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      Lipo-oxytocin-1, a Novel Oxytocin Analog Conjugated with Two Palmitoyl Groups, Has Long-Lasting Effects on Anxiety-Related Behavior and Social Avoidance in CD157 Knockout Mice

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          Abstract

          Oxytocin (OT) is a nonapeptide hormone that is secreted into the brain and blood circulation. OT has not only classical neurohormonal roles in uterine contraction and milk ejection during the reproductive phase in females, but has also been shown to have new pivotal neuromodulatory roles in social recognition and interaction in both genders. A single administration of OT through nasal spray increases mutual recognition and trust in healthy subjects and psychiatric patients, suggesting that OT is a potential therapeutic drug for autism spectrum disorders, schizophrenia, and some other psychiatric disorders. Although the mechanism is not well understood, it is likely that OT can be transported into the brain where it activates OT receptors to exert its function in the brain. However, the amount transported into the brain may be low. To ensure equivalent effects, an OT analog with long-lasting and effective blood-brain barrier penetration properties would be beneficial for use as a therapeutic drug. Here, we designed and synthesized a new oxytocin analog, lipo-oxytocin-1 (LOT-1), in which two palmitoyl groups are conjugated at the amino group of the cysteine9 residue and the phenolic hydroxyl group of the tyrosine8 residue of the OT molecule. To determine whether LOT-1 actually has an effect on the central nervous system, we examined its effects in a CD157 knockout model mouse of the non-motor psychiatric symptoms of Parkinson’s disease. Similar to OT, this analog rescued anxiety-like behavior and social avoidance in the open field test with the social target in a central arena 30 min after intraperitoneal injection in CD157 knockout mice. When examined 24 h after injection, the mice treated with LOT-1 displayed more recovery than those given OT. The results suggest that LOT-1 has a functional advantage in recovery of social behavioral impairment, such as those caused by neurodegenerative diseases, autism spectrum disorders, and schizophrenia.

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          Rapid regulation of depression-related behaviors by control of midbrain dopamine neurons

          Ventral tegmental area (VTA) dopamine (DA) neurons in the brain’s reward circuit play a crucial role in mediating stress responses 1–4 including determining susceptibility vs. resilience to social stress-induced behavioural abnormalities 5 . VTA DA neurons exhibit two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing 6–8 . Phasic firing of the neurons, which is well known to encode reward signals 6,7,9 , is upregulated by repeated social defeat stress, a highly validated mouse model of depression 5,8,10–13 . Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no change in firing rate apparent in resilient individuals 5,8 . However, direct evidence linking—in real-time—DA neuron phasic firing in promoting the susceptible (depression-like) phenotype is lacking. Here, we took advantage of the temporal precision and cell type- and projection pathway-specificity of optogenetics to demonstrate that enhanced phasic firing of these neurons mediates susceptibility to social defeat stress in freely behaving mice. We show that optogenetic induction of phasic, but not tonic, firing, in VTA DA neurons of mice undergoing a subthreshold social defeat paradigm rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference. Optogenetic phasic stimulation of these neurons also quickly induced a susceptible phenotype in previously resilient mice that had been subjected to repeated social defeat stress. Furthermore, we show differences in projection pathway-specificity in promoting stress susceptibility: phasic activation of VTA neurons projecting to the nucleus accumbens (NAc), but not to the medial prefrontal cortex (mPFC), induced susceptibility to social defeat stress. Conversely, optogenetic inhibition of the VTA-NAc projection induced resilience, while inhibition of the VTA-mPFC projection promoted susceptibility. Overall, these studies reveal novel firing pattern- and neural circuit-specific mechanisms of depression.
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            The challenge of translation in social neuroscience: a review of oxytocin, vasopressin, and affiliative behavior.

