Delivery by cesarean section leads to heavier adult bodyweight in prairie voles (Microtus ochrogaster).

Delivery by cesarean section now makes up 32.1 % of all births in the United States. Meta-analyses have estimated that delivery by cesarean section is associated with a > 50 % increased risk for childhood obesity by 5 years of age. While this association is independent of maternal obesity, breastfeeding, and heritable factors, studies in humans have been unable to test for a causal role of cesarean delivery in this regard. Here, we set out to use an animal model to experimentally test whether delivery by cesarean section would increase offspring weight in adulthood. Delivery by cesarean section may exert neurodevelopmental consequences by impacting hormones that are important at birth as well as during metabolic regulation in later life, such as oxytocin and vasopressin. The prairie vole (Microtus ochrogaster) has long been studied to investigate the roles of oxytocin and vasopressin in brain development and social behavior. Here, we establish that prairie voles tolerate a range of ambient temperatures, including conventional 22° housing, which makes them translationally appropriate for studies of diet-induced obesity. We also studied vole offspring for their growth, sucrose preference, home cage locomotor activity, and food consumption after birth by either cesarean section or vaginal delivery. At sacrifice, we collected measures of weight, length, and adipose tissue to analyze body composition in adulthood. Voles delivered by cesarean section had consistently greater bodyweights than those born vaginally, despite having lower food consumption and greater locomotive activity. Cesarean-delivered animals were also longer, though this did not explain their greater body weights. While cesarean delivery had no effect on vasopressin, it resulted in less oxytocin immunoreactivity within the hypothalamus in adulthood. These results support the case that cesarean section delivery plays a causal role in increasing offspring body weight, potentially by affecting the oxytocin system.

Lasting consequences on physiology and social behavior following cesarean delivery in prairie voles.

Cesarean delivery is associated with diminished plasma levels of several 'birth-signaling' hormones, such as oxytocin and vasopressin. These same hormones have been previously shown to exert organizational effects when acting in early life. For example, our previous work found a broadly gregarious phenotype in prairie voles exposed to oxytocin at birth. Meanwhile, cesarean delivery has been previously associated with changes in social behavior and metabolic processes related to oxytocin and vasopressin. In the present study, we investigated the long-term neurodevelopmental consequences of cesarean delivery in prairie voles. After cross-fostering, vole pups delivered either via cesarean or vaginal delivery were studied throughout development. Cesarean-delivered pups responded to isolation differently in terms of their vocalizations (albeit in opposite directions in the two experiments), huddled in less cohesive groups under warmed conditions, and shed less heat. As young adults, we observed no differences in anxiety-like or alloparental behavior. However, in adulthood, cesarean-delivered voles of both sexes failed to form partner preferences with opposite sex conspecifics. In a follow-up study, we replicated this deficit in partner-preference formation among cesarean-delivered voles and were able to normalize pair-bonding behavior by treating cesarean-delivered vole pups with oxytocin (0.25 mg/kg) at delivery. Finally, we detected minor differences in regional oxytocin receptor expression within the brains of cesarean-delivered voles, as well as microbial composition of the gut. Gene expression changes in the gut epithelium indicated that cesarean-delivered male voles have altered gut development. These results speak to the possibility of unintended developmental consequences of cesarean delivery, which currently accounts for 32.9 % of deliveries in the U.S. and suggest that further research should be directed at whether hormone replacement at delivery influences behavioral outcomes in later life.

Is Oxytocin "Nature's Medicine"?

