Breast cancer patients using aromatase inhibitors (AIs) as an adjuvant therapy often report side effects, including hot flashes, mood changes, and cognitive impairment. Despite long-term use in ...humans, little is known about the effects of continuous AI administration on the brain and cognition. We used a primate model of human cognitive aging, the common marmoset, to examine the effects of a 4-week daily administration of the AI letrozole (20 μg, p.o.) on cognition, anxiety, thermoregulation, brain estrogen content, and hippocampal pyramidal cell physiology. Letrozole treatment was administered to both male and female marmosets and reduced peripheral levels of estradiol (E2), but unexpectedly increased E2 levels in the hippocampus. Spatial working memory and intrinsic excitability of hippocampal neurons were negatively affected by the treatment possibly due to increased hippocampal E2. While no changes in hypothalamic E2 were observed, thermoregulation was disrupted by letrozole in females only, indicating some impact on hypothalamic activity. These findings suggest adverse effects of AIs on the primate brain and call for new therapies that effectively prevent breast cancer recurrence while minimizing side effects that further compromise quality of life.
Aromatase inhibitors (AIs) are used as an adjuvant therapy for estrogen-receptor-positive breast cancer and are associated with side effects, including hot flashes, depression/anxiety, and memory deficits severe enough for many women to discontinue this life-saving treatment. AIs are also used by men, yet sex differences in the reported side effects have not been systematically studied. We show that AI-treated male and female marmosets exhibit behavioral changes consistent with these CNS symptoms, as well as elevated hippocampal estradiol and compromised hippocampal physiology. These findings illustrate the need for (1) a greater understanding of the precise mechanisms by which AIs impact brain function and (2) the development of new treatment approaches for breast cancer patients that minimize adverse effects on the brain.
The common marmoset (Callithrix jacchus) is uniquely suited for longitudinal studies of cognitive aging, due to a relatively short lifespan, sophisticated cognitive abilities, and patterns of brain ...aging that resemble those of humans. We examined cognitive function and fine motor skills in male and female marmosets (mean age ∼5 at study entry) followed longitudinally for 2 years. Each year, monkeys were tested on a reversal learning task with three pairs of stimuli (n = 18, 9 females) and a fine motor task requiring them to grasp small rewards from two staircases (Hill and Valley test, n = 12, 6 females). There was little evidence for a decline in cognitive flexibility between the two time points, in part because of practice effects. However, independent of year of testing, females took longer than males to reach criterion in the reversals, indicating impaired cognitive flexibility. Motivation was unlikely to contribute to this effect, as males refused a greater percentage of trials than females in the reversals. With regards to motor function, females were significantly faster than males in the Hill and Valley task. From Year 1 to Year 2, a slight slowing of motor function was observed in both sexes, but accuracy decreased significantly in males only. This study (1) demonstrates that marmosets exhibit sex differences in cognitive flexibility and fine motor function that resemble those described in humans; (2) that changes in fine motor function can already be detected at middle-age; and (3) that males may experience greater age-related changes in fine motor skills than females. Additional data points will determine whether these sex and age differences persist over time.
Aging across the Primate Order is poorly understood because ages of individuals are often unknown, there is a dearth of aged animals available for study, and because aging is best characterized by ...longitudinal studies which are difficult to carry out in long-lived species. The human population is aging rapidly, and advanced age is a primary risk factor for several chronic diseases and conditions that impact healthspan. As lifespan has increased, diseases and disorders of the central nervous system (CNS) have become more prevalent, and Alzheimer's disease and related dementias have become epidemic. Nonhuman primate (NHP) models are key to understanding the aging primate CNS. This Special Issue presents a review of current knowledge about NHP CNS aging across the Primate Order. Similarities and differences to human aging, and their implications for the validity of NHP models of aging are considered. Topics include aging-related brain structure and function, neuropathologies, cognitive performance, social behavior and social network characteristics, and physical, sensory, and motor function. Challenges to primate CNS aging research are discussed. Together, this collection of articles demonstrates the value of studying aging in a breadth of NHP models to advance our understanding of human and nonhuman primate aging and healthspan.
