Oliver J. Bosch

Brain Oxytocin Correlates with Maternal Aggression: Link to Anxiety

The oxytocinergic system is critically involved in the regulation of maternal behavior, which includes maternal aggression. Because aggression has been linked to anxiety, we investigated the maternal aggression and the role of brain oxytocin in lactating Wistar rats selectively bred for high anxiety-related behavior (HAB) or low anxiety-related behavior (LAB) during the 10 min maternal defense test. HAB dams displayed more maternal aggression against a virgin intruder compared with LAB dams, resulting in more defensive behavior and higher anxiety of HAB-defeated virgins. The different levels of aggression were accompanied by opposite oxytocin release patterns within the paraventricular nucleus (PVN; HAB, increase; LAB, decrease). Furthermore, oxytocin release was higher within the central nucleus of the amygdala (CeA) of HAB dams compared with LABs. A direct correlation between the offensive behavior displayed during the maternal defense test and local oxytocin release was found in both the PVN and CeA. Using retrodialysis, blockade of endogenous oxytocin action by infusion of an oxytocin receptor antagonist (des-Gly-NH2,d(CH2)5[Tyr(Me)2,Thr4]OVT) into the PVN or CeA reduced maternal aggression of HAB dams, whereas infusion of synthetic oxytocin into the PVN tended to increase aggression toward the intruder in LAB dams. There were no significant differences in oxytocin receptor mRNA expression or oxytocin receptor binding between lactating HAB and LAB dams. Therefore, differences in intracerebral release patterns of oxytocin, rather than differences at the level of oxytocin receptors, are critical for the regulation of maternal aggressive behavior.

Both oxytocin and vasopressin are mediators of maternal care and aggression in rodents: From central release to sites of action

In the mammalian peripartum period, the activity of both the brain oxytocin and vasopressin system is elevated as part of the physiological adaptations occurring in the mother. This is reflected by increased expression and intracerebral release of oxytocin and vasopressin, as well as increased neuropeptide receptor expression and binding. In this review we discuss the functional role of the brain oxytocin and vasopressin system in the context of maternal behavior, specifically maternal care and maternal aggression in rodents. In order to enable the identification of significant and peptide-specific contributions to the display of maternal behavior, various complementary animal models of maternal care and/or maternal aggression were studied, including rats selectively bred for differences in anxiety-related behavior (HAB and LAB dams), monitoring of local neuropeptide release during ongoing maternal behavior, and local pharmacological or genetic manipulations of the neuropeptide systems. The medial preoptic area was identified as a major site for oxytocin- and vasopressin-mediated maternal care. Furthermore, both oxytocin and vasopressin release and receptor activation in the central amygdala and the bed nucleus of the stria terminalis play an important role for maternal aggression. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.

Brain vasopressin is an important regulator of maternal behavior independent of dams' trait anxiety

The neuropeptide arginine vasopressin (AVP) is arguably among the most potent regulators of social behaviors in mammals identified to date. However, only the related neuropeptide oxytocin (OXT) has been shown to promote maternal behavior. Here, we assess the role of AVP in maternal care, in particular in arched back nursing, pup retrieval, and pup contact by using complementary pharmacological and genetic approaches. Also, experiments were performed in rat dams with differences in trait anxiety, i.e., rats bred for either high (HAB) or low (LAB) anxiety-related behavior as well as nonselected (NAB) dams. Viral vector-mediated up-regulation of AVP V1a receptors (AVP-Rs) within the medial preoptic area of lactating NAB rats and chronic central AVP treatment of NAB and LAB dams improved, whereas local blockade of AVP-R expression by means of antisense oligodeoxynucleotides or central AVP-R antagonism impaired, maternal care in NAB dams. Also, in HAB rats with a genetically determined elevated brain AVP activity, intrinsically high levels of maternal care were reversed by blockade of AVP-R actions. Treatment-induced impairment of AVP-mediated maternal behavior increased adult emotionality and impaired social interactions in male offspring of NAB dams. These findings provide direct evidence for an essential and highly potent role of brain AVP in promoting maternal behavior, which seems to be independent of the dams trait anxiety.

