Biology subjects

Dunn, S. R.

Publications and source records attributed to Dunn, S. R..

4 recordsLinked to original sources

bioRxiv2026

A Scalable Touchscreen-Based Spatial Working Memory Task for Cross-Species Research

The common marmoset is rapidly emerging as a powerful nonhuman primate model in neuroscience, yet the development of scalable, mechanistically informative cognitive paradigms has lagged behind advances in neural recording and genetic tools. Here, we introduce and validate a touchscreen-based spatial working memory task designed for direct cross-species translation between marmosets and humans. The paradigm independently manipulates retention delay and spatial separation between test choice stimuli, enabling parametric control over maintenance and interference demands within a single framework. Twelve marmosets and seventy-one human participants performed a Delayed Non-Match-to-Position task in which memory delay (1, 5, 10 seconds) and angular separation between target and distractor locations were systematically varied. Across species, accuracy declined as delay increased and as spatial separation decreased, demonstrating robust sensitivity to both maintenance demands and similarity-based interference. Critically, delay and separation interacted in both species, indicating that these had additive effects. Choice latency analyses further supported interpretation of performance, with slower responses on incorrect trials in both groups. Together, these findings establish a scalable and translationally aligned spatial working memory paradigm that captures interacting maintenance and interference processes. This task provides a powerful platform for circuit-level investigation and offers a sensitive cognitive assay for future studies of aging, neurodegenerative disease, and therapeutic intervention in the marmoset model.

animal behavior and cognition↗

bioRxiv2025

Pharmacological Reversal of Attention Deficits in Non-Human Primates: Implications for Alzheimer's Disease

Attention deficits emerge early in Alzheimers disease (AD), where cholinergic dysfunction compromises goal-directed behavior and cognitive control. Therefore, attentional impairments may serve as early indicators of cognitive decline, and also as meaningful targets for therapeutic intervention. Despite their clinical importance, attention deficits remain under- targeted by current treatments, which offer only modest benefit. To support development of more effective therapies, preclinical models that closely mirror human neurobiology and behavior are essential. Non-human primates (NHPs), with their high degree of cortical and functional similarity to humans, particularly in prefrontal regions, offer a uniquely translational platform for evaluating cognitive enhancers. We assessed pharmacological interventions targeting sustained attention using the Continuous Performance Test (CPT) in adult male cynomolgus macaques. Monkeys were trained to detect target stimuli while ignoring distractors, achieving individualized stable performance. To simulate cholinergic dysfunction, we administered scopolamine, a muscarinic acetylcholine receptor antagonist, which produced dose-dependent declines in accuracy and reaction time. Mild and severe impairment levels were identified within each animal. We then tested three compounds: nicotine, guanfacine, and donepezil. Nicotine, a nicotinic receptor agonist, fully restored performance across both impairment levels, suggesting potential benefit in both early and advanced AD. Guanfacine, an 2A adrenergic agonist, improved accuracy only under mild impairment, while donepezil, an acetylcholinesterase inhibitor, showed inconsistent effects. None of the compounds reversed scopolamine-induced slowing of reaction time, indicating specificity for attentional control. These findings highlight the utility of the NHP CPT as a pharmacologically sensitive model for detecting attentional dysfunction and evaluating pro-cognitive therapeutics in aging and neurodegeneration.

animal behavior and cognition↗

bioRxiv2025

Behavioral and Pharmacological Validation of the Differential Reinforcement of Low-Rate Behavior Paradigm in Non-Human Primates

Depression remains a leading cause of disability worldwide, yet the predictive validity of many preclinical behavioral assays for antidepressant efficacy remains limited. The Differential Reinforcement of Low-Rate Behavior (DRL) task has classically been used in rodents to identify antidepressant-like effects, but its utility in non-human primates (NHPs) has not been established. Here, we adapted the DRL task for use in adult male cynomolgus macaques (Macaca fascicularis) and evaluated its pharmacological sensitivity and translational relevance across 19 compounds spanning multiple drug classes. Antidepressants, including SSRIs, SNRIs, NRIs, NDRIs, TCAs, MAOIs, and PDE4 inhibitors, generally shifted DRL performance in an antidepressant-like direction, increasing reinforcers earned and inter-response times while decreasing response output. In contrast, benzodiazepine and antipsychotic control compounds did not produce a consistent antidepressant-like profile, whereas stimulant effects were mixed, with nicotine and cocaine also producing overlapping antidepressant-like behavioral effects. Importantly, the primate DRL task identified antidepressant-like effects of PDE4 inhibitors while also capturing emesis, a dose-limiting side effect not observable in rodent models. These findings support the primate DRL task as a translationally relevant platform for screening antidepressant-like efficacy, while also highlighting important design considerations for interpreting pharmacological sensitivity in the NHP setting. By modeling behavioral processes implicated in depression, including response inhibition and temporal regulation, this assay offers a unique opportunity to bridge preclinical and clinical antidepressant development with improved sensitivity to both efficacy and tolerability.

animal behavior and cognition↗

bioRxiv2025

Cognitive strategy accounts for failure on a hippocampal relational memory task in non-human primates

Relational memory, the ability to flexibly encode and retrieve associations among distinct elements, is critically dependent on the hippocampus and declines with age in humans. The Transverse Patterning (TP) task is designed to probe relational memory by requiring learning of hierarchical, circular stimulus relationships (e.g., A+ B-, B+ C-, C+ A-), a structure akin to rock-paper-scissors. In humans, TP performance is reliably impaired by hippocampal damage and aging. In non-human primates, however, findings have been inconsistent with some studies demonstrating clear hippocampal dependence, while others report no impairment, or even improvements, following hippocampal lesions. This raises the possibility that species differences in cognitive strategy use may underlie these divergent outcomes. We hypothesized that non-human primates rely on an elemental learning strategy, supported by corticostriatal systems, even when relational memory is required. To test this, we trained young and aged common marmosets (Callithrix jacchus) on the TP task and several control tasks designed to isolate elemental versus configural learning. Marmosets successfully acquired reward contingencies for individual stimulus pairs but failed when success required integrating all three stimulus relationships. In contrast, all animals readily acquired control tasks solvable via simple stimulus-response associations. Notably, there was no evidence of age-related impairment on TP or control task performance. Given the early vulnerability of the hippocampus to aging and the relative preservation of striatal systems, this pattern further supports the conclusion that marmosets rely on a habit-based learning strategy that is poorly suited to relational demands. These findings suggest that humans and non-human primates may approach the same tasks using different cognitive strategies. This has critical implications for interpreting cross-species differences in memory performance and highlights the need to validate which neural systems a task engages in each species before using it as a translational model of hippocampal function or cognitive aging.

animal behavior and cognition↗