No abstract

Social relationships significantly influence physiology and behavior, including the hypothalamo-pituitary-adrenal axis, anxiety, and mental health. Disruption of social bonds through separation or death often results in profound grieving, depression, and physical illness. As the monogamous prairie vole forms enduring, selective pair bonds with the mating partner, they provide an animal model to study the physiological consequences of pair bonding and, thus, the loss of the bonded partner. Male prairie voles were paired with a novel female or male sibling. After 5 days, half of the males of each group were separated from the partner. Elevated plus-maze, forced swim, and tail suspension tests were used to assess anxiety-like and passive stress-coping behaviors indicative of depressive-like behavior. Following 4 days of separation from the female but not the male partner, experimental males displayed increased passive stress-coping. This effect was abolished by long-term intracerebroventricular infusion of a nonselective corticotropin-releasing factor (CRF) receptor antagonist without disrupting the bond itself. Both CRF type 1 and 2 receptors were involved in the emergence of passive stress-coping behavior. Furthermore, pairing with a female was associated with elevated CRF mRNA in the bed nucleus of the stria terminalis, and partner loss elicited a pronounced increase in circulating corticosteroid and adrenal weight. We speculate that the CRF system may mediate an aversive affect following separation from the female partner, which may facilitate proximity seeking between the pair-bonded individuals. Hence, the prairie vole model may provide insights into brain mechanisms involved in the psychopathological consequences of partner loss.

Sex-specific behaviors are in part based on hormonal regulation of brain physiology. This functional magnetic resonance imaging (fMRI) study demonstrated significant differences in activation of hypothalamic-pituitary-adrenal (HPA) circuitry in adult women with attenuation during ovulation and increased activation during early follicular phase. Twelve normal premenopausal women were scanned twice during the early follicular menstrual cycle phase compared with late follicular/midcycle, using negative valence/high arousal versus neutral visual stimuli, validated by concomitant electrodermal activity (EDA). Significantly greater magnitude of blood oxygenation level-dependent signal changes were found during early follicular compared with midcycle timing in central amygdala, paraventricular and ventromedial hypothalamic nuclei, hippocampus, orbitofrontal cortex (OFC), anterior cingulate gyrus (aCING), and peripeduncular nucleus of the brainstem, a network of regions implicated in the stress response. Arousal (EDA) correlated positively with brain activity in amygdala, OFC, and aCING during midcycle but not in early follicular, suggesting less cortical control of amygdala during early follicular, when arousal was increased. This is the first evidence suggesting that estrogen may likely attenuate arousal in women via cortical-subcortical control within HPA circuitry. Findings have important implications for normal sex-specific physiological functioning and may contribute to understanding higher rates of mood and anxiety disorders in women and differential sensitivity to trauma than men.

Summary Activation of corticotrophin releasing factor (CRF) neurons in the paraventricular nucleus of the hypothalamus (PVN) is necessary for establishing the classic endocrine response to stress, while activation of forebrain CRF neurons mediates affective components of the stress response. Previous studies have reported that mRNA for CRF2 receptor (CRFR2) is expressed in the bed nucleus of the stria terminalis (BNST) as well as hypothalamic nuclei, but little is known about the localization and cellular distribution of CRFR2 in these regions. Using immunofluorescence with confocal microscopy, as well as electron microscopy, we demonstrate that in the BNST CRFR2-immunoreactive fibers represent moderate to strong labeling on axons terminals. Dual-immunofluorescence demonstrated that CRFR2-fibers co-localize oxytocin (OT), but not arginine-vasopressin (AVP), and make perisomatic contacts with CRF neurons. Dual-immunofluorescence and single cell RT-PCR demonstrate that in the hypothalamus, CRFR2 immunoreactivity and mRNA are found in OT, but not in CRF or AVP-neurons. Furthermore, CRF neurons of the PVN and BNST express mRNA for the oxytocin receptor, while the majority of OT/CRFR2 neurons in the hypothalamus do not. Finally, using adenoviral-based anterograde tracing of PVN neurons, we show that OT/CRFR2-immunoreactive fibers observed in the BNST originate in the PVN. Our results strongly suggest that CRFR2 located on oxytocinergic neurons and axon terminals might regulate the release of this neuropeptide and hence might be a crucial part of potential feedback loop between the hypothalamic oxytocin system and the forebrain CRF system that could significantly impact affective and social behaviors, in particular during times of stress.

