3-bromo-7-nitroindazole, a neuronal nitric oxide synthase inhibitor, impairs maternal aggression and citrulline immunoreactivity in prairie voles

Lactating female rodents are aggressive against intruders when they are rearing and protecting pups. In prairie voles, Microtus ochrogaster, females exhibit a dramatic increase in citrulline immunoreactivity (citrulline-IR) in the paraventricular nucleus (PVN), but not in control regions of the brain, in association with maternal aggression. Citrulline is an indirect indicator of nitric oxide (NO) synthesis and it is possible that NO release in the PVN is an important element in the control of maternal aggression in prairie voles. In this study, we sought to examine the role of NO in maternal aggression by selectively inhibiting neuronal nitric oxide synthase (nNOS) in lactating prairie voles. Intraperitoneal injections of the nNOS inhibitor, 3-bromo-7-nitroindazole (3-Br-7NI) (20 mg/kg), three time per day over 4 days resulted in significant impairment of the expression of maternal aggression in terms of the average time in aggressive encounters, the average number of attacks, and the average latency to first attack. These behavioral deficiencies were observable beginning two days following the onset of drug treatment. The average time spent sniffing the intruder was indistinguishable between the 3-Br-7NI- and oil-treated females. In 3-Br-7NI-treated relative to oil-treated females, the number of citrulline-positive cells was reduced by 70% in the PVN and by 50% in the anterior amygdaloid area, a control region of the brain. Taken together, these results indicate that 3-Br-7NI effectively inhibits maternal aggression and NO production in prairie voles and suggest that the central release of NO may play an important role in the production of maternal aggression in prairie voles.     

Vasopressin released within the central amygdala promotes maternal aggression

Vasopressin regulates important aspects of social behaviour. Although vasopressin is more prominent in the expression of male social behaviours, we recently demonstrated its role in the fine‐tuned maintenance of maternal care in lactating rats. Here, we investigate the involvement of brain vasopressin in the regulation of maternal aggression in lactating Wistar rats selectively bred for either high (HAB) or low (LAB) anxiety‐related behaviour. The genetically determined elevation in vasopressin mRNA expression was confirmed within the hypothalamic paraventricular nucleus of virgin and lactating HAB rats and was additionally found in limbic brain areas. Lactating HAB dams are more maternally aggressive as part of their generally higher level of maternal care compared with LAB rats. Using intracerebral microdialysis, we describe increased vasopressin release within the central amygdala, but not the paraventricular nucleus, during maternal aggression only in HAB dams. Moreover, the release of vasopressin within the central amygdala was positively correlated with the display of offensive behaviour. Blockade of local vasopressin actions by bilateral administration of a selective vasopressin V1a receptor antagonist into the central amygdala reduced maternal aggression in HAB dams, whereas synthetic vasopressin increased the low level of aggression in LAB rats. Vasopressin receptor binding within the central amygdala or the paraventricular nucleus was similar in HAB and LAB females. In conclusion, vasopressin is an important neuropeptide regulating maternal aggressive behaviour, thus further extending its involvement in female social behaviour. Differences in intracerebral vasopressin release within the central amygdala rather than local vasopressin receptor binding contribute to the level of maternal aggression.     

Site and behavioral specificity of periaqueductal gray lesions on postpartum sexual, maternal, and aggressive behaviors in rats

Bilateral electrolytic lesions of the lateral and ventrolateral caudal periaqueductal gray (cPAG_l,vl) of lactating rats are known to severely reduce suckling-induced kyphosis (upright crouched nursing), which is necessary for maximal litter weight gains, and impair sexual behavior during the postpartum estrous, while heightening nursing in other postures and attacks on unfamiliar adult male intruders. In the present report, the site specificity of the cPAG with respect to the control of these behaviors was determined by comparing lesions of the cPAG_l,vl with similarly sized lesions within the rostral PAG (rPAG) and surrounding mesencephalon. The previously seen effects of prepartum cPAG_l,vl lesions on kyphotic nursing, sexual proceptivity and receptivity, maternal aggression, and daily litter weight gains were replicated. Additionally, the post-lesion facilitation of aggression was found to be behaviorally specific, first by being directed toward an adult, but not to a nonthreatening juvenile male rat, and second, by requiring the recent presence of the pups, being eliminated or decreased 24 h after removal of the litter. Damage to the rPAG did not affect nursing or sexual behaviors, and had only a minimal effect on maternal aggression. Lesions of the rPAG, however, greatly impaired the dams' ability to rapidly release pups held in the mouth, but not to pick them up or carry them directly to the nest during retrieval. Separate regions of the PAG, therefore, are differentially involved in the control of specific components of behaviors in lactating rats.     

