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Oxytocin modulates social behaviour across diverse vertebrate taxa, but the precise nature of its effects varies across species, individuals and lifetimes. Contributing to this variation is the fact that oxytocin's physiological effects are mediated through interaction with diverse neuromodulatory systems and can depend on the specifics of the local circuits it acts on. Furthermore, those effects can be influenced by both genetics and experience. Here we discuss this complexity through the lens of a specific neuromodulatory system, endocannabinoids, interacting with oxytocin in the nucleus accumbens to modulate prosocial behaviours in prairie voles. We provide a survey of current knowledge of oxytocin–endocannabinoid interactions in relation to social behaviour. We review in detail recent research in monogamous female prairie voles demonstrating that social experience, such as mating and pair bonding, can change how oxytocin modulates nucleus accumbens glutamatergic signalling through the recruitment of endocannabinoids to modulate prosocial behaviour toward the partner. We then discuss potential sex differences in experience-dependent modulation of the nucleus accumbens by oxytocin in voles based on new data in males. Finally, we propose that future oxytocin-based precision medicine therapies should consider how prior social experience interacts with sex and genetics to influence oxytocin actions. This article is part of the theme issue ‘Interplays between oxytocin and other neuromodulators in shaping complex social behaviours’.

Opioids have decreased analgesic potency (but not efficacy) in aged rodents compared with adults; however, the neural mechanisms underlying this attenuated response are not yet known. The present study investigated the impact of advanced age and biological sex on opioid signaling in the ventrolateral periaqueductal gray (vlPAG) in the presence of chronic inflammatory pain. Assays measuring µ-opioid receptor (MOR) radioligand binding, GTPγS binding, receptor phosphorylation, cAMP inhibition, and regulator of G-protein signaling (RGS) protein expression were performed on vlPAG tissue from adult (2–3 months) and aged (16–18 months) male and female rats. Persistent inflammatory pain was induced by intraplantar injection of complete Freund's adjuvant (CFA). Adult males exhibited the highest MOR binding potential (BP) and highest G-protein activation (activation efficiency ratio) in comparison to aged males and females (adult and aged). No impact of advanced age or sex on MOR phosphorylation state was observed. DAMGO-induced cAMP inhibition was highest in the vlPAG of adult males compared with aged males and females (adult and aged). vlPAG levels of RGS4 and RGS9-2, critical for terminating G-protein signaling, were assessed using RNAscope. Adult rats (both males and females) exhibited lower levels of vlPAG RGS4 and RGS9-2 mRNA expression compared with aged males and females. The observed age-related reductions in vlPAG MOR BP, G-protein activation efficiency, and cAMP inhibition, along with the observed age-related increases in RGS4 and RGS9-2 vlPAG expression, provide potential mechanisms whereby the potency of opioids is decreased in the aged population. SIGNIFICANCE STATEMENT Opioids have decreased analgesic potency (but not efficacy) in aged rodents compared with adults; however, the neural mechanisms underlying this attenuated response are not yet known. In the present study, we observed age-related reductions in ventrolateral periaqueductal gray (vlPAG) µ-opioid receptor (MOR) binding potential (BP), G-protein activation efficiency, and cAMP inhibition, along with the observed age-related increases in regulator of G-protein signaling (RGS)4 and RGS9-2 vlPAG expression, providing potential mechanisms whereby the potency of opioids is decreased in the aged population. These coordinated decreases in opioid receptor signaling may explain the previously reported reduced potency of opioids to produce pain relief in females and aged rats.

Background Social determinants of health (SDoHs) are nonmedical factors that significantly impact health and longevity. We found no published reviews on the biology of SDoHs in schizophrenia-spectrum psychotic disorders (SSPD). Study Design We present an overview of pathophysiological mechanisms and neurobiological processes plausibly involved in the effects of major SDoHs on clinical outcomes in SSPD. Study Results This review of the biology of SDoHs focuses on early-life adversities, poverty, social disconnection, discrimination including racism, migration, disadvantaged neighborhoods, and food insecurity. These factors interact with psychological and biological factors to increase the risk and worsen the course and prognosis of schizophrenia. Published studies on the topic are limited by cross-sectional design, variable clinical and biomarker assessments, heterogeneous methods, and a lack of control for confounding variables. Drawing on preclinical and clinical studies, we propose a biological framework to consider the likely pathogenesis. Putative systemic pathophysiological processes include epigenetics, allostatic load, accelerated aging with inflammation (inflammaging), and the microbiome. These processes affect neural structures, brain function, neurochemistry, and neuroplasticity, impacting the development of psychosis, quality of life, cognitive impairment, physical comorbidities, and premature mortality. Our model provides a framework for research that could lead to developing specific strategies for prevention and treatment of the risk factors and biological processes, thereby improving the quality of life and increasing the longevity of people with SSPD. Conclusions Biology of SDoHs in SSPD is an exciting area of research that points to innovative multidisciplinary team science for improving the course and prognosis of these serious psychiatric disorders.

A major issue in neuroscience is the poor translatability of research results from preclinical studies in animals to clinical outcomes. Comparative neuroscience can overcome this barrier by studying multiple species to differentiate between species-specific and general mechanisms of neural circuit functioning. Targeted manipulation of neural circuits often depends on genetic dissection, and use of this technique has been restricted to only a few model species, limiting its application in comparative research. However, ongoing advances in genomics make genetic dissection attainable in a growing number of species. To demonstrate the potential of comparative gene editing approaches, we developed a viral-mediated CRISPR/Cas9 strategy that is predicted to target the oxytocin receptor ( Oxtr ) gene in >80 rodent species. This strategy specifically reduced OXTR levels in all evaluated species ( n = 6) without causing gross neuronal toxicity. Thus, we show that CRISPR/Cas9-based tools can function in multiple species simultaneously. Thereby, we hope to encourage comparative gene editing and improve the translatability of neuroscientific research.