Oxytocin is a pleiotropic, peptide hormone with broad implications for general health, adaptation, development, reproduction, and social behavior. Endogenous oxytocin and stimulation of the oxytocin receptor support patterns of growth, resilience, and healing. Oxytocin can function as a stress-coping molecule, an anti-inflammatory, and an antioxidant, with protective effects especially in the face of adversity or trauma. Oxytocin influences the autonomic nervous system and the immune system. These properties of oxytocin may help explain the benefits of positive social experiences and have drawn attention to this molecule as a possible therapeutic in a host of disorders. However, as detailed here, the unique chemical properties of oxytocin, including active disulfide bonds, and its capacity to shift chemical forms and bind to other molecules make this molecule difficult to work with and to measure. The effects of oxytocin also are context-dependent, sexually dimorphic, and altered by experience. In part, this is because many of the actions of oxytocin rely on its capacity to interact with the more ancient peptide molecule, vasopressin, and the vasopressin receptors. In addition, oxytocin receptor(s) are epigenetically tuned by experience, especially in early life. Stimulation of G-protein-coupled receptors triggers subcellular cascades allowing these neuropeptides to have multiple functions. The adaptive properties of oxytocin make this ancient molecule of special importance to human evolution as well as modern medicine and health; these same characteristics also present challenges to the use of oxytocin-like molecules as drugs that are only now being recognized. SIGNIFICANCE STATEMENT: Oxytocin is an ancient molecule with a major role in mammalian behavior and health. Although oxytocin has the capacity to act as a "natural medicine" protecting against stress and illness, the unique characteristics of the oxytocin molecule and its receptors and its relationship to a related hormone, vasopressin, have created challenges for its use as a therapeutic drug.

Maternal antibiotics disrupt microbiome, behavior, and temperature regulation in unexposed infant mice.

Maternal antibiotic (ABx) exposure can significantly perturb the transfer of microbiota from mother to offspring, resulting in dysbiosis of potential relevance to neurodevelopmental disorders such as autism spectrum disorder (ASD). Studies in rodent models have found long-term neurobehavioral effects in offspring of ABx-treated dams, but ASD-relevant behavior during the early preweaning period has thus far been neglected. Here, we exposed C57BL/6J mouse dams to ABx (5 mg/ml neomycin, 1.25 µg/ml pimaricin, .075% v/v acetic acid) dissolved in drinking water from gestational day 12 through offspring postnatal day 14. A number of ASD-relevant behaviors were assayed in offspring, including ultrasonic vocalization (USV) production during maternal separation, group huddling in response to cold challenge, and olfactory-guided home orientation. In addition, we obtained measures of thermoregulatory competence in pups during and following behavioral testing. We found a number of behavioral differences in offspring of ABx-treated dams (e.g., modulation of USVs by pup weight, activity while huddling) and provide evidence that some of these behavioral effects can be related to thermoregulatory deficiencies, particularly at younger ages. Our results suggest not only that ABx can disrupt microbiomes, thermoregulation, and behavior, but that metabolic effects may confound the interpretation of behavioral differences observed after early-life ABx exposure.

Rewritable fidelity: How repeated pairings and age influence subsequent pair-bond formation in male prairie voles.

The prairie vole has proven a valuable animal model for the neurobiological study of social monogamy and pair bonding. Previous research has focused almost exclusively on virgin prairie voles forming pair-bonds for the first time - a paradigm with limited relevance to human social behavior. In the present study, we used stud males to assess the impact of repeated pair-bond formation and dissolution on the behaviors and neurobiology relevant to subsequent pair-bond formation. Stud males were tested for behavioral and neurobiological effects of repeated pair-bonding after the 1st, 5th, and 10th pairing. Aged breeder males that experienced minimal pair-bond dissolution were included to control for the effects of aging. Results showed that male prairie voles readily form new pair-bonds after repeated pair-bond dissolution. In terms of social monogamy, old age was associated with males spending less time in close social contact with unfamiliar females. There were no effects of age nor number of lifetime pairings on depressive-like behavior or paternal behavior toward pups. Within the brain, the patterns of oxytocin (OTR) and vasopressin type 1a (V1aR) receptors were largely unaffected, with the following exceptions: 1) males with only a single pairing had higher OTR densities in the paraventricular thalamus and bed nucleus of the stria terminalis; 2) there was an age-related increase in the density of OTR in the caudate putamen and an age-related decline in the density of V1aR in the cortical amygdala. The present findings have translational relevance to human social behavior in the context of aging and social experience.

High estrogen and chronic haloperidol lead to greater amphetamine-induced BOLD activation in awake, amphetamine-sensitized female rats.

