People with neuropsychiatric disorders sometimes exhibit anomalous social behaviors, such as antisocial tendencies or dramatic behavioral changes. These changes could be the manifestation of deficits in social memory, the ability to encode and retain information related to social interactions.
Past neuroscientific studies suggest that the hippocampus region in the brain is responsible for the formation of different types of memories, including social memories.
While the role it plays in the formation of social memory is now well documented, how it encodes and represents social information is still poorly understood.
Researchers at Columbia University and the National Institute of Mental Health (NIH) have recently carried out a study aimed at determining how social information is encoded within the hippocampus and more specifically in the hippocampal CA2 region.
This brain region has been often found to be associated with the encoding of social information into declarative memory, a form of long-term memory that allows humans or animals to consciously recall specific facts or events.
Studies that examined tissue samples extracted postmortem from individuals with schizophrenia or bipolar disorder have found that they presented 30% less parvalbumin-positive (PV+) interneurons in the hippocampal CA2 region than those extracted from individuals with no neuropsychiatric conditions.
Moreover, research identified the selective loss of PV+ neurons in the CA2 region in a specific mouse model, called Df(16)+/- .
Interestingly, these mice appeared to have profound social memory deficits even if they interacted with other mice with low levels of inhibition.
A possible explanation for this could be a simultaneous hyperpolarization and lower excitability of their pyramidal neurons (PNs) in the hippocampal CA2 region, which could be in turn be caused by an increased current running through TREK-1 two-pore potassium (K+) channels.
PNs are multipolar brain cells that can be found in many regions of the brain, while TREK-1 K+ channels are membrane proteins expressed in cells that selectively control the flow of potassium ions.
“Whether and how the opposing actions of decreased CA2 PN inhibition and enhanced TREK-1 hyperpolarizating current affect in vivo CA2 PN firing and/or contribute to social memory deficits of the Df(16)A+/-is unknown,” the researchers wrote in their paper.
“In this study, we addressed these questions using extracellular electrophysiological recordings from dorsal CA2 PNs and behavioral analysis in both wild-type and Df(16) +/- mice during spatial exploration and social interactions.”
In their study, the researchers surgically implanted electrode bundles in the brains of nineteen male mice. This allowed them to observe activity in the CA2 hippocampal region of the mice’s brains as they interacted with other mice.
Overall, the findings gathered in these experiments suggest that neuronal firing in the CA2 region accurately encoded changes in social context. For instance, the CA2 region appeared to encode memories that allow mice to determine whether they are interacting with new mice or mice they socialized with before.
“In the Df(16) +/- mouse model of the human 22q11.2 microdeletion, which confers a 30-fold increased risk of schizophrenia, CA2 social coding was impaired, consistent with the social memory deficit observed in these mice; in contrast, spatial coding accuracy was greatly enhanced,” the researchers explained in their paper.
In addition to confirming the key role of the hippocampal CA2 region in encoding social memories, the findings gathered by this team of researchers show that the TREK-1 channel could rescue social memory and coding in the CA2 in Df(16) +/-mice. In the future, their findings could enhance the current understanding of how social stimuli are encoded in the hippocampal CA2 region.
Ultimately, the results of this recent study could shed some light on the specific neural deficits and processes that may underpin the social behavior dysfunctions observed in people with neuropsychiatric disorders, such as bipolar disorder or schizophrenia.
This could in turn inform the development of alternative and more effective treatment strategies for these disorders that promote positive changes in social behavior.
Much of our lives is defined by our interactions with others, and the same goes for many species across the animal kingdom. When our capacity for social relationships breaks down, we are at increased risk for a wide range of neuropsychiatric disorders; indeed, conditions such as autism spectrum disorders (ASD) and social anxiety disorder are defined by abnormalities in social skills.
Despite this, a great deal of research aimed at unraveling the genomic and neural basis of complex behaviors has considered subjects in isolation or limited social contexts. The situation is, however, changing and recent years have seen something of a revival in popularity of studying social systems.
This issue of G2BREVIEWS comprises a series of reviews and original research reports chosen to reflect this renewed attention, as well as recognize the work of scientists with long-standing contributions to this field. Reflecting the journal’s broad scope, there are reports across species, from humans and rodents and from bees to flies to fish.
A recent trend in social neuroscience has been resurgent interest in the social transmission of learning. A number of reviews in this issue provide an excellent overview of this exciting area from some of the laboratories that have pioneered this work.
An excellent starting place is the piece by Kim et al,1 who introduce a paradigm developed in their laboratory in which mice acquire a contextual fear memory solely through observation of a conspecific receiving footshock in that same context.
They make a case that this process represents a primal form of empathy, which can be experimentally employed to provide insight into the neural and genomic basis of the more elaborated forms of empathy shown by higher species including humans.
Observational fear learning is just one of the emerging approaches for studying social information transfer considered by Monfils and Agee2 in their review.