Oxytocin receptor (OXTR) modulates social behaviors in a species-specific manner. Remarkable inter- and intraspecies variation in brain OXTR distribution are associated with diversity in social behavior. To investigate potential genetic mechanisms underlying the phylogenetic plasticity in brainOxtrexpression and its consequences on social behavior, we constructed BAC transgenic mice harboring the entire prairie voleOxtrlocus with surrounding intergenic regulatory elements. Eight independent “volized” (pvOxtr) mouse lines were obtained; remarkably, each line displayed a unique pattern of brain expression distinct from mice and prairie voles. FourpvOxtrlines were selected for further investigation. Despite robust differences in brain expression,Oxtrexpression in mammary gland was conserved across lines, suggesting thatOxtrexpression in brain, but not mammary gland, is highly sensitive to local chromosomal landscape at integration sites. Moreover, different “volized” mouse lines showed differences in partner preference and maternal behaviors. Our results from this cross-species study suggest that species-specific variation in regulatory elements or distribution of transcription factors are not responsible for species-typical brainOxtrexpression patterns. Thus, transcriptional hypersensitivity to surrounding sequence of brainOxtrmay be a key mechanism to generate diversity in brain OXTR distribution and social behaviors. This inherent “evolvability” of brainOxtrexpression constitutes a novel transcriptional mechanism to generate variability in neuropeptide receptor distribution which, through natural selection, can generate diversity in adaptive social behaviors while preserving peripheral expression. The “volized”Oxtrmouse lines are useful for further understanding OXTR regulation and key neural circuits/networks mediating variability in social behaviors.Significance StatementUnlike the essential physiological phenomenon including feeding, sex, parturition and lactation, which are conserved across mammalian species, there is extraordinary diversity of social behaviors between and within species. Comparative studies across species suggest that variation in brain oxytocin receptor expression may mediate diversity in social behavior. Subtle variation in human oxytocin receptor sequence have been related to psychiatric phenotypes. Our studies suggest that the oxytocin receptor gene is hypersensitive to sequence variation at its molecular address which leads to variability in brain expression pattern and social behavior. This research provides new insights into the evolvability of genes producing diversity in social behaviors, which allows efficient adaptation of animals to variable environment and potentially provides insight into psychiatric outcomes related to social behavior.

Positive social relationships are paramount for the survival of mammals and beneficial for mental and physical health, buffer against stressors, and even promote appropriate immune system functioning. By contrast, impaired social relationships, social isolation, or the loss of a bonded partner lead to aggravated physical and mental health. For example, in humans partner loss is detrimental for the functioning of the immune system and heightens the susceptibility for the development of post-traumatic stress disorders, anxiety disorders, and major depressive disorders. To understand potential underlying mechanisms, the monogamous prairie vole can provide important insights. In the present study, we separated pair bonded male and female prairie voles after five days of co-housing, subjected them to the forced swim test on the fourth day following separation, and studied their microglia morphology and activation in specific brain regions. Partner loss increased passive stress-coping in male, but not female, prairie voles. Moreover, partner loss was associated with microglial priming within the parvocellular region of the paraventricular nucleus of the hypothalamus (PVN) in male prairie voles, whereas in female prairie voles the morphological activation within the whole PVN and the prelimbic cortex (PrL) was decreased, marked by a shift towards ramified microglial morphology. Expression of the immediate early protein c-Fos following partner loss was changed within the PrL of male, but not female, prairie voles. However, the loss of a partner did not affect the investigated aspects of the peripheral immune response. These data suggest a potential sex-dependent mechanism for the regulation of microglial activity following the loss of a partner, which might contribute to the observed differences in passive stress-coping. This study furthers our understanding of the effects of partner loss and its short-term impact on the CNS as well as the CNS immune system and the peripheral innate immune system in both male and female prairie voles.

The Bed Nucleus of the Stria Terminalis (BNST) has been studied extensively for its coordination of opposing adaptive behaviors. Previously, we uncovered a critical role for Corticotropin-Releasing Factor (CRF)-expressing neurons of the oval nucleus of the BNST (BNSTovCRF) in maintaining resilience to social defeat through stress-dependent self-sustaining neuronal activity.1However, as mice develop resilience, it is not well-understood how affect and motivation are altered to achieve adaptive behavior in the face of ongoing threat. Here, we explore how this neuronal population exerts a powerful influence over internal state in various stress contexts to promote adaptive social responding. Using cell-type-selective optogenetics, a suite of behavioral paradigms, and transgenic Crf-ChR2 mice, we show that BNSTovCRFneurons induce resiliency by altering the encoding of psychosocial stress, enhancing the appetitiveness of social interaction, and enhancing tolerability to physical stress. Adaptive responses to stress typically emanate as a response to negative internal states by external stimuli; here, we show that in resilient mice, stressful environments are less aversive than susceptible mice, suggesting a different motivational capacity to endure stress in this group. Thus, we describe a novel role for BNSTovCRFneurons in resisting the emotional effects of cumulative stress by reducing the internal experience of aversion

Cumulative stress is a major risk factor for developing major depressive disorder (MDD), yet not everyone experiencing chronic stress develops MDD. In those who do not, it is unclear at what point, or by what mechanism, a trajectory of stable resiliency emerges. Utilizing a 10-day repeated social defeat stress model (RSDS) for MDD, we observed that a critical period between 7 and 10 daily defeats marks the phenotypical divergence of resilient from susceptible mice. In response to ongoing stress, corticotropin-releasing factor (CRF) neurons of the oval nucleus of the bed nucleus of the stria terminalis (BNSTov) display a sustained increased firing rate in resilient, but not susceptible mice. This neurophysiological adaptation was self-sustaining, but only after 7 critical stress exposures, indicating that the process of developing resilience is dependent on stress history. Our study reveals a novel process by which individuals might persist in the face of adversity by way of stress-provoked activation, not inhibition of a key CRF limbic region that establishes a pathway to resilience.

