טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentBen Shofty
SubjectOf Mice, Men and NF1: Contributions Of Neurofibromin
Deficiency to Disrupted System-Specific Brain-Wide
Functional Connectivity
DepartmentDepartment of Medicine
Supervisors Professor Kahn Itamar
Full Professor Shlomo Constantini
Full Thesis textFull thesis text - English Version


Abstract

Neurofibromatosis type one is a single gene, autosomal dominant phakomatosis, that affects approximately 1 in 3000 children world-wide. In this disease, neurofibromin, the product of the neurofibromatosis 1 gene is deficient, causing hyper-activation of the Ras pathway. The disease is mostly known as a tumor pre-disposition syndrome.  Children affected by it suffer a unique cognitive impairment phenotype. In these patients exists a combination of several autistic traits, ADHD, learning disabilities, impaired motor function and spatial perception. Neurofibromin deficiency has been shown to affect GABAergic neurons, resulting in increased inhibitory tone. In addition, Ras hyperactivation has been shown to disrupt normal formation of myelin, resulting in myelin decompaction likely affecting signal transduction in axons. At the macroscopic level, many gross anomalies are seen in the NF1 brain; among them is disruption of the barrel fields of the somatosensory cortex in NF1 mouse models, NF1 “spots” seen in human NF1 patients and more. Mouse models of NF1 present a unique opportunity to study the connection between a localized genetic mutation and the resulting cognitive phenotype, an opportunity not available in other conditions associated with multi-genic and multifactorial pathophysiology.

In this thesis, I have utilized genetically engineered mouse models, and novel whole-brain functional imaging in the awake animal and human patient, to characterize the effect of neurofibromin deficiency on functional connectivity at the system level. First, I have used a heterogeneous NF1 knockout model (Nf1) to explore the basic organization of cerebral networks. In this model, I found that cortico-striatal connectivity is enhanced, and that the organization of motor and sensory systems is altered. Next, I explored the effect of cell-specific deletion of neurofibromin in oligodendrocytes. For this I used a conditional mouse model (Nf1fl/; PLPcre) that enables to direct neurofibromin deficiency specifically to oligodendrocytes. These mice demonstrated impaired motor ability as well as reduced functional connectivity of the motor network, and reduced inter-hemispheric connectivity. These mice, however, did not exhibit altered corticostriatal connectivity, suggesting the decompacted myelin is not linked to increased corticostriatal functional connectivity seen in Nf1. I then proceeded to investigate the global functional organization in a group of pediatric NF1 patients, and compared them to typically developing children. In this group, overall organization of cerebral networks was dramatically altered, as in the NF1 group association networks that depend on long-range connectivity were weakened and local connectivity was more dominant. In addition, cortico-striatal connectivity was enhanced, and the striatum showed considerable topographic reorganization in the NF1 group. Findings from these three studies highlight a few potential distinct pathologies driven by neurofibromin deficiency present in both the mouse models and humans: abnormal long-range, cortico-striatal, and intra-regional functional organization at the mesoscopic level. These studies, for the first time, demonstrate a common functionally disrupted organizational in NF1 mouse models and patients, highlighting targets for rescue and potentially serving as biomarkers of disease severity. The work presented here established a translational pipeline that could now be further explored for drug screening and interventional studies.