Ninan I. Oxytocin suppresses basal glutamatergic transmission but facilitates activity-dependent synaptic potentiation in the medial prefrontal cortex. J Neurochem 119: 324-331

Department of Psychiatry, New York University Langone Medical Center, New York 10016, USA.
Journal of Neurochemistry (Impact Factor: 4.28). 08/2011; 119(2):324-31. DOI: 10.1111/j.1471-4159.2011.07430.x
Source: PubMed


J. Neurochem. (2011) 119, 324–331.
Both oxytocin and oxytocin receptors are implicated in neuropsychiatric disorders, particularly autism which involves a severe deficit in social cognition. Consistently, oxytocin enhances social cognition in humans and animals. The infralimbic medial prefrontal cortex (IL-mPFC) is believed to play an important role in the regulation of social cognition which might involve top-down control of subcortical structures including the amygdala. However, little is known about whether and how oxytocin modulates synaptic function in the IL-mPFC. The effect of oxytocin on excitatory neurotransmission in the IL-mPFC was studied by examining both the evoked and spontaneous excitatory neurotransmission in the IL-mPFC layer V pyramidal neurons before and after perfusion with oxytocin. To investigate the effect of oxytocin on synaptic plasticity, low-frequency stimulation-induced long-lasting depression was studied in oxytocin-treated brain slices. Oxytocin produced a significant suppression of glutamatergic neurotransmission in the IL-mPFC layer V pyramidal neurons which was mediated by a reduction in glutamate release. Activation of the cannabinoid CB1 receptors was involved in this pre-synaptic effect. Treatment of brain slices with oxytocin for 1 h converted long-lasting depression into long-lasting potentiation of glutamatergic neurotransmission. This oxytocin-mediated plasticity was NMDA receptor-dependent and was mediated by the synaptic insertion of calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors. The aforementioned suppression of basal glutamatergic neurotransmission and facilitation of activity-dependent synaptic plasticity in the IL-mPFC might be critical for the effect of oxytocin on social cognition.

