The Role of Oxytocin in Animal Behaviors and Welfare (Advanced Studies on Sustainable Animal Production: Interrelationships among Human, Animal and Environment, 8th International Symposium of Integrated Field Science)

Oral Sessio

Research Overview of the Lab. of Molecula Biology, Tohoku University Graduate School of Agricultural Science(Recent Topics of the Agricultunal Biological Science in Tohoku University)

In our laboratory, mainly three different projects described below are now carried out. 1) "Generation and application of the cell membrane permeabilized protein", 2) "Studies on epigenetic regulation of eukaryotic genes through analyses of actin-related proteins" and 3) "Generation of the oxytocin receptor KO (OXTR-/-) mice, and molecular physiological and behavioral analysis of the oxytocin receptor KO (OXTR-/-) mice." In the first project, we generated recombinant Cre protein fused to TAT PTD (protein transduction domain), and the application of this protein into several primary cells prepared from mouse, showed significant recombinase activity. In the second project, we studied epigenetic regulation of eukaryotic genes through analyses of actin-related proteins. In the third project, we obtained several new findings in reproduction, sociosexual behaviors and in physiology of energy/temperature homeostasis of mice as the functions of oxytocin/oxytocin receptor system in vivo, using the oxytocin and its receptor genes deficient (OXT-/- and OXTR-/-) mice. Here we introduce a little about those three projects, respectively

Pervasive social deficits, but normal parturition, in oxytocin receptor-deficient mice

The oxytocin receptor (OXTR) and its ligand, oxytocin (OXT), regulate reproductive physiology (i.e., parturition and lactation) and sociosexual behaviors. To define the essential functions of OXTR, we generated mice with a null mutation in the Oxtr gene (Oxtr-/-) and compared them with OXT-deficient (Oxt-/-) mice. Oxtr-/- mice were viable and had no obvious deficits in fertility or reproductive behavior. Oxtr-/- dams exhibited normal parturition but demonstrated defects in lactation and maternal nurturing. Infant Oxtr-/- males emitted fewer ultrasonic vocalizations than wild-type littermates in response to social isolation. Adult Oxtr-/- males also showed deficits in social discrimination and elevated aggressive behavior. Ligand Oxt-/- males from Oxt-/- dams, but not from Oxt+/- dams, showed similar high levels of aggression. These data suggest a developmental role for the OXT/OXTR system in shaping adult aggressive behavior. Our studies demonstrate that OXTR plays a critical role in regulating several aspects of social behavior and may have important implications for developmental psychiatric disorders characterized by deficits in social behavior

Targeting oxytocin receptor (Oxtr)-expressing neurons in the lateral septum to restore social novelty in autism spectrum disorder mouse models

© 2020, The Author(s). Autism spectrum disorder (ASD) is a continuum of neurodevelopmental disorders and needs new therapeutic approaches. Recently, oxytocin (OXT) showed potential as the first anti-ASD drug. Many reports have described the efficacy of intranasal OXT therapy to improve the core symptoms of patients with ASD; however, the underlying neurobiological mechanism remains unknown. The OXT/oxytocin receptor (OXTR) system, through the lateral septum (LS), contributes to social behavior, which is disrupted in ASD. Therefore, we selectively express hM3Dq in OXTR-expressing (OXTR+) neurons in the LS to investigate this effect in ASD mouse models developed by environmental and genetic cues. In mice that received valproic acid (environmental cue), we demonstrated successful recovery of impaired social memory with three-chamber test after OXTR+ neuron activation in the LS. Application of a similar strategy to Nl3R451C knock-in mice (genetic cue) also caused successful recovery of impaired social memory in single field test. OXTR+ neurons in the LS, which are activated by social stimuli, are projected to the CA1 region of the hippocampus. This study identified a candidate mechanism for improving core symptoms of ASD by artificial activation of DREADDs, as a simulation of OXT administration to activate OXTR+ neurons in the LS

Классификация экзонов генов человека с использованием алгоритмов автоматического выбора атрибутов экзонов

Volkov AV, Yatskov NN, Grinev VV Classification of exons of human genes using algorithms for automatic selection of exon attributesСекция 2. МЕТОДЫ И ТЕХНОЛОГИИ МАТЕМАТИЧЕСКОГО И ИМИТАЦИОННОГО МОДЕЛИРОВАНИЯ СИСТЕ

Oxytocin Signaling in Mouse Taste Buds

The neuropeptide, oxytocin (OXT), acts on brain circuits to inhibit food intake. Mutant mice lacking OXT (OXT knockout) overconsume salty and sweet (i.e. sucrose, saccharin) solutions. We asked if OXT might also act on taste buds via its receptor, OXTR.Using RT-PCR, we detected the expression of OXTR in taste buds throughout the oral cavity, but not in adjacent non-taste lingual epithelium. By immunostaining tissues from OXTR-YFP knock-in mice, we found that OXTR is expressed in a subset of Glial-like (Type I) taste cells, and also in cells on the periphery of taste buds. Single-cell RT-PCR confirmed this cell-type assignment. Using Ca2+ imaging, we observed that physiologically appropriate concentrations of OXT evoked [Ca2+]i mobilization in a subset of taste cells (EC50 approximately 33 nM). OXT-evoked responses were significantly inhibited by the OXTR antagonist, L-371,257. Isolated OXT-responsive taste cells were neither Receptor (Type II) nor Presynaptic (Type III) cells, consistent with our immunofluorescence observations. We also investigated the source of OXT peptide that may act on taste cells. Both RT-PCR and immunostaining suggest that the OXT peptide is not produced in taste buds or in their associated nerves. Finally, we also examined the morphology of taste buds from mice that lack OXTR. Taste buds and their constituent cell types appeared very similar in mice with two, one or no copies of the OXTR gene.We conclude that OXT elicits Ca2+ signals via OXTR in murine taste buds. OXT-responsive cells are most likely a subset of Glial-like (Type I) taste cells. OXT itself is not produced locally in taste tissue and is likely delivered through the circulation. Loss of OXTR does not grossly alter the morphology of any of the cell types contained in taste buds. Instead, we speculate that OXT-responsive Glial-like (Type I) taste bud cells modulate taste signaling and afferent sensory output. Such modulation would complement central pathways of appetite regulation that employ circulating homeostatic and satiety signals

Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice

金沢大学医薬保健研究域医学系Oxytocin sets the stage for childbirth by initiating uterine contractions, lactation and maternal bonding behaviours. Mice lacking secreted oxcytocin (Oxt -/-, Cd38 -/-) or its receptor (Oxtr -/-) fail to nurture. Normal maternal behaviour is restored by peripheral oxcytocin replacement in Oxt -/- and Cd38 -/-, but not Oxtr -/- mice, implying that circulating oxcytocin crosses the blood-brain barrier. Exogenous oxcytocin also has behavioural effects in humans. However, circulating polypeptides are typically excluded from the brain. We show that oxcytocin is transported into the brain by receptor for advanced glycation end-products (RAGE) on brain capillary endothelial cells. The increases in oxcytocin in the brain which follow exogenous administration are lost in Ager -/- male mice lacking RAGE, and behaviours characteristic to abnormalities in oxcytocin signalling are recapitulated in Ager -/- mice, including deficits in maternal bonding and hyperactivity. Our findings show that RAGE-mediated transport is critical to the behavioural actions of oxcytocin associated with parenting and social bonding.3082047