AbstractEarly life stress (ELS) is one of the biggest known risk factors for the development of a range of psychiatric disorders including depression. Events exceeding a child’s ability to cope lead to elevated glucocorticoid concentrations which cause abnormal brain development with regions involved in reward circuitry such as the hippocampus, amygdala and prefrontal cortex being most impacted. Impairments of reward learning (RL) have been reported to act as an intermediate phenotype in the aetiology of depression. This thesis therefore investigates the hypothesis that ELS predisposes to depression through reprogramming of brain regions associated with reward which causes reward processing deficits that in turn lead to the development of depression.
Reward learning was initially attempted to be assessed in a mouse model of ELS using a modified version of the affective bias test. ELS mice showed no differences in RL compared to controls, however there was evidence for a lack of an affective phenotype in the mouse model. A translational reward learning assay, the probabilistic reversal learning task (PRLT), was therefore validated in a cohort of rats for use in future ELS studies. This task was initially sensitive to manipulations of serotonin but showed non-specific impairments following a range of other manipulations including ketamine and amphetamine administration. Task sensitivity also decreased over time suggesting a window of opportunity for successful use. Next the electrophysiological consequences of ELS were assessed in the hippocampus of rats. Maternally separated rats showed increased NMDA but not AMPA receptor function but no changes in basal transmission. Finally reward learning was assessed in a cohort of humans with high levels of ELS. ELS was associated with decreased positive feedback sensitivity and reduced initial learning in the PRLT. The results from this thesis suggest that the proposed hypothesis is plausible, however further work is needed to both confirm this and translate findings into patient benefit.
|Date of Award||11 May 2021|
|Supervisor||Jack R Mellor (Supervisor) & Emma S J Robinson (Supervisor)|
- Early life stress
- Reward learning
- Mental Health