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In this study we tested the hypothesis that pharmacological modulation of glutamatergic neurotransmission could rescue behavioral deficits exhibited by mice carrying a specific mutation in the Iqsec2 gene. The IQSEC2 protein plays a key role in glutamatergic synapses and mutations in the IQSEC2 gene are a frequent cause of neurodevelopmental disorders. We have recently reported on the molecular pathophysiology of one such mutation A350V and demonstrated that this mutation downregulates AMPA type glutamatergic receptors (AMPAR) in A350V mice. Here we sought to identify behavioral deficits in A350V mice and hypothesized that we could rescue these deficits by PF-4778574, a positive AMPAR modulator. Using a battery of social behavioral tasks, we found that A350V Iqsec2 mice exhibit specific deficits in sex preference and emotional state preference behaviors as well as in vocalizations when encountering a female mouse. The social discrimination deficits, but not the impaired vocalization, were rescued with a single dose of PF-4778574. We conclude that social behavior deficits associated with the A350V Iqsec2 mutation may be rescued by enhancing AMPAR mediated synaptic transmission.

Mice and rats are widely used to explore mechanisms of mammalian social behavior in health and disease, raising the question whether they actually differ in their social behavior. Here we address this question by directly comparing social investigation behavior between two mouse and rat strains used most frequently for behavioral studies and as models of neuropathological conditions: C57BL/6 J mice and Sprague Dawley (SD) rats. Employing novel experimental systems for behavioral analysis of both subjects and stimuli during the social preference test, we reveal marked differences in behavioral dynamics between the strains, suggesting stronger and faster induction of social motivation in SD rats. These different behavioral patterns, which correlate with distinctive c-Fos expression in social motivation-related brain areas, are modified by competition with non-social rewarding stimuli, in a strain-specific manner. Thus, these two strains differ in their social behavior, which should be taken into consideration when selecting an appropriate model organism., Laboratory rat and mouse strains serve as animal models to explore brain mechanisms underlying social behavior. Here, the authors describe differences in social behavior between commonly used rat and mouse strains, which may reflect distinct dynamics of social motivation.

The corticotropin-releasing factor (CRF) system is well known for its major role in coordinating the endocrine, autonomic and behavioral responses to stress. These functions have been shown to be mediated mainly by the binding of the CRF neuropeptide to its specific receptor CRFR1. Yet, the CRF system comprises several more neuropeptides, including the three urocortins, UCN1, UCN2 and UCN3, of which the latter two bind specifically to a distinct receptor-CRFR2. Unlike the brain-wide abundant expression of CRF and CRFR1, the brain expression of the urocortins and CRFR2 is rather restricted and seems to be focused in limbic areas associated with social behavior. Here, we will review accumulating evidence from recent studies that unfold the role of UCN2 and UCN3 in regulating mammalian social behavior, via activation of CRFR2.

Complex behavioral phenotyping techniques are becoming more prevalent in the field of behavioral neuroscience, and thus methods for manipulating neuronal activity must be adapted to fit into such paradigms. Here, we present a head-mounted, magnetically activated device for wireless optogenetic manipulation that is compact, simple to construct, and suitable for use in group-living mice in an enriched semi-natural arena over several days. Using this device, we demonstrate that repeated activation of oxytocin neurons in male mice can have different effects on pro-social and agonistic behaviors, depending on the social context. Our findings support the social salience hypothesis of oxytocin and emphasize the importance of the environment in the study of social neuromodulators. Our wireless optogenetic device can be easily adapted for use in a variety of behavioral paradigms, which are normally hindered by tethered light delivery or a limited environment.

