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Modulation génétique de la dynamique cérébrale dans les troubles neurodéveloppementaux : impact des CNVs pathogéniques sur l’EEG de reposAudet-Duchesne, Elisabeth 08 1900 (has links)
Bien que la majeure partie du génome humain soit présente en deux copies (une copie héritée de chaque parent), certains segments peuvent être délétés (une copie) ou dupliqués (trois copies). La recherche a montré que plusieurs variations du nombre de copies (CNVs) augmentent le risque de troubles neurodéveloppementaux (e.g. autisme, TDAH, schizophrénie). Or, on connait peu les effets des CNVs sur le développement et le fonctionnement cérébral. L’électroencéphalographie (EEG) au repos s’avère être une méthode adaptée pour étudier les perturbations de l’activité neuronale chez les porteurs de CNVs. L’objectif de ce projet était de déterminer s’il existe des signatures EEG à l’état de repos qui sont caractéristiques des enfants porteurs de CNVs pathogéniques. L’activité cérébrale au repos de 109 porteurs de CNVs (66 délétions, 43 duplications) âgés de 3 à 17 ans a été enregistrée en EEG durant 4 minutes. Pour mieux prendre en compte les variations développementales, les indices EEG (puissance spectrale et connectivité fonctionnelle) ont été corrigés avec un modèle normatif estimé à partir de 256 contrôles du Heatlhy Brain Network. Les résultats ont montré une puissance bêta et gamma accrue dans les régions postérieures ainsi qu’une sous-connectivité globale à des échelles temporelles distinctes chez les porteurs de CNVs. Les porteurs d’une délétion et d’une duplication pouvaient être différenciés par leur connectivité dans les fréquences bas-alpha: la connectivité des porteurs d’une duplication était plus perturbée que celle des porteurs d’une délétion. Les perturbations distinctives en connectivité se sont avérées plus proéminentes à l’adolescence. Les résultats suggèrent que les porteurs de CNVs présentent des altérations électrophysiologiques par rapport aux témoins neurotypiques, indépendamment de la région génomique affectée. / Although most of the human genome is present in two copies (one copy inherited from each parent), some segments can be deleted (one copy) or duplicated (three copies). Research has shown that many copy number variations (CNVs) increase the risk of neurodevelopmental disorders (e.g. autism, ADHD, schizophrenia). However, little is known about the effects of CNVs on brain development and function. Resting-state electroencephalography (EEG) is a suitable method to study the disturbances of neuronal functioning in CNVs. We aimed to determine whether there are resting-state EEG signatures that are characteristic of children with pathogenic CNVs. Resting-state brain activity of 109 CNVs carriers (66 deletions, 43 duplications) aged 3 to 17 years was recorded in EEG for 4 minutes. To better account for developmental variations, EEG indices (power spectral density and functional connectivity) were corrected with a normative model estimated from 256 Heatlhy Brain Network controls. Results showed increased beta and gamma power in posterior regions as well as a global under-connectivity at distinct frequency bands in CNVs carriers. Deletion and duplication carriers can be differentiated by their connectivity in low alpha frequencies: the connectivity of the duplication carriers was more disrupted than that of the deletion carriers. The distinctive connectivity perturbations were found to be most prominent during adolescence. The results suggest that CNVs carriers show electrophysiological alterations compared to neurotypical controls, regardless of the gene dosage effect and of their affected genomic region. Moreover, a specific signature of the molecular alterations associated with deletions was found.
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DYRK1A-RELATED TRABECULAR DEFECTS IN MALE TS65DN MICE EMERGE DURING A CRITICAL DEVELOPMENTAL WINDOWJonathan Mark LaCombe (11022450) 06 August 2021 (has links)
<p> Down syndrome (DS) is a complex genetic disorder caused by
the triplication of human chromosome 21 (Hsa21). The presence of an extra copy
of an entire chromosome greatly disrupts the copy number and expression of over
350 protein coding genes. This gene dosage imbalance has far-reaching effects on
normal development and aging, leading to cognitive and skeletal defects that
emerge earlier in life than the general population.</p>
<p> The present
study begins by characterizing skeletal development in young male Ts65Dn mice to
test the hypothesis that skeletal defects in male Ts65Dn mice are developmental
in nature.Femurs from young mice ranging from postnatal day 12- to 42-days of
age (P12-42) were measured and analyzed by microcomputed tomography (μCT). Cortical
defects were present generally throughout development, but trabecular defects emerged
at P30 and persisted until P42. </p>
<p> The gene <i>Dual-specificity
tyrosine-regulated kinase 1a </i>(<i>Dyrk1a</i>) is triplicated in both
DS and in Ts65Dn mice and has been implicated as a putative cause of both
cognitive and skeletal defects. To test the hypothesis that trisomic <i>Dyrk1a</i>
is related to the emergence of trabecular defects at P30, expression of <i>Dyrk1a</i>
in the femurs of male Ts65Dn mice was quantified by qPCR. Expression was shown
to fluctuate throughout development and overexpression generally aligned with
the emergence of trabecular defects at P30.</p>
<p> The growth
rate in trabecular measures between male Ts65Dn and euploid littermates was
similar between P30 and P42, suggesting a closer look into cellular mechanisms
at P42. Assessment of proliferation of BMSCs, differentiation and activity of
osteoblasts showed no significant differences between Ts65Dn and euploid
cellular activity, suggesting that the cellular microenvironment has a greater
influence on cellular activity than genetic background.</p>
These
data led to the hypothesis that reduction of <i>Dyrk1a</i> gene expression and
pharmacological inhibition of DYRK1A could be executed during a critical period
to prevent the emergence of trabecular defects at P30. To tests this hypothesis,
doxycycline-induced cre-lox recombination to reduce <i>Dyrk1a</i> gene copy
number or the DYRK1A inhibitor CX-4945 began at P21. The results of both
genetic and pharmacological interventions suggest that trisomic <i>Dyrk1a</i>
does not influence the emergence of trabecular defects up to P30. Instead, data
suggest that the critical window for the rescue of trabecular defects lies
between P30 and P42.
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