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Anxiety disorders are pervasive psychiatric disorders causing great suffering. The high (HAB) and low (LAB) anxiety-related behaviour rats were selectively bred to investigate neurobiological correlates of anxiety. We compared the level of neuropeptides relevant for anxiety- and depression-related behaviours in selected brain regions of HAB and LAB rats. Increased anxiety and depression-like behaviours of male and female HAB rats in the elevated plus-maze and forced swim tests were accompanied by elevated levels of neuropeptide Y (NPY) in the prefrontal (PFC), frontal (FC) and cingulate cortex (CCx), the striatum, and periaqueductal grey (PAG). Moreover, HAB rats displayed sex-dependent, elevated levels of calcitonin gene-related peptide (CGRP) in PFC, FC, CCx, hippocampus, and PAG. Higher neurokinin A (NKA) levels were detected in CCx, striatum, and PAG in HAB males and in CCx and hypothalamus in HAB females. Increased neurotensin was detected in CCx and PAG in HAB males and in hypothalamus in HAB females. Elevated corticotropin-releasing hormone (CRH) levels appeared in female HAB hypothalamus. Significant correlations were found between anxiety-like behaviour and NPY, CGRP, NKA, and neurotensin, particularly with NPY in CCx and striatum, CGRP in FC and hippocampus, and NKA in entorhinal cortex. This is the first report of NPY, CGRP, NKA, Neurotensin, and CRH measurements in brain regions of HAB and LAB rats, which showed widespread NPY and CGRP alterations in cortical regions, with NKA and neurotensin changes localised in sub-cortical areas. The results may contribute to elucidate pathophysiological mechanisms underlying anxiety and depression and should facilitate identifying novel therapeutic targets.

In contrast to male rats, aggression in virgin female rats has been rarely studied. Here, we established a rat model of enhanced aggression in females using a combination of social isolation and aggression-training to specifically investigate the involvement of the oxytocin (OXT) and arginine vasopressin (AVP) systems within the lateral septum (LS). Using neuropharmacological, optogenetic, chemogenetic as well as microdialysis approaches, we revealed that enhanced OXT release within the ventral LS (vLS), combined with reduced AVP release within the dorsal LS (dLS), is required for aggression in female rats. Accordingly, increased activity of putative OXT receptor-positive neurons in the vLS, and decreased activity of putative AVP receptor-positive neurons in the dLS, are likely to underly aggression in female rats. Finally, in vitro activation of OXT receptors in the vLS increased tonic GABAergic inhibition of dLS neurons. Overall, our data suggest a model showing that septal release of OXT and AVP differentially affects aggression in females by modulating the inhibitory tone within LS sub-networks., Aggression in females is understudied in model organisms. Here, the authors establish a model of enhanced aggression in virgin female rats and show that oxytocin and vasopressin systems differentially modulate aggression in distinct neuronal populations of the lateral septum of female rats.

Social anxiety disorder is characterized by a persistent fear and avoidance of social situations, but available treatment options are rather unspecific. Using an established mouse social fear conditioning (SFC) paradigm, we profiled gene expression and chromatin alterations after the acquisition and extinction of social fear within the septum, a brain region important for social fear and social behaviors. Here, we particularly focused on the successful versus unsuccessful outcome of social fear extinction training, which corresponds to treatment responsive versus resistant patients in the clinics. Validation of coding and non-coding RNAs revealed specific isoforms of the long non-coding RNA (lncRNA) Meg3 regulated, depending on the success of social fear extinction. Moreover, PI3K/AKT was differentially activated with extinction success in SFC-mice. In vivo knockdown of specific Meg3 isoforms increased baseline activity of PI3K/AKT signaling, and mildly delayed social fear extinction. Using ATAC-Seq and CUT&RUN, we found alterations in the chromatin structure of specific genes, which might be direct targets of lncRNA Meg3.

