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, whereas 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 task 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. As 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.

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 Statement: Aging 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.

Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset (Callithrix jacchus).

Morphology and function of the dorsolateral prefrontal cortex (dlPFC), and corresponding working memory performance, are affected early in the aging process, but nearly half of aged individuals are spared of working memory deficits. Translationally relevant model systems are critical for determining the neurobiological drivers of this variability. The common marmoset (Callithrix jacchus) is advantageous as a model for these investigations because, as a non-human primate, marmosets have a clearly defined dlPFC that enables measurement of prefrontal-dependent cognitive functions, and their short (∼10 year) lifespan facilitates longitudinal studies of aging. Previously, we characterized working memory capacity in a cohort of marmosets that collectively covered the lifespan, and found age-related working memory impairment. We also found a remarkable degree of heterogeneity in performance, similar to that found in humans. Here, we tested the hypothesis that changes to synaptic ultrastructure that affect synaptic efficacy stratify marmosets that age with cognitive impairment from those that age without cognitive impairment. We utilized electron microscopy to visualize synapses in the marmoset dlPFC and measured the sizes of boutons, presynaptic mitochondria, and synapses. We found that coordinated scaling of the sizes of synapses and mitochondria with their associated boutons is essential for intact working memory performance in aged marmosets. Further, lack of synaptic scaling, due to a remarkable failure of synaptic mitochondria to scale with presynaptic boutons, selectively underlies age-related working memory impairment. We posit that this decoupling results in mismatched energy supply and demand, leading to impaired synaptic transmission. We also found that aged marmosets have fewer synapses in dlPFC than young, though the severity of synapse loss did not predict whether aging occurred with or without cognitive impairment. This work identifies a novel mechanism of synapse dysfunction that stratifies marmosets that age with cognitive impairment from those that age without cognitive impairment. The process by which synaptic scaling is regulated is yet unknown and warrants future investigation.

Age-Related Learning and Working Memory Impairment in the Common Marmoset.

Aging is the greatest risk factor for the development of neurodegenerative diseases, yet we still do not understand how the aging process leads to pathologic vulnerability. The research community has relied heavily on mouse models, but the considerable anatomic, physiological, and cognitive differences between mice and humans limit their translational relevance. Ultimately, these barriers necessitate the development of novel aging models. As a nonhuman primate (NHP), the common marmoset (Callithrix jacchus) shares many features in common with humans and yet has a significantly shorter lifespan (10 years) than other primates, making it ideally suited to longitudinal studies of aging. Our objective was to evaluate the marmoset as a model of age-related cognitive impairment. To do this, we used the Delayed Recognition Span Task (DRST) to characterize age-related changes in working memory capacity in a cohort of sixteen marmosets, of both sexes, varying in age from young adult to geriatric. These monkeys performed thousands of trials over periods of time ranging up to 50% of their adult lifespan. To our knowledge, this represents the most thorough cognitive profiling of any marmoset aging study conducted to date. By analyzing individual learning curves, we found that aged animals exhibited delayed onset of learning, slowed learning rate after onset, and decreased asymptotic working memory performance. These findings are not accounted for by age-related impairments in motor speed and motivation. This work firmly establishes the marmoset as a model of age-related cognitive impairment.SIGNIFICANCE STATEMENT Understanding the normal aging process is fundamental to identifying therapeutics for neurodegenerative diseases for which aging is the biggest risk factor. Historically, the aging field has relied on animal models that differ markedly from humans, constraining translatability. Here, we firmly establish a short-lived nonhuman primate (NHP), the common marmoset, as a key model of age-related cognitive impairment. We demonstrate, through continuous testing over a substantial portion of the adult marmoset lifespan, that aging is associated with both impaired learning and working memory capacity, unaccounted for by age-related changes in motor speed and motivation. Characterizing individual cognitive aging trajectories reveals inherent heterogeneity, which could lead to earlier identification of the onset of impairment, and extended timelines during which therapeutics are effective.

Neonatal hippocampal lesions facilitate biconditional contextual discrimination learning in monkeys.