In one of the paradigms they discuss (and have themselves developed), rats acquire a fear response simply by being in physical proximity to a conspecific showing a fear response to a conditioned-cue (“fear by proxy”). More generally, they provide a thoughtful discussion of the various factors that can determine the extent to which information is socially transmitted in these types of situations, ranging from social status to prior experiences.
Morozov and Ito3 expand on these themes, discussing findings showing how the behavior of a conspecific can both enhance and buffer fear behavior in an observer. These competing signals can then set off a complex social dynamic which, the authors contend, can produce a variety of outcomes depending on how an experiment is designed, but also a great opportunity to examine the neural basis of social modulation.
Echoing some of these notions, Kondrakiewicz et al4 emphasize how studying the neural basis of socially transmitted fear will benefit from balancing experimental control with an accommodation of an ecological perspective on social behavior in rats and mice. They underscore a number of important points for future research to bear in mind, notably the potential impact domestication has had on the social repertoire of laboratory rodents.
Abnormalities in social behavior are features of many neurodevelopmental disorders, ASD being an exemplar, but an underlying basis for these deficits remains unclear. Ferretti and Papaleo5 contend that proper social communication requires accurate recognition and interpretations of emotions and intentions between individuals, regardless of whether the individuals are humans or “lower” animals.
The authors discuss established and novel approaches to studying these processes in humans and rodents, and are strong proponents of the importance of sound behavioral assays to study the neural basis of emotion recognition. In a nice parallel piece, De Stefani et al6 use the fascinating case of Moebius syndrome—a rare neurological condition in which individuals are unable to form facial expressions—to posit that social understanding might depend upon the ability to mimic the facial musculature of others.
They conclude that the current evidence for a link between mimicry and social deficits in these individuals remains inconclusive, and raise some thought-provoking questions about the nature of social communication. Indeed, one consequence of an inability to gather information about environmental threats by observing others is that it could impair the capacity for recognizing and responding to potential dangers from a position of relative safety.
Kavaliers et al7 argue that this form of social cognition forms the basis of the affective response we as humans experience as disgust. This seems highly plausible given we typically experience disgust in reaction to stimuli that could potentially do us harm through, for example, poisoning or infection.
Drawing from their own elegant studies in mice conducted over many years, the authors describe how social information shapes disgust responses and in turn how disgust guides social preferences.
Although decrements in social behavior are features of many neuro-developmental disorders, ASD being an exemplar, Toth8 points out in a timely review, there are also conditions, such as Williams syndrome, that are characterized by hypersociability. Understanding the ontogenic trajectories of these dichotomous social phenotypes could hold important clues to the biological and genetic factors underlying individual differences in sociability.
Toth8 also notes that early life adversity can itself be a risk factor for pathological hypersociability, which leads us to Stevens and Jovanovic’s9 discussion of another illness associated with stress experienced during childhood, post-traumatic stress disorder (PTSD). They discuss how the social environment affects an individual’s capacity for buffering trauma and, more provocatively, provide evidence from a meta-analysis suggesting that deficits in social cognition pre-exist and increase risk for PTSD; an effect that may be mediated through abnormal perception of threat cues.
A wholly different take on the potential connection between perception and social behavior is provided here by Shultzaberger et al,10 who studied not humans, but fruit flies. Their primary interest lay in the evolution of social traits and they tackled this by assessing social behaviors in multiple species of Drosophila and the impact of social-rearing vs isolation on these behaviors.
Although different species retained the ability to effectively cross-socialize, the effect of early social experience affected social behavior in a manner that varied widely across species. Moreover, while species showed largely comparable transcriptional changes after a social event, there was more marked variation in regulation of chemosensory-perception genes, which, the authors conclude, could reflect the importance of these genes in shaping adaptations in social behavior.
In another excellent report, Shpigler et al11 used gene transcriptional profiling in honey bees to draw inferences about genes regulating different social behaviors. Focusing on the mushroom bodies, a region of the insect brain known for multimodal sensory integration and learning and memory, they compared transcriptional responses to social challenges evoking affiliative or agonistic behaviors to show both shared and divergent gene sets associated with each other.
The authors suggest these could represent transcriptional signatures of valence that serve to guide appropriate behavioral responses to social stimuli.
These two studies show the power of research in invertebrates, but rodents remain a mainstay in much behavioral work. A handful of studies in the special issue illustrate how mutant mice continue to provide valuable insights into genetic factors influencing social behavior, with relevance to, for example, ASD and Fragile X syndrome. Sadigurschi and Golan12 describe a mouse engineered with haploin-sufficiency of methylenetetrahydrofolate reductase (MTHFR); the human version of which contains a polymorphic variant associated with ASD.
They report on a set of social, anxiety-related and cognitive alterations in these mutant mice, and show how maternal genotype can also affect some of these phenotypes. They then go on to link the behavioral deficits, at least in males, to cortical parvalbumin interneuron abnormalities; an observation that resonates with the sex-dependent cortical disturbances reported here by Keil et al13.
