In Vivo Ultrafast Doppler Imaging Combined with Confocal Microscopy and Behavioral Approaches to Gain Insight into the Central Expression of Peripheral Neuropathy in Trembler-J Mice

Abstract

The main human hereditary peripheral neuropathy (Charcot-Marie-Tooth, CMT), manifests in progressive sensory and motor deficits. Mutations in the compact myelin protein gene pmp22 cause more than 50% of all CMTs. CMT1E is a subtype of CMT1 myelinopathy carrying micro-mutations in pmp22. The Trembler-J mice have a spontaneous mutation in pmp22 identical to that present in CMT1E human patients. PMP22 is mainly (but not exclusively) expressed in Schwann cells. Some studies have found the presence of pmp22 together with some anomalies in the CNS of CMT patients. Recently, we identified the presence of higher hippocampal pmp22 expression and elevated levels of anxious behavior in TrJ/+ compared to those observed in wt. In the present paper, we delve deeper into the central expression of the neuropathy modeled in Trembler-J analyzing in vivo the cerebrovascular component by Ultrafast Doppler, exploring the vascular structure by scanning laser confocal microscopy, and analyzing the behavioral profile by anxiety and motor difficulty tests. We have found that TrJ/+ hippocampi have increased blood flow and a higher vessel volume compared with the wild type. Together with this, we found an anxiety-like profile in TrJ/+ and the motor difficulties described earlier. We demonstrate that there are specific cerebrovascular hemodynamics associated with a vascular structure and anxious behavior associated with the TrJ/+ clinical phenotype, a model of the human CMT1E disease.

Functional ultrasound and brain connectivity reveal central nervous system compromise in Trembler-J mice, model of Charcot-Marie-Tooth disease

“…Our results show that TrJ mice present an altered central nervous response in comparison with WT, indicating a compromise of the neurovascular system due to the disease. The present work complements our previous observations around the hippocampal domains, where we showed there is a deterioration of the vascular hemodynamic component in normal murine ageing 40 and an increase in blood flow associated with anxiousness in TrJ mice in comparison to WT mice 41 .…”

“…This may be due to a failure of the global connectivity maintenance mechanisms as a result of an altered vascular physiology, with perhaps a preponderance of spontaneous global vasomotion (Mayer waves) over local neurovascular coupling. We have recently demonstrated that in RS, the CBV of TrJ mice, showed a significantly increased value with respect to WT mice, associated with significant vessel volume values increase, detectable as early as three months old mice 41 .…”