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Region specific up-regulation of oxytocin receptors in the opioid oprm1 (-/-) mouse model of autism.

Gigliucci V, Leonzino M, Busnelli M, Luchetti A, Palladino VS, D'Amato FR, Chini B - Front Pediatr (2014)

Bottom Line: Our behavioral results confirmed that Oprm1 (-/-) male mice displayed social impairments, as indicated by reduced ultrasonic calls, and that these were rescued by a single intranasal administration of OXT.Taken together, our results provide evidence of an interaction between OXT and opioids in socially relevant brain areas and in the modulation of social behavior.Moreover, they suggest that the oxytocinergic system may act as a compensative mechanism to bypass and/or restore alterations in circuits linked to impaired social behavior.

View Article: PubMed Central - PubMed

Affiliation: Institute of Neuroscience, National Research Council , Milan , Italy.

ABSTRACT
Autism spectrum disorders (ASDs) are characterized by impaired communication, social impairments, and restricted and repetitive behaviors and interests. Recently, altered motivation and reward processes have been suggested to participate in the physiopathology of ASDs, and μ-opioid receptors (MORs) have been investigated in relation to social reward due to their involvement in the neural circuitry of reward. Mice lacking a functional MOR gene (Oprm1 (-/-) mice) display abnormal social behavior and major autistic-like core symptoms, making them an animal model of autism. The oxytocin (OXT) system is a key regulator of social behavior and co-operates with the opioidergic system in the modulation of social behavior. To better understand the opioid-OXT interplay in the central nervous system, we first determined the expression of the oxytocin receptor (OXTR) in the brain of WT C57BL6/J mice by quantitative autoradiography; we then evaluated OXTR regional alterations in Oprm1 (-/-) mice. Moreover, we tested these mice in a paradigm of social behavior, the male-female social interaction test, and analyzed the effects of acute intranasal OXT treatment on their performance. In autoradiography, Oprm1 (-/-) mice selectively displayed increased OXTR expression in the Medial Anterior Olfactory Nucleus, the Central and Medial Amygdaloid nuclei, and the Nucleus Accumbens. Our behavioral results confirmed that Oprm1 (-/-) male mice displayed social impairments, as indicated by reduced ultrasonic calls, and that these were rescued by a single intranasal administration of OXT. Taken together, our results provide evidence of an interaction between OXT and opioids in socially relevant brain areas and in the modulation of social behavior. Moreover, they suggest that the oxytocinergic system may act as a compensative mechanism to bypass and/or restore alterations in circuits linked to impaired social behavior.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the brain regions of interest analyzed in the study. Representative sections of autoradiographic labeling of OXTR with [125I]-OVTA 20 pM are displayed in grayscale, flanked by corresponding Nissl stained sections. Red contours outline the regions of interest analyzed. A sagittal schematic representation of a mouse brain is reported in the central panel. Lines indicate the antero-posterior localization of the coronal sections taken into account, defined by the reported distances (millimeter) from bregma (according to the Franklin and Paxinos (41) mouse brain atlas). AHiPM, amygdalohippocampal area, posteromedial part; AON, anterior olfactory nucleus; AONm, anterior olfactory nucleus, medial part; BLA, basolateral amygdaloid nucleus, anterior part; BLP, basolateral amygdaloid nucleus, posterior part; BNST, bed nucleus of the stria terminalis; CeA, central amygdaloid nucleus; CPu, caudate–putamen; Hb, habenular nucleus; Hipp CA3, hippocampus, field CA3; LS, lateral septum; MeA, medial amygdaloid nucleus; NAcc, nucleus accumbens; OB, olfactory bulb; PMCo, posteromedial cortical amygdaloid area.
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Figure 1: Schematic representation of the brain regions of interest analyzed in the study. Representative sections of autoradiographic labeling of OXTR with [125I]-OVTA 20 pM are displayed in grayscale, flanked by corresponding Nissl stained sections. Red contours outline the regions of interest analyzed. A sagittal schematic representation of a mouse brain is reported in the central panel. Lines indicate the antero-posterior localization of the coronal sections taken into account, defined by the reported distances (millimeter) from bregma (according to the Franklin and Paxinos (41) mouse brain atlas). AHiPM, amygdalohippocampal area, posteromedial part; AON, anterior olfactory nucleus; AONm, anterior olfactory nucleus, medial part; BLA, basolateral amygdaloid nucleus, anterior part; BLP, basolateral amygdaloid nucleus, posterior part; BNST, bed nucleus of the stria terminalis; CeA, central amygdaloid nucleus; CPu, caudate–putamen; Hb, habenular nucleus; Hipp CA3, hippocampus, field CA3; LS, lateral septum; MeA, medial amygdaloid nucleus; NAcc, nucleus accumbens; OB, olfactory bulb; PMCo, posteromedial cortical amygdaloid area.

Mentions: To analyze the pattern of OXTR distribution in Oprm1−/− mice, we first analyzed [125I]-OVTA binding data in WT mice on which Oprm1−/− animals are backcrossed. Figure 1 shows representative autoradiographic sections for the selected area and associated Nissl staining of adjacent slices; the reported distances from bregma of the different coronal planes are deduced from a reference mouse brain atlas (41).


