Biology subjects

Jackson, M. G.

Publications and source records attributed to Jackson, M. G..

9 recordsLinked to original sources

bioRxiv2026

Male mouse strain variation reveals divergent phenotypes for extrinsic and intrinsic reward motivation

Motivational deficit is a prevalent symptom across a wide range of neurodegenerative and neuropsychiatric disorders. Despite its clinical importance, first-line treatments for these disorders fail to effectively treat this symptom domain. In animal models, motivation is typically assessed in the context of extrinsic reward, where reward is delivered for completing an effortful action. However, many motivated behaviours occur in the absence of a tangible reward and are instead driven by intrinsic motivation. Previous work has shown that an extrinsic motivation task (effort for reward (EfR)) and an intrinsic motivation task (effort based forage (EBF) task) show opposing responses to a range of pharmacological manipulations. However, it is not clear whether intrinsic and extrinsic motivation dissociate in the context of endogenous behavioural variation. We therefore investigated whether these tasks were sensitive to behavioural variation across three different strains of mice (C57Bl/6JJRi, 129S2/SvPasOrlRj and BALB/cJRi) and whether strain profiles diverged across tasks. Here, we found that BALB/c mice showed the lowest levels of foraging in the EBF task, indicative of a low intrinsic motivational state but showed the highest levels of high effort responding in the EfR task, indicative of a high extrinsic motivational state. These differences were not driven by an anxiety-related phenotype and were therefore indicative of a motivation phenotype divergence across tasks. This work highlights the importance of moving away from considering motivation on a single axis, as findings can diverge depending on the nature of the motivational process. This has important implications for both phenotypic interpretation and the development of treatments targeting motivational dysfunction.

animal behavior and cognition↗

bioRxiv2026

Beyond the Barrier: An Assessment of Social Behaviour in Mice using a Modified 3-Chamber Test

BackgroundThe three-chamber test (3CT) is widely used to assess social behaviour in mice, based on the assumption that time spent near a conspecific reflects motivation for social contact. However, the design of the task constrains interpretation, as behaviour may reflect exploration, novelty seeking, or territorial investigation rather than affiliative social motivation. In addition, key biological factors such as sex differences and social hierarchy are often overlooked. AimsWe hypothesised that the 3CT overestimates sociability and used a direct-interaction phase to investigate motivation for affiliative social contact. We also integrated social status to determine if this modulated behavioural patterns and interacted with sex. MethodsAdult male and female C57BL/6 mice (n = 32) were tested in a standard 3CT, followed by removal of the cage barrier to permit direct contact. Behavioural parameters were quantified, and social status was determined using the tube test. ResultsMales exhibited higher social interest index scores than females. Once the barrier was removed, both sexes displayed a negative direct sociability index, indicating greater environmental exploration than social engagement. Correlation analysis revealed no association between indirect and direct measures. Sex differences emerged primarily among submissive mice, with submissive males showing greater social investigation than submissive females. ConclusionThese findings suggest that standard 3CT indices reflect exploratory rather than affiliative social motivation. The modified paradigm incorporating direct interaction provides a more realistic assessment of social behaviour and challenges assumptions about intrinsic sociability in mice.

neuroscience↗

bioRxiv2026

Novel model combining intrinsic and learned behaviours captures divergent effects of dopaminergic drugs on different types of motivation

Motivation-based symptoms occur in an array of neurological and neurodegenerative disorders, including Schizophrenia and Parkinsons Disease. Unfortunately, there is, as yet, no agreed treatment approach. To establish a better understanding of motivation, and so highlight potential avenues for treatment, motivation is often investigated using operant behavioural paradigms such as the Effort for Reward (EfR) task. Performance on these tasks is thought to be influenced by reinforcement learning (RL) mechanisms, such that disorders of motivation can be described in terms of altered interactions with RL processes. Recently, foraging behaviour has been increasingly adopted as an ethologically valid approach to investigating cognitive mechanisms, including motivation. One example of this is the recently developed Effort Based Foraging task (EBF). Foraging behaviour, unlike the strictly controlled and contrived operant behavioural paradigms, involves a series of complex behavioural processes, each potentially driven by different cognitive processes. It is therefore important to identify which portion of the foraging behavioural sequence is driven by the same RL mechanisms as classical operant behavioural paradigms, and therefore can be used to investigate motivation. In this work we set out to establish whether the same RL mechanisms could be used to account for behaviours observed in both EfR and EBF tasks. We identified where, within the EBF task, RL mechanisms were no long sufficient and developed a novel hybrid model of the behaviour. This model successfully accounted for external influences on motivation, including previously unpredicted effects of clinically used dopaminergic drugs. This work reveals that motivation in complex, naturalistic tasks cannot be fully explained by learning-based models alone. Incorporating intrinsic behavioural drives may be needed as neuroscience moves toward more ethological behavioural assays.

