W Scott Young, M.D., Ph.D.
The Section on Neural Gene Expression investigated 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.
We used 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 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 used those mice 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 last studies examined 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 thus proposed that the CA2 region is necessary for proper social memory formation. 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. 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.
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 eventually became the Chief of the Section on Neural Gene Expression. He began by studying neuropeptide expression in the hypothalamus.
Smith AS, Williams Avram SK, Cymerblit-Sabba A, Song J, Young WS (2016). Targeted activation of the hippocampal CA2 area strongly enhances social memory. Mol Psychiatry 21, 1137-44. https://doi.org/10.1038/mp.2015.189. [Pubmed Link ]
Cymerblit-Sabba A, Smith AS, Williams Avram SK, Stackmann M, Korgan AC, Tickerhoof MC, Young WS (2020). Inducing Partner Preference in Mice by Chemogenetic Stimulation of CA2 Hippocampal Subfield. Front Mol Neurosci 13, 61. https://doi.org/10.3389/fnmol.2020.00061. [Pubmed Link ]
Williams Avram SK, Lee HJ, Fastman J, Cymerblit-Sabba A, Smith A, Vincent M, Song J, Granovetter MC, Lee SH, Cilz NI, Stackmann M, Chaturvedi R, Young WS (2019). NMDA Receptor in Vasopressin 1b Neurons Is Not Required for Short-Term Social Memory, Object Memory or Aggression. Front Behav Neurosci 13, 218. https://doi.org/10.3389/fnbeh.2019.00218. [Pubmed Link ]
Young WS, Song J (2020). Characterization of Oxytocin Receptor Expression Within Various Neuronal Populations of the Mouse Dorsal Hippocampus. Front Mol Neurosci 13, 40. https://doi.org/10.3389/fnmol.2020.00040. [Pubmed Link ]