Opposite effects of maternal separation on intermale and maternal aggression in C57BL/6 mice: link to hypothalamic vasopressin and oxytocin immunoreactivity

Early life stress, in particular child abuse and neglect, is an acknowledged risk factor for the development of pathological anxiety and aggression. In rodents, 3-h daily maternal separation (MS) during the first 2 weeks of life is an established animal model of early life stress and has repeatedly been shown to increase anxiety and stress responsiveness in adulthood. However, preclinical studies on the effects of postnatal stress on adult aggression are limited. The present study investigated whether MS affects intermale aggression and/or maternal aggression in C57BL/6 mice. In both adult male and virgin female mice, MS elevated anxiety-related behavior as tested on the elevated plus-maze, in the open field and during novel object exploration. The latency to attack an unknown male intruder, as assessed with the resident-intruder test, was significantly longer in MS male mice compared with control male mice. In contrast, the latency to attack a novel male intruder was significantly shorter in MS females compared with control females on days 3 and 5 of lactation. These opposite effects of MS can be explained by the fact that intermale and maternal aggression are two different forms of aggression, and hence, might be modulated by different neurobiological pathways. Indeed, in the paraventricular nucleus of the hypothalamus, MS was found to selectively increase vasopressin immunoreactivity in males, whereas MS selectively decreased oxytocin immunoreactivity in lactating females. In conclusion, MS has long-lasting and differential effects on adult intermale and maternal aggression in C57BL/6 mice. Alterations in hypothalamic vasopressin and oxytocin immunoreactivity may, in part, underlie the opposite effects of MS on intermale and maternal aggression. The MS paradigm represents a promising animal model to reveal underlying mechanisms of aggressive behavioral dysfunctions associated with early life stress.     

Reduced brain corticotropin‐releasing factor receptor activation is required for adequate maternal care and maternal aggression in lactating rats

The brain corticotropin‐releasing factor (CRF) system triggers a variety of neuroendocrine and behavioural responses to stress. Whether maternal behaviour and emotionality in lactation are modulated by CRF has rarely been investigated. In the present study, we measured CRF mRNA expression within the parvocellular part of the paraventricular nucleus in virgin and lactating Wistar rats bred for high (HAB) and low (LAB) anxiety‐related behaviour or non‐selected for anxiety (NAB). Further, we intracerebroventricularly infused synthetic CRF or the CRF receptor (CRF‐R) antagonist D‐Phe to manipulate CRF‐R1/2 non‐specifically in lactating HAB, LAB, and NAB dams, and monitored maternal care, maternal motivation, maternal aggression, and anxiety. The CRF mRNA expression in the parvocellular part of the paraventricular nucleus was higher in HAB vs. LAB rats independent of reproductive status. The lactation‐specific decrease of CRF mRNA was confirmed in LAB and NAB dams but was absent in HAB dams. Intracerebroventricular CRF decreased maternal care under basal conditions in the home cage in all breeding lines and reduced attack behaviour in HAB and LAB dams during maternal defence. In contrast, D‐Phe rescued maternal care after exposure to maternal defence in the home cage without influencing maternal aggression. Furthermore, D‐Phe decreased and CRF tended to increase anxiety in HAB/NAB and LAB dams, respectively, suggesting an anxiogenic effect of CRF in lactating females. In conclusion, low CRF‐R activation during lactation is an essential prerequisite for the adequate occurrence of maternal behaviour.     