Oxytocin reduces anxiety via ERK1/2 activation: local effect within the rat hypothalamic paraventricular nucleus

The neuropeptide oxytocin (OT) modulates social behaviours and is an important anxiolytic substance of the brain. However, sites of action and the intracellular signalling pathways downstream of OT receptors (OTR) within the brain remain largely unknown. In the present studies, we localized the anxiolytic effect of OT by bilateral microinfusion of OT (0.01 nmol/0.5 µL) into the hypothalamic paraventricular nucleus (PVN) in male rats using both the elevated plus‐maze and the light–dark box. Moreover, intracerebroventricular administration of OT, but not of the related neuropeptide vasopressin (VP), dose‐dependently activated the extracellular signal‐regulated kinase 1/2 (ERK1/2) cascade. Specifically, OT induced the phosphorylation of Raf‐1, MEK1/2 and ERK1/2 in the hypothalamus in vivo and in hypothalamic H32 neurons via EGF receptors. OT‐induced ERK1/2 phosphorylation was immunohistochemically localized within VP neurons of the PVN and the supraoptic nucleus. Importantly, the anxiolytic effect of OT within the PVN was prevented by local inhibition of the MAP kinase cascade with a MEK1/2 inhibitor (U0126, 0.5 nmol/0.5 µL) locally infused prior to OT, indicating the causal involvement of this intracellular signalling cascade in the behavioural effect of OT. OT effects within the hypothalamus may have far‐reaching implications for the regulation of emotionality and social behaviours and, consequently, for the development of possible therapeutic strategies to treat affective disorders. Thus, OTR agonism or activation of the ERK1/2 cascade, specifically within the hypothalamus, may provide therapeutically relevant mechanisms.

Release of oxytocin in the rat central amygdala modulates stress-coping behavior and the release of excitatory amino acids

Previous experiments have indicated that the release of oxytocin (OXT) occurs in various hypothalamic and extrahypothalamic brain areas. In the present study, we investigated in male rats whether swim stress triggers the release of OXT in the central amygdala (CeA), a key area in processing emotions and stress responses. Further, we examined the physiological significance of OXT released within the CeA for behavioral responses during forced swimming as well as effects on the local release of selected amino acids including glutamate, aspartate, arginine, taurine, and GABA, which are thought to modulate processing of emotions. Exposure to a 10-min forced swimming session caused a significant increase in OXT release (200%, p<0.01) within, but not outside, the CeA as monitored by microdialysis. Administration of the OXT receptor antagonist des-Gly-NH2d(CH2)5(Tyr(Me)2Thr4)OVT via inverse microdialysis into the amygdala before and during exposure to swimming reduced the floating time by 55% (p<0.05) and increased the swimming time by 29% (p<0.05) indicative of a more active stress-coping strategy. Simultaneously, local administration of the OXT receptor antagonist caused a significant increase in the stress-induced release of the excitatory amino acids glutamate and aspartate, whereas the basal release of these amino acids remained unchanged. Taken together, these findings demonstrate a significant activation of the oxytocinergic system in the CeA in response to swim stress. Furthermore, our data indicate that OXT receptor-mediated mechanisms within the amygdala are involved in the generation of passive stress-coping strategies, which might be mediated at least in part via its inhibitory influence on the local release of excitatory amino acids during stress.

The CRF System Mediates Increased Passive Stress-Coping Behavior Following the Loss of a Bonded Partner in a Monogamous Rodent

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.

Prenatal stress increases HPA axis activity and impairs maternal care in lactating female offspring: Implications for postpartum mood disorder

Early life stress is believed to constitute a risk factor for the development of mood disorders later in life. In the present study, we hypothesized that prenatal stress (PS) exerts long-lasting effects in female rat offspring, resulting in impaired adaptations to stress during lactation and, as such, may be a contributory factor to postpartum mood disorders. PS increased anxiety in adult virgin females compared with controls. During lactation, PS dams nursed significantly less and spent less time with pups compared with controls, whereas dams did not differ in pup retrieval or maternal aggression. HPA axis reactivity was elevated in response to a mild stressor in PS dams compared to their controls, but not in virgins, with the delta corticosterone response returning to the higher level seen in virgins. Moreover, corticotropin-releasing hormone (CRH) mRNA expression within the parvocellular region of the paraventricular nucleus (PVN) was increased in both virgins and dams exposed to PS compared with the relative controls, while the attenuation in expression in lactating controls was abolished following PS. In addition, arginine vasopressin (AVP) mRNA was increased in the parvocellular, but not magnocellular part of the PVN, in both PS-exposed virgins and lactating dams compared with their relative controls; although expression was also higher in controls during lactation compared with virgins. Thus, the present study demonstrates that exposure to PS results in long-lasting behavioural and neuroendocrine alterations in the female offspring, which are manifested during the lactation period. Furthermore, it implicates PS as a potential risk factor for the development of postpartum mood disorders, and that alterations in the HPA axis reactivity, at least partially, are involved.

Maternal nurturing is dependent on her innate anxiety: the behavioral roles of brain oxytocin and vasopressin.