Exploring the neurobiological mechanisms of social behavior requires behavioral tests that can be applied to animal models in an unbiased and observer-independent manner. Since the beginning of the millennium, the three-chamber test has been widely used as a standard paradigm to evaluate sociability (social preference) and social novelty preference in small rodents. However, this test suffers from multiple limitations, including its dependence on spatial navigation and negligence of behavioral dynamics. Presented and validated here is a novel experimental system that offers an alternative to the three-chamber test, while also solving some of its caveats. The system requires a simple and affordable experimental apparatus and publicly available open-source analysis system, which automatically measures and analyzes multiple behavioral parameters at individual and population levels. It allows detailed analysis of the behavioral dynamics of small rodents during any social discrimination test. We demonstrate the efficiency of the system in analyzing the dynamics of social behavior during the social preference and social novelty preference tests as performed by adult male mice and rats. Moreover, we validate the ability of the system to reveal modified dynamics of social behavior in rodents following manipulations such as whisker trimming. Thus, the system allows for rigorous investigation of social behavior and dynamics in small rodent models and supports more accurate comparisons between strains, conditions, and treatments.

Rhythmic neuronal activity of multiple frequency bands has been described in many brain areas and attributed to numerous brain functions. Among these, little is known about the mechanism and role of infra-slow oscillations, which have been demonstrated recently in the mouse accessory olfactory bulb (AOB). Along with prolonged responses to stimuli and distinct network connectivity, they inexplicably affect the AOB processing of social relevant stimuli. Here, we show that assemblies of AOB mitral cells are synchronized by lateral interactions through chemical and electrical synapses. Using a network model, we demonstrate that the synchronous oscillations in these assemblies emerge from interplay between intrinsic membrane properties and network connectivity. As a consequence, the AOB network topology, in which each mitral cell receives input from multiple glomeruli, enables integration of chemosensory stimuli over extended time scales by interglomerular synchrony of infra-slow bursting. These results provide a possible functional significance for the distinct AOB physiology and topology. Beyond the AOB, this study presents a general model for synchronous infra-slow bursting in neuronal networks.SIGNIFICANCE STATEMENTInfra-slow rhythmic neuronal activity with a very long (>10 s) duration has been described in many brain areas, but little is known about the role of this activity and the mechanisms that produce it. Here, we combine experimental and computational methods to show that synchronous infra-slow bursting activity in mitral cells of the mouse accessory olfactory bulb (AOB) emerges from interplay between intracellular dynamics and network connectivity. In this novel mechanism, slow intracellular Na+dynamics endow AOB mitral cells with a weak tendency to burst, which is further enhanced and stabilized by chemical and electrical synapses between them. Combined with the unique topology of the AOB network, infra-slow bursting enables integration and binding of multiple chemosensory stimuli over a prolonged time scale.

Maternal care is an indispensable behavioral component necessary for survival and reproductive success in mammals, and postpartum maternal behavior is mediated by an incompletely understood complex interplay of signals including effects of epigenetic regulation. We approached this issue using our recently established mice with targeted deletion of heterochromatin protein 1 binding protein 3 (HP1BP3), which we found to be a novel epigenetic repressor with critical roles in postnatal growth. Here, we report a dramatic reduction in the survival of pups born to Hp1bp3(-/-) deficient mouse dams, which could be rescued by co-fostering with wild-type dams. Hp1bp3(-/-) females failed to retrieve both their own pups and foster pups in a pup retrieval test, and showed reduced anxiety-like behavior in the open-field and elevated-plus-maze tests. In contrast, Hp1bp3(-/-) females showed no deficits in behaviors often associated with impaired maternal care, including social behavior, depression, motor coordination and olfactory capability; and maintained unchanged anxiety-associated hallmarks such as cholinergic status and brain miRNA profiles. Collectively, our results suggest a novel role for HP1BP3 in regulating maternal and anxiety-related behavior in mice and call for exploring ways to manipulate this epigenetic process.