Elevated stress sensitivity in corticotropin-releasing factor receptor 2 deficient mice decreases maternal, but not intermale aggression

Maternal aggression is a form of aggression towards intruders by lactating females that is critical for defense of offspring. During lactation, fear and anxiety are reduced, the CNS is less responsive to the anxiogenic neuropeptide, corticotropin-releasing factor (CRF), and central injections of CRF inhibit maternal aggression. Together, these previous findings suggest that decreased CRF neurotransmission during lactation supports normal maternal aggression expression. Recent work indicates that mice deficient in CRF receptor 2 (CRFR2) display increased anxiety-like behaviors, have a hypersensitive stress response, and overproduce CRF. In this study, we examined both maternal and intermale aggression in wild-type (WT) and CRFR2-deficient mice. CRFR2-mutant mice exhibited significant deficits in maternal aggression on postpartum Day 4 relative to WT mice in terms of percentage displaying aggression, mean number of attacks, and mean time in aggressive encounters. However, time sniffing male intruder, pup retrieval, number of pups, and performance on the elevated plus maze were similar between genotypes. In contrast, intermale aggression did not differ between genotype in any measure on any of three consecutive test days. For neither form of aggression did sites of attacks on the intruder differ between genotype. Taken together, the results suggest that differences in stress sensitivity and the overproduction of CRF of the knockout (KO) mice specifically affects maternal, but not intermale aggression.     

Hypocretin-1 dose-dependently modulates maternal behaviour in mice

Increases in neuronal activity of hypocretin (HCRT), a peptide involved in arousal, and in HCRT-1 receptor mRNA expression have recently been identified in association with lactation. HCRT is released within brain regions regulating maternal behaviour and it is possible that increased HCRT neurotransmission during lactation supports maternal care. The present study examined for the first time the behavioural effects of HCRT on lactating mice. At intermediate doses, intracerebroventricular (i.c.v.) injections of HCRT-1 (0.06 and 0.1 microg) elevated levels of licking and grooming of pups (but not self-grooming) and number of nursing bouts without affecting other behaviours. At the highest dose, HCRT-1 (0.3 microg, i.c.v) delayed latency to nurse, decreased nursing, increased time off nest, and decreased maternal aggression. Intraperitoneal injections of the HCRT-1 receptor antagonist, SB-334867, exhibited a general trend towards increasing time spent low-arched back nursing (P = 0.053) and decreasing licking and grooming of pups while high-arched back nursing (P = 0.052). This suggests that the endogenous release of HCRT, working independently or dependently with other neuromodulators, may be necessary for full maternal behaviour expression. Possible sites of HCRT action in enhancing and impairing maternal care were identified via examinations of c-Fos immunoreactivity in association with i.c.v. HCRT injections. Together, these finding support the idea of HCRT modulating maternal behaviour, with intermediate levels (0.06 and 0.1 microg) supporting (even augmenting) some behaviours, but with levels that are too high (0.3 microg HCRT, i.c.v.), maternal behaviour and aggression are suppressed.     

cFOS and pCREB activation and maternal aggression in mice

Lactating mice exhibit a dramatic increase in aggression, termed maternal aggression, only in association with the rearing and protection of their offspring. Previous work indicates that the neural mechanisms underlying maternal and male aggression are different in rodents. In this study, we sought to examine possible neural regions involved in the control of maternal aggression by combining behavioral testing with immunohistochemistry for both cFOS and pCREB, two indirect markers of neuronal activity. All lactating female mice were exposed to a male intruder for 20 min and those exhibiting maternal aggression were placed in one group and those that were non-aggressive were placed in a second group. Thus, the sensory stimuli were similar and the main difference between the two groups was the behavior. cFOS expression increased significantly in the claustrum, bed nucleus of the stria terminalis, medial preoptic nucleus, paraventricular nucleus, medial amygdala, and cortical amygdala in association with maternal aggression. In contrast, the number of pCREB-positive cells significantly increased only in the ventrolateral portion of the caudal periaqueductal gray and in the lateral septum in aggressive lactating mice. Due to large variance in the counts of pCREB-positive cells, the data were log transformed prior to statistical analysis. Thus, the sites of cFOS and pCREB increases do not overlap, but provide complementary indirect information on neural regions active during maternal aggression. These results complement previous studies of nitric oxide release during maternal aggression to create a possible map of the functional neural circuitry underlying maternal aggression.     

