Wheel access has opposing effects on stress physiology depending on social environment in female prairie voles (Microtus ochrogaster).

Physical exercise and chronic social stress are both known to impact general health and hypothalamic-pituitary-adrenal (HPA) axis function, albeit typically in opposing directions. Therefore, the question we investigated in this study was how these two factors - physical exercise and chronic social isolation - would interact when presented simultaneously in a female rodent model. Adult female prairie voles were separated into four experimental groups: (1) isolated without wheel access, (2) isolated with wheel access, (3) paired without wheel access, and (4) paired with wheel access. Plasma, hair, and adrenal glands were sampled to investigate changes in stress physiology. Our results indicate that, when isolated, wheel access had a mitigating effect on HPA activity. However, in paired animals, wheel access had the opposite effect, as both adrenal mass and increase in hair corticosterone concentrations were greater in paired animals with wheel access. Strong correlations were detected between change in hair corticosterone and adrenal mass, while no correlations were found between plasma corticosterone and either of the other markers. These results imply that the HPA axis is highly sensitive to both the social environment and the physical demands placed on the individual, and that when investigating the effects of chronic isolation, both hair corticosterone and adrenal mass may be more reliable markers than a single plasma corticosterone sample.

Laboratory simulations of mate-guarding as a component of the pair-bond in male titi monkeys, Callicebus cupreus.

Mate-guarding and territorial aggression (both intra- and inter-sexual) are behavioral components of social monogamy seen in male coppery titi monkeys (Callicebus cupreus) both in the field and in the laboratory. Methodology for studying these behaviors in captivity facilitates the translation of questions between field and laboratory. In this study, we tested whether exposure to a mirror would stimulate mate-guarding behavior in male titi monkeys, and whether this exposure was accompanied by hormonal changes. Eight males were exposed to a mirror condition (treatment) or the back of the mirror (control) for five sessions, and behavioral responses were filmed. Blood samples were taken to measure levels of cortisol, oxytocin, and vasopressin. Lipsmacks (P < 0.0001), arching (P < 0.0001), tail-lashing (P = 0.009), restraining (P = 0.015), and approaches to the female (P = 0.0002) were all higher during the mirror condition, while tail-twining tended to decline during the mirror condition (P = 0.076). Hormones did not vary by experimental treatment, but were correlated with certain behaviors during the presentation of the mirror. While social behaviors changed with mirror exposure, self-directed and mirror-guided behaviors did not, indicating a lack of self-recognition. Use of a mirror was a safe and effective means of investigating mate-guarding behavior in response to a simulated intrusion, with the added benefit of not needing another animal to serve as an intruder; and thus may be of use in providing a laboratory model for natural behavior. Especially, as it eliminates the need for a stimulus animal, it would also be of possible use in investigating responses to a simulated intruder in wild populations of titis and other pithecines.

Greater amygdala activity and dorsomedial prefrontal-amygdala coupling are associated with enhanced inflammatory responses to stress.

Psychological stress is implicated in the etiology of many common chronic diseases and mental health disorders. Recent research suggests that inflammation may be a key biological mediator linking stress and health. Nevertheless, the neurocognitive pathways underlying stress-related increases in inflammatory activity are largely unknown. The present study thus examined associations between neural and inflammatory responses to an acute laboratory-based social stressor. Healthy female participants (n=31) were exposed to a brief episode of stress while they underwent an fMRI scan. Blood samples were taken before and after the stressor, and plasma was assayed for markers of inflammatory activity. Exposure to the stressor was associated with significant increases in feelings of social evaluation and rejection, and with increases in levels of inflammation. Analyses linking the neural and inflammatory data revealed that heightened neural activity in the amygdala in response to the stressor was associated with greater increases in inflammation. Functional connectivity analyses indicated that individuals who showed stronger coupling between the amygdala and the dorsomedial prefrontal cortex (DMPFC) also showed a heightened inflammatory response to the stressor. Interestingly, activity in a different set of neural regions was related to increases in feelings of social rejection. These data show that greater amygdala activity in response to a stressor, as well as tighter coupling between the amygdala and the DMPFC, are associated with greater increases in inflammatory activity. Results from this study begin to identify neural mechanisms that might link stress with increased risk for inflammation-related disorders such as cardiovascular disease and depression.