            Social neuroscience is rapidly exploring the complex territory between perception and action where recognition, value, and meaning are instantiated. This review follows the trail of research on oxytocin and vasopressin as an exemplar of one path for exploring the "dark matter" of social neuroscience. Studies across vertebrate species suggest that these neuropeptides are important for social cognition, with gender- and steroid-dependent effects. Comparative research in voles yields a model based on interspecies and intraspecies variation of the geography of oxytocin receptors and vasopressin V1a receptors in the forebrain. Highly affiliative species have receptors in brain circuits related to reward or reinforcement. The neuroanatomical distribution of these receptors may be guided by variations in the regulatory regions of their respective genes. This review describes the promises and problems of extrapolating these findings to human social cognition, with specific reference to the social deficits of autism. (c) 2010 Elsevier Inc. All rights reserved.
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              The polyvagal theory: phylogenetic substrates of a social nervous system.

              The evolution of the autonomic nervous system provides an organizing principle to interpret the adaptive significance of physiological responses in promoting social behavior. According to the polyvagal theory, the well-documented phylogenetic shift in neural regulation of the autonomic nervous system passes through three global stages, each with an associated behavioral strategy. The first stage is characterized by a primitive unmyelinated visceral vagus that fosters digestion and responds to threat by depressing metabolic activity. Behaviorally, the first stage is associated with immobilization behaviors. The second stage is characterized by the sympathetic nervous system that is capable of increasing metabolic output and inhibiting the visceral vagus to foster mobilization behaviors necessary for 'fight or flight'. The third stage, unique to mammals, is characterized by a myelinated vagus that can rapidly regulate cardiac output to foster engagement and disengagement with the environment. The mammalian vagus is neuroanatomically linked to the cranial nerves that regulate social engagement via facial expression and vocalization. As the autonomic nervous system changed through the process of evolution, so did the interplay between the autonomic nervous system and the other physiological systems that respond to stress, including the cortex, the hypothalamic-pituitary-adrenal axis, the neuropeptides of oxytocin and vasopressin, and the immune system. From this phylogenetic orientation, the polyvagal theory proposes a biological basis for social behavior and an intervention strategy to enhance positive social behavior.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Brain Sci
                Brain Sci
                brainsci
                Brain Sciences
                MDPI
                2076-3425
                20 January 2015
                March 2015
                : 5
                : 1
                : 3-13
                Affiliations
                [1 ]Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan; E-Mails: nrh23255@ 123456gmail.com (A.M.); kikuchiym@ 123456ec.hokudai.ac.jp (Y.K.)
                [2 ]Department of Basic Research on Social Recognition, Research Center for Child Mental Development, Kanazawa University, Kanazawa 920-8640, Japan; E-Mails: stas4476@ 123456mail.ru (S.M.C.); akmfazam@ 123456yahoo.com (A.A.F.); akthershirin1182@ 123456yahoo.com (S.A.); toruyosi@ 123456kiea.m.kanazawa-u.ac.jp (T.Y.)
                [3 ]Medical Research Institute, Kanazawa Medical University and Medical Care Proteomics Biotechnology Co., Uchinada, Ishikawa 920-0293, Japan; E-Mail: kdeguchi@ 123456kanazawa-med.ac.jp
                [4 ]Department of Immunology and Molecular Genetics, Kawasaki Medical School, Kurashiki, Okayama 701-0192, Japan; E-Mail: ishihara-im@ 123456med.kawasaki-m.ac.jp
                [5 ]Center for Research and Education on Drug Discovery, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
                Author notes
                [†]

                These authors contributed equally to this work.

                [* ]Authors to whom correspondence should be addressed; E-Mails: shu@ 123456pharm.hokudai.ac.jp (S.S.); haruhiro@ 123456med.kanazawa-u.ac.jp (H.H.); Tel./Fax: +81-11-706-3769 (S.S.); +81-76-234-4213 (H.H.).
                Article
                brainsci-05-00003
                10.3390/brainsci5010003
                4390788
                25612002
                824e20df-ebc9-4f55-aeaa-5452ae254984
                © 2015 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 23 September 2014
                : 12 January 2015
                Categories
                Article

                synthetic oxytocin,oxytocin analog,lipidation,social behavior,social avoidance,autism,bst1,cd157

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