neuroscience↗

bioRxiv2025

Is poor dose selection undermining the translational validity of antidepressant research involving animal models?

BackgroundBehavioural studies in animal models represent a critical component of psychiatric drug development. Positive results in animal studies have identified novel therapeutic targets for major depressive disorder (MDD) but efficacy in humans has largely not been borne out in clinical trials. A possible reason for this failed translation is inappropriate dose selection and the engagement of mechanisms not directly relevant to antidepressant effects in patients. MethodsWe first used PubMed to identify preclinical rodent studies in two assays used to assess antidepressants; the conventional forced swim test, (FST) and more recently developed affective bias test, (ABT). Dose ranges were extracted, as well as information about subjects, timing and route of administration, and justification and efficacy of dose(s). Dose ranges were compared against calculated animal equivalent doses. ResultsThe median FST dose across all antidepressants was 10mg/kg, with median doses for each drug exceeding the relevant animal equivalent dose by 1.5-25x. In contrast, effective doses in the ABT showed closer alignment to those used clinically. In the second study, 232 ketamine and 202 fluoxetine papers involving MDD-related research in rodents were reviewed. The median dose was 10mg/kg for both drugs, exceeding animal equivalent doses by 1.6-3.2x and 3.2-6.5x for ketamine and fluoxetine, respectively. ConclusionsThe results indicate pervasive use of antidepressant doses in conventional models of MDD that may not correspond with doses used in clinical practice. We discuss the implications of using doses which exceed therapeutic levels and the potential to engage receptors and underlying mechanisms which are not relevant to clinical effects.

neuroscience↗

bioRxiv2025

Male mice prefer to live on their own

Around the world, guidance for the management of laboratory mice recommends social housing (1-3). However, fighting in male mice represents a major animal welfare and scientific issue. Despite the risks of stress and injury and associated welfare costs of incage aggression, we currently prioritise group housing. In this study we first validated a trans-species behavioural biomarker of affective state for mice using a chronic corticosterone model of depression. We next used the same methods to quantify affective state in male mice, group or singly housed in conventional versus individually ventilated cages (IVCs). The results revealed group housed male mice are in a negative affective state similar to that induced by chronic corticosterone treatment. IVC housing was also associated with a more negative affective state. These studies provide an objective assessment of the welfare costs of different housing conditions for male mice.

animal behavior and cognition↗

bioRxiv2025

Conditioned versus innate effort-based tasks reveal divergence in antidepressant effect on motivational state in male mice

Antidepressant-induced apathy syndrome is reported in a high number of patients. It is characterised by loss of motivation for daily activities and emotional blunting. It has a negative impact on quality of life and treatment outcome, yet the changes in underlying neurobiology driving this syndrome remain unclear. To begin to address this, a comprehensive understanding of how different classes of antidepressant treatment impact on behaviours relevant to apathy is critical. Rodent motivation for reward is commonly assessed using effort-based operant conditioning paradigms such as the Effort for Reward task. However, motivation to perform spontaneous/innate behaviours may provide additional insight into changes in behaviour reflective of daily activities. We tested the acute and chronic effects of antidepressants on the Effort for Reward task, and the spontaneous/innate Effort Based Forage task. Acute treatment revealed important divergence in drug effect between tasks, where selective serotonin reuptake inhibitor (SSRI)/serotonin and noradrenaline reuptake inhibitor (SNRI) treatment impaired foraging behaviour in the Effort Based Forage task, but enhanced high effort, high value reward responding in the Effort for Reward task. Treatment with a noradrenaline reuptake inhibitor (NRI) or multimodal agent impaired foraging behaviour but did not affect high reward responding in the Effort for Reward task. Conversely, chronic treatment with an SSRI but not SNRI enhanced motivated foraging behaviour but led to a general impairment in Effort for Reward task output. Together, these data demonstrate that SSRI treatment induces opposing effects on conditioned versus innate motivation which may have significant translational relevance when interpreting drug effect.

