Understanding Others' Distress Through Past Experiences: The Role of Memory Engram Cells in Observational Fear.

For individuals to survive and function in society, it is essential that they recognize, interact with, and learn from other conspecifics. Observational fear (OF) is the well-conserved empathic ability of individuals to understand the other's aversive situation. While it is widely known that factors such as prior similar aversive experience and social familiarity with the demonstrator facilitate OF, the neural circuit mechanisms that explicitly regulate experience-dependent OF (Exp OF) were unclear. In this review, we examine the neural circuit mechanisms that regulate OF, with an emphasis on rodent models, and then discuss emerging evidence for the role of fear memory engram cells in the regulation of Exp OF. First, we examine the neural circuit mechanisms that underlie Naive OF, which is when an observer lacks prior experiences relevant to OF. In particular, the anterior cingulate cortex to basolateral amygdala (BLA) neural circuit is essential for Naive OF. Next, we discuss a recent study that developed a behavioral paradigm in mice to examine the neural circuit mechanisms that underlie Exp OF. This study found that fear memory engram cells in the BLA of observers, which form during a prior similar aversive experience with shock, are reactivated by ventral hippocampal neurons in response to shock delivery to the familiar demonstrator to elicit Exp OF. Finally, we discuss the implications of fear memory engram cells in Exp OF and directions of future research that are of both translational and basic interest.

Systems consolidation induces multiple memory engrams for a flexible recall strategy in observational fear memory in male mice.

Observers learn to fear the context in which they witnessed a demonstrator's aversive experience, called observational contextual fear conditioning (CFC). The neural mechanisms governing whether recall of the observational CFC memory occurs from the observer's own or from the demonstrator's point of view remain unclear. Here, we show in male mice that recent observational CFC memory is recalled in the observer's context only, but remote memory is recalled in both observer and demonstrator contexts. Recall of recent memory in the observer's context requires dorsal hippocampus activity, while recall of remote memory in both contexts requires the medial prefrontal cortex (mPFC)-basolateral amygdala pathway. Although mPFC neurons activated by observational CFC are involved in remote recall in both contexts, distinct mPFC subpopulations regulate remote recall in each context. Our data provide insights into a flexible recall strategy and the functional reorganization of circuits and memory engram cells underlying observational CFC memory.

Acute administration of fluoxetine increases social avoidance and risk assessment behaviors in a sex- and social stress-dependent manner in Syrian hamsters (Mesocricetus auratus).

Most studies investigating the effects of acute administration of selective serotonin reuptake inhibitors (SSRI) on responses to social stress have been conducted with males. This is despite the fact that SSRIs remain the primary pharmacotherapy for social stress-related disorders for both sexes and that the prevalence of these disorders is twofold higher in women than in men. To determine whether acute treatment with the SSRI, fluoxetine, alters behavioral responses to social defeat stress in a sex- or social stress-dependent manner, male and female Syrian hamsters were subjected to one of three social defeat conditions: no defeat (placed into an empty resident aggressor (RA) cage), a single defeat by one RA for 15 min, or three consecutive defeats using different RAs for 5 min each. The day following social defeat, subjects were infused with either vehicle or fluoxetine (20 mg/kg, I.P.) 2 h prior to a 5 min social avoidance test. Overall, we found that fluoxetine increased social vigilance regardless of sex or defeat condition. We also found that fluoxetine affected social avoidance in a sex by stress intensity interaction, such that fluoxetine increased avoidance in no defeat males and in males defeated once but significantly increased avoidance in females only after three defeats. These data suggest that treatment with an SSRI could initially exacerbate the effects of social stress in both sexes. These data also emphasize the importance of including sex as a biological variable when investigating the efficacy of pharmacotherapy for stress-related disorders.

Hippocampal-amygdala memory circuits govern experience-dependent observational fear.

