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The Neuropeptide Tac2 Controls a Distributed Brain State Induced by Chronic Social Isolation Stress

Zelikowsky, Moriel and Hui, May and Karigo, Tomomi and Choe, Andrea and Yang, Bin and Blanco, Mario R. and Beadle, Keith and Gradinaru, Viviana and Deverman, Benjamin E. and Anderson, David J. (2018) The Neuropeptide Tac2 Controls a Distributed Brain State Induced by Chronic Social Isolation Stress. Cell, 173 (5). pp. 1265-1279. ISSN 0092-8674. http://resolver.caltech.edu/CaltechAUTHORS:20180518-105323206

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.cell.2018.03.037DOIArticle
ORCID:
AuthorORCID
Gradinaru, Viviana0000-0001-5868-348X
Deverman, Benjamin E. 0000-0002-6223-9303
Additional Information:© 2018 Elsevier. Received 27 September 2017, Revised 29 January 2018, Accepted 15 March 2018, Available online 17 May 2018. 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. Author Contributions: M.Z. and D.J.A. contributed to the study design. M.Z., M.H., A.C., M.R.B., and B.E.D. contributed to the data collection, scoring, and analysis. M.Z. and M.H. conducted the surgeries, behavior experiments, and histological analyses. K.B. performed PHP.B viral packaging, and B.E.D. helped design the PHP.B experiments and performed the retro-orbital viral injections. T.K. contributed the shRNA and Tac2 cDNA constructs. B.Y. contributed to packaging the viral constructs. M.R.B. contributed to the qRT-PCR analyses. V.G. provided funding to support K.B. and B.E.D. and provided comments on the manuscript. M.Z. and D.J.A. wrote the paper. All authors discussed and commented on the manuscript. Declaration of Interests: B.E.D. and V.G. are listed as inventors on a patent related to AAV-PHP.B (#US9585971B2). All other authors declare no competing interests.
Group:Tianqiao and Chrissy Chen Institute for Neuroscience
Funders:
Funding AgencyGrant Number
NIHMH085082
NIHMH112593
NIHMH070053
Gordon and Betty Moore Foundation2646
Ellison Medical FoundationNR-AA-0108-12
Simons FoundationUNSPECIFIED
Brain and Behavior Research Foundation23687
L’OREAL for Women in ScienceUNSPECIFIED
NIHK99 MH108734
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Subject Keywords:Tac2; neuropeptides; social isolation; stress; aggression; fear; amygdala; BNST; DMH; NkB; Nk3R
Record Number:CaltechAUTHORS:20180518-105323206
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20180518-105323206
Official Citation:Moriel Zelikowsky, May Hui, Tomomi Karigo, Andrea Choe, Bin Yang, Mario R. Blanco, Keith Beadle, Viviana Gradinaru, Benjamin E. Deverman, David J. Anderson, The Neuropeptide Tac2 Controls a Distributed Brain State Induced by Chronic Social Isolation Stress, Cell, Volume 173, Issue 5, 17 May 2018, Pages 1265-1279.e19, ISSN 0092-8674, https://doi.org/10.1016/j.cell.2018.03.037. (https://www.sciencedirect.com/science/article/pii/S0092867418303611)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:86450
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:18 May 2018 18:07
Last Modified:18 May 2018 18:07

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