pharmacology and toxicology↗

bioRxiv2024

Characterisation of behaviours relevant to apathy syndrome in the aged male rat

Apathy is a complex psychiatric syndrome characterised by motivational deficit, emotional blunting and cognitive changes. It occurs alongside a broad range of neurological disorders, but also occurs in otherwise healthy ageing. Despite its clinical prevalence, apathy does not yet have a designated treatment strategy. Generation of a translational animal model of apathy syndrome would facilitate the development of novel treatments. Given the multidimensional nature of apathy, a model cannot be achieved with a single behavioural test. Using a battery of behavioural tests we investigated whether aged rats exhibit behavioural deficits across different domains relevant to apathy. Using the effort for reward and progressive ratio tasks we found that aged rats (21-27 months) show intact reward motivation. Using the novelty supressed feeding test and position-based object exploration we found aged rats showed increased anxiety-like behaviour inconsistent with emotional blunting. The sucrose preference test and reward learning assay showed intact reward sensitivity and reward-related cognition in aged rats. However, using a bowl-digging version of the probabilistic reversal learning task, we found a deficit in cognitive flexibility in aged rats that did not translate across to a touchscreen version of the task. While these data reveal important changes in cognitive flexibility and anxiety associated with ageing, aged rats do not show deficits across other behavioural domains relevant to apathy. This suggests that aged rats are not a suitable model for age-related apathy syndrome. These findings contrast with previous work in mice, revealing important species differences in behaviours relevant to apathy syndrome in ageing.

animal behavior and cognition↗

bioRxiv2023

Validation of a non-appetitive effort-based foraging task as a measure of motivational state in male mice

Motivational disorders such as apathy syndrome are highly prevalent across neurological disorders but do not yet have an agreed treatment approach. The use of translational behavioural models can provide a route through which to meaningfully screen novel drug targets. Methods that utilise food deprivation in contrived environments may lack the sensitivity to detect deficits in self-initiated or self-driven behaviour. Animals monitored in more naturalistic environments may display more ethologically-relevant behaviours of greater translational value. Here, we aimed to validate a novel, non-appetitive effort-based foraging task as a measure of motivational state in mice. In this task, the mouse can freely choose to exert effort to forage bedding material and shuttle it back to a safe and enclosed environment. The amount of bedding material foraged is used as a readout of motivational state. Acute dopaminergic modulation with haloperidol, amphetamine and methylphenidate, and two phenotypic models known to induce motivational deficits (healthy ageing and chronic administration of corticosterone) were used to validate this task. Consistent with other effort-based decision-making tasks we find that foraging behaviour is sensitive to acute modulation of dopaminergic transmission. We find that both phenotypic models induce differing deficits in various aspects of foraging behaviour suggesting that the task may be used to parse different behavioural profiles from distinct disease phenotypes. Thus, without requiring extended training periods or physiological deprivation, this task may represent a refined and translational preclinical measure of motivation.

pharmacology and toxicology↗

bioRxiv2020

Evidence for an apathy phenotype in aged mice

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.Competing Interest StatementThe authors have declared no competing interest.AbbreviationsBLAbasolateral amygdalaCeAcentral amygdalaCORTcorticosteroneEBDMeffort-based decision makingEfReffort for rewardESElectrosprayHLPChigh performance liquid chromatographyMSmass spectrometryNORTnovel object recognition testNSFTnovelty supressed feeding testPRprogressive ratioPVNparaventricular nucleus of the hypothalamusSPTsucrose preference testView Full Text

animal behavior and cognition↗