Evidence of compensatory neural hyperactivity in a subgroup of chemotherapy-treated breast cancer survivors and its association with brain aging.

Chemotherapy-related cognitive impairment (CRCI) remains poorly understood in terms of the mechanisms of cognitive decline. Neural hyperactivity has been reported on average in cancer survivors, but it is unclear which patients demonstrate this neurophenotype, limiting precision medicine in this population. We evaluated a retrospective sample of 80 breast cancer survivors and 80 non-cancer controls, age 35-73, for which we had previously identified and validated three data-driven, biological subgroups (biotypes) of CRCI. We measured neural activity using the z-normalized percent amplitude of fluctuation from resting state functional magnetic resonance imaging (MRI). We tested established, quantitative criteria to determine if hyperactivity can accurately be considered compensatory. We also calculated brain age gap by applying a previously validated algorithm to anatomic MRI. We found that neural activity differed across the three CRCI biotypes and controls (F = 13.5, p < 0.001), with Biotype 2 demonstrating significant hyperactivity compared to the other groups (p < 0.004, corrected), primarily in prefrontal regions. Alternatively, Biotypes 1 and 3 demonstrated significant hypoactivity (p < 0.02, corrected). Hyperactivity in Biotype 2 met several of the criteria to be considered compensatory. However, we also found a positive relationship between neural activity and brain age gap in these patients (r = 0.45, p = 0.042). Our results indicated that neural hyperactivity is specific to a subgroup of breast cancer survivors and, while it seems to support preserved cognitive function, it could also increase the risk of accelerated brain aging. These findings could inform future neuromodulatory interventions with respect to the risks and benefits of up or downregulation of neural activity.

The effects of early rearing experiences on mutual eye gaze among captive olive baboons (Papio anubis).

Among human and nonhuman primates, mutual eye gaze (MEG) and gaze following are believed to be important for social cognition and communicative signaling. The goals of this study were to examine how early rearing experiences contribute to individual variation in MEG and to examine the potential role of genetic factors underlying this variation. Subjects included 93 female and 23 male baboons (Papio anubis) ranging from 3 to 20 years of age. Within the sample, there were 55 mother-reared (MR) and 61 nursery-reared (NR) baboons. MEG was assessed in four 60-s test sessions. For each session, the duration, frequency, and bout length were recorded. Mean values were then calculated for each individual from the four sessions. A multivariate analysis of covariance revealed an overall significant main effect for rearing. Subsequent univariate analyses revealed significant rearing effects on mean bout length, but not mean duration or mean frequency, with MR baboons having longer bout lengths compared to NR baboons. Furthermore, mean bout length was found to be significantly heritable. These results indicate that rearing experiences, and to a small extent, genetic factors, affect patterns of mutual eye gaze - in particular, bout length. These results differ from previous findings in MR and NR chimpanzees, further suggesting that rearing may impact MEG in a species-specific manner that reflects the function of gaze in different primate species.

Behavioral and biologic characteristics of cancer-related cognitive impairment biotypes.

Psychiatric diagnosis is moving away from symptom-based classification and towards multi-dimensional, biologically-based characterization, or biotyping. We previously identified three biotypes of chemotherapy-related cognitive impairment based on functional brain connectivity. In this follow-up study of 80 chemotherapy-treated breast cancer survivors and 80 non-cancer controls, we evaluated additional factors to help explain biotype expression: neurofunctional stability, brain age, apolipoprotein (APOE) genotype, and psychoneurologic symptoms. We also compared the discriminative ability of a traditional, symptom-based cognitive impairment definition with that of biotypes. We found significant differences in cortical brain age (F = 10.50, p < 0.001), neurofunctional stability (F = 2.83, p = 0.041), APOE e4 genotype (X2 = 7.68, p = 0.050), and psychoneurological symptoms (Pillai = 0.378, p < 0.001) across the three biotypes. The more resilient Biotype 2 demonstrated significantly higher neurofunctional stability compared to the other biotypes. Symptom-based classification of cognitive impairment did not differentiate biologic or other behavioral variables, suggesting that traditional categorization of cancer-related cognitive effects may miss important characteristics which could inform targeted treatment strategies. Additionally, biotyping, but not symptom-typing, was able to distinguish survivors with cognitive versus psychological effects. Our results suggest that Biotype 1 survivors might benefit from first addressing symptoms of anxiety and fatigue, Biotype 3 might benefit from a treatment plan which includes sleep hygiene, and Biotype 2 might benefit most from cognitive skills training or rehabilitation. Future research should include additional demographic and clinical information to further investigate biotype expression related to risk and resilience and examine integration of more clinically feasible imaging approaches.