The hypothalamic neuropeptide oxytocin (OT) is a powerful modulator of mammalian social behavior and its administration was shown to affect various types of social interactions. However, systematic examinations of the role of endogenous OT release in social behavior have heretofore been done only using genetically modified animal models in which the genes encoding either OT or the OT receptor (OTR) were mutated. While such genetic manipulations revealed various behavioral deficits, these deficits may involve developmental or long-term processes and do not prove the participation of acute OT release in the impaired behavior. Here we used a battery of social discrimination tasks to evaluate the effects of acute systemic OTR blockade, using a non-peptide, orally active OTR antagonist (L368,899), on social behavior of adult male C57BL/6 J mice. We found no effect of the pharmacological manipulation on the social preference and social novelty preference behaviors. However, the preference of a male mouse for investigating a female conspecific more than a male (sex preference behavior), was lost by administration of the OTR antagonist. Finally, we found that blocking OTR activity before social defeat prevented the consequent loss of social preference, suggesting a role for OT in the acquisition of aversive social memory. Overall, our results suggest that OT plays a role in modulating the salience of social stimuli and facilitating their memory, as predicted by the social salience theory, rather than in regulating the internal motivation of the subject for social interactions.

Oxytocin (OT) is a great facilitator of social life but, although its effects on socially relevant brain regions have been extensively studied, OT neuron activity during actual social interactions remains unexplored. Most OT neurons are magnocellular neurons, which simultaneously project to the pituitary and forebrain regions involved in social behaviors. In the present study, we show that a much smaller population of OT neurons, parvocellular neurons that do not project to the pituitary but synapse onto magnocellular neurons, is preferentially activated by somatosensory stimuli. This activation is transmitted to the larger population of magnocellular neurons, which consequently show coordinated increases in their activity during social interactions between virgin female rats. Selectively activating these parvocellular neurons promotes social motivation, whereas inhibiting them reduces social interactions. Thus, parvocellular OT neurons receive particular inputs to control social behavior by coordinating the responses of the much larger population of magnocellular OT neurons. Charlet, Grinevich et al. show that social touch between female rats activates parvocellular oxytocin neurons; these neurons control social behavior by coordinating the responses of the much larger population of magnocellular oxytocin neurons.

The neuropeptide oxytocin (OXT) is a crucial mediator of parturition and milk ejection and a major modulator of various social behaviors, including social recognition, aggression and parenting. In the past decade, there has been significant excitement around the possible use of OXT to treat behavioral deficits in neurodevelopmental disorders, including autism spectrum disorder (ASD). Yet, despite the fast move to clinical trials with OXT, little attention has been paid to the possibility that the OXT system in the brain is perturbed in these disorders and to what extent such perturbations may contribute to social behavior deficits. Large-scale whole-exome sequencing studies in subjects with ASD, along with biochemical and electrophysiological studies in animal models of the disorder, indicate several risk genes that play an essential role in brain synapses, suggesting that deficits in synaptic activity and plasticity underlie the pathophysiology in a considerable portion of these cases. OXT has been repeatedly shown, both in vitro and in vivo, to modify synaptic properties and plasticity and to modulate neural activity in circuits that regulate social behavior. Together, these findings led us to hypothesize that failure of the OXT system during early development, as a direct or indirect consequence of genetic mutations, may impact social behavior by altering synaptic activity and plasticity. In this article, we review the evidence that support our hypothesis.

In mammals, lactating mothers show reduced fear and anxiety. A new study reveals the way by which the lactation-inducing neuropeptide oxytocin attenuates social fear in lactating female mice by inhibiting activity in a single brain area.

