits in humans, including autism spectrum disorders. Thus, evolution of these regions may have contributed to variation in social behavior in primates. We examined the structure of these regions in six ape, six monkey, and one prosimian species. Results Both tandem repeat blocks are present upstream of the AVPR1A coding region in five of the ape species we investigated, while monkeys have only one copy of this region. As in humans, the microsatellites within DupA and DupB are polymorphic in many primate species. Furthermore, both single (lacking DupB) and duplicated alleles (containing both DupA and DupB) are present in chimpanzee (Pan troglodytes) populations with allele frequencies of 0.795 and 0.205 for the single and duplicated alleles, respectively, based on the analysis of 47 wild-caught individuals. Finally, a phylogenetic reconstruction suggests two alternate evolutionary histories for this locus. Conclusion There is no obvious relationship between the presence of the RS3 duplication and social organization in primates. However, polymorphisms identified in some species may be useful in future genetic association studies. In particular, the presence of both single and duplicated alleles in chimpanzees provides a unique opportunity to assess the functional role of this duplication in contributing to variation in social behavior in primates. While our initial studies show no signs of directional selection on this locus in chimps, pharmacological and genetic association studies support a potential role for this region in influencing V1aR expression and social behavior.

Pair bonds represent some of the strongest attachments we form as humans. These relationships positively modulate health and well-being. Conversely, the loss of a spouse is an emotionally painful event that leads to numerous deleterious physiological effects, including increased risk for cardiac dysfunction and mental illness. Much of our understanding of the neuroendocrine basis of pair bonding has come from studies of monogamous prairie voles (Microtus ochrogaster), laboratory-amenable rodents that, unlike laboratory mice and rats, form lifelong pair bonds. Specifically, research using prairie voles has delineated a role for multiple neuromodulatory and neuroendocrine systems in the formation and maintenance of pair bonds, including the oxytocinergic, dopaminergic, and opioidergic systems. However, while these studies have contributed to our understanding of selective attachment, few studies have examined how interactions among these 3 systems may be essential for expression of complex social behaviors, such as pair bonding. Therefore, in this review, we focus on how the social neuropeptide, oxytocin, interacts with classical reward system modulators, including dopamine and endogenous opioids, during bond formation and maintenance. We argue that an understanding of these interactions has important clinical implications and is required to understand the evolution and encoding of complex social behaviors more generally. Finally, we provide a brief consideration of future directions, including a discussion of the possible roles that glia, specifically microglia, may have in modulating social behavior by acting as a functional regulator of these 3 neuromodulatory systems. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques and tau neurofibrillary tangles. APPswe/PS1dE9 (APP/PS1) mice have been developed as an AD model and are characterized by plaque formation at 4-6 months of age. Here, we sought to better understand AD-related cognitive decline by characterizing various types of memory. In order to better understand how memory declines with AD, APP/PS1 mice were bred with ArcCreERT2 mice. In this line, neural ensembles activated during memory encoding can be indelibly tagged and directly compared with neural ensembles activated during memory retrieval (i.e., memory traces/engrams). We first administered a battery of tests examining depressive- and anxiety-like behaviors, as well as spatial, social, and cognitive memory to APP/PS1 × ArcCreERT2 × channelrhodopsin (ChR2)-enhanced yellow fluorescent protein (EYFP) mice. Dentate gyrus (DG) neural ensembles were then optogenetically stimulated in these mice to improve memory impairment. AD mice had the most extensive differences in fear memory, as assessed by contextual fear conditioning (CFC), which was accompanied by impaired DG memory traces. Optogenetic stimulation of DG neural ensembles representing a CFC memory increased memory retrieval in the appropriate context in AD mice when compared with control (Ctrl) mice. Moreover, optogenetic stimulation facilitated reactivation of the neural ensembles that were previously activated during memory encoding. These data suggest that activating previously learned DG memory traces can rescue cognitive impairments and point to DG manipulation as a potential target to treat memory loss commonly seen in AD. [ABSTRACT FROM AUTHOR]

Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants, but the mechanisms by which they influence behavior are only partially resolved. Adult hippocampal neurogenesis is necessary for some of the responses to SSRIs, but it is not known whether mature dentate gyrus granule cells (DG GCs) also contribute. We deleted the serotonin 1A receptor (5HT1AR, a receptor required for the SSRI response) specifically from DG GCs and found that the effects of the SSRI fluoxetine on behavior and the hypothalamic-pituitary-adrenal (HPA) axis were abolished. By contrast, mice lacking 5HT1ARs only in young adult-born GCs (abGCs) showed normal fluoxetine responses. Notably, 5HT1AR-deficient mice engineered to express functional 5HT1ARs only in DG GCs responded to fluoxetine, indicating that 5HT1ARs in DG GCs are sufficient to mediate an antidepressant response. Taken together, these data indicate that both mature DG GCs and young abGCs must be engaged for an antidepressant response. [ABSTRACT FROM AUTHOR]

The serotonin 1A receptor (5-HT1A) has a major role in modulating the effects of serotonin on mood and behavior. Previous studies have shown that knockout of 5-HT1A selectively in the raphe leads to higher levels of anxiety during adulthood. However, it remains unclear whether this phenotype is due to variation in receptor levels specifically during development or throughout life. To test the hypothesis that developmental sensitivity may underlie the effects of 5-HT1A on anxiety, we used an inducible transgenic system to selectively suppress 5-HT1A levels in serotonergic raphe neurons from post-natal days (P) 14 to P30, with a maximal reduction of 40% at P21 and return to regular levels by P30. This developmental decrease in receptor levels has long-lasting consequences, increasing anxiety and decreasing social investigation in adulthood. In addition, post-natal knockdown of autoreceptors leads to long-term increases in the excitability of serotonergic neurons, which may represent a mechanism underlying the effects of post-natal receptor variation on behavior later in life. Finally, we also examined the interplay between receptor variation and juvenile exposure to stress (applied from P14 to P21). Similar to receptor knockdown, juvenile exposure to stress led to increased anxiety phenotypes but did not exacerbate 5-HT1A knockdown-mediated anxiety levels. This work indicates that the effects of 5-HT1A autoreceptors on anxiety and social behaviors are developmentally mediated and suggests that natural variations in the expression of 5-HT1A may act during development to influence individual anxiety levels and contribute to susceptibility to anxiety disorders. [ABSTRACT FROM AUTHOR]

Certain genes exhibit notable diversity in their expression patterns both within and between species. One such gene is the vasopressin receptor 1a gene (Avpr1a), which exhibits striking differences in neural expression patterns that are responsible for mediating differences in vasopressin-mediated social behaviors. The genomic mechanisms that contribute to these remarkable differences in expression are not well understood. Previous work has suggested that both the proximal 5′ flanking region and a polymorphic microsatellite element within that region of the vole Avpr1a gene are associated with variation in V1a receptor (V1aR) distribution and behavior, but neither has been causally linked. Using homologous recombination in mice, we reveal the modest contribution of proximal 5′ flanking sequences to species differences in V1aR distribution, and confirm that variation in V1aR distribution impacts stress-coping in the forced swim test. We also demonstrate that the vole Avpr1a microsatellite structure contributes to Avpr1a expression in the amygdala, thalamus, and hippocampus, mirroring a subset of the inter- and intra-species differences observed in central V1aR patterns in voles. This is the first direct evidence that polymorphic microsatellite elements near behaviorally relevant genes can contribute to diversity in brain gene expression profiles, providing a mechanism for generating behavioral diversity both at the individual and species level. However, our results suggest that many features of species-specific expression patterns are mediated by elements outside of the immediate 5′ flanking region of the gene. [ABSTRACT FROM AUTHOR]

