A translational research framework for enhanced validity of mouse models of psychopathological states in depression

Abstract

Depression presents as a disorder of feelings and thoughts that debilitate daily functioning and can be life threatening. Increased understanding of these specific emotional-cognitive pathological states and their underlying pathophysiologies and neuropathologies is fundamental to an increased understanding of the disorder and, therefore, to development of much-needed improved therapies. Despite this, there is a current lack of emphasis on development and application of translational (i.e. valid) neuropsychological measures in depression research. The appropriate strategy is neuropsychological research translated, bi-directionally, between epidemiological and clinical human research and in vivoex vivo preclinical research conducted, primarily, with mice. This paper presents a translational framework to stimulate and inform such research, in four inter-dependent sections. (1) A depression systems-model describes the pathway between human environment-gene (E-G) epidemiology, pathophysiology, psycho-and neuropathology, symptoms, and diagnosis. This model indicates that G-->emotional-cognitive endophenotypes and E-G/endophenotype-->emotional-cognitive state markers are central to experimental and translational depression research. (2) Human neuropsychological tests with (potential) translational value for the quantitative study of these endophenotypes and state markers are presented. (3) The analogous rodent behavioural tests are presented and their translational validity in terms of providing analogue emotional-cognitive endophenotypes and state markers are discussed. (4) The need for aetiological validity of mouse models in terms of G-->endophenotypes and E-G-->state markers is presented. We conclude that the informed application of the proposed neuropsychological translational framework will yield mouse models of high face, construct and aetiological validity with respect to emotional-cognitive dysfunction in depression. These models, together with the available technological tools, can then be studied to increase understanding of depression pathophysiology and neuropathology, leading to identification and validation of novel therapeutic targets and the development of effective, personalized antidepressant treatments. The need for aetiological validity of mouse models in terms of G → endophenotypes and E-G → state markers is presented. We conclude that the informed application of the proposed neuropsychological translational framework will yield mouse models of high face, construct and aetiological validity with respect to emotional-cognitive dysfunction in depression. These models, together with the available technological tools, can then be studied to increase understanding of depression pathophysiology and neuropathology, leading to identification and validation of novel therapeutic targets and the development of effective, personalized anti-depressant treatments.

Mouse psychosocial stress reduces motivation and cognitive function in operant reward tests: A model for reward pathology with effects of agomelatine

“…The RDoC approach is conducive with translational research aimed at increasing understanding of disorder pathophysiology. This includes evidence obtained from animal models that combine manipulations with aetiological validity with behavioural readout tests with face validity for specific psychopathologies (Pryce and Seifritz, 2011).…”

Establishing a probabilistic reversal learning test in mice: Evidence for the processes mediating reward-stay and punishment-shift behaviour and for their modulation by serotonin

“…There is a current deficiency of animal tests for detailed study of depression-relevant emotional-cognitive processes (Pryce and Seifritz, 2011). This is despite the clinical and therapeutic importance of altered emotional-cognitive processing in depression psychopathology, the availability of non-verbal emotional-cognitive tasks such as PRL to quantify such states, and the potential for these tasks to be adapted to animal species.…”

Altered Associative Learning and Learned Helplessness in Major Depression

“…Mirroring instrumental learning theory, which proposes that subjects learn that their behavior controls reinforcement, learned helplessness proposes that subjects learn that their behavior cannot control reinforcement [49]. In contrast to animal research, however, few studies have used the original (triadic) experimental design to investigate learned helplessness in humans [50]. Moreover, most of these studies did not assess the neural correlates of learned helpless behaviors and they were often conducted in healthy individuals or analogue subjects rather than clinically depressed patients.…”