Bearded capuchin monkeys as a model for Alzheimer's disease.

The absence of a natural animal model is one of the main challenges in Alzheimer's disease research. Despite the challenges of using nonhuman primates in studies, these animals can bridge mouse models and humans, as nonhuman primates are phylogenetically closer to humans and can spontaneously develop AD-type pathology. The capuchin monkey, a New World primate, has recently attracted attention due to its skill in creating and using instruments. We analyzed one capuchin brain using structural 7 T MRI and performed a neuropathological evaluation of three animals. Alzheimer-type pathology was found in the two of the capuchins. Widespread ß-amyloid pathology was observed, mainly in focal deposits with variable morphology and a high density of mature plaques. Notably, plaque-associated dystrophic neurites associated with disruption of axonal transport and early cytoskeletal alteration were frequently found. Unlike in other species of New World monkeys, cerebral arterial angiopathy was not the predominant form of ß-amyloid pathology. Additionally, abnormal aggregates of hyperphosphorylated tau, resembling neurofibrillary pathology, were observed in the temporal and frontal cortex. Astrocyte hypertrophy surrounding plaques was found, suggesting a neuroinflammatory response. These findings indicate that aged capuchin monkeys can spontaneously develop Alzheimer-type pathology, indicating that they may be an advantageous animal model for research in Alzheimer's disease.

Effective connectivity within the corticothalamic circuit in the neuromyelitis optica patients: A comparative study using resting-state fMRI.

Neuromyelitis Optica, which is known as NMO, is a demyelination syndrome and inflammatory condition of the central nervous system that affects the optic nerves. Since structural imaging approaches cannot adequately describe the brain disorders in patients with NMO, functional magnetic resonance imaging (fMRI) can be used. Resting-state fMRI was performed on 25 healthy subjects and 26 NMO patients. After preprocessing the data, the time series belonging to the regions of the middle frontal gyrus (MFG), inferior frontal gyrus (IFG), precuneus (PRE), thalamus (THA), and middle temporal gyrus (MTG) were extracted as components of the corticothalamic circuit. The obtained time series were statistically analyzed as the input of dynamic causal modeling (DCM) in order to evaluate the effective connectivity within the corticothalamic circuit. The statistical analyses showed that the mean of effective connectivity power was significantly higher in the healthy subjects than in the NMO patients. For the healthy subjects, there was no significant difference in effective connectivity power between the two groups of males and females at the significance level of 0.05. In the NMO patients, there was a significant difference between the effective connectivity levels of the male and female groups only for IFG â†’ MFG, in which it was greater in males than in females. The results of our studies showed that resting-state fMRI could exhibit the difference between healthy and NMO subjects.

Continuous Use of Combined Hormonal Contraceptive and the Effect on Blood Coagulation Factors in Female Capuchin Monkeys (Sapajus libidinosus).

This study aimed at evaluating the availability of the primate Sapajus libidinosus as an animal model for research assessing the physiological effects of the continuous use of combined hormonal contraceptives. In order to do this, six reproductively active female S. libidinosus from the Primate Research Center of the University of Brasília were selected to take part in this experiment. Every 21 days or so, each female received a single dose of combined hormonal contraceptive (algestone acetophenide and 17-enanthate estradiol) in a total of five doses throughout the experiment. The physiological parameters were accessed by means of 13 blood samples from each female, whereas three were gathered during the baseline and 10 samples were collected during the treatment phase. The results showed that the contraceptive use provoked changes in hematological coagulation factors such as an increase in the amount of platelets (p = 0.039) and a reduction in both prothrombin (p < 0.001) and thromboplastin coagulation time (p < 0.001). These results are similar to what has been observed in human patients; thus, it is concluded that S. libidinosus can be successfully used in studies about the physiological impact of hormonal contraceptives.

Negative Facial Expressions - But Not Visual Scenes - Enhance Human Working Memory in Younger and Older Participants.