Age differences in cortical thickness and their association with cognition in chimpanzee (Pan troglodytes).

Humans and chimpanzees are genetically similar and share a number of life history, behavioral, cognitive and neuroanatomical similarities. Notwithstanding, our understanding of age-related changes in cognitive and motor functions in chimpanzees remains largely unstudied despite recent evident demonstrating that chimpanzees exhibit many of the same neuropathological features of Alzheimer's disease observed in human postmortem brains. Here, we examined age-related differences in cognition and cortical thickness measured from magnetic resonance images in a sample of 215 chimpanzees ranging in age between 9 and 54 years. We found that chimpanzees showed global and region-specific thinning of cortex with increasing age. Further, within the elderly cohort, chimpanzees that performed better than average had thicker cortex in frontal, temporal and parietal regions compared to chimpanzees that performed worse than average. Independent of age, we also found sex differences in cortical thickness in 4 brain regions. Males had higher adjusted cortical thickness scores for the caudal anterior cingulate, rostral anterior cingulate, and medial orbital frontal while females had higher values for the inferior parietal cortex. We found no evidence that increasing age nor sex was associated with asymmetries in cortical thickness. Moreover, age-related differences in cognitive function were only weakly associated with asymmetries in cortical thickness. In summary, as has been reported in humans and other primates, elderly chimpanzees show thinner cortex and variation in cortical thickness is associated with general cognitive functions.

Vasopressin, and not oxytocin, receptor gene methylation is associated with individual differences in receptive joint attention in chimpanzees (Pan troglodytes).

Joint attention (JA) is an important milestone in human infant development and is predictive of the onset of language later in life. Clinically, it has been reported that children at risk for or with a diagnosis of autism spectrum disorder (ASD) perform more poorly on measures of JA compared to neurotypical controls. JA is not unique to humans but has also been reported in great apes and to a lesser extent in more distantly related monkeys. Further, individual differences in JA among chimpanzees are associated with polymorphisms in the vasopressin and oxytocin genes, AVPR1A and OXTR. Here, we tested whether individual variation in DNA methylation of OXTR and AVPR1A were associated with performance on JA tasks in chimpanzees. We found that individual differences in JA performance was associated with AVPR1A methylation, but not OXTR methylation in the chimpanzees. The collective results provide further evidence of the role of AVPR1A in JA abilities in chimpanzees. The results further suggest that methylation values for AVPR1A may be useful biomarkers for identifying individuals at risk for ASD or related neurodevelopmental disorders associated with impairments in JA abilities.

Neuroanatomical correlates of individual differences in the object choice task in chimpanzees (Pan troglodytes).

Declarative and imperative joint attention or joint engagement are important milestones in human infant development. These have been shown to be a significant predictor of later language development and are impaired in some individuals with, or at risk for, a diagnosis of autism spectrum disorder. Comparatively, while chimpanzees and other great apes have been reported to engage in imperative joint attention, evidence of declarative joint attention remains unclear based on existing studies. Some have suggested that differences in methods of assessing joint attention may have an influence on performance in nonhuman primates. Here, we report data on a measure of receptive joint attention (object choice task) in a sample of captive chimpanzees. Chimpanzees, as a group, performed significantly better than chance. By contrast, when considering individual performance, there was no significant difference in the number of those who passed and those who failed. Using quantitative genetic analyses, we found that performance on the object choice task was not significantly heritable nor were there any significant effects of sex, rearing history, or colony. Lastly, we found significant differences in gray matter covariation, between those who passed or failed the task. Those who passed contributed more to gray matter covariation in several brain regions within the social brain network, consistent with hypotheses regarding the importance of these regions in human and nonhuman primate social cognition.