Region specific up-regulation of oxytocin receptors in the opioid oprm1 (-/-) mouse model of autism.

Gigliucci V, Leonzino M, Busnelli M, Luchetti A, Palladino VS, D'Amato FR, Chini B - Front Pediatr (2014)

Schematic representation of the brain regions of interest analyzed in the study. Representative sections of autoradiographic labeling of OXTR with [125I]-OVTA 20 pM are displayed in grayscale, flanked by corresponding Nissl stained sections. Red contours outline the regions of interest analyzed. A sagittal schematic representation of a mouse brain is reported in the central panel. Lines indicate the antero-posterior localization of the coronal sections taken into account, defined by the reported distances (millimeter) from bregma (according to the Franklin and Paxinos (41) mouse brain atlas). AHiPM, amygdalohippocampal area, posteromedial part; AON, anterior olfactory nucleus; AONm, anterior olfactory nucleus, medial part; BLA, basolateral amygdaloid nucleus, anterior part; BLP, basolateral amygdaloid nucleus, posterior part; BNST, bed nucleus of the stria terminalis; CeA, central amygdaloid nucleus; CPu, caudate–putamen; Hb, habenular nucleus; Hipp CA3, hippocampus, field CA3; LS, lateral septum; MeA, medial amygdaloid nucleus; NAcc, nucleus accumbens; OB, olfactory bulb; PMCo, posteromedial cortical amygdaloid area.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150055&req=5

Figure 1: Schematic representation of the brain regions of interest analyzed in the study. Representative sections of autoradiographic labeling of OXTR with [125I]-OVTA 20 pM are displayed in grayscale, flanked by corresponding Nissl stained sections. Red contours outline the regions of interest analyzed. A sagittal schematic representation of a mouse brain is reported in the central panel. Lines indicate the antero-posterior localization of the coronal sections taken into account, defined by the reported distances (millimeter) from bregma (according to the Franklin and Paxinos (41) mouse brain atlas). AHiPM, amygdalohippocampal area, posteromedial part; AON, anterior olfactory nucleus; AONm, anterior olfactory nucleus, medial part; BLA, basolateral amygdaloid nucleus, anterior part; BLP, basolateral amygdaloid nucleus, posterior part; BNST, bed nucleus of the stria terminalis; CeA, central amygdaloid nucleus; CPu, caudate–putamen; Hb, habenular nucleus; Hipp CA3, hippocampus, field CA3; LS, lateral septum; MeA, medial amygdaloid nucleus; NAcc, nucleus accumbens; OB, olfactory bulb; PMCo, posteromedial cortical amygdaloid area.
Mentions: To analyze the pattern of OXTR distribution in Oprm1−/− mice, we first analyzed [125I]-OVTA binding data in WT mice on which Oprm1−/− animals are backcrossed. Figure 1 shows representative autoradiographic sections for the selected area and associated Nissl staining of adjacent slices; the reported distances from bregma of the different coronal planes are deduced from a reference mouse brain atlas (41).

Bottom Line: Our behavioral results confirmed that Oprm1 (-/-) male mice displayed social impairments, as indicated by reduced ultrasonic calls, and that these were rescued by a single intranasal administration of OXT.Taken together, our results provide evidence of an interaction between OXT and opioids in socially relevant brain areas and in the modulation of social behavior.Moreover, they suggest that the oxytocinergic system may act as a compensative mechanism to bypass and/or restore alterations in circuits linked to impaired social behavior.

View Article: PubMed Central - PubMed

Affiliation: Institute of Neuroscience, National Research Council , Milan , Italy.

ABSTRACT
Autism spectrum disorders (ASDs) are characterized by impaired communication, social impairments, and restricted and repetitive behaviors and interests. Recently, altered motivation and reward processes have been suggested to participate in the physiopathology of ASDs, and μ-opioid receptors (MORs) have been investigated in relation to social reward due to their involvement in the neural circuitry of reward. Mice lacking a functional MOR gene (Oprm1 (-/-) mice) display abnormal social behavior and major autistic-like core symptoms, making them an animal model of autism. The oxytocin (OXT) system is a key regulator of social behavior and co-operates with the opioidergic system in the modulation of social behavior. To better understand the opioid-OXT interplay in the central nervous system, we first determined the expression of the oxytocin receptor (OXTR) in the brain of WT C57BL6/J mice by quantitative autoradiography; we then evaluated OXTR regional alterations in Oprm1 (-/-) mice. Moreover, we tested these mice in a paradigm of social behavior, the male-female social interaction test, and analyzed the effects of acute intranasal OXT treatment on their performance. In autoradiography, Oprm1 (-/-) mice selectively displayed increased OXTR expression in the Medial Anterior Olfactory Nucleus, the Central and Medial Amygdaloid nuclei, and the Nucleus Accumbens. Our behavioral results confirmed that Oprm1 (-/-) male mice displayed social impairments, as indicated by reduced ultrasonic calls, and that these were rescued by a single intranasal administration of OXT. Taken together, our results provide evidence of an interaction between OXT and opioids in socially relevant brain areas and in the modulation of social behavior. Moreover, they suggest that the oxytocinergic system may act as a compensative mechanism to bypass and/or restore alterations in circuits linked to impaired social behavior.

No MeSH data available.


Related in: MedlinePlus