The medial nucleus of the amygdala (MeA) plays a pivotal role in a variety of mammalian social behaviors. Specifically, activity of the hypothalamic pro-social neuropeptide oxytocin in the MeA was shown to be crucial for social recognition memory. The MeA is also a hub of neuroendocrine activity and expresses a large number of receptors of neuropeptides and hormones. These include oxytocin receptor, estrogen receptor alpha and corticotropin-releasing factor (CRF) receptor type 2 (CRFR2). In a previous study we found that intracerebroventricular (ICV) oxytocin application to anesthetized rats promotes long-term depression (LTD) of the MeA response to electrical stimulation of its main sensory input, the accessory olfactory bulb (AOB). We also reported that this type of synaptic plasticity contributes to long-term social recognition memory. Here we used similar methodology to examine the possibility that various neuromodulators pose a combinatorial effect on synaptic plasticity in the MeA. We found that ICV administration of the CRF-related peptide urocortin3 fifteen minutes before oxytocin, caused long-term potentiation (LTP), via CRFR2 activation. Similarly, ICV administration of 17β-estradiol forty-five minutes before oxytocin induced LTP, which was blocked by an antagonist of the estrogen receptors alpha and beta. Notably, none of these two neuromodulators had any effect on its own, suggesting that they both turn the oxytocin-mediated synaptic plasticity from LTD to LTP. Finally, we found that application of 17β-estradiol, forty-five minutes before urocortin3 also caused LTP in the MeA response to AOB stimulation, even without oxytocin application. We suggest that the combinatorial modulation of the bidirectional synaptic plasticity in the AOB-MeA pathway by oxytocin, 17β-estradiol and urocotin-3 serves to modify social information processing according to the animal's internal state.

Background Deciphering the biological mechanisms underlying social behavior in animal models requires standard behavioral paradigms that can be unbiasedly employed in an observer- and laboratory-independent manner. During the past decade, the three-chamber test has become such a standard paradigm used to evaluate social preference (sociability) and social novelty preference in mice. This test suffers from several caveats, including its reliance on spatial navigation skills and negligence of behavioral dynamics. Methods Here, we present a novel experimental apparatus and an automated analysis system which offer an alternative to the three-chamber test while solving the aforementioned caveats. The custom-made apparatus is simple for production, and the analysis system is publically available as an open-source software, enabling its free use. We used this system to compare the dynamics of social behavior during the social preference and social novelty preference tests between male and female C57BL/6J mice. Results We found that in both tests, male mice keep their preference towards one of the stimuli for longer periods than females. We then employed our system to define several new parameters of social behavioral dynamics in mice and revealed that social preference behavior is segregated in time into two distinct phases. An early exploration phase, characterized by high rate of transitions between stimuli and short bouts of stimulus investigation, is followed by an interaction phase with low transition rate and prolonged interactions, mainly with the preferred stimulus. Finally, we compared the dynamics of social behavior between C57BL/6J and BTBR male mice, the latter of which are considered as asocial strain serving as a model for autism spectrum disorder. We found that BTBR mice (n = 8) showed a specific deficit in transition from the exploration phase to the interaction phase in the social preference test, suggesting a reduced tendency towards social interaction. Conclusions We successfully employed our new experimental system to unravel previously unidentified sex- and strain-specific differences in the dynamics of social behavior in mice. Thus, the system presented here facilitates a more thorough and detailed analysis of social behavior in small rodent models, enabling a better comparison between strains and treatments. Electronic supplementary material The online version of this article (10.1186/s13229-017-0169-1) contains supplementary material, which is available to authorized users.

Changes in intracellular Na+ concentration ([Na+]i) are rarely taken into account when neuronal activity is examined. As opposed to Ca2+, [Na+]i dynamics are strongly affected by longitudinal diffusion, and therefore they are governed by the morphological structure of the neurons, in addition to the localization of influx and efflux mechanisms. Here, we examined [Na+]i dynamics and their effects on neuronal computation in three multi-compartmental neuronal models, representing three distinct cell types: accessory olfactory bulb (AOB) mitral cells, cortical layer V pyramidal cells, and cerebellar Purkinje cells. We added [Na+]i as a state variable to these models, and allowed it to modulate the Na+ Nernst potential, the Na+-K+ pump current, and the Na+-Ca2+ exchanger rate. Our results indicate that in most cases [Na+]i dynamics are significantly slower than [Ca2+]i dynamics, and thus may exert a prolonged influence on neuronal computation in a neuronal type specific manner. We show that [Na+]i dynamics affect neuronal activity via three main processes: reduction of EPSP amplitude in repeatedly active synapses due to reduction of the Na+ Nernst potential; activity-dependent hyperpolarization due to increased activity of the Na+-K+ pump; specific tagging of active synapses by extended Ca2+ elevation, intensified by concurrent back-propagating action potentials or complex spikes. Thus, we conclude that [Na+]i dynamics should be considered whenever synaptic plasticity, extensive synaptic input, or bursting activity are examined.