The nonapeptide system modulates numerous social behaviors through oxytocin and vasopressin activation of the oxytocin receptor (OXTR) and vasopressin receptor (AVPR1A) in the brain. OXTRs and AVPR1As are widely distributed throughout the brain and binding densities exhibit substantial variation within and across species. Although OXTR and AVPR1A binding distributions have been mapped for several rodents, this system has yet to be characterized in the spiny mouse (Acomys cahirinus). Here we conducted receptor autoradiography and in situ hybridization to map distributions of OXTR and AVPR1A binding and Oxtr and Avpr1a mRNA expression throughout the basal forebrain and midbrain of male and female spiny mice. We found that nonapeptide receptor mRNA is diffuse throughout the forebrain and midbrain and does not always align with OXTR and AVPR1A binding. Analyses of sex differences in brain regions involved in social behavior and reward revealed that males exhibit higher OXTR binding densities in the lateral septum, bed nucleus of the stria terminalis, and anterior hypothalamus. However, no association with gonadal sex was observed for AVPR1A binding. Hierarchical clustering analysis further revealed that co-expression patterns of OXTR and AVPR1A binding across brain regions involved in social behavior and reward differ between males and females. These findings provide mapping distributions and sex differences in nonapeptide receptors in spiny mice. Spiny mice are an excellent organism for studying grouping behaviors such as cooperation and prosociality, and the nonapeptide receptor mapping here can inform the study of nonapeptide-mediated behavior in a highly social, large group-living rodent.

Oxytocin regulates parturition, lactation, parental nurturing, and many other social behaviors in both sexes. The circuit mechanisms by which oxytocin modulates social behavior are receiving increasing attention. Here, we review recent studies on oxytocin modulation of neural circuit function and social behavior, largely enabled by new methods of monitoring and manipulating oxytocin or oxytocin receptor neurons in vivo. These studies indicate that oxytocin can enhance the salience of social stimuli and increase signal-to-noise ratios by modulating spiking and synaptic plasticity in the context of circuits and networks. We highlight oxytocin effects on social behavior in nontraditional organisms such as prairie voles and discuss opportunities to enhance the utility of these organisms for studying circuit-level modulation of social behaviors. We then discuss recent insights into oxytocin neuron activity during social interactions. We conclude by discussing some of the major questions and opportunities in the field ahead.

Oxytocin regulates social behavior via direct modulation of neurons, regulation of neural network activity, and interaction with other neurotransmitter systems. The behavioral effects of oxytocin signaling are determined by the species-specific distribution of brain oxytocin receptors. The socially monogamous prairie vole has been a useful model organism for elucidating the role of oxytocin in social behaviors, including pair bonding, response to social loss, and consoling. However, there has been no comprehensive mapping of oxytocin receptor-expressing cells throughout the prairie vole brain. Here, we employed a highly sensitive in situ hybridization, RNAscope, to construct an exhaustive, brain-wide map of oxytocin receptor mRNA-expressing cells. We found that oxytocin receptor mRNA expression was widespread and diffused throughout the brain, with specific areas displaying a particularly robust expression. Comparing receptor binding with mRNA revealed that regions of the hippocampus and substantia nigra contained oxytocin receptor protein but lacked mRNA, indicating that oxytocin receptors can be transported to distal neuronal processes, consistent with presynaptic oxytocin receptor functions. In the nucleus accumbens, a region involved in oxytocin-dependent social bonding, oxytocin receptor mRNA expression was detected in both the D1 and D2 dopamine receptor-expressing subtypes of cells. Furthermore, natural genetic polymorphisms robustly influenced oxytocin receptor expression in both D1 and D2 receptor cell types in the nucleus accumbens. Collectively, our findings further elucidate the extent to which oxytocin signaling is capable of influencing brain-wide neural activity, responses to social stimuli, and social behavior. KEY POINTS: Oxytocin receptor mRNA is diffusely expressed throughout the brain, with strong expression concentrated in certain areas involved in social behavior. Oxytocin receptor mRNA expression and protein localization are misaligned in some areas, indicating that the receptor protein may be transported to distal processes. In the nucleus accumbens, oxytocin receptors are expressed on cells expressing both D1 and D2 dopamine receptor subtypes, and the majority of variation in oxytocin receptor expression between animals is attributable to polymorphisms in the oxytocin receptor gene.