ZUSAMMENFASSUNGPsychische Krankheiten treten heutzutage verstärkt auf, allerdings sind die Grundlagen und Mechanismen der Entwicklung weitestgehend unerforscht. Trotz einer erfolgreichen Behandlung bei den meisten Patienten bleiben 30 % behandlungsresistent, daher evaluiert die Forschung fortlaufend alternative Behandlungsmöglichkeiten. Neue Ergebnisse in Nagern zeigen eine veränderte Zusammensetzung der Darmmikrobiota in Tiermodellen für depressionsähnliches Verhalten und eine Adaptation des Verhaltens bei einer Manipulation derselben. Auch in depressiven Patienten ist eine Veränderung der Darmmikrobiota-Komposition zu beobachten. Die Mikrobiota-Darm-Hirn-Achse beschreibt die komplexe Kommunikation zwischen Darm und Gehirn durch verschiedenste Systeme. Eine Dysfunktion der Achsenkomponenten scheint zur Entwicklung psychischer Krankheiten beizutragen und kann daher als neue Behandlungsmöglichkeit dienen. In der vorliegenden Übersichtsarbeit demonstrieren wir Nachweise einer Funktion der Mikrobiota-Darm-Hirn-Achse in der Regulation von tierischem Verhalten und diskutieren den potenziellen Effekt dieser Regulation als Nutzen für die pharmakologische Intervention in Patienten.

Various single nucleotide polymorphisms (SNPs) in the oxytocin receptor (OXTR) gene have been associated with behavioral traits, autism spectrum disorder (ASD) and other diseases. The non-synonymous SNP rs4686302 results in the OXTR variant A218T and has been linked to core characteristics of ASD, trait empathy and preterm birth. However, the molecular and intracellular mechanisms underlying those associations are still elusive. Here, we uncovered the molecular and intracellular consequences of this mutation that may affect the psychological or behavioral outcome of oxytocin (OXT)-treatment regimens in clinical studies, and provide a mechanistic explanation for an altered receptor function. We created two monoclonal HEK293 cell lines, stably expressing either the wild-type or A218T OXTR. We detected an increased OXTR protein stability, accompanied by a shift in Ca2+ dynamics and reduced MAPK pathway activation in the A218T cells. Combined whole-genome and RNA sequencing analyses in OXT-treated cells revealed 7823 differentially regulated genes in A218T compared to wild-type cells, including 429 genes being associated with ASD. Furthermore, computational modeling provided a molecular basis for the observed change in OXTR stability suggesting that the OXTR mutation affects downstream events by altering receptor activation and signaling, in agreement with our in vitro results. In summary, our study provides the cellular mechanism that links the OXTR rs4686302 SNP with genetic dysregulations associated with aspects of ASD.

Oxytocin, a neuropeptide known for its role in reproduction and socioemotional processes, may hold promise as a therapeutic agent in treating social impairments in patient populations. However, research has yet to uncover precisely how to manipulate this system for clinical benefit. Moreover, inconsistent use of standardized and validated oxytocin measurement methodologies—including the design and study of hormone secretion and biochemical assays—present unresolved challenges. Human studies measuring peripheral (i.e., in plasma, saliva, or urine) or central (i.e., in cerebrospinal fluid) oxytocin concentrations have involved very diverse methods, including the use of different assay techniques, further compounding this problem. In the present review, we describe the scientific value in measuring human endogenous oxytocin concentrations, common issues in biochemical analysis and study design that researchers face when doing so, and our recommendations for improving studies using valid and reliable methodologies.

Sexual assault and rape are crimes that impact victims worldwide. Although the psychosocial and eco-evolutionary factors associated with this antisocial behavior have repeatedly been studied, the underlying neurobiological mechanisms are still largely unknown. Here, we established a novel paradigm to provoke and subsequently assess sexual aggression (SxA) in adult male Wistar rats: the sexual aggression test (SxAT). Briefly, male Wistar rats are sexually aroused by a receptive female, which is exchanged by a non-receptive female immediately after the first intromission. This protocol elicits forced mounting and aggressive behavior toward the non-receptive female to different degrees, which can be scored. In a series of experiments we have shown that SxA behavior is a relatively stable trait in rats and correlates positively with sexual motivation. Rats with innate abnormal anxiety and aggressive behavior also show abnormal SxA behavior. In addition, central infusion of oxytocin moderately inhibits aggressive behavior, but increases forced mounting. Finally, we identified the agranular insular cortex to be specifically activated by SxA, however, inhibition of this region did not significantly alter behavior in the SxAT. Altogether, the SxAT is a paradigm that can be readily implemented in behavioral laboratories as a valuable tool to find answers regarding the biological mechanisms underlying SxA in humans, as well as social decision-making in general.

