W Scott Young, M.D., Ph.D.Chief
Section on Neural Gene Expression (SNGE)
Dr. Young received his B.A., M.D. and Ph.D from The Johns Hopkins University. The latter degree, obtained under the guidance of Michael Kuhar, described the development of in vitro receptor autoradiography and the first applications of the technique to the localization of neurotranmsitter receptors in human and other animal brains. Dr. Young then completed an internship in internal medicine at the University of Maryland and a residency in neurology at the University of Virginia. He joined the NIMH in 1984 where he has studied the paraventricular and supraoptic nuclei in the hypothalamus. Dr. Young's laboratory is currently creating and using knock-out and transgenic mice to study the roles of vasopressin and oxytocin in the brain.
The Section on Neural Gene Expression investigates the roles and regulation of expression of vasopressin (Avp) and oxytocin (Oxt) in the central nervous system. They are peptide hormones composed of 9 amino acids and that participate in the regulation of fluid balance, parturition and lactation. In addition, they have important roles in various behaviors, including social and maternal ones, through their actions mediated by at least 3 receptors in the brain. A schematic of their genes is shown below.
Our group uses a variety of techniques, including anatomical (hybridization histochemistry and receptor autoradiography), molecular biological, transgenic animals, optogenetics, and electrophysiology to explore behavior in the mouse. For example, we have generated mice lacking functional Oxt, as well as mice that express green fluorescent protein in Oxt neurons, in our attempts to determine the essential and non-essential roles of this hormone. We also created the first conditional knockout of the oxytocin receptor (Oxtr) and are using them to further our knowledge of Oxt's role in behavior. For example, we showed that the Oxtr is necessary for intra-strain, but not inter-strain, social recognition. Inactivation of the Oxtr in forebrain excitatory neurons decreases fear conditioning. Inactivation of the Oxtr in serotonin neurons in the brainstem reduces agression in males, but not females, without affecting anxiety-like behaviors.
Our latest work examines the role of the vasopressin 1b receptor (Avpr1b) in the brain. It is found predominantly in the CA2 region of the hippocampus, an area that receives innervation from the AVP-producing paraventricular nucleus of the hypothalamus. We made Avpr1b knockout mice to inactivate the receptor and observed that these mice have a marked reduction in social, but not predatory or defensive, aggression in males and females. They also have modest declines in social recognition in males and females. We showed that viral replacement of Avpr1b in the CA2 area of the mouse hippocampus in these knockout mice restores aggression. Furthermore, the Avpr1b (and Oxtr) enables significant potentiation of excitatory synaptic responses in CA2, but not in CA1 or in slices from Avpr1b (and Oxtr, respectively) knockout mice. Most recently, we demonstrated that optogenetic stimulation of vasopressin fibers within the mouse CA2 strongly enhances social, but not object memory. This vasopressin release from fibers arising in the paraventricular nucleus, lengthens the social memory by at least 80 fold and is inhibited by a locally infused Avpr1b antagonist. In addition, the enhancement is produced by stimulation during the acquisition phase of the memory and not during the recall phase.
Our various studies with transgenic, including knockout mice, are listed here.
Targeted activation of the hippocampal CA2 area strongly enhances social memory. Smith AS, Williams Avram SK, Cymerblit-Sabba A, Song J, Young WS.. Mol Psychiatry. 2016 Jan 5. doi: 10.1038/mp.2015.189. [Epub ahead of print] PMID: 26728562.
Raphe serotonin neuron-specific oxytocin receptor knockout reduces aggression without affecting anxiety-like behavior in male mice only. Pagani JH, Williams Avram SK, Cui Z, Song J, Mezey É, Senerth JM, Baumann MH, Young WS.. Genes Brain Behav. 2015 Feb;14(2):167-76. doi: 10.1111/gbb.12202. Epub 2015 Mar 5 PMID: 25677455.
Role of the vasopressin 1b receptor in rodent aggressive behavior and synaptic plasticity in hippocampal area CA2. Pagani JH, Zhao M, Cui Z, Avram SK, Caruana DA, Dudek SM, Young WS.. Mol Psychiatry. 2015 Apr;20(4):490-9. doi: 10.1038/mp.2014.47. Epub 2014 May 27. PMID: 24863146.
Hypothalamic and other connections with dorsal CA2 area of the mouse hippocampus. Cui Z, Gerfen CR, Young WS 3rd.. J Comp Neurol. 2013 Jun 1;521(8):1844-66. doi: 10.1002/cne.23263. PMID: 23172108.
Postweaning, forebrain-specific perturbation of the oxytocin system impairs fear conditioning. Pagani JH, Lee HJ, Young WS 3rd. Genes Brain Behav. 2011 Oct;10(7):710-9. doi: 10.1111/j.1601-183X.2011.00709.x. Epub 2011 Jul 1. PMID: 21668734.
Oxytocin and the oxytocin receptor underlie intrastrain, but not interstrain, social recognition. Pagani JH, Lee HJ, Young WS 3rd.. Genes Brain Behav. 2011 Oct;10(7):710-9. doi: 10.1111/j.1601-183X.2011.00709.x. Epub 2011 Jul 1. PMID: 21668734.
Vasopressin 1b receptor knock-out impairs memory for temporal order. DeVito LM, Konigsberg R, Lykken C, Sauvage M, Young WS 3rd, Eichenbaum H.. J Neurosci.. 2009 Mar 4;29(9):2676-83. doi: 10.1523/JNEUROSCI.5488-08.2009. PMID: 19261862.
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