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Updated: May 22, 2026
Chronic Social Defeat Stress in Early Adolescent Male Mice
Published on: January 24, 2025
Heightened aggressive behavior in mice with lifelong versus postweaning knockout of the oxytocin receptor
Monica B Dhakar1, Megan E Rich, Emily L Reno
1Laboratory of Neuroendocrinology and Behavior, Department of Biological Sciences, Kent State University, Kent, OH 44242, USA.
Abstract:
Previous work implicating the neuropeptide oxytocin (Oxt) in the neural regulation of aggression in males has been limited. However, there are reports of heightened aggression in Oxt knockout and Oxt receptor (Oxtr) knockout male mice when they are born to null mutant mothers; suggesting that intrauterine exposure to Oxt may be important to normal aggression in adulthood. To explore this, we examined aggression in two lines of Oxtr mice, a total knockout (Oxtr-/-), in which the Oxtr gene is absent from the time of conception, and a predominantly forebrain specific knockout (Oxtr FB/FB), in which the Oxtr gene is not excised until approximately 21-28days postnatally. Aggression was measured in males from both lines, as well as control littermates, using a resident-intruder behavioral test. Consistent with previous reports, male Oxtr-/- mice had elevated levels of aggression relative to controls. Oxtr FB/FB mice on the other hand displayed levels of aggression similar to control animals. In addition, following a resident-intruder test, Oxtr+/+ mice that displayed aggression had less c-fos immunoreactivity in the ventral portion of the lateral septum than those that did not. Further, Oxtr-/- mice had increased c-fos immunoreactivity in the medial amygdala relative to controls. These data suggest that Oxt may play an important role during development in the organization of the neural circuits that underlie aggressive behavior in adulthood, with its absence resulting in heightened aggression.
Insights
Intrauterine exposure to oxytocin (Oxt) is crucial for normal adult aggression in male mice. Absence of the oxytocin receptor (Oxtr) from conception leads to heightened aggression, suggesting a developmental role for Oxt signaling.
Area of Science:
- Neuroscience
- Behavioral Neuroscience
- Developmental Neuroscience
Background:
- Limited research has explored the neuropeptide oxytocin's (Oxt) role in regulating male aggression.
- Previous studies suggest intrauterine Oxt exposure may influence adult aggression, as indicated by heightened aggression in Oxt and Oxt receptor (Oxtr) knockout mice born to null mutant mothers.
Purpose of the Study:
- To investigate the role of intrauterine oxytocin signaling in the neural regulation of aggression in adult male mice.
- To examine the impact of early-life Oxtr gene deletion on aggressive behavior and associated neural circuit activation.
Main Methods:
- Aggression was assessed in two lines of Oxtr knockout mice (total knockout Oxtr-/- and forebrain-specific knockout Oxtr FB/FB) and control littermates using the resident-intruder behavioral test.
- C-fos immunoreactivity was analyzed in specific brain regions (ventral lateral septum and medial amygdala) following the behavioral test to assess neural activation.
Main Results:
- Male Oxtr-/- mice exhibited significantly elevated aggression levels compared to controls.
- Oxtr FB/FB mice displayed aggression levels comparable to control animals, indicating that Oxtr function after postnatal day 21-28 does not impact adult aggression.
- Aggressive Oxtr+/+ mice showed reduced c-fos immunoreactivity in the ventral lateral septum, while Oxtr-/- mice had increased c-fos immunoreactivity in the medial amygdala.
Conclusions:
- These findings suggest that oxytocin plays a critical role during development in organizing the neural circuits that regulate aggressive behavior in adulthood.
- The absence of Oxtr signaling during early development leads to heightened aggression in adult male mice, highlighting the importance of intrauterine Oxt exposure.