Autism spectrum disorder (ASD) is a group of complex neurodevelopmental conditions characterized by deficits in social communication and by repetitive and stereotypic patterns of behaviors, with no pharmacological treatments available to treat these core symptoms. Oxytocin is a neuropeptide that powerfully regulates mammalian social behavior and has been shown to exert pro-social effects when administered intranasally to healthy human subjects. In the last decade, there has been a significant interest in using oxytocin to treat social behavior deficits in ASD. However, little attention has been paid to whether the oxytocin system is perturbed in subgroups of individuals with ASD and whether these individuals are likely to benefit more from an oxytocin treatment. This oversight may in part be due to the enormous heterogeneity of ASD and the lack of methods to carefully probe the OXT system in human subjects. Animal models for ASD are valuable tools to clarify the implication of the oxytocin system in ASD and can help determine whether perturbation in this system should be considered in future clinical studies as stratifying biomarkers to inform targeted treatments in subgroups of individuals with ASD. In this chapter, we review the literature on genetic- and environmental-based animal models for ASD, in which perturbations in the oxytocin system and/or the effect of oxytocin administration on the ASD-associated phenotype have been investigated.

Understanding how the CNS functions poses one of the greatest challenges in modern life science and medicine. Studying the brain is especially challenging because of its complexity, the heterogeneity of its cellular composition, and the substantial changes it undergoes throughout its life-span. The complexity of adult-brain neural networks results also from the diversity of properties and functions of neuronal cells, governed, inter alia, by temporally and spatially differential expression of proteins in mammalian brain cell populations. Hence, research into the biology of CNS activity and its implications to human and animal behavior must use novel scientific tools. One source of such tools is the field of molecular genetics – recently utilized more and more frequently in neuroscience research. Transgenic approaches in general, and gene targeting in rodents have become fundamental tools for elucidating gene function in the CNS. Although spectacular progress has been achieved over recent decades by using these approaches, it is important to note that they face a number of restrictions. One of the main challenges is presented by the temporal and spatial regulation of introduced genetic manipulations. Viral vectors provide an alternative approach to temporally regulated, localized delivery of genetic modifications into neurons. In this review we describe available technologies for gene transfer into the adult mammalian CNS that use both viral and non-viral tools. We discuss viral vectors frequently used in neuroscience, with emphasis on lentiviral vector (LV) systems. We consider adverse effects of LVs, and the use of LVs for temporally and spatially controllable manipulations. Especially, we highlight the significance of viral vector-mediated genetic manipulations in studying learning and memory processes, and how they may be effectively used to separate out the various phases of learning: acquisition, consolidation, retrieval, and maintenance.

SummaryPheromone detection by the vomeronasal organ (VNO) is thought to rely on activation of specific receptors from the V1R and V2R gene families, but the central representation of pheromone receptor activation remains poorly understood. We generated transgenic mouse lines in which projections from multiple populations of VNO neurons, each expressing a distinct V1R, are differentially labeled with fluorescent proteins. This approach revealed that inputs from neurons expressing closely related V1Rs intermingle within shared, spatially conserved domains of the accessory olfactory bulb (AOB). Mitral cell-glomerular connectivity was examined by injecting intracellular dyes into AOB mitral cells and monitoring dendritic contacts with genetically labeled glomeruli. We show that individual mitral cells extend dendrites to glomeruli associated with different, but likely closely related, V1Rs. This organization differs from the labeled line of OR signaling in the main olfactory system and suggests that integration of information may already occur at the level of the AOB.