The ovarian hormone estrogen has been implicated in schizophrenia symptomatology. Low levels of estrogen are associated with an increase in symptom severity, while exogenous estrogen increases the efficacy of antipsychotic medication, pointing at a possible interaction between estrogen and the dopaminergic system. The aim of this study is to further investigate this interaction in an animal model of some aspects of schizophrenia using awake functional magnetic resonance imaging. Animals receiving 17ß-estradiol and haloperidol were scanned and BOLD activity was assessed in response to amphetamine. High 17ß-estradiol replacement and chronic haloperidol treatment showed increased BOLD activity in regions of interest and neural networks associated with schizophrenia (hippocampal formations, habenula, amygdala, hypothalamus etc.), compared with low, or no 17ß-estradiol. These data show that chronic haloperidol treatment has a sensitizing effect, possibly on the dopaminergic system, and this effect is dependent on hormonal status, with high 17ß-estradiol showing the greatest BOLD increase. Furthermore, these experiments further support the use of imaging techniques in studying schizophrenia, as modeled in the rat, but can be extended to addiction and other disorders.

Oxytocin promotes functional coupling between paraventricular nucleus and both sympathetic and parasympathetic cardioregulatory nuclei.

The neuropeptide oxytocin (OXT) facilitates prosocial behavior and selective sociality. In the context of stress, OXT also can down-regulate hypothalamic-pituitary-adrenal (HPA) axis activity, leading to consideration of OXT as a potential treatment for many socioaffective disorders. However, the mechanisms through which administration of exogenous OXT modulates social behavior in stressful environmental contexts are not fully understood. Here, we investigate the hypothesis that autonomic pathways are components of the mechanisms through which OXT aids the recruitment of social resources in stressful contexts that may elicit mobilized behavioral responses. Female prairie voles (Microtus ochrogaster) underwent a stressor (walking in shallow water) following pretreatment with intraperitoneal OXT (0.25mg/kg) or OXT antagonist (OXT-A, 20mg/kg), and were allowed to recover with or without their sibling cagemate. Administration of OXT resulted in elevated OXT concentrations in plasma, but did not dampen the HPA axis response to a stressor. However, OXT, but not OXT-A, pretreatment prevented the functional coupling, usually seen in the absence of OXT, between paraventricular nucleus (PVN) activity as measured by c-Fos immunoreactivity and HPA output (i.e. corticosterone release). Furthermore, OXT pretreatment resulted in functional coupling between PVN activity and brain regions regulating both sympathetic (i.e. rostral ventrolateral medulla) and parasympathetic (i.e. dorsal vagal complex and nucleus ambiguous) branches of the autonomic nervous system. These findings suggest that OXT increases central neural control of autonomic activity, rather than strictly dampening HPA axis activity, and provides a potential mechanism through which OXT may facilitate adaptive and context-dependent behavioral and physiological responses to stressors.

Neuroanatomical and functional consequences of oxytocin treatment at birth in prairie voles.

Birth is a critical period for the developing brain, a time when surging hormone levels help prepare the fetal brain for the tremendous physiological changes it must accomplish upon entry into the 'extrauterine world'. A number of obstetrical conditions warrant manipulations of these hormones at the time of birth, but we know little of their possible consequences on the developing brain. One of the most notable birth signaling hormones is oxytocin, which is administered to roughly 50% of laboring women in the United States prior to / during delivery. Previously, we found evidence for behavioral, epigenetic, and neuroendocrine consequences in adult prairie vole offspring following maternal oxytocin treatment immediately prior to birth. Here, we examined the neurodevelopmental consequences in adult prairie vole offspring following maternal oxytocin treatment prior to birth. Control prairie voles and those exposed to 0.25 mg/kg oxytocin were scanned as adults using anatomical and functional MRI, with neuroanatomy and brain function analyzed as voxel-based morphometry and resting state functional connectivity, respectively. Overall, anatomical differences brought on by oxytocin treatment, while widespread, were generally small, while differences in functional connectivity, particularly among oxytocin-exposed males, were larger. Analyses of functional connectivity based in graph theory revealed that oxytocin-exposed males in particular showed markedly increased connectivity throughout the brain and across several parameters, including closeness and degree. These results are interpreted in the context of the organizational effects of oxytocin exposure in early life and these findings add to a growing literature on how the perinatal brain is sensitive to hormonal manipulations at birth.

