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Title: Studies of emotionality in genetic mouse models of altered glutamate or 5-HT function
Author: Barkus, Christopher
ISNI:       0000 0004 2702 5806
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2010
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The role of 5-HT in depression and its treatment is well established but there is also growing evidence for the role of glutamate in emotionality. Several transgenic mouse lines were used to investigate how alterations in the glutamate or 5-HT systems impact upon emotional behaviour and relevant neuronal systems. Transgenic mice with direct manipulations of the glutamate system did not provide a selective model with which to further investigate changes in emotionality. GluA1 knockout mice showed only transient effects on antidepressant-sensitive tests which may alternatively be explained by deficits in habituation. GluN1 hypomorph mice displayed altered behaviours in all tests performed, including global cognitive impairments, making further interpretation of the results difficult. Vesicular glutamate transporter 1 heterozygote mice, which have been implicated as a model depression, were found to have only minor alterations in behaviour, none relating to emotionality. In contrast, the 5-HT transporter overexpressor mice have previously been shown to reliably display reduced anxiety and a fear conditioning deficit in line with results in humans with differing expression levels of the 5-HT transporter. Constant potential amperometry was used to measure local tissue oxygen content as an equivalent to the BOLD response in fMRI, and local field potential recordings of population electrical activity were also recorded in the basolateral amygdala of 5-HT transporter overexpressor and wildtype mice during a differential fear conditioning paradigm. This revealed that 5-HT transporter overexpressor mice have reduced basolateral amygdala oxygen responses to a conditioned stimulus associated with footshock, correlating with fMRI responses to fearful faces, and a reduced theta:delta ratio in this brain area that is most prominent following conditioning, implying a less active amygdala in these mice under these conditions. In summary, gross manipulations of glutamate function may not be useful in investigating the role of this neurotransmitter system in emotionality. Manipulation of the expression levels of the 5-HT transporter that mimics the variation seen across the human population alters neurochemical responses to conditioned fear stimuli, providing a translational model for future investigations into emotional processing.
Supervisor: Bannerman, David M. ; Sharp, Trevor Sponsor: Biotechnology and Biological Sciences Research Council ; GlaxoSmithKline plc
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Behavioural Neuroscience ; Cognition ; Emotion ; Experimental psychology ; Learning ; Amperometry ; behaviour ; anxiety ; depression ; glutamate