Nonhuman primates (NHPs) are an essential research model for gaining a comprehensive understanding of the neural mechanisms of neurocognitive aging in our own species. In the present study, we used ...resting state functional connectivity (rsFC) to investigate the relationship between prefrontal cortical and striatal neural interactions, and cognitive flexibility, in unanaesthetized common marmosets (Callithrix jacchus) at two time points during late middle age (8 months apart, similar to a span of 5-6 years in humans). Based on our previous findings, we also determine the reproducibility of connectivity measures over the course of 8 months, particularly previously observed sex differences in rsFC. Male marmosets exhibited remarkably similar patterns of stronger functional connectivity relative to females and greater cognitive flexibility between the two imaging time points. Network analysis revealed that the consistent sex differences in connectivity and related cognitive associations were characterized by greater node strength and/or degree values in several prefrontal, premotor and temporal regions, as well as stronger intra PFC connectivity, in males compared to females. The current study supports the existence of robust sex differences in prefrontal and striatal resting state networks that may contribute to differences in cognitive function and offers insight on the neural systems that may be compromised in cognitive aging and age-related conditions such as mild cognitive impairment and Alzheimer's disease.
We examined attentional biases for social and non-social emotional stimuli in young adult men and compared the results to those of male rhesus monkeys (
Macaca mulatta
) previously tested in a ...similar dot-probe task (King et al. in Psychoneuroendocrinology 37(3):396–409,
2012
). Recognition memory for these stimuli was also analyzed in each species, using a recognition memory task in humans and a delayed non-matching-to-sample task in monkeys. We found that both humans and monkeys displayed a similar pattern of attentional biases toward threatening facial expressions of conspecifics. The bias was significant in monkeys and of marginal significance in humans. In addition, humans, but not monkeys, exhibited an attentional bias away from negative non-social images. Attentional biases for social and non-social threat differed significantly, with both species showing a pattern of vigilance toward negative social images and avoidance of negative non-social images. Positive stimuli did not elicit significant attentional biases for either species. In humans, emotional content facilitated the recognition of non-social images, but no effect of emotion was found for the recognition of social images. Recognition accuracy was not affected by emotion in monkeys, but response times were faster for negative relative to positive images. Altogether, these results suggest shared mechanisms of social attention in humans and monkeys, with both species showing a pattern of selective attention toward threatening faces of conspecifics. These data are consistent with the view that selective vigilance to social threat is the result of evolutionary constraints. Yet, selective attention to threat was weaker in humans than in monkeys, suggesting that regulatory mechanisms enable non-anxious humans to reduce sensitivity to social threat in this paradigm, likely through enhanced prefrontal control and reduced amygdala activation. In addition, the findings emphasize important differences in attentional biases to social
versus
non-social threat in both species. Differences in the impact of emotional stimuli on recognition memory between monkeys and humans will require further study, as methodological differences in the recognition tasks may have affected the results.
Summary Increasing evidence in humans and other animals suggests that testosterone (T) plays an important role in modulating emotion. We previously reported that T treatment in rhesus monkeys ...undergoing chemically induced hypogonadism results in increased watching time of videos depicting fights between unfamiliar conspecifics ( Lacreuse et al., 2010 ). In the current study, we aimed to further investigate the effect of T manipulations on attention and memory for emotional stimuli in male rhesus monkeys. Six males (7 years old) were administered Depot Lupron to suppress endogenous T levels and treated with either testosterone enanthate (TE, 5 mg/kg) or oil, before crossing over to the alternate treatment. Animals were tested for 16 weeks on two computerized touchscreen tasks with both social and nonsocial emotional and neutral stimuli. The Dot-Probe task was used to measure attention, and the Delayed-Non-Matching-to-Sample task with a 1 s delay (DNMS) was used to measure recognition memory for these stimuli. Performance on the two tasks was examined during each of four month-long phases: Baseline, Lupron alone, Lupron + TE and Lupron + oil. It was predicted that T administration would lead to increased attention to negative social stimuli (i.e., negative facial expressions of unfamiliar conspecifics) and would improve memory for such stimuli. We found no evidence to support these predictions. In the Dot-Probe task, an attentional bias towards negative social stimuli was observed at baseline, but T treatment did not enhance this bias. Instead, monkeys had faster response times when treated with T compared to oil, independently of the emotional valence or social relevance of stimuli, perhaps reflecting an enhancing effect of T on reward sensitivity or general arousal. In the DNMS, animals had better memory for nonsocial compared to social stimuli and showed the poorest performance in the recognition of positive facial expressions. However, T did not affect performance on the task. Thus, even though monkeys were sensitive to the social relevance and emotional valence of the stimuli in the two tasks, T manipulations had no effect on attention or memory for these stimuli. Because habituation to the stimuli may have mitigated the effect of treatment in the attentional task, we suggest that T may increase attentional biases to negative social stimuli only during early exposure to the stimuli with acute treatment or when stimuli are highly arousing (i.e., dynamically presented) with chronic treatment. In addition, the data suggest that T does not enhance working memory for emotional stimuli in young male macaques.
