Investigating circadian disruption in mouse models of neurological and metabolic disorders
<p>Sleep and circadian rhythm disturbance has been widely observed in neurological disorders although the mechanistic basis for this association remains unknown. In order to understand this association further, a combination of rest/activity and molecular profiling was carried out on mouse mod...
| Autor principal: | |
|---|---|
| Otros Autores: | |
| Formato: | Tesis |
| Lenguaje: | English |
| Publicado: |
2013
|
| Materias: |
| _version_ | 1826342855526842368 |
|---|---|
| author | Livieratos, A |
| author2 | Davies, K |
| author_facet | Davies, K Livieratos, A |
| author_sort | Livieratos, A |
| collection | OXFORD |
| description | <p>Sleep and circadian rhythm disturbance has been widely observed in neurological disorders although the mechanistic basis for this association remains unknown. In order to understand this association further, a combination of rest/activity and molecular profiling was carried out on mouse models of Parkinson’s Disease (PD), Lysosomal Storage Disorders (LSDs) and schizophrenia.</p> <p>Data from rest/activity behavioural screening of new BAC (Bacterial Artificial Chromosome) transgenic PD models displayed scotophase hyperactivity and decreased fragmentation patterns. Interestingly, rest/activity profiles of LSD models displayed possible core clock defects under constant conditions (<em>Hexb<sup>-/-</sup></em>) and potential re-entrainment deficits following a 6hr phase advance (<em>Npc1<sup>-/-</sup></em>). Together these data suggest new associations between disruptions in rest/activity cycles and neurodegeneration.</p> <p>The blind-drunk (<em>Bdr</em>) mutant is a mouse model of synaptosomal-associated protein <em>(Snap)-25</em> exocytotic disruption that displays schizophrenic endophenotypes and phase advanced rest/activity cycles. Despite identification of phase advanced expression of signalling neuropeptides (e.g. arginine vasopressin) in the <em>Bdr</em> suprachiasmatic nucleus (SCN), the underlying mechanisms regulating circadian disruption in this model remain elusive; therefore, label-free shotgun proteomics was carried out over 24 hours to elucidate potential post-transcriptional pathways. A number of novel circadian patterns of protein expression were identified including myristoylated alanine-rich C-kinase substrate (MARCKS) which exhibited a robust phase advanced expression profile. This study has identified novel SCN post-transcriptional mechanisms that may link schizoaffective disorder biomarkers to dysfunctional rest/activity cycles.</p> |
| first_indexed | 2024-03-07T07:48:46Z |
| format | Thesis |
| id | oxford-uuid:a03f34d5-285d-464b-b676-21b493db7f56 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:48:46Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:a03f34d5-285d-464b-b676-21b493db7f562023-06-28T12:59:35ZInvestigating circadian disruption in mouse models of neurological and metabolic disordersThesishttp://purl.org/coar/resource_type/c_db06uuid:a03f34d5-285d-464b-b676-21b493db7f56Biology (medical sciences)NeuropathologyPsychiatryEnglishOxford University Research Archive - Valet2013Livieratos, ADavies, K<p>Sleep and circadian rhythm disturbance has been widely observed in neurological disorders although the mechanistic basis for this association remains unknown. In order to understand this association further, a combination of rest/activity and molecular profiling was carried out on mouse models of Parkinson’s Disease (PD), Lysosomal Storage Disorders (LSDs) and schizophrenia.</p> <p>Data from rest/activity behavioural screening of new BAC (Bacterial Artificial Chromosome) transgenic PD models displayed scotophase hyperactivity and decreased fragmentation patterns. Interestingly, rest/activity profiles of LSD models displayed possible core clock defects under constant conditions (<em>Hexb<sup>-/-</sup></em>) and potential re-entrainment deficits following a 6hr phase advance (<em>Npc1<sup>-/-</sup></em>). Together these data suggest new associations between disruptions in rest/activity cycles and neurodegeneration.</p> <p>The blind-drunk (<em>Bdr</em>) mutant is a mouse model of synaptosomal-associated protein <em>(Snap)-25</em> exocytotic disruption that displays schizophrenic endophenotypes and phase advanced rest/activity cycles. Despite identification of phase advanced expression of signalling neuropeptides (e.g. arginine vasopressin) in the <em>Bdr</em> suprachiasmatic nucleus (SCN), the underlying mechanisms regulating circadian disruption in this model remain elusive; therefore, label-free shotgun proteomics was carried out over 24 hours to elucidate potential post-transcriptional pathways. A number of novel circadian patterns of protein expression were identified including myristoylated alanine-rich C-kinase substrate (MARCKS) which exhibited a robust phase advanced expression profile. This study has identified novel SCN post-transcriptional mechanisms that may link schizoaffective disorder biomarkers to dysfunctional rest/activity cycles.</p> |
| spellingShingle | Biology (medical sciences) Neuropathology Psychiatry Livieratos, A Investigating circadian disruption in mouse models of neurological and metabolic disorders |
| title | Investigating circadian disruption in mouse models of neurological and metabolic disorders |
| title_full | Investigating circadian disruption in mouse models of neurological and metabolic disorders |
| title_fullStr | Investigating circadian disruption in mouse models of neurological and metabolic disorders |
| title_full_unstemmed | Investigating circadian disruption in mouse models of neurological and metabolic disorders |
| title_short | Investigating circadian disruption in mouse models of neurological and metabolic disorders |
| title_sort | investigating circadian disruption in mouse models of neurological and metabolic disorders |
| topic | Biology (medical sciences) Neuropathology Psychiatry |
| work_keys_str_mv | AT livieratosa investigatingcircadiandisruptioninmousemodelsofneurologicalandmetabolicdisorders |