Many studies have investigated the influence of emotion on memory processes across the human lifespan. Some results have shown older adults (OA) performing better with positive stimuli, some with negative items, whereas some found no impact of emotional valence. Here we tested, in two independent studies, how younger adults (YA) and OA would perform in a visuospatial working memory (VSWM) task with positive, negative, and neutral images. The task consisted of identifying the new location of a stimulus in a crescent set of identical stimuli presented in different locations in a touch-screen monitor. In other words, participants should memorize the locations previously occupied to identify the new location. For each trial, the number of occupied locations increased until 8 or until a mistake was made. In study 1, 56 YA and 38 OA completed the task using images from the International Affective Picture System (IAPS). Results showed that, although YA outperformed OA, no effects of emotion were found. In study 2, 26 YA and 25 OA were tested using facial expressions as stimuli. Data from this study showed that negative faces facilitated performance and this effect did not differ between age groups. No differences were found between men and women. Taken together, our findings suggest that YA and OA's VSWM can be influenced by the emotional valence of the information, though this effect was present only for facial stimuli. Presumably, this may have happened due to the social and biological importance of such stimuli, which are more effective in transmitting emotions than IAPS images. Critically, our results also indicate that the mixed findings in the literature about the influence of aging on the interactions between memory and emotion may be caused by the use of different stimuli and methods. This possibility should be kept in mind in future studies about memory and emotion across the lifespan.

Computerized spatial delayed recognition span task: a specific tool to assess visuospatial working memory.

A new tablet device version (IOS platform) of the Spatial Delayed Recognition Span Task (SDRST) was developed with the aim of investigating visuospatial Working Memory (WM) abilities based on touchscreen technology. This new WM testing application will be available to download for free in Apple Store app ("SDRST app"). In order to verify the feasibility of this computer-based task, we conducted three experiments with different manipulations and groups of participants. We were interested in investigating if (1) the SDRST is sensitive enough to tap into cognitive differences brought by aging and dementia; (2) different experimental manipulations work successfully; (3) cortical brain activations seen in other WM tasks are also demonstrated here; and (4) non-human primates are able to answer the task. Performance (scores and response time) was better for young than older adults and higher for the latter when compared to Alzheimer's disease (AD) patients. All groups performed better with facial stimuli than with images of scenes and with emotional than with neutral stimuli. Electrophysiology data showed activation on prefrontal and frontal areas of scalp, theta band activity on the midline area, and gamma activity in left temporal area. There are all scalp regions known to be related to attention and WM. Besides those data, our sample of adult captive capuchin monkeys (Sapajus libidinosus) answered the task above chance level. Taken together, these results corroborate the reliability of this new computer-based SDRST as a measure of visuospatial WM in clinical and non-clinical populations as well as in non-human primates. Its tablet app allows the task to be administered in a wide range of settings, including hospitals, homes, schools, laboratories, universities, and research institutions.

Anatomical analysis of thumb opponency movement in the capuchin monkey (Sapajus sp).

Capuchin monkeys present a wide variety of manipulatory skills and make routine use of tools both in captivity and in the wild. Efficient handling of objects in this genus has led several investigators to assume near-human thumb movements despite the lack of anatomical studies. Here we perform an anatomical analysis of muscles and bones in the capuchin hand. Trapezo-metacarpal joint surfaces observed in capuchins indicate that medial rotation of metacarpal I is either absent or very limited. Overall, bone structural arrangement and thumb position relative to the other digits and the hand's palm suggest that capuchins are unable to perform any kind of thumb opponency, but rather a 'lateral pinch' movement. Although the capuchin hand apparatus bears other features necessary for complex tool use, the lack thumb opposition movements suggests that a developed cognitive and motor nervous system may be even more important for high manipulatory skills than traditionally held.

Age-related differences in cortical activity during a visuo-spatial working memory task with facial stimuli.

Emotion, importantly displayed by facial expressions, is one of the most significant memory modulators. The interaction between memory and the different emotional valences change across lifespan, while young adults (YA) are expected to better recall negative events (Negativity Bias Hypothesis), older adults (OA) tend to focus on positive stimuli (Positivity Effect Hypothesis). This research work aims at verifying whether cortical electrical activity of these two age groups would also be differently influenced by emotional valences in a visuo-spatial working memory task. 27 YA (13 males) and 25 OA (14 males), all healthy volunteers, underwent electroencephalographic recordings (21 scalp electrodes montage), while performing the Spatial Delayed Recognition Span Task using a touch screen with different stimuli categories: neutral, positive and negative faces and geometric pictures. YA obtained higher scores than OA, and showed higher activation of theta and alpha bands in the frontal and midline regions, besides a more evident right-hemispheric asymmetry on alpha band when compared to OA. For both age groups, performance in the task was worse for positive faces than to negative and to neutral faces. Facial stimuli induced a better performance and higher alpha activation on the pre-frontal region for YA, and on the midline, occipital and left temporal regions for OA when compared to geometric figures. The superior performance of YA was expected due to the natural cognitive deficits connected to ageing, as was a better performance with facial stimuli due to the evolutionary importance of faces. These results were related to cortical activity on areas of importance for action-planning, decision making and sustained attention. Taken together, they are in accordance with the Negativity Bias but do not support the Positivity Effect. The methodology used was able to identify age-related differences in cortical activity during emotional mnemonic processing and may be interesting to future investigations.

