Biology subjects

Asch, P. A.

Publications and source records attributed to Asch, P. A..

3 recordsLinked to original sources

bioRxiv2024

The Common Marmoset as a Translational Model for Longitudinal Studies of Cognitive Aging and Individual Vulnerability to Decline

In humans, cognitive aging is highly variable, with some individuals experiencing decline while others remain stable, and different cognitive domains exhibiting uneven vulnerability to aging. The neural mechanisms driving this intra- and inter-individual variability are not fully understood, making longitudinal studies in translational models essential for elucidating the timelines and processes involved. The common marmoset (Callithrix jacchus), a short-lived nonhuman primate, offers an unprecedented opportunity to conduct longitudinal investigations of aging and age-related disease over a condensed time frame, in a highly translatable animal model. The potential of the marmoset as a model for cognitive aging is indisputable, but a comprehensive cognitive battery tailored for longitudinal aging studies has not yet been developed, applied, or validated. This represents a critical missing piece for evaluating the marmoset as a model and understanding the extent to which marmoset cognitive aging mirrors the patterns found in humans, including whether marmosets have individual variability in their vulnerability to age-related cognitive decline. To address this, we developed a comprehensive touchscreen-based neuropsychological test battery for marmosets (MarmoCog), targeting five cognitive domains: working memory, stimulus-reward association learning, cognitive flexibility, motor speed, and motivation. We tested a large cohort of marmosets, ranging from young adults to geriatrics, over several years. We found significant variability in cognitive aging, with the greatest decline occurring in domains dependent on the prefrontal cortex and hippocampus. Additionally, we observed significant inter-individual variability in vulnerability to age-related cognitive decline: some marmosets declined across multiple domains, others in just one, and some showed no decline at all. This pattern mirrors human cognitive aging, solidifies the marmoset as an advantageous model for age-related cognitive decline, and provides a strong foundation for identifying the neural mechanisms involved.

animal behavior and cognition↗

bioRxiv2024

Parallel patterns of cognitive aging in marmosets and macaques

As humans age, some experience cognitive impairment while others do not. When impairment does occur, it is not expressed uniformly across cognitive domains and varies in severity across individuals. Translationally relevant model systems are critical for understanding the neurobiological drivers of this variability, which is essential to uncovering the mechanisms underlying the brains susceptibility to the effects of aging. As such, non-human primates are particularly important due to shared behavioral, neuroanatomical, and age-related neuropathological features with humans. For many decades, macaque monkeys have served as the primary non-human primate model for studying the neurobiology of cognitive aging. More recently, the common marmoset has emerged as an advantageous model for this work due to its short lifespan that facilitates longitudinal studies. Despite their growing popularity as a model, whether marmosets exhibit patterns of age-related cognitive impairment comparable to those observed in macaques and humans remains unexplored. To address this major limitation for the development and evaluation of the marmoset as a model of cognitive aging, we directly compared working memory ability as a function of age in macaques and marmosets on the identical working memory task. Our results demonstrate that marmosets and macaques exhibit remarkably similar age-related working memory deficits, highlighting the value of the marmoset as a model for cognitive aging research within the neuroscience community.

animal behavior and cognition↗

bioRxiv2023

Domain-specific cognitive impairment reflects prefrontal dysfunction in aged common marmosets

Age-related cognitive impairment is not expressed uniformly across cognitive domains. Cognitive functions that rely on brain areas that undergo substantial neuroanatomical changes with age often show age-related impairment, while those that rely on brain areas with minimal age-related change typically do not. The common marmoset has grown in popularity as a model for neuroscience research, but robust cognitive phenotyping, particularly as a function of age and across multiple cognitive domains, is lacking. This presents a major limitation for the development and evaluation of the marmoset as a model of cognitive aging, and leaves open the question of whether they exhibit age-related cognitive impairment that is restricted to some cognitive domains, as in humans. In this study, we characterized stimulus-reward association learning and cognitive flexibility in young adults to geriatric marmosets using a Simple Discrimination and a Serial Reversal task, respectively. We found that aged marmosets show transient impairment in "learning-to-learn" but have conserved ability to form stimulus-reward associations. Furthermore, aged marmosets have impaired cognitive flexibility driven by susceptibility to proactive interference. Since these impairments are in domains critically dependent on the prefrontal cortex, our findings support prefrontal cortical dysfunction as a prominent feature of neurocognitive aging. This work positions the marmoset as a key model for understanding the neural underpinnings of cognitive aging. Significance StatementAging is the greatest risk factor for neurodegenerative disease development, and understanding why is critical for the development of effective therapeutics. The common marmoset, a short-lived non-human primate with neuroanatomical similarity to humans, has gained traction for neuroscientific investigations. However, the lack of robust cognitive phenotyping, particularly as a function of age and across multiple cognitive domains limits their validity as a model for age-related cognitive impairment. We demonstrate that aging marmosets, like humans, have impairment that is specific to cognitive domains reliant on brain areas that undergo substantial neuroanatomical changes with age. This work validates the marmoset as a key model for understanding region-specific vulnerability to the aging process.

neuroscience↗