Maternal cultural values and parenting practices: longitudinal associations with Chinese adolescents' aggression

Interrelations among cultural values, parenting practices, and adolescent aggression were examined using longitudinal data collected from Chinese adolescents and their mothers. Adolescents' overt and relational aggression were assessed using peer nominations at Time 1 (7th grade) and Time 2 (9th grade). Mothers reported endorsement of cultural values (collectivism and social harmony) and parenting practices (psychological control and inductive reasoning) at Time 1. While controlling for Time 1 adolescent aggression, maternal collectivism and social harmony indirectly and longitudinally linked to adolescent aggression through maternal parenting practices. Specifically, maternal collectivism was positively related to inductive reasoning, which, in turn, negatively related to adolescent overt aggression at Time 2. Similarly, maternal social harmony negatively related to psychological control that positively predicted later adolescent relational aggression. Results of the present study shed light on mechanisms through which culture may indirectly influence adolescent aggression.     

Hormone-dependent aggression in male and female rats: experiential, hormonal, and neural foundations.

Hormone-dependent aggression in both male and female rats includes the distinctive behavioral characteristics of piloerection and lateral attack. In males the aggression is dependent on testicular testosterone and is commonly known as intermale aggression. In females, the aggression is most commonly observed as maternal aggression and is dependent on hormones whose identity is only beginning to emerge. The present review examines the experiential events which activate hormone-dependent aggression, the relation of the aggression to gonadal hormones, and the neural structures that participate in its modulation. In males and females, the aggression is activated by cohabitation with a conspecific of the opposite sex, by competitive experience, and by repeated exposure to unfamiliar conspecifics. In the female, the presence of pups also activates aggression. In both males and females, hormones are necessary for the full manifestation of the aggression. The essential hormone appears to be testosterone in males and a combination of testosterone and estradiol in females. The information available suggests the neural control systems for hormone-dependent aggression may be similar in males and females. It is argued that hormone-dependent aggression is behaviorally and biologically homologous in male and female rats.     

Effects of early life stress on adult male aggression and hypothalamic vasopressin and serotonin

Early life stress in humans enhances the risk for psychopathologies, including excessive aggression and violence. In rodents, maternal separation is a potent early life stressor inducing long-lasting changes in emotional and neuroendocrine responsiveness to stress, associated with depression- and anxiety-like symptoms. However, effects of maternal separation on adult male aggression and underlying neurobiological mechanisms remain unknown. Therefore, we investigated the effects of maternal separation on adult intermale aggression in Wistar rats and on hypothalamic arginine vasopressin (AVP) mRNA expression, and AVP and serotonin (5-HT) immunoreactivity, as both AVP and 5-HT have been implicated in stress-coping and aggression. We showed that maternal separation induced depression-like behaviour (increased immobility) and higher adrenocorticotropin hormone responses to an acute stressor (forced swimming). Intermale aggression (lateral threat, offensive upright and keep down) was significantly higher in maternally separated rats compared with control rats. AVP mRNA expression and AVP immunoreactivity were higher in the hypothalamic paraventricular and supraoptic nuclei upon resident-intruder test exposure, whereas 5-HT immunoreactivity was decreased in the anterior hypothalamus of maternally separated rats. Moreover, 5-HT immunoreactivity in the anterior hypothalamus and supraoptic nucleus correlated negatively with aggression. These findings show that exposure to early life stress increases adult male aggression in an animal model of maternal separation. Furthermore, the maternal separation-induced changes in hypothalamic AVP and 5-HT systems may underlie these behavioural alterations.     

Maternal well-being and child behavior in families with fragile X syndrome

The purpose of this study was to examine the bidirectional relationships relationship between maternal mental health status, maternal stress, family environment and behavioral functioning of children with fragile X syndrome (FXS), the leading cause of inherited intellectual disability. Children with FXS commonly demonstrate challenging behavior related to anxiety, attention, and aggression, whereas mothers of children with FXS have been identified as susceptible to mental health challenges due to their status as genetic carriers of the FXS premutation, as well as the environmental stressors of raising children with special needs. The longitudinal design of this study builds upon prior work that established a concurrent relationship among these factors in families of children with other intellectual disorders. Findings indicated that maternal mental health status was not significantly related to changes in levels of child challenging behavior, heightened child challenging behavior was related to improvements in maternal depression over time, and heightened levels of child challenging behavior was related to increased feelings of maternal closeness toward the child over time. The unexpected nature of the results regarding maternal depression and closeness provides new and more complex hypotheses about how mothers of special needs children demonstrate adaptation and resilience. The findings have implications for maternal and familial mental health treatment as well as future research.     