Transcriptional diversity of the oxytocin receptor in prairie voles: mechanistic implications for behavioral neuroscience and maternal physiology.

The neurohormone oxytocin regulates many aspects of physiology primarily by binding to its receptor, the oxytocin receptor. The oxytocin receptor gene (Oxtr) has been shown to have alternative transcripts in the mouse brain which may each have different biological functions or be used in specific contexts. A popular animal model for studying oxytocin-dependent social behaviors is the prairie vole, a biparental and monogamous rodent. Alternative transcriptional capacity of Oxtr in prairie voles is unknown. We used 5' rapid amplification of cDNA ends to identify alternative Oxtr transcription start sites in prairie vole brain tissue and uterine tissue. We then validated expression of specific transcripts in fetal brains and assessed the impact of exogenous oxytocin administration in utero on offspring brain development. We identified seven distinct Oxtr transcripts, all of which are present in both brain and uterine tissue. We then demonstrated that maternal oxytocin administration alters expression of a specific subset of Oxtr transcripts and that these different transcripts are under unique epigenetic regulation, such that in the perinatal period only one of the alternative transcripts is associated with DNA methylation in the Oxtr promoter. These data establish the existence of multiple Oxtr transcripts in prairie vole brain and uterine tissue and implicate oxytocin in the regulation of alternative transcript expression. These data have significant implications for our understanding of null mutant models in both mice and voles and translation in human birth and behavior.

Birth signalling hormones and the developmental consequences of caesarean delivery.

Rates of delivery by caesarean section (CS) are increasing around the globe and, although several epidemiological associations have already been observed between CS and health outcomes in later life, more are sure to be discovered as this practice continues to gain popularity. The components of vaginal delivery that protect offspring from the negative consequences of CS delivery in later life are currently unknown, although much attention to date has focused on differences in microbial colonisation. Here, we present the case that differing hormonal experiences at birth may also contribute to the neurodevelopmental consequences of CS delivery. Levels of each of the 'birth signalling hormones' (oxytocin, arginine vasopressin, epinephrine, norepinephrine and the glucocorticoids) are lower following CS compared to vaginal delivery, and there is substantial evidence for each that manipulations in early life results in long-term neurodevelopmental consequences. We draw from the research traditions of neuroendocrinology and developmental psychobiology to suggest that the perinatal period is a sensitive period, during which hormones achieve organisational effects. Furthermore, there is much to be learned from research on developmental programming by early-life stress that may inform research on CS, as a result of shared neuroendocrine mechanisms at work. We compare and contrast the effects of early-life stress with those of CS delivery and propose new avenues of research based on the links between the two bodies of literature. The research conducted to date suggests that the differences in hormone signalling seen in CS neonates may produce long-term neurodevelopmental consequences.

A Neuroscientist's Guide to the Vole.

Prairie voles have emerged as an important rodent model for understanding the neuroscience of social behavior. Prairie voles are well known for their capacity for pair bonding and alloparental care. These behavioral phenomena overlap with human social behavior but are not commonly observed in traditional rodent models. In this article, we highlight the many benefits of using prairie voles in neuroscience research. We begin by describing the advantages of using diverse and non-traditional study models. We then focus on social behaviors, including pair bonding, alloparental care, and peer interactions, that have brought voles to the forefront of social neuroscience. We describe many additional features of prairie vole biology and behavior that provide researchers with opportunities to address an array of research questions. We also survey neuroethological methods that have been used with prairie voles, from classic to modern techniques. Finally, we conclude with a discussion of other vole species, particularly meadow voles, and their own unique advantages for neuroscience studies. This article provides a foundation for researchers who are new to working with voles, as well as for experienced neuroscientists who want to expand their research scope. © 2021 Wiley Periodicals LLC.

Genetic, epigenetic, and environmental factors controlling oxytocin receptor gene expression.

