Anatomy and Neuroscience - Theses
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ItemNo Preview AvailableTracing Diet and Mobility of Past Human Populations in Greater Mtskheta, Georgia( 2021)The region of Greater Mtskheta (Republic of Georgia) lies in the Southern Caucasus and presents a near continuous record of human occupation throughout the Late Bronze-Early Iron Age (LBA-EIA, 1500-500 BC), Hellenistic Period (400-1 BC) and Roman-Late Antique Period (RLA; AD 1-700). Greater Mtskheta became increasingly urbanised, densely populated and hosted an increasingly complex society during these time periods. Contemporary written sources provide little insight into the lifestyles and social organisation maintained by Mtskheta’s inhabitants; researchers rely heavily on the trace remains of Mtskheta settlements and cemeteries to reconstruct how the inhabitants lived and what resources they consumed. Archaeological investigations reveal that by the 1st century AD, the resident society was multi-cultural, socially stratified and maintained far-reaching trade networks with the Greeks, Romans, Parthians, and Sassanid Persians. Following the 4th century AD a series of cultural changes emerge in Greater Mtskheta cemeteries including a shift in burial customs, the appearance of people with intentionally modified crania and new ‘Eurasian’ styles of grave goods. These changes suggest a novel cultural influence arrived in Mtskheta at this time, which has been tentatively attributed to contact with Eurasian nomadic-pastoralists from the steppe of southern Russia. Stable Isotope analysis of archaeological human and faunal remains can provide insight into the diet composition and mobility of people from ancient times. This research examines carbon, nitrogen and strontium isotope ratios (d13C, d15N, and 87Sr/86Sr) of humans excavated from Greater Mtskheta cemeteries remains dating between 1500 BC-AD 700. Diet was compared between time periods, sites, demographic groups (age-at-death, sex) and cultural groups (burial types, modified/unmodified skulls) to illustrate how dietary access or preferences differed over time and between these groups. Further, analyses were used to examine the role migration played in the onset of cultural changes after the 4th century. d13C and d15N results show Greater Mtskheta residents consumed a mixed C3 and C4 diet in the LBA-EIA, which is consistent with a trend in similar studies of human populations in Inner Asia and the South Caucasus during this time. The human diet in Mtskheta transitioned to a C3-dominated diet by the RLA Period, a trend which was also displayed by 87Sr/86Sr populations in the Kislovodsk basin (North Caucasus). LBA-EIA diets differed between men and women, possibly indicating greater animal product consumption among males of this period; while diets became isotopically homogeneous between sites and demographic groups in the RLA period, at a time when social stratification and complexity in Mtskheta was at its peak. The 87Sr/86Sr results demonstrate some individuals with intentionally modified skulls immigrated to Mtskheta after the 4th century, and these individuals may have originated from the vicinity of the North Caucasus or Alazani Valley. This study demonstrates the Greater Mtskheta human diet changed significantly between the LBA-EIA and the RLA with increasing social complexity, and indicates the Greater Mtskheta inhabitants maintained cultural connections with the surrounding regions throughout these time periods, apparently mirroring regional isotopic trends in diet, and evidently accommodating migrants after the 4th century AD.
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ItemGenetic, metabolic and pharmacological modulation of seizure susceptibility in mouse models of genetic epilepsy( 2013)Epilepsy is a common neurological disorder that is poorly understood. A large proportion of epilepsies have a strong familial component. The GABAA γ2 (R43Q) mutation was discovered in an Australian family with genetic epilepsy with febrile seizures + (GEFS+) that predominantly have febrile seizures (FS) and childhood absence epilepsy (CAE). A mouse model based on the mutation recapitulates these seizure types and is sensitive to first-line antiepileptic drugs. The model therefore provides an opportunity to study aspects of the genesis of epilepsy with relevance to the human condition. The work performed in this thesis describes the use of this syndrome specific mouse model to investigate aspects of seizure genesis and modulation. Three research questions are addressed; the genetic mechanisms underlying seizure genesis, metabolic and dietary modulation of seizure activity and pharmacological sensitivity to new anti-epileptic drugs in the GABAA γ2 (R43Q) mouse. Clinical heterogeneity in genetic epilepsy is common and is typically characterized by multiple seizure types and incomplete penetrance for a given protein mutation. However, the molecular and genetic basis of clinical heterogeneity is not well understood. Here, two models, GABAA γ2 (R43Q) knock-in and GABAA γ2 knock-out were used to determine the fundamental molecular mechanisms of the GABAA γ2 (R43Q) mutation underlying individual seizure phenotype. Spike-wave discharges (SWD) recorded on electroencephalogram from the GABAA γ2 (R43Q) mouse are associated with behavioural arrest and model absence epilepsy. A reduced latency to first heat-induced tonic-clonic seizure is consistent with a FS phenotype. Both the knock-in and knock-out models expressed SWDs while only the knock-in had a reduced latency to thermogenic seizures. This comparison demonstrates that two fundamental molecular mechanisms independently cause the two major seizure types in the mouse model. Haploinsufficiency could account for the SWD phenotype while a dominant impact of the mutation must be required for the FS phenotype. Subsequent investigation using mice of varying genetic background showed that the SWD phenotype required additional genetic susceptibility. In contrast, FS phenotype occurred independently of background genetics consistent with its higher penetrance compared to absence epilepsy in the GABAA γ2 (R43Q) family. Environmental modulation of neuronal excitability has been long known to alter seizure susceptibility. Altered metabolism using dietary intervention, such as the ketogenic diet, is a well recognized epilepsy therapy. The ketogenic diet conveys its anticonvulsant effects presumably through the stabilization of blood glucose and/or providing an alternative energy substrate. Here, the impact of a number of metabolic manipulations was investigated in the GABAA γ2 (R43Q) mouse model. Overnight fasting lowered blood glucose levels and increased SWD occurrence suggesting it as a potential seizure precipitant. Low-GI and triheptanoin diets on the other hand reduced SWD activities suggesting that both stabilization of blood glucose levels and provision of additional energy substrates may independently offer anticonvulsant effects. Importantly, these diets have less tolerability issues making them a potential alternative to the poorly tolerated ketogenic diet. In-vivo drug testing is a critical step for drug discovery. Oxcarbazepine (OXC) is a second-generation drug that is typically used to control partial seizures. Like its older generation carbamazepine, OXC is contraindicated in patients with generalized epilepsy. OXC is metabolized to monohydroxy derivatives (MHD) in two enantiomeric-forms, S-(+)-licarbazepine and R-(+)-licarbazepine. The effects of individual metabolites have not been adequately characterized. In this study, OXC increased the frequency of SWDs in the GABAA γ2 (R43Q) model, consistent with clinical observation. Similarly, both MHDs also caused seizure aggravation. However, OXC and MHDs were ineffective at altering the sensitivity of mice to thermogenic seizures. The findings indicate that like OXC, its derivatives may be contraindicated in certain forms of generalized epilepsy.