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    • "Several lines of evidence suggest that another component of this network may include the medial prefrontal cortex (mPFC). First, in addition to expressing OTR (Insel and Shapiro, 1992; Gould and Zingg, 2003; Liu et al., 2005; Smeltzer et al., 2006), the mPFC contains OT-sensitive neurons (Ninan, 2011) and receives long-range axonal projections from OT producing neurons in the hypothalamus (Sofroniew, 1983; Knobloch et al., 2012). Second, the mPFC of postpartum rats becomes activated by suckling or OT administration (Febo et al., 2005; Febo, 2012) as well as during the display of maternal aggression (Gammie et al., 2004; Nephew et al., 2009). "
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    ABSTRACT: The neuropeptide oxytocin (OT) acts on a widespread network of brain regions to regulate numerous behavioral adaptations during the postpartum period including maternal care, maternal aggression, and anxiety. In the present study, we examined whether this network also includes the medial prefrontal cortex (mPFC). We found that bilateral infusion of a highly specific oxytocin receptor antagonist (OTR-A) into the prelimbic (PL) region of the mPFC increased anxiety-like behavior in postpartum, but not virgin, females. In addition, OTR blockade in the postpartum mPFC impaired maternal care behaviors and enhanced maternal aggression. Overall, these results suggest that OT in the mPFC modulates maternal care and aggression, as well as anxiety-like behavior, during the postpartum period. Although the relationship among these behaviors is complicated and further investigation is required to refine our understanding of OT actions in the maternal mPFC, these data nonetheless provide new insights into neural circuitry of OT-mediated postpartum behaviors.
    Frontiers in Behavioral Neuroscience 08/2014; 8:258. DOI:10.3389/fnbeh.2014.00258 · 3.27 Impact Factor
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    • "Lesion, inactivation, and molecular approaches have shown that the prelimbic (PL) subregion of the mPFC plays a role in regulating anxiety-like behavior as assessed in a variety of rodent behavioral paradigms including the elevated plus maze (EPM), open field (OF), and social interaction (SI) test (Maaswinkel et al., 1996; Gonzalez et al., 2000; Lacroix et al., 2000; Sullivan and Gratton, 2002; Shah and Treit, 2003; Shah et al., 2004; Resstel et al., 2008; Stack et al., 2010; Stern et al., 2010). The mPFC also contains OTsensitive neurons (Ninan, 2011), abundantly expresses OT receptors (Insel and Shapiro, 1992; Gould and Zingg, 2003; Liu et al., 2005; Smeltzer et al., 2006), and may receive long range axonal projections from OT producing neurons in the hypothalamus (Sofroniew, 1983; Knobloch et al., 2012). Taken together, these findings suggest that the mPFC may be a target where OT acts to diminish anxiety. "
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    ABSTRACT: **Accepted for publication. The neuropeptide oxytocin (OT) has anxiolytic effects in rodents and humans. However, the specific brain regions where OT acts to regulate anxiety requires further investigation. The medial prefrontal cortex (mPFC) has been shown to play a role in the modulation of anxiety-related behavior. In addition, the mPFC contains OT-sensitive neurons, expresses OT receptors, and receives long range axonal projections from OT-producing neurons in the hypothalamus, suggesting that the mPFC may be a target where OT acts to diminish anxiety. To investigate this possibility, females rats were administered OT bilaterally into the prelimbic (PL) region of the mPFC and anxiety-like behavior assessed. In addition, to determine if the effects of OT on anxiety-like behavior are sex dependent and to evaluate the specificity of OT, male and female anxiety-like behavior was tested following delivery of either OT or the closely related neuropeptide arginine vasopressin (AVP) into the PL mPFC. Finally, the importance of endogenous OT in the regulation of anxiety-like behavior was examined in male and female rats that received PL infusions of an OT receptor antagonist (OTR-A). Overall, even though males and females showed some differences in their baseline levels of anxiety-like behavior, OT in the PL region of the mPFC decreased anxiety regardless of sex. In contrast, neither AVP nor an OTR-A affected anxiety-like behavior in males or females. Together, these findings suggest that although endogenous OT in the PL region of the mPFC does not influence anxiety, the PL mPFC is a site where exogenous OT may act to attenuate anxiety-related behavior independent of sex.
    Psychoneuroendocrinology 04/2014; 45:31-42. DOI:10.1016/j.psyneuen.2014.03.009 · 4.94 Impact Factor
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    • "Because there are very few OXTR receptors in the adult neocortex, it is possible that this activation difference in adult OXT KO reflects atypical or labored neural processing of social information after a developmental trajectory that could not use OXT signals to shape experience-dependent neocortical development. As observed in the hippocampus (Sala et al., 2011; Owen et al., 2013) and the infralimbic medial prefrontal cortex (Ninan, 2011), OXTR may contribute to signal-to-noise processing throughout the entire neocortex by regulating excitatory and inhibitory balance during post-natal development. The hypothesis that OXT, via OXTR, shapes the experience-dependent plasticity of the entire neocortex during the onset of multisensory integration could be tested using conditional mouse lines in which gene expression would be manipulated with temporal specificity. "
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    ABSTRACT: Oxytocin (OXT) has drawn increasing attention as a developmentally relevant neuropeptide given its role in the brain regulation of social behavior. It has been suggested that OXT plays an important role in the infant brain during caregiver attachment in nurturing familial contexts, but there is incomplete experimental evidence. Mouse models of OXT system genes have been particularly informative for the role of the OXT system in social behavior, however, the developing brain areas that could respond to ligand activation of the OXT receptor (OXTR) have yet to be identified in this species. Here we report new data revealing dynamic ligand-binding distribution of OXTR in the developing mouse brain. Using male and female C57BL/6J mice at postnatal days (P) 0, 7, 14, 21, 35, and 60 we quantified OXTR ligand binding in several brain areas which changed across development. Further, we describe OXTR ligand binding in select tissues of the near-term whole embryo at E18.5. Together, these data aid in the interpretation of findings in mouse models of the OXT system and generate new testable hypotheses for developmental roles for OXT in mammalian systems. We discuss our findings in the context of developmental disorders (including autism), attachment biology, and infant physiological regulation. Summary: Quantitative mapping of selective OXTR ligand binding during postnatal development in the mouse reveals an unexpected, transient expression in layers II/III throughout the mouse neocortex. OXTR are also identified in several tissues in the whole late embryo, including the adrenal glands, brown adipose tissue, and the oronasal cavity.
    Frontiers in Behavioral Neuroscience 12/2013; 7:195. DOI:10.3389/fnbeh.2013.00195 · 3.27 Impact Factor
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