Chemogenetics provides cell type-specific remote control of neuronal activity. Here, we describe the application of chemogenetics used to specifically activate oxytocin (OT) neurons as representatives of a unique class of neuroendocrine cells. We injected recombinant adeno-associated vectors, driving the stimulatory subunit hM3Dq of a modified human muscarinic receptor into the rat hypothalamus to achieve cell type-specific expression in OT neurons. As chemogenetic activation of OT neurons has not been reported, we provide systematic analysis of the temporal dynamics of OT neuronal responses in vivo by monitoring calcium fluctuations in OT neurons, and intracerebral as well as peripheral release of OT. We further provide evidence for the efficiency of chemogenetic manipulation at behavioral levels, demonstrating that evoked activation of OT neurons leads to social motivation and anxiolysis. Altogether, our results will be profitable for researchers working on the physiology of neuroendocrine systems, peptidergic modulation of behaviors and translational psychiatry.

Social interactions are essential for mammalian life and are regulated by evolutionary conserved neuronal mechanisms. An individual's internal state, experiences, and the nature of the social stimulus are critical for determining apt responses to social situations. The lateral septum (LS) - a structure of the basal forebrain - integrates abundant cortical and subcortical inputs, and projects to multiple downstream regions to generate appropriate behavioral responses. Although incoming cognitive information is indispensable for contextualizing a social stimulus, neuromodulatory information related to the internal state of the organism significantly influences the behavioral outcome as well. This review article provides an overview of the neuroanatomical properties of the LS, and examines its neurochemical (neuropeptidergic and hormonal) signaling, which provide the neuromodulatory information essential for fine-tuning social behavior across the lifespan.

The neuropeptide oxytocin (OXT) has generated considerable interest as potential treatment for psychiatric disorders, including anxiety and autism spectrum disorders. However, the behavioral and molecular consequences associated with chronic OXT treatment and chronic receptor (OXTR) activation have scarcely been studied, despite the potential therapeutic long-term use of intranasal OXT. Here, we reveal that chronic OXT treatment over two weeks increased anxiety-like behavior in rats, with higher sensitivity in females, contrasting the well-known anxiolytic effect of acute OXT. The increase in anxiety was transient and waned 5 days after the infusion has ended. The behavioral effects of chronic OXT were paralleled by activation of an intracellular signaling pathway, which ultimately led to alternative splicing of hypothalamic corticotropin-releasing factor receptor 2α (Crfr2α), an important modulator of anxiety. In detail, chronic OXT shifted the splicing ratio from the anxiolytic membrane-bound (mCRFR2α) form of CRFR2α towards the soluble CRFR2α (sCRFR2α) form. Experimental induction of alternative splicing mimicked the anxiogenic effects of chronic OXT, while sCRFR2α-knock down reduced anxiety-related behavior of male rats. Furthermore, chronic OXT treatment triggered the release of sCRFR2α into the cerebrospinal fluid with sCRFR2α levels positively correlating with anxiety-like behavior. In summary, we revealed that the shifted splicing ratio towards expression of the anxiogenic sCRFR2α underlies the adverse effects of chronic OXT treatment on anxiety.

Social anxiety disorder (SAD) is primarily caused by traumatic social events and is characterized by intense fear and avoidance of socially enriched contexts. Formation of such intense social aversion requires learning of the association between trauma and originally neutral social stimuli. Acetylation of histones in response to learning is critical for long-term memory formation. Class I histone deacetylases (HDACs) have emerged as powerful negative regulators of long-term memory formation. However, the lack of clarity in isoform and spatial specificity in HDAC function exists. Utilizing the social fear conditioning (SFC) as well as cued fear conditioning (CFC) paradigms, we aimed to functionally characterize the role of class I HDACs, especially HDAC1, in the regulation of aversive memories in social versus non-social contexts. Using cFos expression as a marker of cellular activity, we revealed that the lateral septum (LS) was specifically activated post-acquisition in socially fear conditioned (SFC+) mice. We further measured an increase in activity-inducing HDAC1 phosphorylation at serine residues within the septum of SFC+ mice during extinction of social fear. Pharmacological inhibition of HDAC1 within the LS facilitated, while viral overexpression of septal HDAC1 impaired extinction of social fear. Finally, we found that the abovementioned facilitation of extinction memory by HDAC1 inhibition was long-lasting and persists even after 30 days of extinction. Our results show that LS-HDAC1 is a key regulator of long-lasting social fear extinction, which points towards HDAC1 as a potential therapeutic target for SAD.