Digestive efficiency mediated by serum calcium predicts bone mineral density in the common marmoset (Callithrix jacchus).

Two health problems have plagued captive common marmoset (Callithrix jacchus) colonies for nearly as long as those colonies have existed: marmoset wasting syndrome and metabolic bone disease. While marmoset wasting syndrome is explicitly linked to nutrient malabsorption, we propose metabolic bone disease is also linked to nutrient malabsorption, although indirectly. If animals experience negative nutrient balance chronically, critical nutrients may be taken from mineral stores such as the skeleton, thus leaving those stores depleted. We indirectly tested this prediction through an initial investigation of digestive efficiency, as measured by apparent energy digestibility, and serum parameters known to play a part in metabolic bone mineral density of captive common marmoset monkeys. In our initial study on 12 clinically healthy animals, we found a wide range of digestive efficiencies, and subjects with lower digestive efficiency had lower serum vitamin D despite having higher food intakes. A second experiment on 23 subjects including several with suspected bone disease was undertaken to measure digestive and serum parameters, with the addition of a measure of bone mineral density by dual-energy X-ray absorptiometry (DEXA). Bone mineral density was positively associated with apparent digestibility of energy, vitamin D, and serum calcium. Further, digestive efficiency was found to predict bone mineral density when mediated by serum calcium. These data indicate that a poor ability to digest and absorb nutrients leads to calcium and vitamin D insufficiency. Vitamin D absorption may be particularly critical for indoor-housed animals, as opposed to animals in a more natural setting, because vitamin D that would otherwise be synthesized via exposure to sunlight must be absorbed from their diet. If malabsorption persists, metabolic bone disease is a possible consequence in common marmosets. These findings support our hypothesis that both wasting syndrome and metabolic bone disease in captive common marmosets are consequences of inefficient nutrient absorption.

Hormonal and experiential predictors of infant survivorship and maternal behavior in a monogamous primate (Callicebus cupreus).

To better understand the roles that hormones and experience play in infant survival and maternal behavior in a biparental primate species, we analyzed urinary estrone (E(1)C) and pregnanediol glucuronide (PdG) from 24 socially housed titi monkey (Callicebus cupreus) females over 54 pregnancies (N = 1,430 samples). Pregnancies were categorized according to whether the infant survived (N = 35) or not (N = 19), and by maternal parity (primiparous: N = 9; multiparous: N = 45). Mothers of infants that survived had a significantly greater drop in PdG from the third trimester to the first week postpartum than mothers of infants that did not survive. Multiparous mothers had a greater increase in PdG from the first to the third trimester as well as greater increases in the E(1)C:PdG ratio from the first to the third trimester and from the third trimester to the first week postpartum. There were positive relationships between third trimester PdG and maternal carrying and nursing during the first week postpartum, and between maternal age and carrying during the infant's first month of life. There was a negative correlation between maternal age and PdG during the third trimester. These results suggest that elevated progesterone during late pregnancy followed by progesterone withdrawal immediately following parturition is associated with greater probability of infant survivorship and maternal behavior in this species, and that older females engage in more postpartum maternal care.

Pair bond formation leads to a sustained increase in global cerebral glucose metabolism in monogamous male titi monkeys (Callicebus cupreus).