Fear generalization and deficits in extinction learning are debilitating dimensions of Post-Traumatic Stress Disorder (PTSD). Most understanding of the neurobiology underlying these dimensions comes from studies of cortical and limbic brain regions. While thalamic and subthalamic regions have been implicated in modulating fear, the potential for incerto-thalamic pathways to suppress fear generalization and rescue deficits in extinction recall remains unexplored. We first used patch-clamp electrophysiology to examine functional connections between the subthalamic zona incerta and thalamic reuniens (RE). Optogenetic stimulation of GABAergic ZI → RE cell terminals in vitro induced inhibitory post-synaptic currents (IPSCs) in the RE. We then combined high-intensity discriminative auditory fear conditioning with cell-type-specific and projection-specific optogenetics in mice to assess functional roles of GABAergic ZI → RE cell projections in modulating fear generalization and extinction recall. In addition, we used a similar approach to test the possibility of fear generalization and extinction recall being modulated by a smaller subset of GABAergic ZI → RE cells, the A13 dopaminergic cell population. Optogenetic stimulation of GABAergic ZI → RE cell terminals attenuated fear generalization and enhanced extinction recall. In contrast, optogenetic stimulation of dopaminergic ZI → RE cell terminals had no effect on fear generalization but enhanced extinction recall in a dopamine receptor D1-dependent manner. Our findings shed new light on the neuroanatomy and neurochemistry of ZI-located cells that contribute to adaptive fear by increasing the precision and extinction of learned associations. In so doing, these data reveal novel neuroanatomical substrates that could be therapeutically targeted for treatment of PTSD.

Posttranslational modification of a protein with glycosylphosphatidylinositol (GPI) is a conserved mechanism exists in all eukaryotes. Thus far, >150 human GPI-anchored proteins have been discovered and ~30 enzymes have been reported to be involved in the biosynthesis and maturation of mammalian GPI. Phosphatidylinositol glycan biosynthesis class A protein (PIGA) catalyzes the very first step of GPI anchor biosynthesis. Patients carrying a mutation of the PIGA gene usually suffer from inherited glycosylphosphatidylinositol deficiency (IGD) with intractable epilepsy and intellectual developmental disorder. We generated three mouse models with PIGA deficits specifically in telencephalon excitatory neurons (Ex-M-cko), inhibitory neurons (In-M-cko) or thalamic neurons (Th-H-cko), respectively. Both Ex-M-cko and In-M-cko mice showed impaired long-term fear memory and were more susceptible to kainic acid-induced seizures. In addition, In-M-cko demonstrated a severe limb-clasping phenotype. Hippocampal synapse changes were observed in Ex-M-cko mice. Our Piga conditional knockout mouse models provide powerful tools to understand the cell-type specific mechanisms underlying inherited GPI deficiency and to test different therapeutic modalities., Human Molecular Genetics, 30 (9), ISSN:0964-6906, ISSN:1460-2083

BackgroundThe incidence of adolescent mental health disorders is on the rise. Epidemiological studies suggest that poor nutrition is a significant contributor to this public health crisis, specifically through exposure to high level of dietary sugar, including fructose, during critical periods of development. Previous studies have shown that elevated fructose exposure during adolescence disrupts mental health. Further, it seems that infants display the highest level of exposure to fructose based on nutritional surveys. Despite these data, it is currently unknown how fructose exposure, specifically during infancy, may impact adolescent mental health.MethodsWe developed an experimental protocol in rats to investigate the effects of fructose exposure during infancy on behavioral, cognitive and metabolic endpoints in adolescence. Specifically, rat pups were exposed to fructose from birth until weaning through maternal diet. Metabolic assays, quantitative PCR and behavioral protocols such as open field, elevated O maze and a Go/ No-Go operant task, were used to determine whether high fructose exposure during infancy may set the stage for behavioral and metabolic dysfunction in adolescence.ResultsWe found that exposing rats to high fructose from birth to weaning resulted in higher circulating glucose, insulin and leptin levels in adolescence. High fructose during infancy also increased bodyweight, disrupted metabolic homeostasis in the basolateral amygdala (BLA) as indicated by decreased activity of the cellular energy sensor AMPK, and impaired attention and impulsivity in a male-specific manner. This impaired attention observed in adolescent male rats following neonatal fructose exposure was partially rescued by viral-mediated, in vivo expression of a constitutively active form of AMPK in principal neurons of the BLA.ConclusionOur results suggest that exposure to high level of fructose during infancy may impact adolescent mental health in a male-specific manner and that manipulation of AMPK activity may mitigate this impact.

Social bonds such as parent-infant attachment or pair bonds can be critical for mental and physical well-being. The monogamous prairie vole (Microtus ochrogaster) has proven useful for examining the neural substrates regulating social behaviors, including social bonding. Oxytocin (OXT) and oxytocin receptor (OXTR) play critical roles in alloparental care, pair bonding and consoling behavior in prairie voles. While OXTR in a few regions, such as the nucleus accumbnes (NAcc), prefrontal cortex (PFC) and anterior cingulate cortex (ACC), have been implicated in regulating these behaviors, the extent to which other OXT sensitive areas modulate social behaviors has not been investigated. The NAcc is a central hub for modulating OXTR dependent social behaviors. To identify neurons expressing Oxtr in prairie vole brain, we generated gene knock-in voles expressing Cre recombinase in tandem with Oxtr (Oxtr-ires-Cre) using CRISPR/Cas9 genome editing. We confirmed Oxtr and Cre mRNA co-localization in NAcc, validating this model. Next, we identified putative Oxtr-expressing neurons projecting to NAcc by infusing retrograde CRE-dependent EGFP AAV into NAcc and visualizing fluorescence. We found enhanced green fluorescent protein (EGFP) positive neurons in anterior olfactory nucleus, PFC, ACC, insular cortex (IC), paraventricular thalamus (PVT), basolateral amygdala (BLA), and posteromedial and posterolateral cortical amygdaloid area (PMCo, PLCo). The ACC to NAcc OXTR projection may represent a species-specific circuit since Oxtr-expressing neurons in the ACC of mice were reported not to project to the NAcc. This is the first delineation of Oxtr-expressing neural circuits in the prairie vole, and demonstrates the utility of this novel genetically modified organism for characterizing OXTR circuits involved in social behaviors.