The empathic ability to vicariously experience the other's fearful situation, a process called observational fear (OF), is critical to survive in nature and function in society. OF can be facilitated by both prior similar fear experience in the observer and social familiarity with the demonstrator. However, the neural circuit mechanisms of experience-dependent OF (Exp OF) remain unknown. Here, we demonstrate that hippocampal-basolateral amygdala (HPC-BLA) circuits in mice without involving the anterior cingulate cortex, considered a center of OF, mediate Exp OF. Dorsal HPC neurons generate fear memory engram cells in BLA encoding prior similar fear experiences, which are essential for Exp OF. On the other hand, ventral HPC neurons respond to the familiar demonstrator's aversive situation during Exp OF, which reactivates the fear memory engram cells in BLA to elicit Exp OF. Our study provides new insights into the memory engram-dependent perception-action coupling that underlies empathic behaviors like Exp OF.

Learning and memory: Shuffling memory traces by relearning.

Memory engram cells are a subpopulation of neurons activated during learning, and are necessary and sufficient for memory recall. New findings show that relearning induces the turnover of the memory engram cell population involved in fear memory recall.

Adult hippocampal neurogenesis for systems consolidation of memory.

The hippocampus (HPC) is required for the initial process of permanent memory formation. After memory acquisition, HPC-dependency of memory recall gradually decreases with time, whereas cortical-dependency of memory recall increases. This phenomenon is often referred to as systems consolidation of memory. In the HPC, adult neurogenesis has been described in many mammalian species and is involved in the process of learning and memory. In this review, we first examine the neural circuit mechanisms that underlie the systems consolidation of episodic memories, focusing on adult neurogenesis within the HPC. Recently, several studies have examined the characterization of memory engram cells, their biochemical and physiological changes, and the circuits for systems consolidation of memory. Therefore, we discuss the possible role of adult neurogenesis on functional states of memory engram cells, and speculate the implications of this transition of memory type for psychiatric disorders such as post-traumatic stress disorder.

Sex-dependent regulation of social reward by oxytocin receptors in the ventral tegmental area.

Social reward is critical for social relationships, and yet we know little about the characteristics of social interactions that are rewarding or the neural mechanisms underlying that reward. Here, we investigate the sex-dependent role of oxytocin receptors within the ventral tegmental area (VTA) in mediating the magnitude and valence of social reward. Operant and classical conditioning tests were used to measure social reward associated with same-sex social interactions. The effects of oxytocin, selective oxytocin receptor agonists, antagonists, and vehicle injected into the VTA on social reward was determined in male and female Syrian hamsters. The colocalization of FOS and oxytocin in sites that project to the VTA following social interaction was also determined. Females find same-sex social interactions more rewarding than males and activation of oxytocin receptors in the VTA is critical for social reward in females, as well as males. These studies provide support for the hypothesis that there is an inverted U relationship between the duration of social interaction and social reward, mediated by oxytocin; and that in females the dose-response relationship is initiated at lower doses compared with males. Same-sex social interaction is more rewarding in females than in males, and an inverted U relationship mediated by oxytocin may have a critical role in assigning positive and negative valence to social stimuli. Understanding these sex differences in social reward processing may be essential for understanding the sex differences in the prevalence of many psychiatric disorders and the development of gender-specific treatments of neuropsychiatric disorders.

Sex Differences in the Regulation of Offensive Aggression and Dominance by Arginine-Vasopressin.

Arginine-vasopressin (AVP) plays a critical role in the regulation of offensive aggression and social status in mammals. AVP is found in an extensive neural network in the brain. Here, we discuss the role of AVP in the regulation of aggression in the limbic system with an emphasis on the critical role of hypothalamic AVP in the control of aggression. In males, activation of AVP V1a receptors (V1aRs) in the hypothalamus stimulates offensive aggression, while in females activation of V1aRs inhibits aggression. Serotonin (5-HT) also acts within the hypothalamus to modulate the effects of AVP on aggression in a sex-dependent manner. Activation of 5-HT1a receptors (5-HT1aRs) inhibits aggression in males and stimulates aggression in females. There are also striking sex differences in the mechanisms underlying the acquisition of dominance. In males, the acquisition of dominance is associated with the activation of AVP-containing neurons in the hypothalamus. By contrast, in females, the acquisition of dominance is associated with the activation of 5-HT-containing neurons in the dorsal raphe. AVP and 5-HT also play critical roles in the regulation of a form of social communication that is important for the maintenance of dominance relationships. In both male and female hamsters, AVP acts via V1aRs in the hypothalamus, as well as in other limbic structures, to communicate social status through the stimulation of a form of scent marking called flank marking. 5-HT acts on 5-HT1aRs as well as other 5-HT receptors within the hypothalamus to inhibit flank marking induced by AVP in both males and females. Interestingly, while AVP and 5-HT influence the expression of aggression in opposite ways in males and females, there are no sex differences in the effects of AVP and 5-HT on the expression of social communication. Given the profound sex differences in the incidence of many psychiatric disorders and the increasing evidence for a relationship between aggressiveness/dominance and the susceptibility to these disorders, understanding the neural regulation of aggression and social status will have significant import for translational studies.