In contrast to males, aggression in females has been rarely studied. Here, we established a rat model of enhanced female aggression using a combination of social isolation and aggression-training to specifically investigate the involvement of the oxytocin (OXT) and vasopressin (AVP) systems within the lateral septum (LS). Using neuropharmacological, optogenetic, chemogenetic as well as microdialyses approaches, we revealed that enhanced OXT release within the ventral LS (vLS), combined with reduced AVP release within the dorsal LS (dLS), are required for female aggression. Accordingly, increased excitability of OXT-responsive neurons in the vLS and decreased excitability of AVP-responsive neurons in the dLS were essential to evoke female aggression. Finally, in vitro activation of OXT receptors in the vLS increased tonic GABAergic inhibition of dLS neurons. Overall, our data demonstrate that septal release of OXT and AVP affects female aggression by differential regulation of the excitatory-inhibitory balance within subnetworks of the LS.

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.

During pandemics, governments take drastic actions to prevent the spreading of the disease, as seen during the present COVID-19 crisis. Sanctions of lockdown, social distancing and quarantine urge people to exclusively work and teach at home and to restrict social contacts to a minimum; lonely people get into further isolation, while families` nerves are strained to the extreme. Overall, this results in a dramatic and chronic increase in the level of psychosocial stress over several months mainly caused by i) social isolation and ii) psychosocial stress associated with overcrowding, social tension in families, and domestic violence. Moreover, pandemic-associated social restrictions are accompanied by loss of an essential stress buffer and important parameter for general mental and physical health: social support. Chronic psychosocial stress and, in particular, social isolation and lack of social support affect not only mental health, but also the brain oxytocin system and the immune system. Hence, pandemic-associated social restrictions are expected to increase the risk of developing psychopathologies, such as depression, anxiety-related and posttraumatic stress disorders, on the one hand, but also to induce a general inflammatory state and to impair the course of infectious disorders on the other. Due to its pro-social and stress-buffering effects, resulting in an anti-inflammatory state in case of disease, the role of the neuropeptide oxytocin will be discussed and critically considered as an emerging treatment option in cases of pandemic-induced psychosocial stress, viral infection and during recovery. In this review, we aim to critically focus on possible short- and long-term consequences of social restrictions on mental health and the immune system, while discussion oxytocin as a possible treatment option.

Oxytocin (OXT) shows anxiolytic and stress-reducing effects, but salivary OXT response to laboratory-induced stress has only been assessed in one study in healthy adults. The present study aimed at extending these findings by assessing salivary OXT stress reactivity in healthy adolescents (aged 11-18) compared to a control condition. A higher salivary OXT response to stress compared to the control condition was expected. In addition, the association between OXT, cortisol (CORT) and psychological reactivity patterns was explored. Psychosocial stress was induced using the Trier Social Stress Test (TSST; 13 males, 15 females), while the Control-TSST (14 males, 15 females) served as a non-stress control condition. Salivary OXT increased in response to the TSST with a peak at +1 and decline at +10 min after stress. Baseline OXT correlated negatively with experienced anxiety and insecurity, while both correlated positively with OXT reactivity. OXT and CORT increase as well as OXT increase and CORT recovery were positively correlated. Results indicate that salivary OXT in response to the TSST is a valid method to assess biological effects of laboratory-induced stress also in adolescents. Due to a rapid increase and decline, salivary OXT needs to be assessed directly after stress exposure. Given the interplay of OXT with affective symptoms and CORT response, the combined measure of salivary OXT and CORT reactivity adds to studying stress reactivity in typically developing and clinical samples.

