Lack of FKBP51 Shapes Brain Structure and Connectivity in Male Mice

Abstract

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

Sex-specific and opposed effects of FKBP51 in glutamatergic and GABAergic neurons: Implications for stress susceptibility and resilience

“…Structural brain changes have been demonstrated before in relation to FKBP51. A previous study involving Fkbp5 −/− mice exposed volumetric changes in limbic, periaqueductal grey and dorsal raphe nuclei regions as a result of full body loss of FKBP51, but, in line with our findings, also detected changes in WM structures such as the anterior commissure ( 80 ). In our study, the thalamus was also affected in both Fkbp5 Dlx and Fkbp5 Nex mice.…”

The effect of the PARK16 rs11240572 variant on brain structure in Parkinson's disease

“…Previous study has reported positive results of VBM using volumetric threshold of p < 0.005 and cluster level of p < 0.05. (Engelhardt, Boulat et al 2020). No ndings survived with a threshold of voxel p < 0.001 and cluster p < 0.05.…”

Contribuciones al estudio de la sensibilidad de la morfometría basada en vóxel aplicada al estudio de la anatomía cerebral de roedores

“…La mayoría de ellos se centran en el estudio de los cambios morfológicos en el tejido gris asociados a diferentes síndromes o enfermedades como: Alzheimer [29,30,41,59,65,117], enfermedad de Huntington [94,95], esquizofrenia [112], autismo [36], [81], SIDA [24], Síndrome de Down [85], déficit de atención [61] distrofia muscular de Duchenne [9], depresión [118] y cáncer [35,101]. Por otro lado también se estudió cómo afecta en la morfometría cerebral el ejercicio [13,14,40,103], el sexo [75], la reproducción [11], la exposición al estrés [38], el envejecimiento [92,109], el dolor neuropático [15], la resurrección cardiopulmonar [105], la exposición al plomo durante la niñez [67], la dieta [33,89] y la raza [46], entre otros.…”