Social bonds, especially attachment relationships, are crucial to our health and happiness. However, what we know about the neural substrates of these bonds is almost exclusively limited to rodent models and correlational experiments in humans. Here, we used socially monogamous non-human primates, titi monkeys (Callicebus cupreus) to experimentally examine changes in regional and global cerebral glucose metabolism (GCGM) during the formation and maintenance of pair bonds. Baseline positron emission tomography (PET) scans were taken of thirteen unpaired male titi monkeys. Seven males were then experimentally paired with females, scanned and compared, after one week, to six age-matched control males. Five of the six control males were then also paired and scanned after one week. Scans were repeated on all males after four months of pairing. PET scans were coregistered with structural magnetic resonance imaging (MRI), and region of interest (ROI) analysis was carried out. A primary finding was that paired males showed a significant increase in [18F]-fluorodeoxyglucose (FDG) uptake in whole brain following one week of pairing, which is maintained out to four months. Dopaminergic, "motivational" areas and those involved in social behavior showed the greatest change in glucose uptake. In contrast, control areas changed only marginally more than GCGM. These findings confirm the large effects of social bonds on GCGM. They also suggest that more studies should examine how social manipulations affect whole-brain FDG uptake, as opposed to assuming that it does not change across condition.

Cryptic diversity in Black rats Rattus rattus of the Galápagos Islands, Ecuador.

Human activity has facilitated the introduction of a number of alien mammal species to the Galápagos Archipelago. Understanding the phylogeographic history and population genetics of invasive species on the Archipelago is an important step in predicting future spread and designing effective management strategies. In this study, we describe the invasion pathway of Rattus rattus across the Galápagos using microsatellite data, coupled with historical knowledge. Microsatellite genotypes were generated for 581 R. rattus sampled from 15 islands in the archipelago. The genetic data suggest that there are at least three genetic lineages of R. rattus present on the Galápagos Islands. The spatial distributions of these lineages correspond to the main centers of human settlement in the archipelago. There was limited admixture among these three lineages, and these finding coupled with low rates of gene flow among island populations suggests that interisland movement of R. rattus is rare. The low migration among islands recorded for the species will have a positive impact on future eradication efforts.

Neural mechanisms linking social status and inflammatory responses to social stress.

Social stratification has important implications for health and well-being, with individuals lower in standing in a hierarchy experiencing worse outcomes than those higher up the social ladder. Separate lines of past research suggest that alterations in inflammatory processes and neural responses to threat may link lower social status with poorer outcomes. This study was designed to bridge these literatures to investigate the neurocognitive mechanisms linking subjective social status and inflammation. Thirty-one participants reported their subjective social status, and underwent a functional magnetic resonance imaging scan while they were socially evaluated. Participants also provided blood samples before and after the stressor, which were analysed for changes in inflammation. Results showed that lower subjective social status was associated with greater increases in inflammation. Neuroimaging data revealed lower subjective social status was associated with greater neural activity in the dorsomedial prefrontal cortex (DMPFC) in response to negative feedback. Finally, results indicated that activation in the DMPFC in response to negative feedback mediated the relation between social status and increases in inflammatory activity. This study provides the first evidence of a neurocognitive pathway linking subjective social status and inflammation, thus furthering our understanding of how social hierarchies shape neural and physiological responses to social interactions.

Challenges to the Pair Bond: Neural and Hormonal Effects of Separation and Reunion in a Monogamous Primate.

Social monogamy at its most basic is a group structure in which two adults form a unit and share a territory. However, many socially monogamous pairs display attachment relationships known as pair bonds, in which there is a mutual preference for the partner and distress upon separation. The neural and hormonal basis of this response to separation from the adult pair mate is under-studied. In this project, we examined this response in male titi monkeys (Callicebus cupreus), a socially monogamous New World primate. Males underwent a baseline scan, a short separation (48 h), a long separation (approximately 2 weeks), a reunion with the female pair mate and an encounter with a female stranger (with nine males completing all five conditions). Regional cerebral glucose metabolism was measured via positron emission tomography (PET) imaging using [18F]-fluorodeoxyglucose (FDG) co-registered with structural magnetic resonance imaging (MRI), and region of interest (ROI) analysis was carried out. In addition, plasma was collected and assayed for cortisol, oxytocin (OT), vasopressin (AVP), glucose and insulin concentrations. Cerebrospinal fluid (CSF) was collected and assayed for OT and AVP. We used generalized estimating equations (GEE) to examine significant changes from baseline. Short separations were characterized by decreases in FDG uptake, in comparison to baseline, in the lateral septum (LS), ventral pallidum (VP), paraventricular nucleus of the hypothalamus (PVN), periaqueductal gray (PAG), and cerebellum, as well as increases in CSF OT, and plasma cortisol and insulin. Long separations differed from baseline in reduced FDG uptake in the central amygdala (CeA), reduced whole brain FDG uptake, increased CSF OT and increased plasma insulin. The response on encounter with a stranger female depended on whether or not the male had previously reproduced with his pair mate, suggesting that transitions to fatherhood contribute to the neurobiology underlying response to a novel female. Reunion with the partner appeared to stimulate coordinated release of central and peripheral OT. The observed changes suggest the involvement of OT and AVP systems, as well as limbic and striatal areas, during separation and reunion from the pair mate.