Executive function (EF) is a complex construct that reflects multiple higher-order cognitive processes such as planning, updating, inhibiting and set-shifting. Decline in these functions is a ...hallmark of cognitive ageing in humans, and age differences and changes in EF correlate with age-related differences and changes in association cortices, particularly the prefrontal areas. Here, we review evidence for age-related decline in EF and associated neurobiological changes in prosimians, New World and Old World monkeys, apes and humans. While EF declines with age in all primate species studied, the relationship of this decline with age-related alterations in the prefrontal cortex remains unclear, owing to the scarcity of neurobiological studies focusing on the ageing brain in most primate species. In addition, the influence of sex, vascular and metabolic risk, and hormonal status has rarely been considered. We outline several methodological limitations and challenges with the goal of producing a comprehensive integration of cognitive and neurobiological data across species and elucidating how ageing shapes neurocognitive trajectories in primates with different life histories, lifespans and brain architectures. Such comparative investigations are critical for fostering translational research and understanding healthy and pathological ageing in our own species.
This article is part of the theme issue ‘Evolution of the primate ageing process’.
•First longitudinal study of cognition in aging marmosets (Callithrix jacchus).•Practice effects preceded age-related cognitive decline.•Females exhibited cognitive decline at earlier age than ...males.•No sex differences in aging for motor abilities, behavior or social stress reactivity.
Longitudinal studies are essential to understand healthy and pathological neurocognitive aging such as Alzheimer's Disease, but longitudinal designs are rare in both humans and non-human primate models of aging because of the difficulty of tracking cognitive change in long-lived primates. Common marmosets (Callithrix jacchus) are uniquely suited for aging studies due to their naturally short lifespan (10–12 years), sophisticated cognitive and social abilities and Alzheimer Disease-like neuropathology. We report the first longitudinal study of cognitive aging in marmosets (N = 28) as they transitioned from middle- (∼5 years) to old age (∼9 years). We characterized aging trajectories using reversal learning with different stimuli each year. Marmosets initially improved on cognitive performance due to practice, but worsened in the final year, suggesting the onset of age-related decline. Cognitive impairment emerged earlier in females than males and was more prominent for discrimination than for reversal learning. Sex differences in cognitive aging could not be explained by differences in motivation or motor abilities, which improved or remained stable across aging. Likewise, males and females did not differ in aging trajectories of overall behavior or reactivity to a social stressor, with the exception of a progressive decline in the initiation of social behavior in females. Patterns of cognitive aging were highly variable across marmosets of both sexes, suggesting the potential for pathological aging for some individuals. Future work will link individual cognitive trajectories to neuropathology in order to better understand the relationships between neuropathologic burden and vulnerability to age-related cognitive decline in each sex.
Data on cognitive aging in chimpanzees are extremely sparse, yet can provide an invaluable phylogenetic perspective, especially because Alzheimer disease (AD)–like neuropathology has recently been ...described in the oldest chimpanzee brains. This finding underscores the importance of data on cognitive aging in this fellow hominin, our closest biological relative. We tested 30 female chimpanzees, 12–56 years old, on a computerized analog of the Wisconsin Card Sort test. This test assesses cognitive flexibility, which is severely impaired in normal aging and AD. Subjects selected stimuli according to color or shape; the rewarded dimension (i.e., color or shape) switched without warning and the chimpanzee had to adapt her responses accordingly. We found that increasing age was associated with an increased number of perseverative errors and an increased number of trials to reach criterion in each switching dimension. The number of aborted trials was similar across age groups. These data show that similar to humans, chimpanzees show a clear age-related decline in cognitive flexibility that is already observed at middle age.
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