
Intranasal Oxytocin Mitigates Maternal Separation-Induced Anxiety: Distinct Outcomes in Male and Female Offspring
Mahshid Shamsi 1 ℗, Leila Karimi-Zandi 2 ©, Mehrdad Jahanshahi 3
Abstract
Introduction: Anxiety and depression affect over 280 million people globally, representing a leading cause of global disability and imposing significant burdens on healthcare systems and caregivers. Emerging evidence highlights early-life stress, such as maternal separation, as a critical environmental risk factor for these disorders. Adverse childhood experiences like maternal separation trigger enduring alterations in brain development, including epigenetic modifications and impaired neurogenesis, with the hippocampus region central to mood regulation and stress adaptation, showing particular vulnerability. Oxytocin, a hypothalamic neuropeptide with anti-inflammatory, anxiolytic, and prosocial properties, offers a promising therapeutic avenue. In this study, we aim to evaluate the therapeutic effects of oxytocin on anxiety-like and depression-like behaviors in a rat model of maternal separation. Methods and Materials: Male and female Wistar rats were mated, and the birth day was designated as postnatal day 0 (PND0). From PND2 to PND21, pups in the maternal separation group were separated from their mothers for 3 hours daily, while pups in the control group remained undisturbed. After weaning on PND21, pups in treated groups received intranasal oxytocin treatment (1μg/μl) until PND60. Behavioral assessments, including the Elevated Plus Maze and Forced Swim Test, were performed on PND60 to evaluate anxiety-like and depressive-like behaviors, respectively. Results: The results indicate that maternal separation significantly increased depressive-like (female:p=0.0007, male: p=0.002) and anxiety-like behaviors (female:p=0.0001, male: p=0.0001)in male and female offspring. Notably, these behavioral impairments were ameliorated following oxytocin administration. Furthermore, comparison between sexes revealed that male offspring exhibited greater vulnerability to anxiety-like behaviors than females (p=0.01). Conclusion and Discussion: Maternal separation during early postnatal development increases depressive- and anxiety-like behaviors in both male and female Wistar rats. Intranasal oxytocin treatment effectively reverses these behavioral deficits, highlighting its potential therapeutic role. These findings underscore the importance of considering sex differences in stress-related research and suggest that oxytocin holds promise as a therapeutic intervention to mitigate early-life stress effects on emotional development, particularly by addressing the heightened anxiety vulnerability observed in males.
Keywords: Maternal separation, oxytocin, Anxiety, depression