Translational new approaches for investigating mood disorders in rodents and what they may reveal about the underlying neurobiology of major depressive disorder

Abstract

Mood disorders represent one of society's most costly and challenging health burdens. The drug treatments used today were initially discovered serendipitously in the 1950s. Animal models were then developed based on the ability of these drugs to alter specific behaviours. These models have played a major role in the development of the second generation of antidepressants. However, their use has been heavily criticized, particularly in relation to whether they recapitulate similar underlying biology to the psychiatric disorder they are proposed to represent. This article considers our work in the field of affective bias and the development of a translational research programme to try to develop and validate better animal models. We discuss whether the new data that have arisen from these studies support an alternative perspective on the underlying neurobiological processes that lead to major depressive disorder (MDD). Specifically, this article will consider whether a neuropsychological mechanism involving affective biases plays a causal role in the development of MDD and its associated emotional and behavioural symptoms. These animal studies also raise the possibility that neuropsychological mechanisms involving affective biases are a precursor to, rather than a consequence of, the neurotrophic changes linked to MDD.This article is part of a discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'.

Keywords: affective bias; animal model; major depressive disorder; neuropsychology; neurotrophic.

Figure 1.

Schematic representation of a strategy for the development and validation of novel, translational behavioural methods for translational psychiatry. The choice of behavioural measure is key and should be specific to the condition of interest, objective and quantifiable. The process of developing the task and validation is illustrated through to the ideal scenario whereby the resulting behavioural approach can be across species to investigate novel biology, identify and develop new therapeutics and ultimately, test these in the same behavioural test in both pre-clinical and clinical drug development.

Figure 2.

Summary of the pharmacological and psychosocial manipulations tested in the validation of the affective bias test (ABT). The results show that changes in absolute reward value as well as antidepressant drugs and social enrichment induce positive biases following acute treatment. In contrast, risk factors linked to the development of MDD in humans cause negative biases in this task. Adapted from [56,74,75]. LPS, lipopolysaccharide.

Figure 3.

Summary of results for the modified ABT (mABT) showing reward-induced positive bias and its attenuation in putative models of depression. Animals exposed to early life adversity, chronic treatment with corticosterone, interferon alpha or retinoic acid all show impairments in their ability to learn the reward value and fail to bias their choices based on the higher value reward. In contrast to this anticipatory anhedonia, deficits in sucrose preference were only observed in animals receiving the chronic corticosterone treatment. ([75]; SA Stuart and ESJ Robinson 2015, unpublished). (Online version in colour.)

Figure 4.

The neurotrophic hypothesis (a) and an alternative affective bias hypothesis (b), which illustrate the different relationship between behavioural symptoms of MDD and changes in brain morphology. The novel model proposed here reverses the relationship between neuroplasticity and brain atrophy, suggesting these occur because of the behavioural changes induced by negative affective biases. *See [89] for more detailed discussion of relevant signalling pathways. BDNF, brain-derived neurotrophic factor.