@article{8ed377edac9b4cec8940b902415f37fb,
title = "The Neuropeptide Tac2 Controls a Distributed Brain State Induced by Chronic Social Isolation Stress",
abstract = "Chronic social isolation causes severe psychological effects in humans, but their neural bases remain poorly understood. 2 weeks (but not 24 hr) of social isolation stress (SIS) caused multiple behavioral changes in mice and induced brain-wide upregulation of the neuropeptide tachykinin 2 (Tac2)/neurokinin B (NkB). Systemic administration of an Nk3R antagonist prevented virtually all of the behavioral effects of chronic SIS. Conversely, enhancing NkB expression and release phenocopied SIS in group-housed mice, promoting aggression and converting stimulus-locked defensive behaviors to persistent responses. Multiplexed analysis of Tac2/NkB function in multiple brain areas revealed dissociable, region-specific requirements for both the peptide and its receptor in different SIS-induced behavioral changes. Thus, Tac2 coordinates a pleiotropic brain state caused by SIS via a distributed mode of action. These data reveal the profound effects of prolonged social isolation on brain chemistry and function and suggest potential new therapeutic applications for Nk3R antagonists. The Tac2 neuropeptide system orchestrates the complex behavioral effects of chronic social isolation stress by acting locally in multiple brain regions, suggesting the therapeutic potential of Nk3R antagonists for managing behavioral changes upon prolonged social isolation.",
keywords = "aggression, amygdala, BNST, DMH, fear, neuropeptides, Nk3R, NkB, social isolation, stress, Tac2",
author = "Moriel Zelikowsky and May Hui and Tomomi Karigo and Andrea Choe and Bin Yang and Blanco, {Mario R.} and Keith Beadle and Viviana Gradinaru and Deverman, {Benjamin E.} and Anderson, {David J.}",
note = "Funding Information: We thank X. Da and X. Wang for help with behavior scoring and histology; M. McCardle and Y. Huang for genotyping; J. Costanza for mouse colony management; C. Chiu and G. Mancuso for lab management and administrative assistance; A. Choe for help with behavioral testing, the diagrams in Figure 2A, and fruitful discussions; A. Kennedy for generating MATLAB code for behavioral data processing and the models in Figure 7H; Z. Turan and M. Meister for help implementing the LD assay; W. Wu for initial help on the acoustic startle assay; P. Kunwar for initial help on the ultrasonic sound stimulus assay; T. Anthony for initial help with RNA isolation and purification; and all the members of the Anderson lab for their support. We thank Ben Deneen for providing the NFIA antibody, Mitchell Guttman and his lab for providing resources and sharing use of the qRT-PCR reagents and equipment, the Beckman Institute CLOVER Center for generating the PHP.B constructs, and the Perona lab for continued help with customized behavioral tracking and analyses software. This work was supported by grants from the National Institutes Health (MH085082, MH112593, and MH070053), Gordon Moore Foundation (2646), Ellison Medical Research Foundation (NR-AA-0108-12), and Simons Foundation (to D.J.A.) and by a NARSAD Young Investigator Award (23687), the L'OREAL for Women in Science award, and an NIMH K99 Pathway to Independence Award (MH108734 to M.Z.). D.J.A. is an Investigator of the Howard Hughes Medical Institute. Funding Information: We thank X. Da and X. Wang for help with behavior scoring and histology; M. McCardle and Y. Huang for genotyping; J. Costanza for mouse colony management; C. Chiu and G. Mancuso for lab management and administrative assistance; A. Choe for help with behavioral testing, the diagrams in Figure 2 A, and fruitful discussions; A. Kennedy for generating MATLAB code for behavioral data processing and the models in Figure 7 H; Z. Turan and M. Meister for help implementing the LD assay; W. Wu for initial help on the acoustic startle assay; P. Kunwar for initial help on the ultrasonic sound stimulus assay; T. Anthony for initial help with RNA isolation and purification; and all the members of the Anderson lab for their support. We thank Ben Deneen for providing the NFIA antibody, Mitchell Guttman and his lab for providing resources and sharing use of the qRT-PCR reagents and equipment, the Beckman Institute CLOVER Center for generating the PHP.B constructs, and the Perona lab for continued help with customized behavioral tracking and analyses software. This work was supported by grants from the National Institutes Health ( MH085082 , MH112593 , and MH070053 ), Gordon Moore Foundation ( 2646 ), Ellison Medical Research Foundation ( NR-AA-0108-12 ), and Simons Foundation (to D.J.A.) and by a NARSAD Young Investigator Award ( 23687 ), the L{\textquoteright}OREAL for Women in Science award , and an NIMH K99 Pathway to Independence Award ( MH108734 to M.Z.). D.J.A. is an Investigator of the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = may,
day = "17",
doi = "10.1016/j.cell.2018.03.037",
language = "English (US)",
volume = "173",
pages = "1265--1279.e19",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "5",
}