This study examined whether selective neonatal hippocampal lesions in monkeys (Macaca mulatta), which left the surrounding cortical areas (parahippocampal cortex) intact, affect contextual learning and memory compared with controls. Monkeys were tested with an automated touch-screen apparatus so that stimuli and contextual cues could be manipulated independently of one another. The data suggest that animals with neonatal hippocampal lesions have sparing of function with regard to contextual learning and memory when (a) contextual information is irrelevant or (b) relevant for good discrimination performance, and (c) when transferring a contextual rule to new discriminations. These findings are at odds with studies examining contextual learning and memory in monkeys with selective adult-onset hippocampal lesions, and those with nonselective neonatal hippocampal lesions, which have demonstrated impairment in contextual learning and memory. Therefore, the sparing of function seen in this study may be attributable to the early nature of the damage and the plastic nature of the infant brain, as well as the intact medial temporal lobe cortical areas as a result of the lesion methodology. Specifically, by removing the hippocampus early in life, before it has begun to function, the parahippocampal (TH/TF) and perirhinal cortices and its interactions with the lateral prefrontal cortex may be able to support context processing throughout life. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Peripheral complement interactions with amyloid ß peptide in Alzheimer's disease: 2. Relationship to amyloid ß immunotherapy.

INTRODUCTION: Our previous studies have shown that amyloid ß peptide (Aß) is subject to complement-mediated clearance from the peripheral circulation, and that this mechanism is deficient in Alzheimer's disease. The mechanism should be enhanced by Aß antibodies that form immune complexes (ICs) with Aß, and therefore may be relevant to current Aß immunotherapy approaches. METHODS: Multidisciplinary methods were employed to demonstrate enhanced complement-mediated capture of Aß antibody immune complexes compared with Aß alone in both erythrocytes and THP1-derived macrophages. RESULTS: Aß antibodies dramatically increased complement activation and opsonization of Aß, followed by commensurately enhanced Aß capture by human erythrocytes and macrophages. These in vitro findings were consistent with enhanced peripheral clearance of intravenously administered Aß antibody immune complexes in nonhuman primates. DISCUSSION: Together with our previous results, showing significant Alzheimer's disease deficits in peripheral Aß clearance, the present findings strongly suggest that peripheral mechanisms should not be ignored as contributors to the effects of Aß immunotherapy.

Peripheral complement interactions with amyloid ß peptide: Erythrocyte clearance mechanisms.

INTRODUCTION: Although amyloid ß peptide (Aß) is cleared from the brain to cerebrospinal fluid and the peripheral circulation, mechanisms for its removal from blood remain unresolved. Primates have uniquely evolved a highly effective peripheral clearance mechanism for pathogens, immune adherence, in which erythrocyte complement receptor 1 (CR1) plays a major role. METHODS: Multidisciplinary methods were used to demonstrate immune adherence capture of Aß by erythrocytes and its deficiency in Alzheimer's disease (AD). RESULTS: Aß was shown to be subject to immune adherence at every step in the pathway. Aß dose-dependently activated serum complement. Complement-opsonized Aß was captured by erythrocytes via CR1. Erythrocytes, Aß, and hepatic Kupffer cells were colocalized in the human liver. Significant deficits in erythrocyte Aß levels were found in AD and mild cognitive impairment patients. DISCUSSION: CR1 polymorphisms elevate AD risk, and >80% of human CR1 is vested in erythrocytes to subserve immune adherence. The present results suggest that this pathway is pathophysiologically relevant in AD.

Alterations in High-Frequency Neuronal Oscillations in a Cynomolgus Macaque Test of Sustained Attention Following NMDA Receptor Antagonism.

A growing body of evidence indicates that neuronal oscillations in the gamma frequency range (30-80 Hz) are disturbed in schizophrenic patients during cognitive processes and may represent an endophenotype of the disease. N-methyl-D-aspartate (NMDA) receptor antagonists have been used experimentally to induce schizophrenia-like symptoms including cognitive deficits in animals and humans. Here we characterized neuronal oscillations and event-related potentials (ERPs) in Cynomolgus macaques fully trained to perform a continuous performance test (CPT) in the presence and absence of the NMDA antagonist phencyclidine (PCP). Macaques (n=8) were trained to touch 'target' stimuli and ignore 'distractor' stimuli presented randomly on a touchscreen. Subsequently, all subjects were implanted with epidural EEG electrodes over frontal (FC) and parietal cortices (PC) and later tested under vehicle (saline, i.m.) or acute PCP (0.1-0.3 mg/kg, i.m.) conditions. Compared with vehicle treatment, PCP produced a significant dose-dependent decrease in CPT performance accuracy and increased reaction times. Furthermore, PCP elevated the amplitudes of 'low' (30-50 Hz) and 'high' (51-80 Hz) gamma oscillations in FC and PC around target presentations for all correct responses. The CPT accuracy was inversely correlated with the gamma band amplitude in the presence of PCP. Additionally, PCP delayed the N100 peak latency in FC, and prolonged and suppressed the cognitively relevant P300 component of mean ERPs in FC and PC, respectively. The NMDA receptor antagonist-induced alteration in neuronal oscillations and ERPs may contribute to the observed cognitive deficits in macaques, and enhance our understanding of EEG recordings as a translatable biomarker.

