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Activation of endogenous arginine vasopressin neurons inhibit food intake: by using a novel transgenic rat line with DREADDs system.

ABSTRACT: Various studies contributed to discover novel mechanisms of central arginine vasopressin (AVP) system responsible for the behaviour albeit endogenous vasopressin activation. We established a novel transgenic rat line which expresses both human muscarinic acetylcholine receptors (hM3Dq), of which ligand is clozapine-N-oxide (CNO), and mCherry fluorescence specifically in AVP neurons. The mCherry neurons that indicate the expression of the hM3Dq gene were observed in the suprachiasmatic (SCN), supraoptic (SON), and paraventricular nuclei (PVN). hM3Dq-mCherry fluorescence was localized mainly in the membrane of the neurons. The mCherry neurons were co-localized with AVP-like immunoreactive (LI) neurons, but not with oxytocin-LI neurons. The induction of Fos, which is the indicator for neuronal activity, was observed in approximately 90% of the AVP-LI neurons in the SON and PVN 90 min after intraperitoneal (i.p.) administration of CNO. Plasma AVP was significantly increased and food intake, water intake, and urine volume were significantly attenuated after i.p. administration of CNO. Although the detailed mechanism has unveiled, we demonstrated, for the first time, that activation of endogenous AVP neurons decreased food intake. This novel transgenic rat line may provide a revolutionary insight into the neuronal mechanism regarding central AVP system responsible for various kind of behaviours.

SUBMITTER: Yoshimura M

PROVIDER: S-EPMC5691068 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Activation of endogenous arginine vasopressin neurons inhibit food intake: by using a novel transgenic rat line with DREADDs system.

Yoshimura Mitsuhiro M Nishimura Kazuaki K Nishimura Haruki H Sonoda Satomi S Ueno Hiromichi H Motojima Yasuhito Y Saito Reiko R Maruyama Takashi T Nonaka Yuki Y Ueta Yoichi Y

Scientific reports 20171116 1

Various studies contributed to discover novel mechanisms of central arginine vasopressin (AVP) system responsible for the behaviour albeit endogenous vasopressin activation. We established a novel transgenic rat line which expresses both human muscarinic acetylcholine receptors (hM3Dq), of which ligand is clozapine-N-oxide (CNO), and mCherry fluorescence specifically in AVP neurons. The mCherry neurons that indicate the expression of the hM3Dq gene were observed in the suprachiasmatic (SCN), sup ...[more]

PMID: 29146932

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Project description:Mammalian birth is accompanied by a period of obligatory asphyxia, which consists of hypoxia (drop in blood O2 levels) and hypercapnia (elevation of blood CO2 levels). Prolonged, complicated birth can extend the asphyxic period, leading to a pathophysiological situation, and in humans, to the diagnosis of clinical birth asphyxia, the main cause of hypoxic-ischemic encephalopathy (HIE). The neuroendocrine component of birth asphyxia, in particular the increase in circulating levels of arginine vasopressin (AVP), has been extensively studied in humans. Here we show for the first time that normal rat birth is also accompanied by an AVP surge, and that the fetal AVP surge is further enhanced in a model of birth asphyxia, based on exposing 6-day old rat pups to a gas mixture containing 4% O2 and 20% CO2 for 45 min. Instead of AVP, which is highly unstable with a short plasma half-life, we measured the levels of copeptin, the C-terminal part of prepro-AVP that is biochemically much more stable. In our animal model, the bulk of AVP/copeptin release occurred at the beginning of asphyxia (mean 7.8 nM after 15 min of asphyxia), but some release was still ongoing even 90 min after the end of the 45 min experimental asphyxia (mean 1.2 nM). Notably, the highest copeptin levels were measured after hypoxia alone (mean 14.1 nM at 45 min), whereas copeptin levels were low during hypercapnia alone (mean 2.7 nM at 45 min), indicating that the hypoxia component of asphyxia is responsible for the increase in AVP/copeptin release. Alternating the O2 level between 5 and 9% (CO2 at 20%) with 5 min intervals to mimic intermittent asphyxia during prolonged labor resulted in a slower but quantitatively similar rise in copeptin (peak of 8.3 nM at 30 min). Finally, we demonstrate that our rat model satisfies the standard acid-base criteria for birth asphyxia diagnosis, namely a drop in blood pH below 7.0 and the formation of a negative base excess exceeding -11.2 mmol/l. The mechanistic insights from our work validate the use of the present rodent model in preclinical work on birth asphyxia.

Project description:BackgroundSome studies have shown that arginine vasopressin (AVP) can significantly improve the social interaction disorder of autism, but the mechanism remains unclear.MethodsFemale Wistar rats were intraperitoneally injected with VPA or normal saline at embryonic day 12.5 to establish an autism model or normal control in their offspring. Male offspring prenatally exposed to VPA were randomly assigned to two groups: the VPA-induced autism model group and the AVP group. The rats in the AVP group were treated with intranasal AVP at postnatal day (PND) 21 and for 3 weeks. The VPA-induced autism model group was given the same dose of normal saline in the same way. Behavioral responses were evaluated in the open field and three-chambered social test apparatus; the expression levels of AVP in serum were detected by enzyme-linked immunosorbent assay kit, and the gene expression levels on the amygdala were measured by RNA-seq at PND42.ResultsIntranasal administration of AVP can significantly improve the social interaction disorder and elevate the levels of AVP in serum. Transcriptome sequencing results showed that 518 differently expressed genes (DEGs) were identified in the VPA-induced autism model group compared with the control in this study. Gene Ontology biological process enrichment analysis of DEGs showed that the VPA-induced autism model group had significant nervous system developmental impairments compared with the normal group, particularly in gliogenesis, glial cell differentiation, and oligodendrocyte differentiation. Gene Set Enrichment Analysis (GSEA) enrichment analysis also showed that biological process of oligodendrocyte differentiation, axoneme assembly, and axon ensheathment were inhibited in the VPA-induced autism model group. Pathway enrichment analysis of DEGs between the control and VPA-induced autism model group showed that the PI3K/AKT and Wnt pathways were significantly dysregulated in the VPA-induced autism model group. Few DEGs were found when compared with the transcriptome between the VPA-induced autism model group and the AVP treatment group. GSEA enrichment analysis showed deficits in oligodendrocyte development and function were significantly improved after AVP treatment; the pathways were mainly enriched in the NOTCH, mitogen-activated protein kinase, and focal adhesion signaling pathways, but not in the PI3K/AKT and Wnt pathways. The expression patterns analysis also showed the same results.ConclusionAVP can significantly improve the social interaction disorder of VPA-induced autism model, and AVP may target behavioral symptoms in autism by modulating the vasopressin pathways, rather than primary disease mechanisms.

Dataset Information

Activation of endogenous arginine vasopressin neurons inhibit food intake: by using a novel transgenic rat line with DREADDs system.

Publications

Activation of endogenous arginine vasopressin neurons inhibit food intake: by using a novel transgenic rat line with DREADDs system.

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