Are conspecific social videos rewarding to chimpanzees (Pan troglodytes)? A test of the social motivation theory.

Many claim that social stimuli are rewarding to primates, but few, if any, studies have explicitly demonstrated their reward value. Here, we examined whether chimpanzees would produce overt responses for the opportunity to view conspecific social, compared to dynamic (video: Experiment 1) and static (picture: Experiment 2) control content. We also explored the relationships between variation in social reward and social behavior and cognition. We provided captive chimpanzees with access to a touchscreen during four, one-hour sessions (two 'conspecific social' and two 'control'). The sessions consisted of ten, 15-second videos (or pictures in Experiment 2) of either chimpanzees engaging in a variety of behaviors (social condition) or vehicles, humans, or other animals engaged in some activity (control condition). For each chimpanzee, we recorded the number of responses to the touchscreen and the frequency of watching the stimuli. Independent t-tests revealed no sex or rearing differences in touching and watching the social or control videos (p>0.05). Repeated measures ANOVAs showed chimpanzees touched and watched the screen significantly more often during the social compared to control video sessions. Furthermore, although chimpanzees did not touch the screen more often during social than control picture sessions in Experiment 2, they did watch the screen more often. Additionally, chimpanzees that previously performed better on a task of social cognition and engaged in more affiliative behavior watched a higher percentage of social videos during the touchscreen task. These results are consistent with the social motivation theory, and indicate social stimuli are intrinsically rewarding, as chimpanzees made more overt responses for the opportunity to view conspecific social, compared to control, content.

Gray Matter Variation in the Posterior Superior Temporal Gyrus Is Associated with Polymorphisms in the KIAA0319 Gene in Chimpanzees (Pan troglodytes).

Determining the impact that the KIAA0319 gene has on primate brain morphology can provide insight into the evolution of human cognition and language systems. Here, we tested whether polymorphisms in KIAA0319 in chimpanzees account for gray matter volumetric variation in brain regions implicated in language and communication (particularly within the posterior superior temporal gyrus and inferior frontal gyrus). First, we identified the nature and frequencies of single nucleotide variants (SNVs) in KIAA0319 in a sample of unrelated chimpanzees (Pan troglodytes spp.). Next, we genotyped a subset of SNVs (those important for gene regulation or likely to alter protein structure/function) in a sample of chimpanzees for which in vivo T1-structural magnetic resonance imaging scans had been obtained. We then used source-based morphometry (SBM) to test for whole-brain gray matter covariation differences between chimpanzees with different KIAA0319 alleles. Finally, using histologic sections of 15 postmortem chimpanzee brains, we analyzed microstructural variation related to KIAA0319 polymorphisms in the posterior superior temporal cortex. We found that the SNVs were associated with variation in gray matter within several brain regions, including the posterior superior temporal gyrus (a region associated with language comprehension and production in humans). The microstructure analysis further revealed hemispheric differences in neuropil fraction, indicating that KIAA0319 expression may be involved in regulation of processes related to the formation and maintenance of synapses, dendrites, or axons within regions associated with communication.

Age- and cognition-related differences in the gray matter volume of the chimpanzee brain (Pan troglodytes): A voxel-based morphometry and conjunction analysis.

