Evidence that neuropsychological deficits following early life adversity may underlie vulnerability to depression

Abstract

Early life adversity (ELA) is a risk factor for major depressive disorder (MDD), however the underlying mechanisms are not well understood. Clinical studies suggest that negative affective biases (the process whereby cognitive processes such as learning and memory and decision-making are modified by emotional state) represent a vulnerability factor for MDD. In this study we investigate the impact of ELA on affective biases and reward-associated behaviours in rats. Sprague Dawley rat pups underwent 14 days of postnatal maternal separation (180min/day from postnatal day 1: MS180) whilst control pups remained unhandled. In adulthood, affective biases associated with reward learning and decision-making were assessed using the affective bias test (ABT), or judgement bias task (JBT) respectively. Changes in motivation and reward sensitivity were tested in a progressive ratio (PR) schedule of operant responding and the sucrose preference test (SPT) respectively. We observed that MS180 animals expressed enhanced negative biases in response to acute corticosterone treatment but without effects on antidepressant-induced positive biases. ELA animals were impaired in their ability to develop appropriate biases in response to changes in reward value in a modified ABT but in the absence of any changes in reward sensitivity or motivation. No effects on decision-making were observed in the JBT but MS180 animals failed to develop the same more optimistic behavioural profile as controls in response to an increase in reward value. These findings suggest that ELA in rats increases vulnerability to negative affective biases and impairs animals' ability to appropriately learn reward value, independent of a reward sensitivity or changes in motivation. These data provide important evidence linking ELA with relevant neuropsychological impairments that may explain increased risk of developing MDD.

Cognitive flexibility mediates the association between early life stress and habitual behavior

“…However, excessive or chronic stress during early sensitive periods has been associated with impaired cognitive functions, including cognitive flexibility which may impede the ability to generate alternative choices and adaptive behavior in the context of changing environmental contexts (e.g. Harms et al, 2018;Stuart, Hinchcliffe, & Robinson, 2019). Cognitive flexibility represents an important resource to adaptively cope with stressful life events (Murphy et al, 2012) and ELS-induced impairments in this domain may shift the balance towards automatic habitual behavior.…”

Evidence for deficits in behavioural and physiological responses in aged mice relevant to the psychiatric symptom of apathy

“…Training was similar to that reported by Stuart et al (2019). Mice were trained in sound-proof operant boxes (Med Associates Inc) which were run on Klimbic software (Conclusive Solutions Ltd., UK).…”

“…Rodents are known to supress feeding in response to novelty and the time taken to eat in this novel context provides a behavioural readout of this stress response. The NSFT is based on this principle and has been used for decades in the pre-clinical testing of anxiolytics and antidepressants (Nestler and Hyman, 2010;Shephard and Broadhurst, 1982) and in phenotypic studies of depression models including ELA and chronic social defeat stress (Stuart et al, 2019;Venzala et al, 2012). In the NSF test, aged mice were quicker to consume food in a novel environment, suggesting lower novelty-induced hyponeophagia.…”

“…We chose to use the novelty supressed feeding test (NSFT) and then quantify both baseline and stress-induced corticosterone and post-mortem c-Fos expression to investigate the effects of ageing on stress reactivity at a behavioural, physiological and cellular level. The NSFT has been used to investigate stress-related behaviours in depression and anxiety research in phenotypic models, and studies in models such as early life adversity (ELA) has shown both behavioural changes in the NSFT and stress reactivity at a physiological and molecular level (Stuart et al, 2019;Uchida et al, 2010). We also tested animals using the sucrose preference test to quantify reward sensitivity and performed a novel object recognition test to look at their associative recognition memory.…”

Early-life stress and inflammation: A systematic review of a key experimental approach in rodents

“…Furthermore, there are many reports suggesting that RMS causes long-lasting effects on a diverse array of not just immunological outcomes but also depressive-like behaviour, anxiety-like behaviour, and gastrointestinal tract function, among others (Dallé et al, 2017; Mizoguchi et al, 2019; Oines et al, 2012). Equally, however, for some of these outcomes, there are many reports that find no long-lasting effect (Bassey and Gondré-Lewis, 2019; Harrison et al, 2014; Stuart et al, 2019).…”