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Evolution of brain-wide activity in the awake behaving mouse after acute fear by longitudinal manganese-enhanced MRI

Uselman, Taylor W. and Barto, Danial R. and Jacobs, Russell E. and Bearer, Elaine L. (2020) Evolution of brain-wide activity in the awake behaving mouse after acute fear by longitudinal manganese-enhanced MRI. NeuroImage, 222 . Art. No. 116975. ISSN 1053-8119. PMCID PMC7805483.

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Life threatening fear after a single exposure evolves in a subset of vulnerable individuals to anxiety, which may persist for their lifetime. Yet neither the whole brain's response to innate acute fear nor how brain activity evolves over time is known. Sustained neuronal activity may be a factor in the development of a persistent fear response. We couple two experimental protocols to provoke acute fear leading to prolonged fear: Predator stress (PS), a naturalistic approach to induce fear in rodents; and Serotonin transporter knockout mouse (SERT-KO) that responds to PS with sustained defensive behavior. Behavior was monitored before, during and at short and long times after PS in wild type (WT) and SERT-KO mice. Both genotypes responded to PS with defensive behavior. SERT-KO retained defensive behavior for 23 days, while WT mice returned to baseline exploratory behavior by 9 days. Thus, differences in neural activity between WT and SERT-KO 9 days after PS identifies neural correlates of persistent defensive behavior, in mice. We used longitudinal manganese-enhanced magnetic resonance imaging (MEMRI) to identify brain-wide neural activity associated with different behaviors. Mn²⁺ accumulation in active neurons occurs in awake, behaving mice and is retrospectively imaged. Following the same two cohorts of mice, WT and SERT-KO, longitudinally allowed unbiased quantitative comparisons of brain-wide activity by statistical parametric mapping (SPM). During natural behavior in WT, only low levels of activity-induced Mn²⁺-accumulation were detected, while much more accumulation appeared immediately after PS in both WT and SERT-KO, and evolved at 9 days to a new activity pattern (p < 0.0001, uncorr., T = 5.4). Patterns of accumulation differed between genotypes, with more regions of the brain and larger volumes within regions involved in SERT-KO than WT. A new computational segmentation analysis, using our InVivo Atlas based on a manganese-enhanced MR image of a living mouse, revealed dynamic changes in the volume of significantly enhanced voxels within each segment that differed between genotypes across 45 of 87 segmented regions. At Day 9 after PS, the striatum and ventral pallidum were active in both genotypes but more so in the SERT-KO. SERT-KO also displayed sustained or increased volume of Mn²⁺ accumulations between Post-Fear and Day 9 in eight segments where activity was decreased or silenced in WT. C-fos staining, an alternative neural activity marker, of brains from the same mice fixed at conclusion of imaging sessions confirmed that MEMRI detected active neurons. Intensity measurements in 12 regions of interest (ROIs) supported the SPM results. Between group comparisons by SPM and of ROI measurements identified specific regions differing between time points and genotypes. We report brain-wide activity in response to a single exposure of acute fear, and, for the first time, its evolution to new activity patterns over time in individuals vulnerable to persistent fear. Our results show multiple regions with dynamic changes in neural activity and that the balance of activity between segments is disordered in the SERT-KO. Thus, longitudinal MEMRI represents a powerful approach to discover how brain-wide activity evolves from the natural state either after an experience or during a disease process.

Item Type:Article
Related URLs:
URLURL TypeDescription Paper CentralArticle
Jacobs, Russell E.0000-0002-1382-8486
Bearer, Elaine L.0000-0002-8390-8529
Alternate Title:Evolution of neural activity from fear to anxiety
Additional Information:© 2020 Published by Elsevier Inc. Received 12 May 2020, Accepted 19 May 2020, Available online 28 May 2020. We thank Christopher S. Medina for guiding us in his processing protocols; Aaron Gonzales for pilot behavior sessions; Kathleen Kilpatrick for technical support with histologic preparation; Xiaowei Zhang for MRI session recordings; Sharon Wu Lin for animal staff support; and Kevin P. Reagan, Kyla Sorenson, Angela Miller and Daniel Perez Rodriguez for administrative assistance, and to Sandya Narayanswami of S. Narayanswami Consulting for assistance with editing. We are grateful to Jonathan Brigman for help setting up the behavioral studies, Afonso Silva for critique of the protocol and the MS, and to Ralph Adolphs and Harry Gray of the Beckman Institute at California Institute of Technology for helpful discussions on data analysis, and to the Caltech Beckman Institute where all MR imaging was performed. Bearer acknowledges Jack Roberts (1918–2016) for teaching her the basics of magnetic resonance. This research was supported in part by NIH NIMH RO1 MH096093 (EB), P50 GM085273 (EB) and the Harvey Family Endowment (EB). Additional support was provided by Postdoctoral Research Fund ASERT NIH NIGMS 5K12GM088021(DB) and UNM Brain and Behavioral Health Institute Mini-Grant BBHI 2019-20-005 (ELB).
Funding AgencyGrant Number
NIHRO1 MH096093
NIHP50 GM085273
Harvey Family EndowmentUNSPECIFIED
NIH Postdoctoral Fellowship5K12GM088021
University of New MexicoBBHI 2019-20-005
Subject Keywords:Magnetic Resonance Imaging; neuroimaging; statistical parametric mapping; serotonin transporter knock-out mouse; predator stress; innate unconditioned fear; anxiety; mouse models
PubMed Central ID:PMC7805483
Record Number:CaltechAUTHORS:20200515-084920122
Persistent URL:
Official Citation:Taylor W. Uselman, Daniel R. Barto, Russell E. Jacobs, Elaine L. Bearer, Evolution of brain-wide activity in the awake behaving mouse after acute fear by longitudinal manganese-enhanced MRI, NeuroImage, Volume 222, 2020, 116975, ISSN 1053-8119, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103225
Deposited By: Tony Diaz
Deposited On:15 May 2020 16:28
Last Modified:30 Aug 2021 22:39

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