BACKGROUND: The neuropeptide oxytocin regulates mammalian social behavior. Disruptions in oxytocin signaling are a feature of many psychopathologies. One commonly studied biomarker for oxytocin involvement in psychiatric diseases is DNA methylation at the oxytocin receptor gene (OXTR). Such studies focus on DNA methylation in two regions of OXTR, exon 3 and a region termed MT2 which overlaps exon 1 and intron 1. However, the relative contribution of exon 3 and MT2 in regulating OXTR gene expression in the brain is currently unknown. RESULTS: Here, we use the prairie vole as a translational animal model to investigate genetic, epigenetic, and environmental factors affecting Oxtr gene expression in a region of the brain that has been shown to drive Oxtr related behavior in the vole, the nucleus accumbens. We show that the genetic structure of Oxtr in prairie voles resembles human OXTR. We then studied the effects of early life experience on DNA methylation in two regions of a CpG island surrounding the Oxtr promoter: MT2 and exon 3. We show that early nurture in the form of parental care results in DNA hypomethylation of Oxtr in both MT2 and exon 3, but only DNA methylation in MT2 is associated with Oxtr gene expression. Network analyses indicate that CpG sites in the 3' portion of MT2 are most highly associated with Oxtr gene expression. We also identify two novel SNPs in exon 3 of Oxtr in prairie voles and a novel alternative transcript originating from the third intron of the gene. Expression of the novel alternative transcript is associated with genotype at SNP KLW2. CONCLUSIONS: These results identify putative regulatory features of Oxtr in prairie voles which inform future studies examining OXTR in human social behaviors and disorders. These studies indicate that in prairie voles, DNA methylation in MT2, particularly in the 3' portion, is more predictive of Oxtr gene expression than DNA methylation in exon 3. Similarly, in human temporal cortex, we find that DNA methylation in the 3' portion of MT2 is associated with OXTR expression. Together, these results suggest that among the CpG sites studied, DNA methylation of MT2 may be the most reliable indicator of OXTR gene expression. We also identify novel features of prairie vole Oxtr, including SNPs and an alternative transcript, which further develop the prairie vole as a translational model for studies of OXTR.

Corpus Colossal: A Bibliometric Analysis of Neuroscience Abstracts and Impact Factor.

A field's priorities are reflected by the contents of its high-impact journals. Researchers in turn may choose to pursue research objectives based on what is believed to be most highly valued by their peers. However, these assessments of the field's priorities are often subjective, owing to a lack of formal quantification of high-impact journals' contents. By compiling a corpus of abstracts from within the field neuroscience, I was able to analyze which terms had differential frequencies between 13 high-impact and 14 medium-impact journals. Approximately 50,000 neuroscience abstracts were analyzed over the years 2014-2018. Several broad trends emerged from the analysis of which terms were biased toward high-impact journals. Generally speaking, high-impact journals tended to feature: genetic studies, use of the latest and most sophisticated methods, examinations of the orbitofrontal cortex or amygdala, and/or use of human or non-mammalian subjects. Medium-impact journals tended to feature motor or cardiovascular studies, use of older methods, examinations of caudal brain regions, and/or rats as subjects. This approach also allowed for the comparison of high-impact bias among: brain regions, methods, neurotransmitters, study species, and broad themes within neuroscience. A systematic approach to the contents of high-impact journals offers the field an objective view of itself.

Oxycodone Exposure: A Magnetic Resonance Imaging Study in Response to Acute and Chronic Oxycodone Treatment in Rats.

