A classical view claims that oxytocin (OT) fosters affiliative behaviors and arginine vasopressin (VP) enhances aggression. But a lot of data conflict with this. The confusion is not due purely to neuroanatomical details, or gender or species. I will use two novel approaches to compare OT and VP responsive systems: (I.) Using molecular tools and some new behavioral thinking;and (II.) Using estrogens (E) as biologically relevant probes. In order to take maximal advantage of genetic knowledge and preliminary evidence we will use female mice. Specifically:
Aim I. I will perturb OT gene expression and OT receptors using gene knockouts - with all interesting results followed up by a novel antisense DNA technique - and measure an interesting behavior maternal aggression (as part of reproduction), compared to an 'affiliative behavior', maternal care compared to testosterone-facilitated aggression. (I have already shown that seminatural environment living helps to reveal hitherto unrealized behavioral phenotypes.) Aim II. Estrogenic regulations of these systems offer the opportunity to probe with novel E-related molecular tools. Will ER gene knockout mice, antisense oligos, and selective agonists and antagonists change the three behaviors above in the predicted directions? Aim III. Will verify major discoveries of this project in normal pregnant and lactating mice. In all Aims, important targets for molecular manipulations will be in the amygdala: The basolateral nuclei are involved in fear;the central nucleus in anxiety;and the mediocortical region in signaling by pheromones. All of these functions could influence the three behaviors measured in this project. Also important: The dorsolateral preoptic area for maternal behavior, and the dorsal raphe for serotonin and aggression. This project uses the multidisciplinary capacity of my laboratory and the Rockefeller University campus, and is written in an """"""""if/then"""""""" style to show how we will maximize the impact of 5 years of work. These experiments will increase our understanding of two extremely important transcriptional systems, OT and VP, with widespread projections and significant autonomic and behavioral effects. Impact: OT may be involved in postpartum depression. OT systems certainly facilitate social recognition, disorders of which are prominent in autism and in schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
3R01MH038273-23S1
Application #
8035687
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Simmons, Janine M
Project Start
2010-03-01
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2012-02-28
Support Year
23
Fiscal Year
2010
Total Cost
$242,589
Indirect Cost
Name
Rockefeller University
Department
Biology
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Clipperton-Allen, Amy E; Lee, Anna W; Reyes, Anny et al. (2012) Oxytocin, vasopressin and estrogen receptor gene expression in relation to social recognition in female mice. Physiol Behav 105:915-24
Pfaff, Donald; Waters, Elizabeth; Khan, Quaiser et al. (2011) Minireview: estrogen receptor-initiated mechanisms causal to mammalian reproductive behaviors. Endocrinology 152:1209-17
Pfaff, Donald W; Rapin, Isabelle; Goldman, Sylvie (2011) Male predominance in autism: neuroendocrine influences on arousal and social anxiety. Autism Res 4:163-76
Schober, Justine; Weil, Zachary; Pfaff, Donald (2011) How generalized CNS arousal strengthens sexual arousal (and vice versa). Horm Behav 59:689-95
Quinkert, Amy Wells; Vimal, Vivek; Weil, Zachary M et al. (2011) Quantitative descriptions of generalized arousal, an elementary function of the vertebrate brain. Proc Natl Acad Sci U S A 108 Suppl 3:15617-23
Martin, Eugene M; Pavlides, Constantine; Pfaff, Donald (2010) Multimodal sensory responses of nucleus reticularis gigantocellularis and the responses' relation to cortical and motor activation. J Neurophysiol 103:2326-38
Devidze, Nino; Fujimori, Ko; Urade, Yoshihiro et al. (2010) Estradiol regulation of lipocalin-type prostaglandin D synthase promoter activity: evidence for direct and indirect mechanisms. Neurosci Lett 474:17-21
Milner, Teresa A; Thompson, Louisa I; Wang, Gang et al. (2010) Distribution of estrogen receptor ? containing cells in the brains of bacterial artificial chromosome transgenic mice. Brain Res 1351:74-96
Clipperton Allen, Amy E; Cragg, Cheryl L; Wood, Alexis J et al. (2010) Agonistic behavior in males and females: effects of an estrogen receptor beta agonist in gonadectomized and gonadally intact mice. Psychoneuroendocrinology 35:1008-22
Spiteri, Thierry; Musatov, Sergei; Ogawa, Sonoko et al. (2010) Estrogen-induced sexual incentive motivation, proceptivity and receptivity depend on a functional estrogen receptor alpha in the ventromedial nucleus of the hypothalamus but not in the amygdala. Neuroendocrinology 91:142-54

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