Comparative anatomy of the hind limb vessels of the bearded capuchins (Sapajus libidinosus) with apes, baboons, and Cebus capucinus: with comments on the vessels' role in bipedalism.

Capuchin monkeys are known to exhibit sporadic bipedalism while performing specific tasks, such as cracking nuts. The bipedal posture and locomotion cause an increase in the metabolic cost and therefore increased blood supply to lower limbs is necessary. Here, we present a detailed anatomical description of the capuchin arteries and veins of the pelvic limb of Sapajus libidinosus in comparison with other primates. The arterial pattern of the bearded capuchin hind limb is more similar to other quadrupedal Cebus species. Similarities were also found to the pattern observed in the quadruped Papio, which is probably due to a comparable pelvis and the presence of the tail. Sapajus' traits show fewer similarities when compared to great apes and modern humans. Moreover, the bearded capuchin showed unique patterns for the femoral and the short saphenous veins. Although this species switches easily from quadrupedal to bipedal postures, our results indicate that the bearded capuchin has no specific or differential features that support extended bipedal posture and locomotion. Thus, the explanation for the behavioral differences found among capuchin genera probably includes other aspects of their physiology.

Estrogen, cognitive functions and emotion: an overview on humans, non-human primates and rodents in reproductive years.

Accumulating evidence has highlighted a number of important, global issues regarding the influence of estrogen on emotion and cognitive functions,including learning and memory processes, both in animal models and humans. The influence of estrogen on cognition and emotion can be explained by taking into account its modulator role on several neurotransmitter systems, acetylcholine in particular, but also catecholamines,serotonin and GABA in rodents, primates and humans. Another reason may lie in the wide spread presence of the two classes (a and~) of estrogen receptors in many brain regions involved in emotion and cognition, including the hippocampal formation, amygdala and cerebral cortex. The present review reports on research conducted in our laboratory and others with the objective of identifying the action of estrogens on cognition and emotion in rodents, monkeys and humans in youth. In particular, the first section,focused on the mechanisms of estrogens action in the brain, illustrates the involvement of estrogen receptors and neurotransmitters in the cognitive and emotional processes; the second section deals with the estrogen effects on cognitive and emotional mechanisms, with particular emphasis on memory and the involvement of estrogen in emotion and cognition across the estrous/menstrual cycle.

EEG and autonomic responses during performance of matching and non-matching to sample working memory tasks with emotional content.

Working memory (WM) is a memory system responsible for the temporary storage of information and its utilization in problem solving. The central executive is theorized as the controller of storage functions that support WM. Neurophysiological data suggest that electroencephalographic (EEG) theta and alpha oscillations in frontal and midline regions are involved in neural communication between the central executive and storage functions during WM performance. Emotion is known to modulate several memory systems, including WM, through central and peripheral pathways. However, the physiological effect (EEG; autonomic nervous activity) of emotion over WM are not well described. In this study we aimed to identify physiological responses related to emotional WM performance. EEG (21 channels), heart rate (HR), and galvanic skin response (GSR) recordings were obtained from 54 volunteers while performing delayed matching and non-matching to sample tasks (DMTS/DNMTS). Emotional and neutral pictures from the International Affective Picture System and geometric figures were used as stimuli. As expected, WM performance was accompanied by presence of theta (frontal and midline electrodes) and alpha power (parietal electrodes). Beta and gamma oscillations were concentrated in frontopolar and left temporal regions. The DNMTS task was accompanied by higher increases in beta power, HR, and GSR compared to the DMTS task. Correlation analyses showed a positive tendency for gamma in the Fp2 site, ratio of LF/HF and skin conductance in both tasks. The HR results indicate an inverse reaction related to parasympathetic and sympathetic nervous system during the performance of the tasks. Taken together, our results contribute to elucidate the complex interactions between central and autonomic nervous systems in the modulation of emotional WM tasks.