The present study was designed to use blood-oxygen-level dependent (BOLD) imaging to "fingerprint" the change in activity in response to oxycodone (OXY) in drug naïve rats before and after repeated exposure to OXY. It was hypothesized that repeated exposure to OXY would initiate adaptive changes in brain organization that would be reflected in an altered response to opioid exposure. Male rats exposed to OXY repeatedly showed conditioned place preference, evidence of drug-seeking behavior and putative neuroadaptation. As these studies were done on awake rats we discovered it was not possible to image rats continuously exposed to OXY due to motion artifact judged to be withdrawal while in the scanner. To circumvent this problem manganese-enhanced MRI (MEMRI) was used to map the distributed integrated activity pattern resulting from continuous OXY exposure. Rats were administered OXY (2.5 mg/kg, i.p.) during image acquisition and changes in BOLD signal intensity were recorded and the activation and deactivation of integrated neural circuits involved in olfaction and motivation were identified. Interestingly, the circuitry of the mesencephalic dopaminergic system showed little activity to the first exposure of OXY. In the MEMRI study, rats received OXY treatments (2.5 mg/kg, twice daily) for four consecutive days following intraventricular MnCl2. Under isoflurane anesthesia, T1-weighted images were acquired and subsequently analyzed showing activity in the forebrain limbic system, ventral striatum, accumbens, amygdala and hippocampus. These results show brain activity is markedly different when OXY is presented to drug naïve rats versus rats with prior, repeated exposure to drug.

Early nurture epigenetically tunes the oxytocin receptor.

Mammalian sociality is regulated in part by the neuropeptide oxytocin. In prairie voles, subtle variation in early life experience changes oxytocin receptor-mediated social behaviors. We report that low levels of early care in voles leads to de novo DNA methylation at specific regulatory sites in the oxytocin receptor gene (Oxtr), impacting gene expression and protein distribution in the nucleus accumbens. DNA methylation state of the blood predicts expression in the brain indicating the utility of the blood as a biomarker for the transcription state of the brain. These experience-sensitive CpG sites are conserved in humans, are related to gene expression in the brain, and have been associated with psychiatric disorders and individual differences in neural response to social stimuli. These results identify a mechanism by which early care regulates later displays of typical prairie vole social behavior and suggest the potential for nurture driven epigenetic tuning of OXTR in humans.

The neurobiological causes and effects of alloparenting.

Alloparenting, defined as care provided by individuals other than parents, is a universal behavior among humans that has shaped our evolutionary history and remains important in contemporary society. Dysfunctions in alloparenting can have serious and sometimes fatal consequences for vulnerable infants and children. In spite of the importance of alloparenting, they still have much to learn regarding the underlying neurobiological systems governing its expression. Here, they review how a lack of alloparental behavior among traditional laboratory species has led to a blind spot in our understanding of this critical facet of human social behavior and the relevant neurobiology. Based on what is known, they draw from model systems ranging from voles to meerkats to primates to describe a conserved set of neuroendocrine mechanisms supporting the expression of alloparental care. In this review we describe the neurobiological and behavioral prerequisites, ontogeny, and consequences of alloparental care. Lastly, they identified several outstanding topics in the area of alloparental care that deserve further research efforts to better advance human health and wellbeing. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 214-232, 2017.

Voluntary exercise facilitates pair-bonding in male prairie voles.

The neuropeptides oxytocin and vasopressin have been implicated in exercise, as well as monogamy and parental behavior. In this study, we compared behavioral and neuroendocrine effects of access to an exercise wheel vs. the sedentary state typical in lab animal housing. Male prairie voles (Microtus ochrogaster) were studied because of their extensive repertoire of social behaviors including pair bond formation and biparental care, which are influenced by oxytocin and vasopressin. Subjects in one group had access to a running wheel in their cage (wheel), and voluntarily ran approximately 1.5 km/day for six weeks; these animals were compared to males in standard housing conditions (n=10/group). Males allowed to exercise formed partner preferences significantly faster than controls and exhibited fewer oxytocin neurons, as measured by immunohistochemistry in the bed nucleus of the stria terminalis. We observed no differences in terms of anxiety-related behavior, or alloparental responsiveness. Males with a running wheel equipped cage gained more total body weight, and by the end of the six weeks were found to have less subcutaneous fat and larger testes as a percentage of bodyweight. The changes to gonadal regulation and pair-bonding behavior associated with voluntary exercise are discussed in terms of their possible relevance to the natural history of this species.

Cardioacceleration in alloparents in response to stimuli from prairie vole pups: the significance of thermoregulation.