Several primate species have been shown to exhibit age-related changes in cognition, brain, and behavior. However, severe neurodegenerative illnesses, such as Alzheimer's disease (AD), were once thought to be uniquely human. Recently, some chimpanzees naturally were documented to develop both neurofibrillary tangles and amyloid plaques, the main characteristics of AD pathology. In addition, like humans and other primates, chimpanzees show similar declines in cognition and motor function with age. Here, we used voxel-based morphometry to examine the relationships among gray matter volume, age, and cognition using magnetic resonance imaging scans previously acquired from chimpanzees (N = 216). We first determined the relationship between age and gray matter volume, identifying the regions that declined with age. With a subset of our sample (N = 103), we also determined differences in gray matter volume between older chimpanzees with higher cognition scores than expected for their age, and older chimpanzees with lower than expected scores. Finally, we ran a conjunction analysis to determine any overlap in brain regions between these two analyses. We found that as chimpanzees age, they lose gray matter in regions associated with cognition. In addition, cognitively healthy older chimpanzees (those performing better for their age) have greater gray matter volume in many brain regions compared with chimpanzees who underperform for their age. Finally, the conjunction analysis revealed that regions of age-related decline overlap with the regions that differ between cognitively healthy chimpanzees and those who underperform. This study provides further evidence that chimpanzees are an important model for research on the neurobiology of aging. Future studies should investigate the effects of cognitive stimulation on both cognitive performance and brain structure in aging nonhuman primates.

Behavioral Management is a Key Component of Ethical Research.

Behavioral management programs aim to enhance the welfare of animal subjects that participate in research, thereby enhancing our ability to conduct ethical research projects. Socialization strategies, environmental enrichment techniques, opportunities for subjects to voluntarily participate in research procedures, and the provision of Functionally Appropriate Captive Environments are 4 major components of most behavioral management programs. The appropriate implementation of behavioral management programs should provide animals with opportunities to engage in species-typical activity patterns, contributing to valid and reliable animal models that require the smallest number of subjects to achieve meaningful results. The role that socialization strategies, environmental enrichment techniques, and positive reinforcement training can play in maintaining and enhancing welfare through the stimulation of species-typical behavior and the prevention of abnormal behavior is discussed. The value of empirically assessing the effects of behavioral management techniques is emphasized. Additionally, the necessity of adjusting the relative prioritization of needs related to the convenience of human caregivers and the animals themselves is addressed. For the purposes of this discussion, research projects are considered to be ethical if they (1) involve animals with high welfare, (2) provide data that are reliable and valid, (3) involve appropriate numbers of subjects, and (4) involve animals that are appropriate models to test meaningful hypotheses.

Differences in the mutual eye gaze of bonobos (Pan paniscus) and chimpanzees (Pan troglodytes).

Eye gaze is widespread in nonhuman primate taxa and important for social cognition and communicative signaling. Bonobos and chimpanzees, two closely related primate species, differ in social organization, behavior, and cognition. Chimpanzees' eye gaze and gaze following has been studied extensively, whereas less is known about bonobos' eye gaze. To examine species differences using a more ecologically relevant measure than videos or pictures, the current study compared bonobo and chimpanzee mutual eye gaze with a human observer. A multivariate analysis of variance revealed significant species differences in frequency and total duration, but not bout length, of mutual eye gaze (p < .001). Specifically, bonobos engage in mutual eye gaze more frequently and for longer total duration than chimpanzees. These results are likely related to species differences in social behavior and temperament and are consistent with eye-tracking studies in which bonobos looked at the eye region of conspecifics (in pictures and videos) longer than chimpanzees. Future research should examine the relationship between mutual eye gaze and gaze following, as well as examine its genetic and neurological correlates. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

The role of early social rearing, neurological, and genetic factors on individual differences in mutual eye gaze among captive chimpanzees.

Mutual eye gaze plays an important role in primate social development and communication. In the current study, we examined the underlying experiential, genetic, and neuroanatomical basis of mutual eye gaze variation in adult captive chimpanzees. A multivariate analysis of variance revealed a significant rearing effect on bout length, with human-reared chimpanzees engaging in longer bouts of mutual gaze compared to mother-reared and wild-born individuals. Next, we utilized source-based morphometry (SBM) to examine gray matter covariation in magnetic resonance imaging scans and determine the relationship between the resulting gray matter covariation components and mutual eye gaze. One SBM component was negatively correlated with gaze duration (nucleus accumbens and anterior insular cortex), while two components were positively correlated with bout length (posterior cingulate cortex, inferior occipital cortex, middle temporal cortex, hippocampus, and the precentral sulcus). Finally, heritability analyses revealed mutual eye gaze to be modestly heritable and significant genetic correlations between bout length and two gray matter covariation components. This study reveals that non-genetic factors, and to a lesser extent, genetic factors appear to influence mutual eye gaze in adult chimpanzees, and is the first to report neuroanatomical correlates of mutual eye gaze variation in chimpanzees.