Oxytocin and vasopressin are peptide hormones secreted from the pituitary that are well known for their peripheral endocrine effects on childbirth/nursing and blood pressure/urine concentration, respectively. However, both peptides are also released in the brain, where they modulate several aspects of social behaviors. Oxytocin promotes maternal nurturing and bonding, enhances social reward, and increases the salience of social stimuli. Vasopressin modulates social communication, social investigation, territorial behavior, and aggression, predominantly in males. Both peptides facilitate social memory and pair bonding behaviors in monogamous species. Here we review the latest research delineating the neural circuitry of the brain oxytocin and vasopressin systems and summarize recent investigations into the circuit-based mechanisms modulating social behaviors. We highlight research using modern molecular genetic technologies to map, monitor activity of, or manipulate neuropeptide circuits. Species diversity in oxytocin and vasopressin effects on social behaviors are also discussed. We conclude with a discussion of the translational implications of oxytocin and vasopressin for improving social functioning in disorders with social impairments, such as autism spectrum disorder.

Oxytocin is a central neuromodulator required for facilitating mate preferences for familiar individuals in a monogamous rodent (prairie vole), irrespective of sex. While the role of oxytocin in mate choice is only understood in a few monogamous species, its function in nonmonogamous species, comprising the vast majority of vertebrate species, remains unclear. To address this issue, we evaluated the involvement of an oxytocin homolog (isotocin, referred herein as oxt) in mate choice in medaka fish ( Oryzias latipes ). Female medaka prefer to choose familiar mates, whereas male medaka court indiscriminately, irrespective of familiarity. We generated mutants of the oxt ligand ( oxt ) and receptor genes ( oxtr1 and oxtr2 ) and revealed that the oxt-oxtr1 signaling pathway was essential for eliciting female mate preference for familiar males. This pathway was also required for unrestricted and indiscriminate mating strategy in males. That is, either oxt or oxtr1 mutation in males decreased the number of courtship displays toward novel females, but not toward familiar females. Further, males with these mutations exhibited enhanced mate-guarding behaviors toward familiar females, but not toward novel females. In addition, RNA-sequencing (seq) analysis revealed that the transcription of genes involved in gamma-amino butyric acid metabolism as well as those encoding ion-transport ATPase are up-regulated in both oxt and oxtr1 mutants only in female medaka, potentially explaining the sex difference of the mutant phenotype. Our findings provide genetic evidence that oxt-oxtr1 signaling plays a role in the mate choice for familiar individuals in a sex-specific manner in medaka fish.

The analgesic effects of opioids are attenuated in aged rats. Opioids such as morphine have decreased analgesic potency (but not efficacy) in aged rodents compared to adults; however, the neural mechanisms underlying this attenuated response are not yet known. The present study investigated the impact of advanced age and biological sex on opioid signaling in the ventrolateral periaqueductal gray (vlPAG) in the presence of chronic inflammatory pain. Assays measuring mu-opioid receptor (MOR) radioligand binding, GTPγS binding, receptor phosphorylation, cAMP inhibition, and regulator of G-protein signaling (RGS) protein expression were performed on vlPAG tissue from adult (2-3mos) and aged (16-18mos) male and female rats. Persistent inflammatory pain was induced by intraplantar injection of Complete Freund’s Adjuvant (CFA). Adult males exhibited the highest MOR binding potential and the highest G-protein activation (activation efficiency ratio) in comparison to aged males and females (adult and aged). No impact of advanced age or sex on MOR phosphorylation state was observed. DAMGO-induced cAMP inhibition was highest in the vlPAG of adult males compared to aged males and females (adult and aged). vlPAG levels of RGS4 and RGS9-2, critical for terminating G-protein signaling, were assessed using RNAscope. Adult rats (both males and females) exhibited lower levels of vlPAG RGS4 and RGS9-2 mRNA expression compared to aged males and females. The observed age-related reductions in vlPAG MOR binding potential, G-protein activation efficiency, and cAMP inhibition, along with the observed age-related increases in RGS4 and RGS9-2 vlPAG expression, provide potential mechanisms whereby the potency of opioids is decreased in the aged population. These results have significant implications for pain management in this population.HighlightsAged males and females (adult and aged) exhibit reduced vlPAG μ-opioid receptor binding potential compared to adult males.Aged males and females (adult and aged) exhibit reduced opioid-induced vlPAG G-protein activation compared to adult males.Aged males and females (adult and aged) exhibit reduced vlPAG MOR mediated cAMP inhibition compared to adult males.Aged rats (males and females) exhibit increased vlPAG mRNA expression of Regulator of G-Protein Signaling (RGS) proteins RGS4 and RGS9-2 compared to adult rats (males and females), which may explain the reduced receptor signaling observed in aged animals.These coordinate decreases in opioid receptor signaling may explain the previously reported reduced potency of opioids to produce pain relief in females and aged rats.

Early life social experiences shape neural pathways in infants to develop lifelong social skills. This review presents the first unified circuit-based model of social learning that can be applied to early life social development, drawing together unique human developmental milestones, sensitive learning periods, and behavioral and neural scaffolds. Circuit domains for social learning are identified governing Activation, Integration, Discrimination, Response and Reward (AIDRR) to sculpt and drive human social learning. This unified model can be used to identify social delays earlier in development. We propose social impairments observed in Autism Spectrum Disorder are underpinned by early mistimed sensitive periods in brain development and alterations in amygdala development to disrupt the AIDRR circuits. This model directs how interventions can target neural circuits for social development and be applied early in life. To illustrate, the role of oxytocin and its use as an intervention is explored. The AIDRR model shifts focus away from delivering broad treatments based only on diagnostic classifications, to specifying and targeting the relevant circuits, at the right time of development, to optimize social learning.