Autonomic responses, including changes in heart rate and respiratory sinus arrhythmia (RSA) can provide indications of emotional reactivity to social stimuli in mammals. We have previously reported that male prairie voles (Microtus ochrogaster) spontaneously care for unfamiliar infants, showing a robust and sustained increase in heart rate in the presence of a pup, thus providing an opportunity to examine the physiology of care-giving in reproductively naïve animals. However, the purpose of such heart rate increases has not been explained by previous efforts. In the present study, we first compared male and female prairie vole cardiac responses in the presence of a pup and found no evidence of sex differences in heart rate or RSA. Using male prairie voles, we then examined the characteristics of pups that were capable of eliciting physiological responses, including age of the pup and pup odors. As prairie vole pups increased in age they vocalized less and there was an associated decline in alloparental cardioacceleration. Exposure to pup-related odors induced cardioacceleration in adult males, and this effect also diminished with increasing pup age. Finally, we were able to block the cardioacceleratory effect when the testing environment was warmed to a temperature of 36°C [vs ambient room temperature (approximately 22°C)]. These findings suggest that pup-induced cardioacceleration is a robust phenomenon across alloparental prairie voles of both sexes, and depends on multi-modal processing of different stimuli from the pups. Young pups require care-giving behavior, which appears to drive cardioacceleration in the alloparents. This study also supports the usefulness of autonomic measures in the evaluation of social experiences.

Distinct BOLD Activation Profiles Following Central and Peripheral Oxytocin Administration in Awake Rats.

A growing body of literature has suggested that intranasal oxytocin (OT) or other systemic routes of administration can alter prosocial behavior, presumably by directly activating OT sensitive neural circuits in the brain. Yet there is no clear evidence that OT given peripherally can cross the blood-brain barrier at levels sufficient to engage the OT receptor. To address this issue we examined changes in blood oxygen level-dependent (BOLD) signal intensity in response to peripheral OT injections (0.1, 0.5, or 2.5 mg/kg) during functional magnetic resonance imaging (fMRI) in awake rats imaged at 7.0 T. These data were compared to OT (1 µg/5 µl) given directly to the brain via the lateral cerebroventricle. Using a 3D annotated MRI atlas of the rat brain segmented into 171 brain areas and computational analysis, we reconstructed the distributed integrated neural circuits identified with BOLD fMRI following central and peripheral OT. Both routes of administration caused significant changes in BOLD signal within the first 10 min of administration. As expected, central OT activated a majority of brain areas known to express a high density of OT receptors, e.g., lateral septum, subiculum, shell of the accumbens, bed nucleus of the stria terminalis. This profile of activation was not matched by peripheral OT. The change in BOLD signal to peripheral OT did not show any discernible dose-response. Interestingly, peripheral OT affected all subdivisions of the olfactory bulb, in addition to the cerebellum and several brainstem areas relevant to the autonomic nervous system, including the solitary tract nucleus. The results from this imaging study do not support a direct central action of peripheral OT on the brain. Instead, the patterns of brain activity suggest that peripheral OT may interact at the level of the olfactory bulb and through sensory afferents from the autonomic nervous system to influence brain activity.

Acoustic features of prairie vole (Microtus ochrogaster) ultrasonic vocalizations covary with heart rate.

Vocalizations serve as a conspecific social communication system among mammals. Modulation of acoustic features embedded within vocalizations is used by several mammalian species to signal whether it is safe or dangerous to approach conspecific and heterospecific mammals. As described by the Polyvagal Theory, the phylogenetic shift in the evolution of mammals involved an adaptive neuroanatomical link between the neural circuits regulating heart rate and the muscles involved in modulating the acoustic features of vocalizations. However, few studies have investigated the covariation between heart rate and the acoustic features of vocalizations. In the current study, we document that specific features of vocalizations covary with heart rate in a highly social and vocal mammal, the prairie vole (Microtus ochrogaster). Findings with the prairie vole illustrate that higher pitch (i.e., fundamental frequency) and less variability in acoustic features of vocalizations (i.e., less vocal prosody) are associated with elevated heart rate. The study provides the first documentation that the acoustic features of prairie vole vocalizations may function as a surrogate index of heart rate.