- Title
- Exploring mismatch negativity, a neurophysiological biomarker of schizophrenia, in a rat model
- Creator
- Jalewa, Jaishree
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2021
- Description
- Research Doctorate - PhD Psychology
- Description
- Schizophrenia is a chronic and debilitating mental illness with onset in late adolescence to early adulthood, resulting in lifetime disability. In addition to the psychotic symptoms, cognitive impairments impede the ability of patients to perform everyday tasks and are a major cause of poor functional outcome, thus adding to the social and economic burden of the disorder. Despite substantial progress since the development of the first antipsychotic medication, chlorpromazine and other dopamine receptor (D2) antagonists more than fifty years ago, these drugs have little effect on the cognitive impairments and thus there is urgent unmet need for new effective therapeutic interventions. To date, the neurobiology of schizophrenia remains unclear, highlighting the need for an improved understanding of the neurobiological basis of the negative and cognitive symptoms. Animal models play a significant role in investigating the disease mechanism and the efficacy of new treatments at pre-clinical level. However, it is difficult to address the human-like schizophrenia symptoms in rodents because the abnormalities associated with schizophrenia are of unique human nature and diagnosis of the illness is often based on self-reported symptoms. So far, several behavioural tasks are available as validation tools, but they have limitations. Furthermore, a lack of appropriate preclinical models of schizophrenia that could be used to accurately identify, test and assess the validity of potential pharmacological targets, is a major hurdle in the path of development of novel schizophrenia treatment. The objective of this PhD thesis is to explore a quantitative neurophysiological biomarker of schizophrenia - mismatch negativity (MMN) in a rat model. Chapter 1 provides a detailed overview of developmental risk factors of schizophrenia – maternal immune activation and adolescent cannabinoid exposure. Chapter 2 provides a literature review on MMN and presents novel data investigating whether mismatch responses (MMRs) in rats are sensitive to the same parameters as MMN in humans – deviance difference, deviant probability and timing variability. Chapter 3 examines the effect of cumulative schizophrenia risk factor exposure on these measures. Chapter 4 explores another MMN attribute in rats, the Primacy bias, which refers to an order-dependent bias found to affect the MMN amplitude in humans. Chapter 5 investigates if prenatal and adolescent insults affect rat sensitivity to ascending and descending deviants in the primacy paradigm. Chapter 6 is a proof-of-concept study designed to elucidate the functional significance of MMR in rats using a distraction paradigm to explore whether MMR in rats consumes attentional resources in a similar fashion as MMN in humans. Overall, this thesis provides evidence that rat MMRs exhibit human MMN attributes, though not for the primacy bias and distraction effects. In addition, this work observes an impact of schizophrenia risk factors on the MMR amplitude, which are applied in a context-, latency- and sex-specific manner. Taken together, my PhD research work addresses two major questions, firstly, how human-like is the rat MMR, and secondly, how schizophrenia-like is the two-hit rat MMR? The thesis findings demonstrates MMR, an electrophysiological measure in rats, as a promising outcome measure for schizophrenia preclinical research. The results obtained in this thesis has revealed that a two-hit rat model for schizophrenia has a potential for the pre-clinical assessment of efficacy of new pharmacological targets and development of new treatments for mental illness. The significance of this thesis lies in new opportunities for validating the pre-clinical schizophrenia rodent models, testing novel drug targets, testing specific hypotheses of computational modelling, and advancing knowledge of prediction error processes in the mammalian brain, overall contributing towards the advancement of neuropsychiatric research.
- Subject
- mismatch negativity; schizophrenia; thesis by publication; mismatch responses; electroencephalogram; deviance difference; deviant probability; jitter; primacy; predictive coding; attention
- Identifier
- http://hdl.handle.net/1959.13/1509519
- Identifier
- uon:56254
- Rights
- Copyright 2021 Jaishree Jalewa
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 7 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 308 KB | Adobe Acrobat PDF | View Details Download |