Adverse posttraumatic neuropsychiatric sequelae (APNS) are common among civilian trauma survivors and military veterans. These APNS, as traditionally classified, include posttraumatic stress, post-concussion syndrome, depression, and regional or widespread pain. Traditional classifications have come to hamper scientific progress because they artificially fragment APNS into siloed, syndromic diagnoses unmoored to discrete components of brain functioning and studied in isolation. These limitations in classification and ontology slow the discovery of pathophysiologic mechanisms, biobehavioral markers, risk prediction tools, and preventive/treatment interventions. Progress in overcoming these limitations has been challenging, because such progress would require studies that both evaluate a broad spectrum of posttraumatic sequelae (to overcome fragmentation) and also perform in-depth biobehavioral evaluation (to index sequelae to domains of brain function). This article summarizes the methods of the Advancing Understanding of RecOvery afteR traumA (AURORA) Study. AURORA conducts a large scale (n = 5,000 target sample) in-depth assessment of APNS development using a state-of-the-art battery of self-report, neurocognitive, physiologic, digital phenotyping, psychophysical, neuroimaging, and genomic assessments, beginning in the early aftermath of trauma and continuing for one year. The goals of AURORA are to achieve improved phenotypes, prediction tools, and understanding of molecular mechanisms to inform the future development and testing of preventive and treatment interventions.

Background: Males and females often exhibit different behaviour, life histories and ecology, and sex differences are typically reflected in their brains. Neuronal protection and maintenance include complex processes led by the microglia that also interact with metabolites such as hormones or immune components. Despite increasing interest in sex-specific brain activation in laboratory animals, the crucial significance of immune function protecting in the brain of wildlife is widely lacking. Here, we study sex-specific expression of immune genes in the brain of a small shorebird, the Kentish plover (Charadrius alexandrinus), that is an emerging model of mating system evolution and speciation. We compare immune gene expression patterns between adult males and adult females in two wild breeding populations in contrasting habitats: a coastal sea-level population and a high-altitude inland population in China.Results: Our analysis yielded 379 genes associated with immune function. We show a significant male-biased immune gene upregulation, which is in line with ecological studies that showed higher survival in males than in females. Immune gene expression in the brain did not differ in upregulation between the coastal and inland populations.Conclusions: We discuss the role of dosage compensation in our findings and their evolutionary significance mediated by sex-specific survival and neuronal deterioration. Similar expression profiles in the coastal and inland populations suggest comparable pathogen pressures between the habitats. We call for further studies on gene expressions of males and females in wild population to understand the implications of immune function for life-histories and demography in natural systems.

Objectives To enable non-invasive real-time quantification of vasopressin 1A (V1A) receptors in peripheral organs, we sought to develop a suitable PET probe that would allow specific and selective V1A receptor imaging in vitro and in vivo. Methods We synthesized a high-affinity and -selectivity ligand, designated compound 17. The target structure was labeled with carbon-11 and tested for its utility as a V1A-targeted PET tracer by cell uptake studies, autoradiography, in vivo PET imaging and ex vivo biodistribution experiments. Results Compound 17 (PF-184563) and the respective precursor for radiolabeling were synthesized in an overall yield of 49% (over 7 steps) and 40% (over 8 steps), respectively. An inhibitory constant of 0.9 nM towards the V1A receptors was measured, while excellent selectivity over the related V1B, V2 and OT receptor (IC50 >10,000 nM) were obtained. Cell uptake studies revealed considerable V1A binding, which was significantly reduced in the presence of V1A antagonists. Conversely, there was no significant blockade in the presence of V1B and V2 antagonists. In vitro autoradiography and PET imaging studies in rodents indicated specific tracer binding mainly in the liver. Further, the pancreas, spleen and the heart exhibited specific binding of [11C]17 ([11C]PF-184563) by ex vivo biodistribution experiments. Conclusion We have developed the first V1A-targeted PET ligand that is suitable for subtype-selective receptor imaging in peripheral organs including the liver, heart, pancreas and spleen. Our findings suggest that [11C]PF-184563 can be a valuable tool to study the role of V1A receptors in liver diseases, as well as in cardiovascular pathologies.

Despite our close genetic relationship with chimpanzees, there are notable differences between chimpanzee and human social behavior. Oxytocin and vasopressin are neuropeptides involved in regulating social behavior across vertebrate taxa, including pair bonding, social communication, and aggression, yet little is known about the neuroanatomy of these systems in primates, particularly in great apes. Here, we used receptor autoradiography to localize oxytocin and vasopressin V1a receptors, OXTR and AVPR1a respectively, in seven chimpanzee brains. OXTR binding was detected in the lateral septum, hypothalamus, medial amygdala, and substantia nigra. AVPR1a binding was observed in the cortex, lateral septum, hypothalamus, mammillary body, entire amygdala, hilus of the dentate gyrus, and substantia nigra. Chimpanzee OXTR/AVPR1a receptor distribution is compared to previous studies in several other primate species. One notable difference is the lack of OXTR in reward regions such as the ventral pallidum and nucleus accumbens in chimpanzees, whereas OXTR is found in these regions in humans. Our results suggest that in chimpanzees, like in most other anthropoid primates studied to date, OXTR has a more restricted distribution than AVPR1a, while in humans the reverse pattern has been reported. Altogether, our study provides a neuroanatomical basis for understanding the function of the oxytocin and vasopressin systems in chimpanzees.