Rearing condition may alter neonatal development of captive Bolivian squirrel monkeys (Saimiri boliviensis boliviensis).

Nursery rearing has well-known consequences for primate species. Relative to some other primate species, research has indicated a reduced impact of nursery rearing on squirrel monkeys, particularly in terms of rates, severity, and persistence of abnormal behavior. We administered the Primate Neonatal Neurobehavioral Assessment to 29 dam-reared and 13 nursery-reared squirrel monkeys (Saimiri boliviensis boliviensis) at 2 and 6 weeks of age. Mixed-model ANOVAs comparing composite scores and individual assessment items across age, rearing status, and sex revealed a number of developmental differences. Dam-reared infants scored higher on all four composite measures compared to nursery-reared infants (p < .05) indicating that nursery-reared animals had slower motor development, were less active and attentive, and were more passive than their dam-reared counterparts. Consistent with infant rhesus macaques, nursery-reared squirrel monkeys showed an increased sensitivity to tactile stimulation (p < .05). Altogether, these results suggest a disruption of species-typical development when squirrel monkey infants are reared in a nursery setting, with activity, orientation, and state control areas most affected, though experimental research is needed to determine if this is a causal relationship. Contrary to previous behavioral research, there are likely developmental differences between dam-reared infant squirrel monkeys and those reared in a nursery setting.

AVPR1A variation is linked to gray matter covariation in the social brain network of chimpanzees.

The vasopressin system has been implicated in the regulation of social behavior and cognition in humans, nonhuman primates and other social mammals. In chimpanzees, polymorphisms in the vasopressin V1a receptor gene (AVPR1A) have been associated with social dimensions of personality, as well as to responses to sociocommunicative cues and mirror self-recognition. Despite evidence of this association with social cognition and behavior, there is little research on the neuroanatomical correlates of AVPR1A variation. In the current study, we tested the association between AVPR1A polymorphisms in the RS3 promotor region and gray matter covariation in chimpanzees using magnetic resonance imaging and source-based morphometry. The analysis identified 13 independent brain components, three of which differed significantly in covariation between the two AVPR1A genotypes (DupB-/- and DupB+/-; P < .05). DupB+/- chimpanzees showed greater covariation in gray matter in the premotor and prefrontal cortex, basal forebrain, lunate and cingulate cortex, and lesser gray matter covariation in the superior temporal sulcus and postcentral sulcus. Some of these regions were previously found to differ in vasopressin and oxytocin neural fibers between nonhuman primates, and in AVPR1A gene expression in humans with different RS3 alleles. This is the first report of an association between AVPR1A and gray matter covariation in nonhuman primates, and specifically links an AVPR1A polymorphism to structural variation in the social brain network. These results further affirm the value of chimpanzees as a model species for investigating the relationship between genetic variation, brain structure and social cognition with relevance to psychiatric disorders, including autism.

Does Rattling Deter? The Case of Domestic Dogs.

Although the rattling of rattlesnakes (Crotalus and Sistrurus) is widely accepted as being aposematic, the hypothesis that rattling deters approach from the snake's potentially dangerous adversaries has not been well tested. In a controlled study using rattling recorded from captive rattlesnakes (C. oreganus helleri) and a variety of comparison sounds or no-sound controls, domestic dogs (Canis familiaris) showed no hesitation to approach camouflaged speakers projecting the recorded rattles. The dogs were equally likely to approach speakers projecting rattling as they were to approach speakers playing control sounds, or speakers that were silent. Furthermore, the dogs spent no less time in front of the speakers projecting the rattles than they did in front of speakers projecting control sounds or no sound. The dogs' reactions may not be representative of other species with whom rattlesnakes come into contact, but the data suggest a need for some circumspection about the role of rattling in the rattlesnake's defensive repertoire. Our results also suggest that dogs may be vulnerable to envenomation because they fail to react to the sound of rattling with avoidance.

