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    754—Aggression and Defensive Behavior

    Wednesday, November 13, 2013, 8:00 am - 12:00 noon

    754.09: Oxytocin reduces aggressive behavior in virgin female rats

    Location: Halls B-H

    ">*T. R. DE JONG, D. B. BEIDERBECK, I. D. NEUMANN;
    Mol. and Behavioural Neuroendocrinology, Univ. of Regensburg, Regensburg, Germany

    Abstract Body: Whereas aggression is an important species-dependent behavior to obtain and maintain resources, exaggerated or abnormal aggression can cause considerable physical and psychological harm and, in humans, is a burden to society. Despite the putative sex-specific neurobiology of aggression, aggressive behavior has been almost exclusively studied in male rodents, whereas (non-lactating) female rodents have been largely neglected due to their expected low level of aggression toward conspecifics. To fill this gap, we have established a novel female resident-intruder (FRI) test in rats, and quantified neuronal activity (pERK) within the hypothalamic paraventricular nucleus (PVN) in response to the FRI-test. In a 2nd experiment, we tested the potential anti-aggressive effect of oxytocin (OXT). Female Wistar rats (n=19) were tested on the elevated plus maze (EPM) at 7 weeks of age (mid-adolescence), followed by isolation in an experimental cage. After 48 hours, the FRI-test was started, placing an intruder female (appr. 5-6 weeks of age) into the female’s cage for 10 min. Immediately thereafter, resident females were deeply anesthetized and perfused intracardially. The behavior of the females could be categorized as follows: non-aggressive (n=12, no attacks, 0-8% aggressive behavior) or aggressive (n=7, at least 1 attack, 21-58% aggressive behavior); these behaviors were independent of both estrus cycle and anxiety behavior (EPM). Immunohistochemistry showed that aggressive females had significantly less pERK-IR in the magnocellular (putatively oxytocinergic) portion of the PVN (p=0.008 vs. non-aggressive females). In the 2nd experiment, following a 1st FRI-test exposure, female Wistar rats (n=12) were placed back in their group cage for 5 days. After stereotaxic implantation of an icv guide cannula, females were again isolated. 48h later, they were infused with either Ringer (5ul) or OXT (0.1ug/5ul) and re-exposed to the FRI-test. Although OXT did not alter the attack frequency or latency, it did significantly reduce (p=0.016) the percentage of total time spent in aggressive behavior (threat, lateral threat, keep down, offensive upright, offensive grooming). Our data suggest that the FRI-test is a suitable behavioral test for female aggression. To our knowledge this is the first report that reduced OXT neurotransmission may play a role in spontaneous female aggressive behavior, and that synthetic OXT can reverse high aggression scores. Future experiments need to localize these OXT effects.

    Lay Language Summary: We present here for the first time a translational behavior test to study aggression in young female rats, which was designed to investigate the female-specific neurobiology of offensive behavior. Using the female intruder test (FIT) in rats, we demonstrate the involvement of the brain oxytocin system in female aggression regulation and an important aggression-inhibiting effect of synthetic oxytocin.
    Since decades, neurobiologists have attempted to unravel the causes and consequences of aggression in animals (mostly rats and mice) and humans. The main aims are to help violent individuals control their behavior, thereby preventing the harm of victims as well as improving the quality of life of the perpetrators. Unfortunately, at present there is a mismatch between the knowledge of the underlying neurobiologal mechanisms of aggression derived from classic animal aggression tests, which are virtually all performed in males, and the demographics of violence in our society, which includes a considerable and currently growing amount of aggressive adolescent and young adult women. We cannot simply extrapolate results obtained in males to understand aggression in females, since the sexes are thought to differ not only in their motivation to behave aggressively (the principle of sexual selection predicts that males mostly compete for access to fertile females, whereas females mostly compete for access to resources), but also in the neurobiology of many factors that control aggression (i.e., steroid hormones, serotonin, vasopressin, oxytocin).
    Despite the long-standing hypothesis that aggression is controlled in a sex-specific way, neurobiologists avoided doing research in female animals because of the belief that female rodents simply do not attack other females unless they are defending their pups (maternal defense, which is under strict hormonal control). Challenging this belief, we could demonstrate that young (8-10 week old) female rats that had been isolated for 48 hours and then were confronted with a smaller intruder female typically spend 10% of the time threatening and pinning down the intruder. In addition, about 40% of the females attacked the intruder at least once. This rate is independent of the estrus cycle or level of anxiety, but we did observe that females became more aggressive when the FIT was repeated one week later, suggesting that a prior confrontation with an intruder facilitates aggression toward a novel intruder.
    We could further demonstrate that females that tolerated their intruder had more activated oxytocin-releasing neurons than females that attacked their intruder. In a follow-up study, infusion of oxytocin into the ventricles in the brain (reaching virtually all brain areas) significantly inhibited offensive behaviors compared to infusion of a control substance. Although the inhibiting effect of oxytocin has been demonstrated in male rats as well, females needed a 10-fold lower dose to show the same effect.
    Our test paradigm is currently used for further experiments aimed to narrow down which brain areas are responsible for the effects of oxytocin on female aggression. In addition, the sex-specific role of vasopressin, steroid hormones and serotonin in aggression will be investigated.