Early social attachments lie at the heart of emotional and social development in many mammals, including humans. In nature, monogamous prairie voles (Microtus ochrogaster) experience considerable natural variation in early social attachment opportunities due to differences in family structure [e.g., single-mothers (SM), solitary breeding pairs, and communal groups]. We exploited some of this natural variation in family structure to examine the influence of early social environment on the development of adult social behavior. First, we characterized the parental care received by pups reared biparentally (BP) or by SM in the laboratory. Second, we examined whether BP- and SM-reared offspring differed in adult nurturing, bonding, and emotional behaviors. Finally, we investigated the effects of rearing condition on neuropeptide systems that regulate adult social behavior [oxytocin (OT), vasopressin, and corticotropin-releasing factor, (CRF)]. Observations revealed that SM-reared pups were exposed more frequently (P < 0.01), licked and groomed less (P < 0.01), and matured more slowly (P < 0.01) than BP-reared pups. In adulthood, there were striking socio-behavioral differences: SM-reared females showed low spontaneous, pup-directed alloparental behavior (P < 0.01) and both males and females from the SM-reared condition showed delayed partner preference formation. While rearing did not impact neuropeptide receptor densities in the ventral forebrain as we predicted, SM-reared animals, particularly females, had increased OT content (P < 0.01) and greater dorsal raphe CRF2 densities (P < 0.05) and both measures correlated with licking and grooming experienced during the first 10 days of life. These results suggest that naturalistic variation in social rearing conditions can introduce diversity into adult nurturing and attachment behaviors.

Loss of a partner can have severe effects on mental health. Here we explore the neural mechanisms underlying increased passive stress-coping, indicative of depressive-like behavior, following the loss of the female partner in the monogamous male prairie vole. We demonstrate that corticotropin-releasing factor receptor 2 (CRFR2) in the nucleus accumbens shell mediates social loss-induced passive coping. Further, we show that partner loss compromises the oxytocin system through multiple mechanisms. Finally, we provide evidence for an interaction of the CRFR2 and oxytocin systems in mediating the emotional consequences of partner loss. Our results suggest that chronic activation of CRFR2 and suppression of striatal oxytocin signaling following partner loss result in an aversive emotional state that may share underlying mechanisms with bereavement. We propose that the suppression of oxytocin signaling is likely adaptive during short separations to encourage reunion with the partner and may have evolved to maintain long-term partnerships. Additionally, therapeutic strategies targeting these systems should be considered for treatment of social loss-mediated depression.

Two cardinal features of Parkinson's disease (PD) pathophysiology are a loss of glutamatergic synapses paradoxically accompanied by an increased glutamatergic transmission to the striatum. The exact substrate of this increased glutamatergic drive remains unclear. The striatum receives glutamatergic inputs from the thalamus and the cerebral cortex. Using vesicular glutamate transporters (vGluTs) 1 and 2 as markers of the corticostriatal and thalamostriatal afferents, respectively, we examined changes in the synaptology and relative prevalence of striatal glutamatergic inputs in methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys using electron microscopic immunoperoxidase and confocal immunofluorescence methods. Our findings demonstrate that the prevalence of vGluT1-containing terminals is significantly increased in the striatum of MPTP-treated monkeys (51.9 +/- 3.5% to 66.5 +/- 3.4% total glutamatergic boutons), without any significant change in the pattern of synaptic connectivity; more than 95% of vGluT1-immunolabeled terminals formed axo-spinous synapses in both conditions. In contrast, the prevalence of vGluT2-immunoreactive terminals did not change after MPTP treatment (21.7 +/- 1.3% vs. 21.6 +/- 1.2% total glutamatergic boutons). However, a substantial increase in the ratio of axo-spinous to axo-dendritic synapses formed by vGluT2-immunoreactive terminals was found in the pre-caudate and post-putamen striatal regions of MPTP-treated monkeys, suggesting a certain degree of synaptic reorganization of the thalamostriatal system in parkinsonism. About 20% of putative glutamatergic terminals did not show immunoreactivity in striatal tissue immunostained for both vGluT1 and vGluT2, suggesting the expression of another vGluT in these boutons. These findings provide striking evidence that suggests a differential degree of plasticity of the corticostriatal and thalamostriatal system in PD.

Family relationships help shape species-typical social and emotional development, but our understanding of how this shaping occurs is still relatively limited. Prairie voles are a socially monogamous and biparental species that is well situated to complement traditional animal models, such as rats and mice, in investigating the effects of family experience. In this series of studies, we aimed to test hypotheses relating to how prairie vole families function under undisturbed, standard laboratory conditions. In the first study, we compared the parental behavior of primiparous biparental (BP) and single-mother (SM) prairie vole family units for 12 postnatal days and then tested for sex differences, behavioral coordination, and family structure effects. Under BP conditions, nest attendance was coordinated and shared equally by both sexes, while pup-directed and partner-directed licking and grooming (LG) were coordinated in a sex and social-context-dependent manner. Contrary to our expectations, SMs showed no evidence of strong parental compensation in response to the lack of the father, indicating a minimal effect of family structure on maternal behavior but a large effect on pup care. In the second study, we examined the effects of these BP and SM rearing conditions on family dynamics in the next generation and found that SM-reared adult parents exhibited lower rates of pup-directed LG in comparison to BP-reared counterparts. Situated in the context of human family dynamics and psychology, these results suggest that the study in prairie voles may help improve our understanding of family systems and how perturbations to these systems can affect adults and offspring.