The maternal brain undergoes remarkable physiological and behavioral changes in the peripartum period to meet the demands of the offspring. Here, the brain neuropeptides oxytocin and vasopressin, together with prolactin, play important roles. These neuropeptides are critically involved in the regulation of maternal behavior. Furthermore, reduced anxiety in lactation is another adaptation of the maternal brain. Therefore, a link between maternal behavior and maternal anxiety has been repeatedly postulated. This is supported by our studies in rats bred for high (HAB) and low (LAB) anxiety-related behavior. While female HAB rats become less anxious in lactation, their anxiety level is still four times higher compared with LAB dams. Interestingly, HAB dams display an intense and protective mothering style including increased arched back nursing and pup retrieval whereas LAB dams display only low levels of maternal care. The amount of maternal care directed towards the pups correlates with the mothers innate anxiety. In addition to differences in maternal care, HAB dams are also more protective as they show heightened aggression against a virgin intruder compared with the less aggressive LAB dams. The level of maternal aggression correlates with both their innate anxiety level as well as with the release of oxytocin and vasopressin in hypothalamic and limbic brain areas. Importantly, manipulations of the brain oxytocin and vasopressin systems alter maternal behavior and - depending on the brain region - can also alter the dams anxiety. Thus, the mothers innate anxiety determines her maternal performance and oxytocin and vasopressin are involved in both parameters.

Prenatal stress reduces postnatal neurogenesis in rats selectively bred for high, but not low, anxiety: possible key role of placental 11β‐hydroxysteroid dehydrogenase type 2

Prenatal stress (PS) produces persistent abnormalities in anxiety‐related behaviors, stress responsivity, susceptibility to psychopathology and hippocampal changes in adult offspring. The hippocampus shows a remarkable degree of structural plasticity, notably in response to stress and glucocorticoids. We hypothesized that PS would differentially affect hippocampal neurogenesis in rats selectively bred for genetic differences in anxiety‐related behaviors and stress responsivity. Pregnant dams of high anxiety‐related behavior (HAB) and low anxiety‐related behavior (LAB) strains were stressed between days 5 and 20 of pregnancy. The survival of newly generated hippocampal cells was found to be significantly lower in 43‐day‐old HAB than in LAB male offspring of unstressed pregnancies. PS further reduced newly generated cell numbers only in HAB rats, and this was paralleled by a reduction in doublecortin‐positive cell numbers, indicative of reduced neurogenesis. As maternal plasma corticosterone levels during PS were similar in both strains, we examined placental 11β‐hydroxysteroid dehydrogenase type 2 (11β‐HSD2), which catalyses rapid inactivation of maternal corticosterone to inert 11‐dehydrocorticosterone and thus serves as a physiological ‘barrier’ to maternal glucocorticoids. PS significantly increased placental 11β‐HSD2 activity in LAB, but not HAB, rats. We conclude that PS differentially affects the number of surviving newly generated cells and neurogenesis in HAB and LAB rats. The high sensitivity of hippocampal neurogenesis to PS in HAB rats is paralleled by a failure to increase placental 11β‐HSD2 activity after stress rather than by different maternal corticosterone responses. Hence, stress‐induced placental 11β‐HSD2 expression may be critical in protecting the fetal brain from maternal stress‐induced effects on adult neurogenesis.

Prenatal stress: opposite effects on anxiety and hypothalamic expression of vasopressin and corticotropin-releasing hormone in rats selectively bred for high and low anxiety.

We studied the mechanisms of genetic–early environmental interactions to modulate adult stress‐coping and tested the hypothesis that prenatal stress (PS) can differentially alter the consequences of a genetic predisposition to either hyper‐ or hypo‐anxiety. Exposure of male Wistar rats, bred for high (HAB) or low (LAB) anxiety‐related behaviour, to PS between pregnancy days 4 and 18 resulted in opposite effects on anxiety in adulthood, i.e. HAB rats became less and LAB rats became more anxious compared with their unstressed controls (plus‐maze and holeboard). The high anxiety of HAB controls was accompanied by elevated expression of vasopressin and corticotropin‐releasing hormone (CRH) mRNA within the hypothalamic paraventricular nucleus compared with LAB rats. PS reduced CRH mRNA expression in HAB rats but increased vasopressin mRNA expression in LAB rats, which may explain the opposite effects of PS on adult emotionality. Differential effects of PS were also found with respect to hypothalamo‐pituitary‐adrenal axis reactivity; the hypothalamo‐pituitary‐adrenal hyper‐response in virgin female HAB controls became attenuated after PS, without affecting plasma corticosterone concentrations in LAB rats. Differences in maternal plasma corticosterone measured between pregnancy days 6 and 14 of HAB and LAB dams or differential effects of PS on maternal behaviour can be excluded. In conclusion, exposure of rats with genetically determined high or low emotionality to PS mitigates the extremes in behavioural and neuroendocrine stress‐coping, thus allowing adequate and similar behavioural responses to potentially dangerous stimuli in adulthood. Differential effects of PS on the activity of the brain vasopressin and CRH systems might represent possible underlying molecular mechanisms.