The incidence of adolescent mental health disorders is on the rise. Epidemiological studies suggest that poor nutrition is a significant contributor to this public health crisis, specifically through exposure to high level of dietary sugar, including fructose, during critical periods of development. Previous studies have shown that elevated fructose exposure during adolescence disrupts mental health. Despite these data, it is currently unknown how fructose exposure, specifically during infancy, may impact adolescent mental health. We developed a rat experimental protocol to investigate the effects of fructose exposure during infancy on behavioral, cognitive and metabolic endpoints in adolescence. We found that exposing rats to high fructose from birth to weaning resulted in higher circulating glucose, insulin and leptin levels in adolescence. High fructose during infancy also increased bodyweight, disrupted metabolic homeostasis in the basolateral amygdala (BLA) as indicated by decreased activity of the cellular energy sensor AMPK, and impaired attention and impulsivity in a male-specific manner. This impaired attention observed in adolescent male rats following neonatal fructose exposure was partially rescued by viral-mediated, in vivo expression of a constitutively active form of AMPK in principal neurons of the BLA. Our results suggest that exposure to high level of fructose during infancy may impact adolescent mental health in a male-specific manner and that manipulation of AMPK activity may mitigate this impact.

Behavioral neuroendocrinology has benefited tremendously from the use of a wide range of model organisms that are ideally suited for particular questions. However, in recent years the ability to manipulate the genomes of laboratory strains of mice has led to rapid advances in our understanding of the role of specific genes, circuits and neural populations in regulating behavior. While genome manipulation in mice has been a boon for behavioral neuroscience, the intensive focus on the mouse restricts the diversity in behavioral questions that can be investigated using state-of-the-art techniques. The CRISPR/Cas9 system has great potential for efficiently generating mutants in non-traditional animal models and consequently to reinvigorate comparative behavioral neuroendocrinology. Here we describe the efficient generation of oxytocin receptor (Oxtr) mutant prairie voles (Microtus ochrogaster) using the CRISPR/Cas9 system, and describe initial behavioral phenotyping focusing on behaviors relevant to autism. Oxtr mutant male voles show no disruption in pup ultrasonic vocalization, anxiety as measured by the open field test, alloparental behavior, or sociability in the three chamber test. Mutants did however show a modest elevation in repetitive behavior in the marble burying test, and an impairment in preference for social novelty. The ability to efficiently generate targeted mutations in the prairie vole genome will greatly expand the utility of this model organism for discovering the genetic and circuit mechanisms underlying complex social behaviors, and serves as a proof of principle for expanding this approach to other non-traditional model organisms.

In humans and rodent animal models, the brain oxytocin system is paramount for facilitating social bonds, from the formation and consequences of early-life parent-infant bonds to adult pair bond relationships. In social species, oxytocin also mediates the positive effects of healthy social bonds on the partners’ well-being. However, new evidence suggests that the negative consequences of early neglect or partner loss may be mediated by disruptions in the oxytocin system as well. With a focus on oxytocin and its receptor, we review studies from humans and animal models, i.e. mainly from the biparental, socially monogamous prairie vole (Microtus orchogaster), on the beneficial effects of positive social relationships both between offspring and parents and in adult partners. The abundance of social bonds and benevolent social relationships, in general, are associated with protective effects against psycho- and physiopathology not only in the developing infant, but also during adulthood. Furthermore, we discuss the negative effects on well-being, emotionality and behaviour, when these bonds are diminished in quality or are disrupted, for example through parental neglect of the young or the loss of the partner in adulthood. Strikingly, in prairie voles, oxytocinergic signalling plays an important developmental role in the ability to form bonds later in life in the face of early-life neglect, while disruption of oxytocin signalling following partner loss results in the emergence of depressive-like behaviour and physiology. This review demonstrates the translational value of animal models for investigating the oxytocinergic mechanisms that underlie the detrimental effects of developmental parental neglect and pair bond disruption, encouraging future translationally relevant studies on this topic that is so central to our daily lives.

Research on oxytocin (OT) has revealed a substantial involvement of this neuropeptide in social cognition processes and attachment behavior. The rationale of the present project was to decipher the differential role of OT in basic social cognition processes towards non-erotic attachment stimuli vs. reproduction-related stimuli in human subjects. In a randomized double-blind repeated-measures cross-over design, N = 82 participants were investigated twice and received either intranasal OT or placebo at the first assessment followed by placebo or OT at second assessment. Participants were presented with standardized pictures of parent-child dyads, romantic couples engaging in non-erotic or explicit sexual activities, and non-social pictures while we assessed pupil dilation and eye focus on specific pre-defined areas of interest. Multilevel analyses suggest that during the initial presentation, OT increased pupil dilation towards all categories of stimuli and led the eye focus towards the eyes and body regions, followed by a strong decrease in pupil dilation and fixations at the second session. These carry-over effects indicate that hormonal treatment at an initial contact to social stimuli can determine how these stimuli are processed later. These results might have implications for OT as a treatment in interventions with repeated exposure to social material.

