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Depression and dementia: The effect of amyloid pathology and therapeutic interventions on affective and cognitive processes in mice

Brelsford, Adam Richard 2019. Depression and dementia: The effect of amyloid pathology and therapeutic interventions on affective and cognitive processes in mice. PhD Thesis, Cardiff University.
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Preclinical mouse models of Alzheimer’s disease capture cognitive impairments which can be attributed to β-amyloid (Aβ) pathology. Aβ pathology may also be an antecedent of depressive symptoms in these mouse models, though this has been less rigorously investigated. This thesis reports a longitudinal investigation of both the depressive symptom of anhedonia (a reduction in pleasurable reactions), and memory of specific object-location associations, in the Tg2576 mouse model of Alzheimer’s disease. The effectiveness of sub-anaesthetic ketamine, largely as an anti-depressant treatment, was also examined in anhedonic and cognitively impaired Tg2576 mice. Possible biochemical underpinnings of these deficits were then investigated, namely the glutamate, serotonin and opioid signalling systems. Tg2576 mice displayed an age-dependent reduction in hedonic reactions, consistent with an Aβ-related deficit. While object-in-place testing did not explicitly reveal an age-dependent dysfunction, Tg2576 mice were only impaired later in life, consistent with aging and Aβ underlying their diminished performance. An additional T-maze task revealed that aged Tg2576 mice retained a preference for spatial novelty. While ketamine treatment increased expression of measures relating to the AMPA receptor GluR1 subunit, it did not improve hedonic or cognitive dysfunction in Tg2576 mice. Tg2576 mice displayed a relative reduction in Y1472 phosphorylation of the NMDA receptor NR2B subunit in the hippocampus, suggesting an NMDAR-mediated dysfunction underlying their object-in-place deficit. Investigation of the opioid system in Tg2576 mice revealed elevations of cortical kappa and hippocampal mu receptor expression. An unbalanced opioid system may therefore diminish hedonic tone in Tg2576 mice. Tg2576 mice also displayed elevated cortical serotonin transporter expression, though the relation of this to behavioural deficits was less clear. This thesis demonstrates that Aβ and its potential effects on the glutamate and opioid systems can underlie both amnesic and affective symptoms in Tg2576 mice, though an attempt to remedy these impairments was unsuccessful.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Psychology
Subjects: B Philosophy. Psychology. Religion > BF Psychology
Funders: School of Psychology, School of Pharmacy
Date of First Compliant Deposit: 2 March 2020
Date of Acceptance: 17 February 2020
Last Modified: 02 Mar 2020 11:27

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