Serotonin and arginine-vasopressin mediate sex differences in the regulation of dominance and aggression by the social brain.

There are profound sex differences in the incidence of many psychiatric disorders. Although these disorders are frequently linked to social stress and to deficits in social engagement, little is known about sex differences in the neural mechanisms that underlie these phenomena. Phenotypes characterized by dominance, competitive aggression, and active coping strategies appear to be more resilient to psychiatric disorders such as posttraumatic stress disorder (PTSD) compared with those characterized by subordinate status and the lack of aggressiveness. Here, we report that serotonin (5-HT) and arginine-vasopressin (AVP) act in opposite ways in the hypothalamus to regulate dominance and aggression in females and males. Hypothalamic injection of a 5-HT1a agonist stimulated aggression in female hamsters and inhibited aggression in males, whereas injection of AVP inhibited aggression in females and stimulated aggression in males. Striking sex differences were also identified in the neural mechanisms regulating dominance. Acquisition of dominance was associated with activation of 5-HT neurons within the dorsal raphe in females and activation of hypothalamic AVP neurons in males. These data strongly indicate that there are fundamental sex differences in the neural regulation of dominance and aggression. Further, because systemically administered fluoxetine increased aggression in females and substantially reduced aggression in males, there may be substantial gender differences in the clinical efficacy of commonly prescribed 5-HT-active drugs such as selective 5-HT reuptake inhibitors. These data suggest that the treatment of psychiatric disorders such as PTSD may be more effective with the use of 5-HT-targeted drugs in females and AVP-targeted drugs in males.

Atypical Social Development in Vasopressin-Deficient Brattleboro Rats.

Over the past 3 decades, a large body of evidence has accumulated demonstrating that the neuropeptide arginine vasopressin (AVP) plays a critical role in regulating social behavior. The overwhelming majority of this evidence comes from adults, leaving a gap in our understanding of the role of AVP during development. Here, we investigated the effect of chronic AVP deficiency on a suite of juvenile social behaviors using Brattleboro rats, which lack AVP due to a mutation in the Avp gene. Social play behavior, huddling, social investigation & allogrooming, and ultrasonic vocalizations (USVs) of male and female rats homozygous for the Brattleboro mutation (Hom) were compared with their wild-type (WT) and heterozygous (Het) littermates during same-sex, same-genotype social interactions. Male and female Hom juveniles exhibited less social play than their Het and WT littermates throughout the rise, peak, and decline of the developmental profile of play. Hom juveniles also emitted fewer prosocial 50 kHz USVs, and spectrotemporal characteristics (call frequency and call duration) of individual call types differed from those of WT and Het juveniles. However, huddling behavior was increased in Hom juveniles, and social investigation and 22 kHz USVs did not differ across genotypes, demonstrating that not all social interactions were affected in the same manner. Collectively, these data suggest that the Avp gene plays a critical role in juvenile social development.

Sexually dimorphic role for vasopressin in the development of social play.