Pain experience is known to be modified by social factors, but the brain mechanisms remain unspecified. We recently established an animal model of social stress-induced hyperalgesia (SSIH) using a socially monogamous rodent, the prairie vole, in which males separated from their female partners (loss males) became anxious and displayed exacerbated inflammatory pain behaviors compared to males with partners (paired males). In the present study, to explore the neural pathways involved in SSIH, a difference in neuronal activation in pain-related brain regions, or "pain matrix", during inflammatory pain between paired and loss males was detected using Fos immunoreactivity (Fos-ir). Males were paired with a female and pair bonding was confirmed in all subjects using a partner preference test. During formalin-induced inflammatory pain, both paired and loss males showed a significant induction of Fos-ir throughout the analyzed pain matrix components compared to basal condition (without injection), and no group differences in immunoreactivity were found among the injected males in many brain regions. However, the loss males had significantly lower Fos-ir following inflammatory pain in the medial prefrontal cortex and nucleus accumbens shell than the paired males, even though base Fos-ir levels were comparable between groups. Notably, both regions with different Fos-ir are major components of the dopamine and oxytocin systems, which play critical roles in both pair bonding and pain regulation. The present results suggest the possibility that pain exacerbation by social stress emerges through alteration of signaling in social brain circuitry.

ObjectivesVasopressin 1A (V1A) receptors have been linked to autism spectrum disorder, heart failure, diabetes and renal disease. Currently, there is a lack of validated probes for clinical V1A-targeted imaging and previous PET studies have primarily focused on the brain. To enable non-invasive real-time quantification of V1A receptors in peripheral organs, we sought to develop a suitable PET radioligand that would allow specific and selective V1A receptor imaging in vivo. MethodsThe previously reported triazolobenzodiazepine-based V1A antagonist, PF-184563, served as a structural basis for the development of a suitable V1A-targeted PET probe. Initially, PF-184563 and the respective desmethyl precursor for radiolabeling were synthesized via multistep organic synthesis. Inhibitory constants of PF-184563 for V1A, V1B, V2 and oxytocin (OT) receptors were assessed by competitive radioligand binding or fluorescent-based assays. Molecular docking of PF-184563 to the V1A receptor binding pocket was performed to corroborate the high binding affinity, while carbon-11 labeling was accomplished via radiomethylation. To assess the utility of the resulting PET radioligand, [11C]17, cell uptake studies were performed in a human V1A receptor Chinese hamster ovary (CHO) cell line under baseline and blockade conditions, using a series of V1A, V1B and V2 antagonists in >100-fold excess. Further, to show in vivo specificity, we conducted PET imaging and biodistribution experiments, thereby co-administering the clinical V1A-antagonist, balovaptan (3mg/kg), as a blocking agent. ResultsPF-184563 and the respective desmethyl precursor were synthesized in an overall yield of 49% (over 7 steps) and 40% (over 8 steps), respectively. A subnanomolar inhibitory constant (Ki) of 0.9 nM towards the V1A receptor was observed for PF-184563, while the triazolobenzodiazepine derivative concurrently exhibited excellent selectivity over the related V1B, V2 and OT receptor (IC50 >10,000 nM). [11C]17 was obtained in high radiochemical purity (> 99%), molar activities ranging from 37 - 46 GBq/mol and a non-decay-corrected radiochemical yield of 8%. Cell uptake studies revealed considerable tracer binding, which was significantly reduced in the presence of V1A antagonists. Conversely, there was no significant blockade in the presence of V1B and V2 antagonists. PET imaging and biodistribution studies in CD-1 mice indicated specific tracer binding in the thyroid, pancreas, spleen and the heart. ConclusionWe report the development of a V1A-targeted PET radioligand that is suitable for subtype-selective in vitro and in vivo receptor imaging. Indeed, [11C]17 proved to specifically visualize V1A receptors in several organs including the heart, pancreas, spleen and thyroid. These results suggest that [11C]17 can be a valuable tool to study the role of V1A receptors in cardiovascular and immune-mediated pathologies.

A recent paper by Naderi et al. published in eLife shows that pair bonding in monogamous mice is protective against tumor growth, likely via changes in serum factors and cancer cell transcription. We propose that studying the pathway linking social stimuli to cancer cell gene regulation offers a means to identify novel pharmacological targets.

Previous studies have related pair-bonding in Microtus ochrogaster, the prairie vole, with plastic changes in several brain regions. However, the interactions between these socially relevant regions have yet to be described. In this study, we used resting-state magnetic resonance imaging to explore bonding behaviors and functional connectivity of brain regions previously associated with pair-bonding. Thirty-two male and female prairie voles were scanned at baseline, 24 hr, and 2 weeks after the onset of cohabitation. By using network-based statistics, we identified that the functional connectivity of a corticostriatal network predicted the onset of affiliative behavior, while another predicted the amount of social interaction during a partner preference test. Furthermore, a network with significant changes in time was revealed, also showing associations with the level of partner preference. Overall, our findings revealed the association between network-level functional connectivity changes and social bonding.

Background Schizophrenia (SCZ) is a neurodevelopmental disorder that leads to poor social function. Oxytocin (OXT), a neuropeptide involved in social cognition, is a potential therapeutic agent for alleviating social dysfunction. Therefore, we investigated the effects of intranasal oxytocin (IN-OXT) on emotional processes in experimental interactive social contexts in individuals with SCZ. Methods In a male-only parallel randomized placebo-controlled double-blind trial, we investigated the effects of IN-OXT (24 IU) on visual fixation on pictures of faces and emotion recognition in an interactive ball-tossing game that probed processing of social and nonsocial stimuli. Results Intranasal oxytocin enhanced the recognition of emotions during an emotion-based ball-tossing game. This improvement was specific to the game that included social cue processing. Intranasal oxytocin did not affect eye gaze duration or gaze dwell time on faces in these patients. Conclusions An acute low dose of IN-OXT had a modest effect on social cue processing and was limited to emotion recognition. Higher doses and long-term trials targeting emotional processing in SCZ may lead to improved social function.