The neuropeptide arginine vasopressin (AVP) modulates a variety of species-specific social behaviors. In socially monogamous male prairie voles, AVP acts centrally via vasopressin VI a receptor (VIaR) to facilitate mating induced partner preferences. The display of a partner preference requires at least 2 temporally distinct processes: social bond formation as well as its recall, or expression. Studies to date have not determined in which of these processes V1aR acts to promote partner preferences. Here, male prairie voles were administered intracerebroventricularly a VIaR antagonist (AVPA) at different time points to investigate the role of VIaR in social bond formation and expression. Animals receiving AVPA prior to cohabitation with mating or immediately prior to partner preference testing failed to display a partner preference, while animals receiving AVPA immediately after cohabitation with mating and control animals receiving vehicle at all 3 time points displayed partner preferences. These results suggest that V1aR signaling is necessary for both the formation and expression of partner preferences and that these processes are dissociable. [ABSTRACT FROM AUTHOR]

Background: The arginine vasopressin V1a receptor (V1aR) modulates social cognition and behavior in a wide variety of species. Variation in a repetitive microsatellite element in the 5' flanking region of the V1aR gene (AVPR1A) in rodents has been associated with variation in brain V1aR expression and in social behavior. In humans, the 5' flanking region of AVPR1A contains a tandem duplication of two ~350 bp, microsatellite-containing elements located approximately 3.5 kb upstream of the transcription start site. The first block, referred to as DupA, contains a polymorphic (GT)25 microsatellite; the second block, DupB, has a complex (CT)4-(TT)-(CT)8-(GT)24 polymorphic motif, known as RS3. Polymorphisms in RS3 have been associated with variation in sociobehavioral traits in humans, including autism spectrum disorders. Thus, evolution of these regions may have contributed to variation in social behavior in primates. We examined the structure of these regions in six ape, six monkey, and one prosimian species. Results: Both tandem repeat blocks are present upstream of the AVPR1A coding region in five of the ape species we investigated, while monkeys have only one copy of this region. As in humans, the microsatellites within DupA and DupB are polymorphic in many primate species. Furthermore, both single (lacking DupB) and duplicated alleles (containing both DupA and DupB) are present in chimpanzee (Pan troglodytes) populations with allele frequencies of 0.795 and 0.205 for the single and duplicated alleles, respectively, based on the analysis of 47 wild-caught individuals. Finally, a phylogenetic reconstruction suggests two alternate evolutionary histories for this locus. Conclusion: There is no obvious relationship between the presence of the RS3 duplication and social organization in primates. However, polymorphisms identified in some species may be useful in future genetic association studies. In particular, the presence of both single and duplicated alleles in chimpanzees provides a unique opportunity to assess the functional role of this duplication in contributing to variation in social behavior in primates. While our initial studies show no signs of directional selection on this locus in chimps, pharmacological and genetic association studies support a potential role for this region in influencing V1aR expression and social behavior. [ABSTRACT FROM AUTHOR]

Many species have been reported to form roosting (resting, sleeping) aggregations at ‘traditional’ sites, but the alternative hypothesis that specific sites are used repeatedly because of habitat limitation is rarely tested. We studied the roosting behavior of a species of harvestman (Opiliones, Prionostemma sp.) at a lowland rainforest site in Nicaragua. Both sexes roosted by day in spiny palm trees, dispersed at dusk to forage, and rejoined aggregations just before dawn. The distribution of harvestmen among spiny palms was significantly clumped, and harvestman density did not correlate with spiny palm density. Aggregations formed repeatedly in a small subset of the available spiny palms and the same sites were used in two different years (2001, 2003). Nevertheless, the membership of aggregations was fluid; individual harvestmen were found at multiple roosts and moved up to 0.2 km per night. Translocated animals often returned to the roost where they had been released or nearby roosts but were never found at previously unused sites. The high consistency of site use but low site fidelity of individuals suggests that roost sites differed conspicuously (to the harvestmen) from sites that were not used. We found no univariate or multivariate differences between used and unused sites, however, in the characteristics of the trees or microclimate. These results conflict with the habitat limitation hypothesis but are consistent with the traditional site use hypothesis. The tradition may be mediated by a site-labeling chemical, a mechanism that does not require individual site fidelity. We discuss these results in relation to the proposed functions of roosting aggregations. [ABSTRACT FROM AUTHOR]