Superior colliculus lesions impair threat responsiveness in infant capuchin monkeys.

The ability to react fast and efficiently in threatening situations is paramount for the survival of organisms and has been decisive in our evolutionary history. Defense mechanisms in primates rely on the fast recognition of potential predators and facial expressions of conspecifics. The neural circuitry responsible for the detection of threat is generally thought to be centered on the amygdala. Although it is a pivotal structure in the processing of emotional stimuli, the amygdala does not seem necessary for the early stages of this process. Here we show that bilateral neurotoxic lesions of the superior colliculus in infant capuchins monkeys impaired the recognition of a rubber-snake in a threat-reward conflict task. Lesioned monkeys were uninhibited by a snake in a food-reward retrieval task. Lack of inhibition in the task was observed over the course of 15 weeks. The long lasting recognition impairment of a natural predator observed here is similar to the tameness aspects of Kluver-Bucy syndrome, indicating an important role of this structure in threat recognition.

The Müller-Lyer illusion as a tool for schizophrenia screening.

The perceptual deficit hypothesis for schizophrenia is based on more general models of normal human visual perception, which have traditionally postulated that objects must compete for attention and processing space in the visual system. Recent evidence suggests that susceptibility of schizophrenics to the Müller-Lyer (ML) illusion may be a marker of vulnerability, detectable in prodromic patients, but disappearing with the progression of the illness. This illusion consists of overestimating the length of a straight line with converging arrowheads at the ends, while underestimating those with diverging arrowheads. Although the ML illusion has been shown to occur in touch as well as vision, it is not known whether abnormal contextual suppression extends to other sensory modalities in schizophrenics. Another challenge consists in verifying whether different visual parameters of the illusion which favor the magnocellular and parvocellular systems would have diverse ML illusion effects in schizophrenia. In this review we present data showing the degree of illusion in capuchin monkeys (Cebus spp.), a possible animal model for schizophrenia. To this end, a computer program was developed to conduct experiments in humans and non-human primates, allowing the display of illusory figures, manipulation of the stimuli's exposure time, interval between stimuli and number of trials. In the non-primate experiments, the visual illusion test based on achromatic ML illusion figures indicated the presence of the ML illusory effect in 10 capuchin monkeys. These results suggest that Cebus might be a good model for the experimental study of schizophrenia.

Working memory for emotional facial expressions: role of estrogen in humans and non-human primates.

In recent years, numerous studies focusing on the role of sex steroid hormones on neuropsychological functions have been reported. The influence of estrogens on cognition can be explained by the widespread presence of estrogen receptors (ERs) in limbic and cortical areas, and the modulator role of estrogens on numerous neurotransmitter systems. There is a great deal of evidence suggesting that estrogen can enhance memory processes and improve performance in working memory (WM) tasks, including face-tasks, delayed matching-to-sample (DMTS) and delayed non-matching-to-sample (DNMTS). The modulator effects exerted by estrogens are complex and may vary according to task, gender, and phase of the menstrual cycle. For many years, physiological hormonal fluctuations during the menstrual cycle, postpartum, and menopause have been said to influence mood, cognition, and affective disorders. In addition, it has been hypothesised that estrogens have a protective role in schizophrenia and Alzheimer's disease (AD). Taking into account that women's performance in memory tasks can also fluctuate with circulating hormone levels across the menstrual cycle, data related to the cognitive performance in a WM task for emotional facial expressions were reported. The findings described in this review can contribute to clarifying the role of the steroid hormone estrogen in the modulation of cognitive functions, particularly memory, and indicate the possible usefulness of applying a new paradigm, employing a DNMTS task with emotional facial expressions, in studies focused on emotional WM in relevant models of nonhuman primates. Such data could also represent a useful tool in individualizing effective therapy for the treatment of disturbances linked to menstrual cycle phases and menopause in women.

Response toward novel stimuli in a group of tufted capuchins (Cebus libidinosus) in Brasília National Park, Brazil.