Maternal aggression: new insights from Egr-1

Lactating mice display fierce aggression towards novel, male mice. This study compares neuronal activity in the brains of aggression-tested (T) and -untested (U) mice using early growth response factor 1 (Egr-1; also known as Krox 24, NGFI-A, Zif268, Tis8, and ZENK) as a measure of neuronal activity. Animals were sampled 90 min after either a sham or real 7-min test with a male intruder, after which their brains were examined for immunoreactivity to Egr-1 (Egr-IR). Significant increases in Egr-IR in T mice were identified in 11 of 40 brain regions, including paraventricular nucleus of the hypothalamus; anterior and lateral hypothalamus (both posterior portion); ventromedial hypothalamus; lateral periaqueductal gray; and medial, central, and basolateral amygdala. Posterodorsal (MePD) and posteroventral medial amygdala were examined for the first time in association with maternal aggression. MePD, a region associated with both sexual and aggressive behaviors in rats, hamsters, and mice, showed increased Egr-IR in association with testing. Taken together, the results from this study provide new insights into the neural circuits regulating maternal behaviors.     

International note: Maternal warmth,behavioral control,and psychological control: Relations to adjustment of Ghanaian early adolescents

This investigation addressed the relation between maternal warmth, behavioral control, psychological control, and psychological adjustment in a sample of 119 Ghanaian adolescents (42% boys) living in an urban area (mean age = 14.19). Adolescents in the sample reported clinically elevated levels of depression and anxiety. Significant associations were found between warmth, behavioral control, and psychological control and adolescents' anxiety, physical aggression, relational aggression, positive friendship quality, and conflict with friends. Warmth moderated the effect of behavioral control on anxiety, physical aggression, and relational aggression such that higher levels of warmth in combination with higher levels of behavioral control were related to more positive adjustment. Higher levels of warmth in conjunction with higher psychological control were related to higher levels of anxiety. Boys who reported lower levels of warmth in combination with higher behavioral control reported higher levels of physical aggression. For boys reporting higher levels of warmth, higher behavioral control was associated with lower physical aggression.     

Changes in the intensity of maternal aggression and central oxytocin and vasopressin V1a receptors across the peripartum period in the rat

Maternal aggressive behaviour, which protects the offspring from harm, is one component of maternal behaviour. Not only maternal aggression, but also maternal care and social behaviour in general, is regulated by the brain oxytocin (OXT) and vasopressin (AVP) systems. In the present study, we quantified the intensity of maternal aggression using the maternal defence test at key time points throughout pregnancy, parturition and lactation. Furthermore, we quantified changes in central OXT and arginine AVP V1a receptor (V1a-R) binding in brain regions known to be important in regulating maternal aggression, aiming to investigate whether central changes coincide with the intensity of this behaviour. The intensity of aggression was found to dramatically change over the peripartum period, with its first appearance on the day before parturition. Aggression intensity fell immediately after parturition, although it increased during days 4-7 of lactation, before almost disappearing at weaning. OXT receptor (OTR) and V1a-R binding also showed changes through the peripartum period. OTR binding was highest at parturition within the bed nucleus of the stria terminalis and medial preoptic area and on days 4-7 of lactation in the lateral septum (LS) compared to any other time point during the peripartum period. OTR binding positively correlated with the peak of maternal aggression, suggesting that OXT may act in the LS to facilitate the expression of aggressive behaviour. At parturition, V1a-R binding was at its highest levels in the paraventricular nucleus and central amygdala (CeA) and, in the LS, V1a-R binding positively correlated with aggressive behaviour. V1a-R mRNA expression was also increased within the CeA at parturition. Taken together, the observed fluctuations in OTR and V1a-R binding in the neural circuitry important for regulating maternal behaviour may ensure that maternal aggression is expressed at the correct time during the peripartum period.     