These authors describe mice with humanized mutations in one or both of two calcium signaling related genes encoding the ryanodine receptor 1 and fragile X mental retardation gene 1. Analysis of neuronal dendritic arborization in the somatosensory cortex and hippocampus of these mutants showed morphological disturbances in both regions, although these were most prominent in females in the cortex but, for males, in the hippocampus.
Consistent with the authors’ hypothesis that variation in calcium signaling genes shaping dendritic morphology can act as risk factors for neurodevelopmental disorders characterized by social impairment, they find low sociability in the mutants.
The symptomatology of neurodevelopmental disorders is not confined to social abnormalities, but often extends to emotional disturbances. Goulding et al14 report on mutant mice lacking specific genes found in a locus on a chromosomal region (3p21) that genome-wide association studies have implicated in mood disorders.
They describe how deletion of either the Ambp or bikunin genes, both of which regulate the function of inter-alpha-trypsin inhibitor heavy chain H1 (ITIH1) and inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) complexes, leads to abnormal social approach, as well as increased fear and anxiety-related behaviors.
The close connection between sociability and emotion is further underscored in this issue by a pair of empirical papers examining the impact of stress and pain on social behavior. In the first of these, Cathomas et al15 employ a mouse model of chronic social defeat stress, known to produce depression-relevant abnormalities, to examine changes in oligodendrocyte gene expression in various limbic regions using RNA-sequencing.
On finding that social stress downregulated a number of myelin-associated genes in the amygdala, the authors go on to show that haploinsufficiency of the oligodendrocyte gene cyclic nucleotide phosphodiesterase (Cnp1) exacerbated social impairments resulting from stress.
The fact that the experience of adversity can affect sociability, as much social interactions can shape how individuals respond to aversive situations, is shown in a different way by the article by Tansley et al.16 In their study, the authors report how the induction of chronic pain produces some surprising effects on social behaviors in mice.
Using a simple tube co-occupancy test, these authors show that individuals that were previously unknown to one another spend more time together, akin to familiar mice, when both have experienced long-lasting pain. The reasons for this switch in response to neuropathic pain remains enigmatic and a subject for further study, but these findings will likely be of significant interest to researchers investigating how sociability is affected in people with neuropathic pain.
These kinds of insights in rodent models can be of clinical relevance in a variety of ways and can provide a stepping stone to deciphering the molecular and signaling mechanisms regulating social behaviors which one day might suggest new therapeutic approaches. Many potential candidate mechanisms have now been proposed.
Here, Ito et al17 show that mice with deletion of brain-derived neurotrophic factor (Bdnf), specifically within the CA3 subregion of the hippocampus, showed deficient interaction with a familiar, but anesthetized, conspecific. Their reason for developing this novel procedure was to minimize the hyper-aggression that is normally elicited by an awake social partner in these mutants and thereby better parse out this social deficit.
Like BDNF, prostaglandin E2 (PGE2) is another molecule important for brain development. PGE2 synthesis is in turn regulated by cyclooxygenase-2 (COX2). Wong et al18 report on a phenotype of ASD-related behaviors, including social disturbances, and associated gene expression changes, in COX2 null mutant mice. In doing so, they build upon emerging evidence linking COX2/PGE2 signaling to ASD.
Two neuropeptide systems that have received a great deal of interest for their role in social behaviors are oxytocin (Oxt) and arginine vasopressin (AVP), and the burgeoning literature on these peptides is considered in two scholarly reviews. In the first, Cilz et al19 focus on the emerging evidence implicating Oxt and AVP in the modulation of hippocampal-dependent forms of social cognition.
They summarize the known anatomy and expression of the two neuropeptides and their receptors within the hippocampal formation and document studies describing how disruption of these systems affects social behaviors, in particular social memory, through their effects on hippocampal function.
In the accompanying review, Bayerl and Bosch20 describe genetic, pharmacological and microdialysis studies that show how AVP transmission, acting through the V1a and V1b receptor sub-types, have potent effects on rodent maternal behaviors via actions at specific brain-regions. They also allude to intriguing initial evidence that indicates recruitment of AVP in humans during mothering, raising the prospect of future work into the potential link between AVP function and developmentally originating social disorders.
To end this Special Issue, Saul et al21 offer a creative and potentially very powerful approach to studying social behavior. Using a computational-experimental approach, applied across three different species (mouse, honey bee and stickleback fish), these authors performed RNA-seq to generate time-dependent profiles of transcriptional responses to social challenge.
The resultant analysis provided a rich dataset of specific genetic changes to follow-up in future work but, perhaps most intriguingly, allowed the authors to build a system-level model of mechanisms that appear to have been conserved across species to support social behavior. Such mechanistic frameworks, spanning species and employing state of the art techniques, will provide the type of valuable heuristic that can guide future research aimed at advancing our knowledge of the neural, molecular and genomic substrates of social behavior.
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More information: Coding of social novelty in the hippocampal CA2 region and its disruption and rescue in a 22q11.2 microdeletion mouse model. Nature Neuroscience(2020). DOI: 10.1038/s41593-020-00720-5.