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Social defeat and oxytocin regulation of social avoidance and stress-related signaling proteins
Nerio Morales, Lina Karina
Nerio Morales, Lina Karina
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Abstract
Social anxiety disorder (SAD) is one of the most common and disabling anxiety disorders. SAD is characterized by generalized social avoidance and high comorbidity with other psychiatric disorders. Despite its adverse prognosis, the molecular mechanism underlying this condition and its high prevalence in female population is poorly understood. The social defeat paradigm is considered one of the most representative animal models to study the neural mechanisms associated with stress-induced social avoidance. Particularly, social defeat in prairie voles (Microtus ochrogaster) advantageously allows the study of female subjects due to their spontaneous display of aggression towards unfamiliar conspecifics after pair bond formation. Once defeated, prairie voles exhibit social avoidance to unfamiliar individuals, an important indicator in the diagnosis of SAD in humans. Recently, we have documented that social defeat robustly affects the oxytocin system in brain regions relevant for affiliative behaviors. Specifically, oxytocin receptor binding was progressively reduced in the nucleus accumbens (NAc), basal lateral amygdala (BLA), and anterior cingulate cortex (ACC) of defeated female prairie voles over an eight-week period, suggesting a regulatory role of this neuropeptide in the etiology of SAD. Oxytocin stimulation of its receptor leads to the activation of the mitogen-activated protein kinase (MAPK) pathway. This cascade has been previously associated with the regulation of the anxiolytic effects of oxytocin, making it an intriguing molecular target in the study of SAD. Here, we used female prairie voles to study the regulation of social defeat and oxytocin receptor on social preference and the MAPK pathway in the NAc, ACC and BLA of female prairie voles. Additionally, we explored the response of these biological markers to a behavioral test involving social novelty as opposed to assessing the effects of a social challenge in a model of SAD. First, we demonstrated that social defeat and oxytocin receptor knockdown in the NAc, ACC and BLA induces a social avoidance phenotype. Next, we showed that oxytocin receptor knockdown induced region- and stimuli-specific effects on the MAPK pathway that resembles some of the features observed in defeat. Finally, this research provides the foundation for future studies exploring regional changes in neuronal plasticity, potentially mediated by defeat and oxytocin, to induce the behavioral effects observed in this model.
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Date
2022-01-01
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University of Kansas
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Keywords
Neurosciences, Behavioral sciences, Molecular biology, MAPK pathway, Oxytocin, Oxytocin receptor, Prairie vole, Social anxiety disorder, Social defeat