Refine
Document Type
- Article (2)
Language
- English (2)
Has Fulltext
- yes (2)
Is part of the Bibliography
- no (2)
Keywords
- - (1)
- Anxiety, fear conditioning (1)
- Functional magnetic resonance imaging (1)
- HPTLC (1)
- Niemann–Pick disease type C1 (1)
- S1P (1)
- Vestibular system (1)
- Voxel-based meta-analysis (1)
- brain (1)
- fibroblasts (1)
Institute
Publisher
- MDPI (1)
- Springer Nature (1)
Niemann–Pick type C1 (NPC1) is a lysosomal storage disorder, inherited as an
autosomal-recessive trait. Mutations in the Npc1 gene result in malfunction of the NPC1 protein,
leading to an accumulation of unesterified cholesterol and glycosphingolipids. Beside visceral
symptoms like hepatosplenomegaly, severe neurological symptoms such as ataxia occur. Here,
we analyzed the sphingosine-1-phosphate (S1P)/S1P receptor (S1PR) axis in different brain regions
of Npc1−/− mice and evaluated specific effects of treatment with 2-hydroxypropyl-β-cyclodextrin
(HPβCD) together with the iminosugar miglustat. Using high-performance thin-layer chromatography
(HPTLC), mass spectrometry, quantitative real-time PCR (qRT-PCR) and western blot analyses, we
Int. J. Mol. Sci. 2020, 21, 4502; doi:10.3390/ijms21124502 www.mdpi.com/journal/ijms
Int. J. Mol. Sci. 2020, 21, 4502 2 of 31
studied lipid metabolism in an NPC1 mouse model and human skin fibroblasts. Lipid analyses
showed disrupted S1P metabolism in Npc1−/− mice in all brain regions, together with distinct changes
in S1pr3/S1PR3 and S1pr5/S1PR5 expression. Brains of Npc1−/− mice showed only weak treatment
effects. However, side effects of the treatment were observed in Npc1+/+ mice. The S1P/S1PR axis
seems to be involved in NPC1 pathology, showing only weak treatment effects in mouse brain. S1pr
expression appears to be affected in human fibroblasts, induced pluripotent stem cells (iPSCs)-derived
neural progenitor and neuronal differentiated cells. Nevertheless, treatment-induced side effects
make examination of further treatment strategies indispensable
Background
A bidirectional functional link between vestibular and fear-related disorders has been previously suggested.
Objective
To test a potential overlap of vestibular and fear systems with regard to their brain imaging representation maps.
Methods
By use of voxel-based mapping permutation of subject images, we conducted a meta-analysis of earlier functional magnetic resonance imaging (fMRI) studies applying vestibular stimulation and fear conditioning in healthy volunteers.
Results
Common clusters of concordance of vestibular stimulation and fear conditioning were found in the bilateral anterior insula cortex, ventrolateral prefrontal cortex and the right temporal pole, bilaterally in the adjacent ventrolateral prefrontal cortex, cingulate gyrus, secondary somatosensory cortex, superior temporal and intraparietal lobe, supplementary motor area and premotor cortex, as well as subcortical areas, such as the bilateral thalamus, mesencephalic brainstem including the collicular complex, pons, cerebellar vermis and bilateral cerebellar hemispheres. Peak areas of high concordance for activations during vestibular stimulation but deactivations during fear conditioning were centered on the posterior insula and S2.
Conclusions
The structural overlap of both networks allows the following functional interpretations: first, the amygdala, superior colliculi, and antero-medial thalamus might represent a release of preprogramed sensorimotor patterns of approach or avoidance. Second, the activation (vestibular system) and deactivation (fear system) of the bilateral posterior insula is compatible with the view that downregulation of the fear network by acute vestibular disorders or unfamiliar vestibular stimulation makes unpleasant perceived body accelerations less distressing. This also fits the clinical observation that patients with bilateral vestibular loss suffer from less vertigo-related anxiety.