Neuropeptide S (NPS) has attracted the attention of the scientific community due to its potent anxiolytic-like and fear-attenuating effects studied in rodents. Therefore, NPS might represent a treatment option for neuropsychiatric disorders, such as anxiety disorders, even more so as single nucleotide polymorphisms in the human NPS receptor gene have been associated with increased anxiety traits that contribute to the pathogenesis of fear- and anxiety-related disorders. However, the signaling mechanisms underlying the behavioral effects of NPS and the interaction with other brain neuropeptides are still rather unknown. To illuminate how NPS modulates the expression of selected emotional and social behaviors, the present review focuses on neuroanatomical and electrophysiological studies, as well as intracellular signaling mechanisms following NPS receptor stimulation in rodents. We will also discuss interactions of the NPS system with two well-described neuropeptides, namely corticotropin-releasing factor and oxytocin, which may contribute to the fear- and anxiety-reducing effects.

Conduct disorder (CD) is a common and highly impairing psychiatric disorder of childhood and adolescence that frequently leads to poor physical and mental health outcomes in adulthood. The prevalence of CD is substantially higher in males than females, and partly due to this, most research on this condition has used all-male or predominantly male samples. Although the number of females exhibiting CD has increased in recent decades, the majority of studies on neurobiological measures, neurocognitive phenotypes, and treatments for CD have focused on male subjects only, despite strong evidence for sex differences in the aetiology and neurobiology of CD. Here, we selectively review the existing literature on CD and related phenotypes in females, focusing in particular on sex differences in CD symptoms, patterns of psychiatric comorbidity, and callous–unemotional personality traits. We also consider studies investigating the neurobiology of CD in females, with a focus on studies using genetic, structural and functional neuroimaging, psychophysiological, and neuroendocrinological methods. We end the article by providing an overview of the study design of the FemNAT-CD consortium, an interdisciplinary, multi-level and multi-site study that explicitly focuses on CD in females, but which is also investigating sex differences in the causes, developmental course, and neurobiological correlates of CD.

When fathers leave the family, mothers are at increased risk of developing depression and anxiety disorders. In biparental, socially monogamous prairie voles (Microtus ochrogaster), sudden bond disruption increases passive stress-coping, indicative of depressive-like behavior, and acts as chronic stressor in both males and females. However, the consequences of separation in lactating prairie vole mothers are unknown. In the present study, following 18 days of cohousing, half of the prairie vole pairs were separated by removing the male. In early lactation, maternal care was unaffected by separation, whereas anxiety-related behavior and passive stress-coping were significantly elevated in separated mothers. Separation significantly increased corticotropin-releasing factor (CRF) mRNA expression in the paraventricular nucleus of the hypothalamus under basal conditions, similar to levels of paired females after acute exposure to forced swim stress. A second cohort of lactating prairie voles was infused intracerebroventricularly with either vehicle or the CRF receptor antagonist D-Phe just prior to behavioral testing. The brief restraining during acute infusion significantly decreased arched back nursing in vehicle-treated paired and separated groups, whereas in the D-Phe-treated separated group the behavior was not impaired. Furthermore, in the latter, anxiety-related behavior and passive stress-coping were normalized to levels similar to vehicle-treated paired mothers. In conclusion, maternal investment is robust enough to withstand loss of the partner, whereas the mother’s emotionality is affected, which may be - at least partly - mediated by a CRF-dependent mechanism. This animal model has potential for mechanistic studies of behavioral and physiological consequences of partner loss in single mothers.