Sex,violence, & rock n' roll: Longitudinal effects of music on aggression,sex, and prosocial behavior during adolescence

The current study examined longitudinal associations between listening to aggression, sex, and prosocial behavior in music on a number of behavioral outcomes across a one-year period during adolescence. Adolescents (N = 548, M age = 15.32, 52% female) completed a number of questionnaires on musical preferences, general media use, aggression, sexual outcomes, and prosocial behavior at two different time points separated by about one year. Using structural equation modeling to analyze the data, results revealed that listening to aggression in music was associated with increased aggression and decreased prosocial behavior over time, even when controlling for initial levels of these behaviors. Listening to sexual content in music was associated with earlier initiation of sexual intercourse and a trend for a higher number of sexual partners (reported at Time 2). Prosocial behavior in music was not associated with any behavioral outcome longitudinally. Collectively, these results suggest that listening to certain types of content in music can have a longitudinal effect on behavior during adolescence.     

Depression,aggression, and suicidal ideation in first graders: a school-based cross-sectional study

Objective

This study explored the clinical characteristics and risk factors of suicidal ideation in a sample of first graders from South Korea. Children's depression and aggression and maternal depression were examined as possible risk factors.

Methods

This study is a school-based, cross-sectional study of 5 elementary schools in Gunpo City, South Korea. Participants were 707 first graders (mean age, 6.54 years) and their mothers. We assessed children's depressive and aggressive symptoms using the Behavior Assessment System for Children-2 (BASC-2) and maternal depression using the Beck Depression Inventory (BDI). Two items from BASC-2 and 1 item from BDI identified children's and maternal suicidal ideation.

Results

Twenty-seven (3.8%) children evidenced suicidal ideation. Children with suicidal ideation had higher mean scores of depression domain (10.11 ± 5.34 vs 4.57 ± 3.44, P < .0001) and aggression domain (7.78 ± 3.84 vs 3.80 ± 2.85, P < .0001) on BASC-2 and maternal depression (9.78 ± 6.45 vs 7.28 ± 5.38, P = .02) on BDI. In regression analysis, children's depression (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.07-1.32; P = .001) and aggression (OR, 1.24; 95% CI, 1.08-1.41; P = .002) contributed significantly to children's suicidal ideation, whereas maternal depression was not significantly related to children's suicidal ideation (OR, 0.99; 95% CI, 0.92-1.06; P = .75).

Conclusions

This study demonstrated that even first graders had a considerable prevalence of suicidal ideation and that depression and aggression were associated with suicidal ideation in young children.     

Intracerebroventricular infusions of morphine, and blockade with naloxone, modify the olfactory preferences for pup odors in lactating rats

Systemic morphine exposure disrupts both maternal behavior (MB) and postpartum aggression, possibly through alterations of olfactory preferences [29]. In the current studies, adult female rats were timed mated and implanted with a unilateral cannula in the lateral ventricle. On day 5 or 6 of lactation, the females were infused with either morphine (2.0 μg) or saline (5 μl) (Experiment 1); or, they were infused with 2.0 μg morphine and saline or morphine plus 0.5 μg naloxone (Experiment 2). One hour later, they were exposed to bedding soiled by pups, or to clean bedding. The amount of time spent investigating the two bedding types was compared. Morphine produced an aversion to the odor of pups, relative to the saline condition, wherein the females expressed a preference for the odor of pups. Naloxone reversed the effect of the morphine, restoring the preference for pup odors in the females. Thus, morphine disruption of MB may be due to central action on olfactory sensory mechanisms.     

Aggression by Children Exposed to IPV: Exploring the Role of Child Depressive Symptoms,Trauma-Related Symptoms, &amp; Warmth in Family Relationships

Multi-informant reports of aggression by siblings in families with and without a history of IPV were compared. Associations between aggressive behavior and child depressive and trauma-related symptoms, as well as maternal and sibling warmth were also explored. Mothers, observers and the siblings themselves reported on aggressive behaviour. Mothers reported on child trauma-related symptoms while children provided self-report on depressive symptoms and mother–child and sibling warmth. The frequency of observed aggression did not differ across groups on average, although more sibling dyads exposed to IPV engaged in aggression than those not exposed. Child reports of sibling aggression did not differ across groups but mothers reported significantly less aggressive behavior by children exposed to IPV than those not exposed. Regression results indicated that depressive and trauma-related symptoms were significant risk factors for aggression, while the role of mother–child and sibling warmth was more complex. Results were discussed within a developmental psychopathology framework.