Neonatal activity and state control differences among three squirrel monkey subspecies (Saimiri sciureus sciureus, S. boliviensis boliviensis, and S. boliviensis peruviensis).

Squirrel monkeys are a long-standing biomedical model, with multiple species and subspecies housed in research facilities. Few studies have examined the developmental differences between these subspecies, which may affect research outcomes. The primate neonatal neurobehavioral assessment was completed at 2 weeks of age with 279 dam-reared squirrel monkeys (188 Saimiri boliviensis boliviensis, 45 S. b. peruviensis, and 46 Saimiri. sciureus sciureus). Activity, orientation to stimuli, state control, and motor maturity scores, as well as startle responses and number of vocalizations were compared across subspecies and sex using factorial analysis of covariance (ANCOVAs) controlling for birthweight. There were no differences in orientation or motor maturity scores (p > .05) among the three subspecies or between sexes; however, there were significant subspecies differences in motor activity and state control scores. Of the three subspecies, S. s. sciureus has the lowest state control and activity scores (p < .05). They also had the most exaggerated startle response/aversion to a sudden loud noise, vocalized significantly less, and were less likely to resist restraint during the assessment (p < .05). The three subspecies of squirrel monkeys did not differ in motor development and attention to external stimuli but were significantly different in state control and activity levels. Overall S. s. sciureus were less active, agitated, irritable, and easier to console compared to S. b. boliviensis and S. b. peruviensis. This supports field research on socioecology which documented different social structure and behavior in wild populations of S. s. sciureus compared to S. b. boliviensis and S. b. peruviensis.

Alterations of acoustic features of 50 kHz vocalizations by nicotine and phencyclidine in rats.

Ultrasonic vocalizations are widely used to examine affective states in rats, yet relatively few studies explore the acoustic features of vocalizations, especially in relation to drug exposure, and no studies have explored alterations in acoustic features over time. The goal of this study was to examine nicotine- and phencyclidine-induced alterations of bandwidth, duration, and frequency of 50 kHz vocalizations. The minimum and maximum frequency, bandwidth, and duration of calls were examined after 7 days of daily subcutaneous administration of phencyclidine (2.0 mg/kg) and nicotine (0.2 and 0.4 mg/kg) in male Sprague-Dawley rats. Bandwidth was significantly decreased in rats treated with both nicotine (0.2 and 0.4 mg/kg) and phencyclidine. Maximum frequency was lowest on the first day of exposure compared with all other days and was not altered by drug exposure. Call duration was not affected by time or drug exposure. These findings suggest the importance of studying alterations in acoustic features in time, especially those induced by drug exposure.

Effects of the phencyclidine model of schizophrenia and nicotine on total and categorized ultrasonic vocalizations in rats.

Patients with schizophrenia smoke cigarettes at a higher rate than the general population. We hypothesized that a factor in this comorbidity is sensitivity to the reinforcing and reinforcement-enhancement effects of nicotine. Phencyclidine (PCP) was used to model behavioral changes resembling negative symptoms of schizophrenia in rats. Ultrasonic vocalizations (USVs) in rats have been used to measure emotional states, with 50 kHz USVs indicating positive states and 22 kHz USVs indicating negative states. Total and categorized numbers of 22 and 50 kHz USVs and USVs during a visual stimulus (e.g. a potential measure of reinforcement-enhancement) were examined in rats following injection of PCP (2.0 mg/kg) and/or nicotine (0.2 or 0.4 mg/kg) daily for 7 days. PCP was then discontinued and all rats received nicotine (0.2 and 0.4 mg/kg) and PCP (2.0 mg/kg) on three challenge days. PCP acutely decreased 50 kHz vocalizations, whereas repeated nicotine potentiated rates of vocalizations, with similar patterns during light presentations. Rats in the PCP and nicotine combination groups made more 50 kHz vocalizations compared with rats in the control groups on challenge days. We conclude that PCP may produce a reward deficit, which is shown by decreased 50 kHz USVs, and behaviors post-PCP exposure may best model the comorbidity between schizophrenia and nicotine.