Despite the well-established role of arginine vasopressin (AVP) in adult social behavior, its role in social development is relatively unexplored. In this paper, we focus on the most prominent social behavior of juvenile rats, social play. Previous pharmacological experiments in our laboratory suggested that AVP regulates play in a sex- and brain region-specific manner in juvenile rats. Here we investigate the role of specific AVP systems in the emergence of social play. We first characterize the development of play in male and female Wistar rats and then ask whether the development of AVP mRNA expression correlates with the emergence of play. Unexpectedly, play emerged more rapidly in weanling-aged females than in males, resulting in a sex difference opposite of that typically reported for older, juvenile rats. AVP mRNA and play were correlated in males only, with a negative correlation in the bed nucleus of the stria terminalis (BNST) and a positive correlation in the paraventricular nucleus of the hypothalamus (PVN). These findings support the hypothesis that AVP acts differentially on multiple systems in a sex-specific manner to regulate social play and suggest a role for PVN and BNST AVP systems in the development of play. Differential neuropeptide regulation of male and female social development may underlie well-documented sex differences in incidence, progression, and symptom severity of behavioral disorders during development.

An open system for automatic home-cage behavioral analysis and its application to male and female mouse models of Huntington's disease.

Changes in routine mouse home-cage behavioral activities have been used recently to study alterations of neural circuits caused by genetic and environmental modifications and by drug administration. Nevertheless, automatic assessment of mouse home-cage behaviors remains challenging due to the cost of proprietary systems and to the difficulty in adjusting systems to different monitoring conditions. Here we present software for the automatic quantification of multiple facets of mouse home-cage behaviors, suitable for continuous 24 h video monitoring. We used this program to assess behavioral changes in male and female R6/2 transgenic mouse models of Huntington's disease over a 10-week period. Consistent with the well-known progressive motor coordination deficits of R6/2 mice, their hanging, rearing, and climbing activity declined as the disease progressed. R6/2 mice also exhibited frequent disturbances in their resting activity compared to wild-type mice, suggesting that R6/2 mice are more restless and wakeful. Behavioral differences were seen earlier for male R6/2 mice than female R6/2 mice, and "behavioral signatures" based on multiple behaviors enabled us to distinguish male R6/2 mice from sex- and age-matched wild-type controls as early as 5 weeks of age. These results demonstrate that the automated behavioral classification software that we developed ("OpenCage") provides a powerful tool for analyzing natural home-cage mouse behaviors, and for constructing behavioral signatures that will be useful for assessing therapeutic strategies. The OpenCage software is available under an open-source GNU General Public License, allowing other users to freely modify and extend it to suit their purposes.

Inefficient conjunction search made efficient by concurrent spoken delivery of target identity.

Visual search based on a conjunction of two features typically elicits reaction times that increase linearly as a function of the number of distractors, whereas search based on a single feature is essentially unaffected by set size. These and related findings have often been interpreted as evidence of a serial search stage that follows a parallel search stage. However, a wide range of studies has been showing a form of blending of these two processes. For example, when a spoken instruction identifies the conjunction target concurrently with the visual display, the effect of set size is significantly reduced, suggesting that incremental linguistic processing of the first feature adjective and then the second feature adjective may facilitate something approximating a parallel extraction of objects during search for the target. Here, we extend these results to a variety of experimental designs. First, we replicate the result with a mixed-trials design (ruling out potential strategies associated with the blocked design of the original study). Second, in a mixed-trials experiment, the order of adjective types in the spoken query varies randomly across conditions. In a third experiment, we extend the effect to a triple-conjunction search task. A fourth (control) experiment demonstrates that these effects are not due to an efficient odd-one-out search that ignores the linguistic input. This series of experiments, along with attractor-network simulations of the phenomena, provide further evidence toward understanding linguistically mediated influences in real-time visual search processing.

Putting language back in the body: speech and gesture on three time frames.

This article investigates the role that nonverbal actions play in language processing over 3 different time frames. First, we speculate that nonverbal actions played a role in how formal language systems emerged from our primate ancestors over evolutionary time. Next, we hypothesize that if nonverbal behaviors played a foundational role in the emergence of language over evolution, these actions should influence how children learn language in the present. Finally, we argue that nonverbal actions continue to play a role for adults in the moment-to-moment processing of language. Throughout, we take an embodied view of language and argue that the neural, cognitive, and social components of language processing are firmly grounded in bodily action.