Neuropeptides, such as neuropeptide S (NPS) and oxytocin (OXT), represent potential options for the treatment of anxiety disorders due to their potent anxiolytic profile. In this study, we aimed to reveal the mechanisms underlying the behavioral action of NPS, and present a chain of evidence that the effects of NPS within the hypothalamic paraventricular nucleus (PVN) are mediated via actions on local OXT neurons in male Wistar rats. First, retrograde studies identified NPS fibers originating in the brainstem locus coeruleus, and projecting to the PVN. FACS identified prominent NPS receptor expression in PVN-OXT neurons. Using genetically encoded calcium indicators, we further demonstrated that NPS reliably induces a transient increase in intracellular Ca2+concentration in a subpopulation of OXT neurons, an effect mediated by NPS receptor. In addition, intracerebroventricular (i.c.v.) NPS evoked a significant somatodendritic release of OXT within the PVN as assessed by microdialysis in combination with a highly sensitive radioimmunoassay. Finally, we could show that the anxiolytic effect of NPS seen after i.c.v. or intra-PVN infusion requires responsive OXT neurons of the PVN and locally released OXT. Thus, pharmacological blockade of OXT receptors as well as chemogenetic silencing of OXT neurons within the PVN prevented the effect of synthetic NPS. In conclusion, our results indicate a significant role of the OXT system in mediating the effects of NPS on anxiety, and fill an important gap in our understanding of brain neuropeptide interactions in the context of regulation of emotional behavior within the hypothalamus.SIGNIFICANCE STATEMENTGiven the rising scientific interest in neuropeptide research in the context of emotional and stress-related behaviors, our findings demonstrate a novel intrahypothalamic mechanism involving paraventricular oxytocin neurons that express the neuropeptide S receptor. These neurons respond with transient Ca2+increase and somatodendritic oxytocin release following neuropeptide S stimulation. Thereby, oxytocin neurons seem essential for neuropeptide S-induced anxiolysis, as this effect was blocked by pharmacological and chemogenetic inhibition of the oxytocin system.

Pharmacological modulation of metabotropic glutamate receptor subtype 5 (mGluR5) and 7 (mGluR7) was shown to attenuate the acquisition and to facilitate the extinction of cued and contextual, non-social, fear. Using the allosteric mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and the allosteric mGluR7 agonist N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082), we aimed to study how pharmacological blockade of mGluR5 and activation of mGluR7 influence acquisition and extinction of social fear in mice. We could show that when administered before social fear conditioning, neither MPEP nor AMN082 affected acquisition and extinction of social fear, suggesting that mGluR5 inactivation and mGluR7 activation do not alter social fear. However, when administered before social fear extinction, both MPEP and AMN082 impaired social fear extinction and extinction recall. These findings suggest that mGluR5 inactivation and mGluR7 activation are unlikely to prevent the formation of traumatic social memories. Furthermore, medication strategies aimed at augmenting exposure-based therapies for psychiatric disorders associated with social deficits via modulation of mGluR5 and mGluR7 must be pursued cautiously because of their potential to delay social fear extinction processes.

In humans, associations between anxiety and nausea (including motion-induced) are reported but the underlying mechanisms are not known. Hypothermia is proposed to be an index of nausea in rats. Utilising hypothermia and heart rate as outcome measures we investigated the response to provocative motion in rats selectively bred for high (HAB) and low (LAB) anxiety-related behaviors and in non-selected (NAB) rats to further elucidate the potential relationship between hypothermia and nausea-like state. Core temperature and electrocardiogram were monitored in each group (n=10 per group) using telemetry, with or without circular motion (40min; 0.75Hz) and vehicle or diazepam (2mg/kg, i.p.) pre-treatment. Heart rate and time- and frequency-domain parameters of heart rate variability were derived from the electrocardiogram. There was no baseline difference in core temperature between the three groups (mean 38.0±0.1°C), but HAB animals had a significantly lower resting heart rate (330±7bpm) compared to LAB (402±5bpm) and NAB (401±9bpm). Animals in all groups exhibited hypothermia during motion (HAB: 36.3±0.1°C; NAB: 36.4±0.1°C; LAB: 34.9±0.2°C) with the magnitude (area under the curve, AUC) of the response during 40-min motion being greater in LAB compared to NAB and HAB rats, and this was also the case for the motion-induced bradycardia. Diazepam had minimal effects on baseline temperature and heart rate in all groups, but significantly reduced the hypothermia response (AUC) to motion in all groups by ~30%. Breeding for extremes in anxiety-related behavior unexpectedly selects animals with low trait anxiety that have enhanced bradycardia and hypothermic responses to motion; consequently, this animal model appears to be not suitable for exploring relationships between anxiety and autonomic correlates of nausea. Thermal and cardiovascular responses to motion were little different between HAB and NAB rats indicating that either hypothermia is not an index of a nausea-like state in rats, or that the positive correlation between anxiety and nausea demonstrated in humans does not exist in rats. The mechanism underlying the enhanced physiological responses in LAB requires more detailed study and may provide a novel model to investigate factors modulating motion sensitivity.

