Changes in cognitive function and behavioural responses associated with neuropsychiatric disorders

  • Madeleine Elizabeth Cleal

Student thesis: Doctoral Thesis

Abstract

Neuropsychiatric disorders are on the rise and many are subject to memory and cognitive deficits, which have poor treatment options, generating a great need to better understand the underlying mechanisms to aid future therapeutics. Schizophrenia and drug abuse are neuropsychiatric disorders that are characterised by symptoms of cognitive and behavioural deficits. As with many psychiatric disorders they are the result of genetic and environmental influences that converge on altered behaviour and cognitive processing. Two cognitive domains frequently found to be disrupted in neuropsychiatric disorders are working memory and cognitive flexibility.
Zebrafish are growing in use as a model of complex neuropsychiatric disorders. High genetic homology to humans and ease of genetic manipulation have resulted in a number of zebrafish lines characteristic of many human neuropsychiatric conditions, including schizophrenia and substance abuse. The primary aim of this thesis is the development and validation of a new cross-species task of cognitive assessment. Here I describe the first uses of the Free-Movement Pattern (FMP) Y-maze, a robust and reliable test of cognitive function with both preclinical and clinical applications. The work of this thesis has provided the foundation of future cognitive assessments in zebrafish and paved the way to increased translatability of therapeutic strategies targeting cognitive function from zebrafish models to humans and have been the first to describe comparative deficits in working memory in healthy ageing in zebrafish and humans. I have described the first longitudinal study of cognitive and neuroendocrine development from larvae to young adult and found several biomarkers that could be used to identify critical periods of increased susceptibility to the development of neuropsychiatric disorders. I have also described the first model of cognitive sensitization in zebrafish. Additionally, through the design of a new model of schizophrenia-like phenotypes, I have described a possible genetic link between schizophrenia and nicotine addiction. Finally, this is the first description of cognitive deficits in a zebrafish disc1 model of schizophrenia.
Date of Award2020
Original languageEnglish
SupervisorMatthew Parker (Supervisor) & Jerome Swinny (Supervisor)

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