Animal paradigms to assess cognition with translation to humans.

Cognition is a complex brain function that represents processes such as learning and memory, attention, working memory, and executive functions amongst others. Impairments in cognition are prevalent in many neuropsychiatric and neurological disorders with few viable treatment options. The development of new therapies is challenging, and poor efficacy in clinical development continues to be one of the most consistent reasons compounds fail to advance, suggesting that traditional animal models are not predictive of human conditions and behavior. An effort to improve the construct validity of neuropsychological testing across species with the intent of facilitating therapeutic development has been strengthening over recent years. With an emphasis on understanding the underlying biology, optimizing the use of appropriate systems (e.g., transgenic animals) to model targeted disease states, and incorporating non-rodent species (e.g., non-human primates) that may enable a closer comparison to humans, an improvement in the translatability of the results will be possible. This chapter focuses on some promising translational cognitive paradigms for use in rodents, non-human primates, and humans.

Neonatal hippocampal damage impairs specific food/place associations in adult macaques.

This study describes a novel spatial memory paradigm for monkeys and reports the effects of neonatal damage to the hippocampus on performance in adulthood. Monkeys were trained to forage in eight boxes hung on the walls of a large enclosure. Each box contained a different food item that varied in its intrinsic reward value, as determined from food preference testing. Monkeys were trained on a spatial and a cued version of the task. In the spatial task, the boxes looked identical and remained fixed in location whereas in the cued task, the boxes were individuated with colored plaques and changed location on each trial. Ten adult Rhesus macaques (5 neonatal sham-operated and 5 with neonatal neurotoxic hippocampal lesions) were allowed to forage once daily until they preferentially visited boxes containing preferred foods. The data suggest that all monkeys learned to discriminate preferred from nonpreferred food locations, but that monkeys with neonatal hippocampal damage committed significantly more working memory errors than controls in both tasks. Furthermore, following selective satiation, controls altered their foraging pattern to avoid the satiated food, whereas lesioned animals did not, suggesting that neonatal hippocampal lesions prohibit learning of specific food-place associations. We conclude that whereas an intact hippocampus is necessary to form specific item-in-place associations, in its absence, cortical areas may support more broad distinctions between food types that allow monkeys to discriminate places containing highly preferred foods.

Acute ethanol reduces reversal cost in discrimination learning by reducing perseverance in adolescent rhesus macaques.

BACKGROUND: Acute alcohol exposure produces cognitive deficits in adults but less is known about the acute cognitive effects of alcohol in adolescents. The cognitive impact of acute alcohol exposure includes deficits in discrimination and reversal learning, but traditional experimental approaches make it difficult to distinguish the effect of alcohol on discrimination learning from the effect of alcohol on reversal learning. Young rhesus macaques can be used to model some aspects of human adolescence because of their anatomical, neurophysiological, and cognitive similarities with humans. METHODS: Adolescent male rhesus monkeys (n = 10) were trained to respond to visual stimuli on touch-sensitive LCD panels controlled by the nonhuman primate version of CANTAB software. Discrimination and reversal learning tasks were subsequently assessed after monkeys were allowed to consume varying amounts of ethanol (EtOH) in a flavored vehicle (vehicle only, up to 0.5 g/kg EtOH, up to 1.0 g/kg EtOH, and up to 1.5 g/kg EtOH). RESULTS: Acute exposure to EtOH reduced perseverance, increased response accuracy, and reduced errors during reversal learning when the task was completed within 90 minutes of EtOH consumption. No reduction in reversal errors was observed when EtOH was consumed 3 or 24 hours prior to reversal learning. EtOH only impaired discrimination learning when monkeys had very little previous EtOH exposure. CONCLUSIONS: The temporal relationship between EtOH consumption and reversal learning was consistent with selective EtOH-induced impairment of retrieval, but not storage, processes. This was evidenced by diminished perseverance on the previously correct stimulus leading to decreased errors to criterion.