We investigated responses toward novel foods and novel objects by wild capuchins that routinely exploit visitors' foods in Brasília National Park. Given the capuchins' daily exposure to human foods and objects, we expected them to be more explorative toward novel foods and objects compared to capuchins that are not habituated to visitors. However, since the safety and palatability of potential foods have to be learned, we also expected the capuchins to be cautious about eating novel foods, as has been reported for wild and captive capuchins. Stimuli were presented on a platform in four experimental conditions: familiar food (FF), novel food (NF), familiar food plus novel object (FF+O), and novel food plus novel object (NF+O). Latencies to approach and contact the platform, and to approach and to ingest food did not differ across conditions. Nevertheless, the capuchins were significantly more responsive (measured in terms of interest, manipulation, etc.) toward familiar foods than novel foods, and ate significantly more of the former. In other words, their explorative response toward novel foods led to little consumption. Our results do not support the "readiness to eat" hypothesis, according to which a lower readiness to eat and food neophobia are the consequences of the presence of a distracting novel object. The finding that capuchins explore novel stimuli but remain cautious about eating novel foods supports the view that neophilia and neophobia are motivationally independent responses.

Ontogenetic dissociation between habit learning and recognition memory in capuchin monkeys (Cebus apella).

The performance of young and adult capuchin monkeys (Cebus apella) on a Concurrent Discrimination Learning (CDL) test and a Delayed Non-Matching to Sample (DNMS) task were investigated. Results indicate that all subjects were able to learn the CDL test with 20-pairs simultaneously and retain this stimulus/reward association within 24-h interval. In contrast, young subjects did not perform the DNMS task with the same proficiency as adults. While adults' scores were above chance across all memory test delays, the young capuchin monkeys performed the test by chance level. These results support the hypothesis that these two tasks require different cognitive processes mediated by two independent neural systems with a differentiated ontogenetic development. Moreover, they provide evidence that this dissociation occurs not only in humans and Old World monkeys but also in the New World capuchin monkeys indicating that this species can be a valuable alternative model for investigations of the neurobiological basis of memory.

Working memory in capuchin monkeys (Cebus apella).

It has been suggested that delayed (non-) matching to sample (DNMTS/DMTS) tasks using trial-unique stimuli and short, as well as longer delay intervals, can provide important insights into animal cognition. Therefore, this research examined the capability of the New World capuchin monkey (Cebus apella) in perform trial-unique DMTS and DNMTS tasks across delay intervals ranging between 8 s and 10 min. Subjects were tested using a version of the Wisconsin General Test Apparatus mounted in front of the animal's home cage. They were first trained on a basic DMTS/DNMTS task with an 8 s interval until they reached a learning criterion of nine correct responses in ten consecutive trials. All subjects reached the learning criterion in both DMTS/DNMTS tasks, and the number of trials to criterion did not differ between tasks. After reaching the criterion, subject's memory performance was successively assessed at delay intervals of 15 s, 60 s, 120 s and 10 min. For both DMTS/DNMTS tasks, the mean percentage of correct responses across delays was above chance and, interestingly, performance did not significantly decrease as function of delay increments. Comparisons based on each group's scores, averaged across the four delays, showed no difference between DMTS and DNMTS memory performance. These results indicate that capuchin monkeys are able to learn DMTS/DNMTS tasks in which they are required to respond to new pairs of stimuli on every trial. This demonstrates the capability of 'concept' learning in this species. Moreover, above chance performance on the memory tests indicates a working memory ability similar to that reported for the genus Macaca. Taken together, these data indicates that capuchin monkeys can be a valuable alternative model for investigations of the neuropsychological basis of memory.

Effect of practice on hand preference on a color visual discrimination task by capuchin monkeys (Cebus apella).

Effects of practice on hand preference in nonhuman primates have indicated an initial right-hemispheric advantage in new tasks that can be reversed or disappear after a long period of training. The aim of this study was to examine the effects of 6-mo. practice on hand preference in capuchin monkeys (Cebus apella) performing a color visual discrimination task which requires attention and learning or memory processes. For this purpose, an early period of practice (first 200 trials) was compared with a late period of practice (the last 200 trials after 6 mo. practice). No population-level biases were observed between the use of hands either early in training or after 6 mo. of practice. Individual analysis indicated that two of the five subjects tested strengthened their initial hand preference but three subjects changed their preference with the practice. No correlation was observed between hand use and performance. These results suggest that hand preference in capuchin monkeys can be influenced by practice and is not only a direct function of hemispheric specialization.