Apathy is widely reported in patients with neurological disorders or post viral infection but is also seen in otherwise-healthy aged individuals. This study investigated whether aged male mice express behavioural and physiological changes relevant to an apathy phenotype. Using measures of motivation to work for reward, we found deficits in the progressive ratio task related to rate of responding. In an effort-related decision-making task, aged mice were less willing to exert effort for high value reward. Aged mice exhibited reduced reward sensitivity but also lower measures of anxiety in the novelty supressed feeding test and an attenuated response to restraint stress with lower corticosterone and reduced paraventricular nucleus c-fos activation. This profile of affective changes did not align with those observed in models of depression but suggested emotional blunting. In a test of cognition (novel object recognition), aged mice showed no impairments, but activity was lower in a measure of exploration in a novel environment. Together, these data suggest aged mice show changes across the domains of motivated behaviour, reward sensitivity and emotional reactivity and may be a suitable model for the pre-clinical study of the psychiatric symptom of apathy.

The advancement and quality of science rely on research that is robust and unbiased in its experimental design, execution, analysis, and reproducibility. In preclinical research, a better understanding of animal emotions and refinement of their husbandry, housing, and handling are important goals in providing good animal welfare in a laboratory setting which underpins rigorous research quality. Induction of positive emotional state in animals is a key component of their well-being, and one approach is to increase their environmental complexity using, for example, ball pits or playpens in rats. In this study, we recorded 50 kHz ultrasonic vocalisations (USVs) during animals’ exposure to the ball pit and playpen. We have previously shown that 50 kHz USVs provide a graded and quantifiable measure of an animal’s emotional state, and here find that access to the ball pit and playpen increases 50 kHz USVs, indicative of a more positive affective state. Using our affective bias test (ABT) we next quantified the animals’ emotional response to an aversive intervention and whether this could be attenuated by access to a playpen. The playpen exposure completely mitigated the negative affective state induced by an anxiogenic drug when compared with animals who experienced the drug in the home cage. Together, these findings suggest ball pits and playpens provide a simple and effective method to improve the welfare of laboratory rats and reduce the cumulative suffering they experience from their housing conditions and minor, aversive procedures.

Both the neuropsychiatric syndrome of apathy and major depressive disorder comprise a heterogenous cluster of symptoms which span multiple behavioural domains. Despite this heterogeneity, there is a tendency in the preclinical literature to conclude a MDD or apathy-like phenotype from a single dimensional behavioural task used in isolation, which may lead to inaccurate phenotypic interpretation. This is significant, as apathy and major depressive disorder are clinically distinct with different underlying mechanisms and treatment approaches. At the clinical level, apathy and major depressive disorder can be dissociated in the negative valence (loss) domain of the Research Domain Criteria. Symptoms of MDD in the negative valence (loss) domain can include an exaggerated response to emotionally salient stimuli and low mood, while in contrast apathy is characterised by an emotionally blunted state. In this article, we highlight how using a single dimensional approach can limit psychiatric model interpretation. We discuss how integrating behavioural findings from both the positive and negative (loss) valence domains of the Research Domain Criteria can benefit interpretation of findings. We focus particularly on behaviours relating to the negative valence (loss) domain, which may be used to distinguish between apathy and major depressive disorder at the preclinical level. Finally, we consider how future approaches using home cage monitoring may offer a new opportunity to detect distinct behavioural profiles and benefit the overall translatability of findings.

Rationale Motivational deficits are a common symptom shared across multiple psychiatric and neurodegenerative disorders. Effort-based decision-making tasks are a translatable method for assessing motivational state. Much of the preclinical validation of the task derives from acute pharmacological manipulations in rats. However, mice currently offer a greater genetic toolkit to study risk genes and phenotypic models. Despite this, there is limited characterisation of their behaviour in this type of motivation task. Objectives Here, we investigate the effort for reward (EfR) task as a measure of motivational state in mice using drugs previously shown to modulate effort-based decision-making in rats and humans. Method Using male C57bl/6j mice, we test the effects of drugs which modulate DA transmission. We also test the effects of CP101-606 which does not act directly via DA modulation but has been shown to exert beneficial effects on motivational state. Finally, we test the sensitivity of the task to a chronic corticosterone (CORT) treatment. Results Amphetamine, methylphenidate, and CP101606 in mice increased high-effort responses for high-value reward, while administration of haloperidol decreased high-effort responses. Surprisingly, tetrabenazine had no effect at the doses tested. Chronic, low-dose CORT consumption did not alter task performance. Conclusion These data suggest that the EfR task is sensitive to acute dopaminergic modulation and NR2B selective antagonism in mice. However, it may lack sensitivity to non-acute phenotypic models. Further work is required to demonstrate the utility of the task in this context.

Apathy is widely reported in patients with neurological disorders or post viral infection but is also seen in otherwise-healthy aged individuals. This study investigated whether aged mice express behavioural and physiological changes indicative of an apathy phenotype. Using measures of motivation to work for reward, we found deficits in the progressive ratio task related to rate of responding. In an effort for reward task, aged mice were less willing to exert effort for high value reward. Aged mice exhibited reduced reward sensitivity and expressed lower measures of anxiety in the novelty supressed feeding test. In a test of cognition (novel object recognition) aged mice showed no impairments but activity was lower in a measure of exploration in a novel environment.Aged mice also showed an attenuated response to restraint stress with lower corticosterone and reduced paraventricular nucleus c-fos activation. Together, these data suggest aged mice show reduced goal-directed behaviour and reduced reward sensitivity and stress reactivity, reflective of emotional blunting and may be a suitable model for pre-clinical apathy research.