BACKGROUND: Stress exposure as well as psychiatric disorders are often 
associated with abnormalities in brain structure or connectivity. The 
co-chaperone FK506-binding protein 51 (FKBP51) is a regulator of the stress 
system and is associated with a risk to develop stress-related mental illnesses.
PURPOSE: To assess the effect of a general FKBP51 knockout on brain structure 
and connectivity in male mice.
STUDY TYPE: Animal study.
ANIMAL MODEL: Two cohorts of FKBP51 knockout (51KO) and wildtype (WT) mice. The 
first cohort was comprised of n = 18 WT and n = 17 51KOs; second cohort n = 10 
WT and n = 9 51KOs.
FIELD STRENGTH/SEQUENCE: 9.4T/3D gradient echo (VBM), DTI-EPI (DTI).
ASSESSMENT: Voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). 
For VBM, all procedures were executed in SPM12. DTI: FMRIB Software Library 
(FSL) Tract Based Statistics (TBSS) were integrated within DTI-TK, allowing the 
creation of a mean FA skeleton. A voxelwise statistical analysis was applied 
between WT and 51KO mice.
STATISTICAL TEST: Volumetric differences were collected at a threshold of 
P < 0.005, and only clusters surviving a familywise error correction on the 
cluster level (pFWE, cluster <0.05) were further considered. VBM data were 
analyzed using a two-sample t-test. The Threshold Free Cluster Enhancement 
(TFCE) method was used to derive uncorrected-P statistical results at a P-level 
of 0.01.
RESULTS: The structural analysis revealed two clusters of significantly larger 
volumes in the hypothalamus, periaqueductal gray, and dorsal raphe region of WT 
animals. DTI measurements, however, demonstrated statistically higher fractional 
anisotropy (FA) values for 51KO animals in locations including the anterior 
commissure, fornix, and posterior commissure/superior colliculus commissure 
region.
DATA CONCLUSION: This study used in vivo structural MRI and DTI to demonstrate 
that a lack of FKBP51 leads to alterations in brain architecture and 
connectivity in male mice. These findings are of particular translational 
relevance for our understanding of the neuroanatomy underlying the interaction 
of FKBP5 genetic status, stress susceptibility, and psychiatric disorders.
LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 1.