Perivascular astrocyte processes (PAP) surround cerebral endothelial cells (ECs) and modulate the strengthening of tight junctions to influence blood-brain barrier (BBB) permeability. Morphologically altered astrocytes may affect barrier properties and trigger the onset of brain pathologies. However, astrocyte-dependent mediators of these events remain poorly studied. Here, we show a pharmacologically driven elevated expression and release of growth/differentiation factor 15 (GDF15) in rat primary astrocytes and cerebral PAP. GDF15 has been shown to possess trophic properties for motor neurons, prompting us to hypothesize similar effects on astrocytes. Indeed, its increased expression and release occurred simultaneously to morphological changes of astrocytes in vitro and PAP, suggesting modulatory effects of GDF15 on these cells, but also neighboring EC. Administration of recombinant GDF15 was sufficient to promote astrocyte remodeling and enhance barrier properties between ECs in vitro, whereas its pharmacogenetic abrogation prevented these effects. We validated our findings in male high anxiety-related behavior rats, an animal model of depressive-like behavior, with shrunk PAP associated with reduced expression of the junctional protein claudin-5, which were both restored by a pharmacologically induced increase in GDF15 expression. Thus, we identified GDF15 as an astrocyte-derived trigger of astrocyte process remodeling linked to enhanced tight junction strengthening at the BBB.

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.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, whose core symptoms consist of deficits in social interaction and communication as well as restricted and repetitive behavior. Brain oxytocin (OXT) has been associated with various prosocial behaviors, and might, therefore, be involved in the pathogenesis of disorders associated with socio-emotional dysfunctions such as ASD. However, significant associations between central and peripheral OXT levels may only be present in response to physiological or stressful stimuli but were not shown under baseline conditions. In this study, we, therefore, investigated salivary and plasma OXT in response to physical exercise in adults with ASD (n ​= ​33, mean age: 36.8 ​± ​10.7 years) without intellectual impairment (IQ ​> ​70) and neurotypical controls (n ​= ​31, mean age: 31.0 ​± ​11.7 years). To stimulate the OXT system, we used rapid cycling and measured cortisol (CORT) concentrations to monitor the physiological stress response. When controlling for age, neither salivary OXT (p ​= ​.469), plasma OXT (p ​= ​.297) nor CORT (p ​= ​.667) concentrations significantly differed between groups at baseline. In addition, neither OXT nor CORT concentrations significantly differed between groups after physical exercise. Social anxiety traits were negatively correlated with plasma, but not saliva OXT concentrations in neurotypicals at baseline, while empathetic traits were positively correlated with saliva, but not plasma concentrations in autistic patients at baseline. No significant correlations between salivary and plasma OXT concentrations were found at any time point. Future studies including adult participants should investigate the effect of age on CORT and OXT concentrations in response to stress.

Neuropeptide S (NPS) has anxiolytic effects and facilitates extinction of cued fear in rodents. Here, we investigated whether NPS reverses social fear and social avoidance induced by social fear conditioning (SFC) and acute social defeat (SD), respectively, in male CD1 mice. Our results revealed that intracerebroventricular NPS (icv; 10 and 50 nmol/2 μl) reversed fear of unknown con-specifics induced by SFC and dose-dependently reduced avoidance of known aggressive con-specifics induced by SD. While 50 nmol of NPS completely reversed social avoidance and reinstated social preference, 10 nmol of NPS reduced social avoidance, but did not completely reinstate social preference in socially-defeated mice. Further, a lower dose (1 nmol/2 μl) of NPS facilitated the within-session extinction of cued fear, while a higher dose (10 nmol/2 μl) reduced the expression of cued fear. We could also confirm the anxiolytic effects of NPS (1, 10 and 50 nmol/2 μl) on the elevated plus-maze (EPM), which were not accompanied by alterations in locomotor activity either on the EPM or in the home cage. Finally, we could show that icv infusion of the NPS receptor 1 antagonist D-Cys((t)Bu)(5)-NPS (10 nmol/2 μl) did not alter SFC-induced social fear, general anxiety and locomotor activity. Taken together, our study extends the potent anxiolytic profile of NPS to a social context by demonstrating the reduction of social fear and social avoidance, thus providing the framework for studies investigating the involvement of the NPS system in the regulation of different types of social behaviour.