Presence of a pair-mate regulates the behavioral and physiological effects of opioid manipulation in the monogamous titi monkey (Callicebus cupreus).

The role of opioid receptors in infant-mother attachment has been well established. Morphine, a preferential µ opioid receptor (MOR) agonist, attenuates separation distress vocalizations and decreases physical contact between infant and mother. However, there is little research on how opioid receptors are involved in adult attachment. The present study used the monogamous titi monkey (Callicebus cupreus) to explore the role of opioid receptors in the behavioral and physiological components of pair-bonding. In Experiment 1, paired male titi monkeys (N=8) received morphine (0.1, 0.5, or 1.0mg/kg), the opioid antagonist naloxone (1.0mg/kg), vehicle, or a disturbance control and were filmed with their pair-mate for 1h. In Experiment 2, the same eight males received morphine (0.25mg/kg), naloxone (1.0mg/kg), vehicle, or a disturbance control and were filmed for an hour without their pair-mates. All video sessions were scored for social and non-social behaviors. Blood was sampled immediately prior to drug administration and at the end of the hour session. Plasma was assayed for cortisol, oxytocin, and vasopressin. In Experiment 1, opioid manipulation had no effect on affiliative behaviors; however, morphine dose-dependently decreased locomotor behavior and increased scratching. In Experiment 2 in which males were separated from their pair-mates, naloxone increased locomotion. Morphine dose-dependently attenuated the rise in cortisol, while naloxone potentiated the increase of cortisol. The cortisol increase following naloxone administration was greater when a male was alone compared to when the male was with his pair-mate. Naloxone increased vasopressin but only when the male was tested without his pair-mate. The present study found that the absence of a pair-mate magnified naloxone's effects on stress-related hormones and behaviors, suggesting that the presence of a pair-mate can act as a social buffer against the stress-inducing effects of naloxone.

Dysregulated diurnal cortisol pattern is associated with glucocorticoid resistance in women with major depressive disorder.

Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is believed to play a role in the pathophysiology of depression. To investigate mechanisms that may underlie this effect, we examined several indices of HPA axis function - specifically, diurnal cortisol slope, cortisol awakening response, and suppression of cortisol release following dexamethasone administration - in 26 pre-menopausal depressed women and 23 never depressed women who were matched for age and body mass index. Salivary cortisol samples were collected at waking, 30 min after waking, and at bedtime over three consecutive days. On the third day, immediately after the bedtime sample, participants ingested a 0.5mg dexamethasone tablet; they then collected cortisol samples at waking and 30 min after waking the following morning. As predicted, depressed women exhibited flatter diurnal cortisol rhythms and more impaired suppression of cortisol following dexamethasone administration than non-depressed women over the three sampling days. In addition, flatter diurnal cortisol slopes were associated with reduced cortisol response to dexamethasone treatment, both for all women and for depressed women when considered separately. Finally, greater self-reported depression severity was associated with flatter diurnal cortisol slopes and with less dexamethasone-related cortisol suppression for depressed women. Depression in women thus appears to be characterized by altered HPA axis functioning, as indexed by flatter diurnal cortisol slopes and an associated impaired sensitivity of cortisol to dexamethasone. Given that altered HPA axis functioning has been implicated in several somatic conditions, the present findings may be relevant for understanding the pathophysiology of both depression and depression-related physical disease.