Macaque Brainnetome Atlas: A multifaceted brain map with parcellation, connection, and histology.

The rhesus macaque (Macaca mulatta) is a crucial experimental animal that shares many genetic, brain organizational, and behavioral characteristics with humans. A macaque brain atlas is fundamental to biomedical and evolutionary research. However, even though connectivity is vital for understanding brain functions, a connectivity-based whole-brain atlas of the macaque has not previously been made. In this study, we created a new whole-brain map, the Macaque Brainnetome Atlas (MacBNA), based on the anatomical connectivity profiles provided by high angular and spatial resolution ex vivo diffusion MRI data. The new atlas consists of 248 cortical and 56 subcortical regions as well as their structural and functional connections. The parcellation and the diffusion-based tractography were evaluated with invasive neuronal-tracing and Nissl-stained images. As a demonstrative application, the structural connectivity divergence between macaque and human brains was mapped using the Brainnetome atlases of those two species to uncover the genetic underpinnings of the evolutionary changes in brain structure. The resulting resource includes: (1) the thoroughly delineated Macaque Brainnetome Atlas (MacBNA), (2) regional connectivity profiles, (3) the postmortem high-resolution macaque diffusion and T2-weighted MRI dataset (Brainnetome-8), and (4) multi-contrast MRI, neuronal-tracing, and histological images collected from a single macaque. MacBNA can serve as a common reference frame for mapping multifaceted features across modalities and spatial scales and for integrative investigation and characterization of brain organization and function. Therefore, it will enrich the collaborative resource platform for nonhuman primates and facilitate translational and comparative neuroscience research.

Mechanical and morphometric approaches to body mass estimation in rhesus macaques: A test of skeletal variables.

OBJECTIVES: Estimation of body mass from skeletal metrics can reveal important insights into the paleobiology of archeological or fossil remains. The standard approach constructs predictive equations from postcrania, but studies have questioned the reliability of traditional measures. Here, we examine several skeletal features to assess their accuracy in predicting body mass. MATERIALS AND METHODS: Antemortem mass measurements were compared with common skeletal dimensions from the same animals postmortem, using 115 rhesus macaques (male: n = 43; female: n = 72). Individuals were divided into training (n = 58) and test samples (n = 57) to build and assess Ordinary Least Squares or multivariate regressions by residual sum of squares (RSS) and AIC weights. A leave-one-out approach was implemented to formulate the best fit multivariate models, which were compared against a univariate and a previously published catarrhine body-mass estimation model. RESULTS: Femur circumference represented the best univariate model. The best model overall was composed of four variables (femur, tibia and fibula circumference and humerus length). By RSS and AICw, models built from rhesus macaque data (RSS = 26.91, AIC = -20.66) better predicted body mass than did the catarrhine model (RSS = 65.47, AIC = 20.24). CONCLUSION: Body mass in rhesus macaques is best predicted by a 4-variable equation composed of humerus length and hind limb midshaft circumferences. Comparison of models built from the macaque versus the catarrhine data highlight the importance of taxonomic specificity in predicting body mass. This paper provides a valuable dataset of combined somatic and skeletal data in a primate, which can be used to build body mass equations for fragmentary fossil evidence.

Quantifying the relationship between bone and soft tissue measures within the rhesus macaques of Cayo Santiago.

OBJECTIVES: Interpretations of the primate and human fossil record often rely on the estimation of somatic dimensions from bony measures. Both somatic and skeletal variation have been used to assess how primates respond to environmental change. However, it is unclear how well skeletal variation matches and predicts soft tissue. Here, we empirically test the relationship between tissues by comparing somatic and skeletal measures using paired measures of pre- and post-mortem rhesus macaques from Cayo Santiago, Puerto Rico. MATERIALS AND METHODS: Somatic measurements were matched with skeletal dimensions from 105 rhesus macaque individuals to investigate paired signals of variation (i.e., coefficients of variation, sexual dimorphism) and bivariate codependence (reduced major axis regression) in measures of: (1) limb length; (2) joint breadth; and (3) limb circumference. Predictive models for the estimation of soft tissue dimensions from skeletons were built from Ordinary Least Squares regressions. RESULTS: Somatic and skeletal measurements showed statistically equivalent coefficients of variation and sexual dimorphism as well as high epiphyses-present ordinary least square (OLS) correlations in limb lengths (R2 >0.78, 0.82), joint breadths (R2 >0.74, 0.83) and, to a lesser extent, limb circumference (R2 >0.53, 0.68). CONCLUSION: Skeletal measurements are good substitutions for somatic values based on population signals of variation. OLS regressions indicate that skeletal correlates are highly predictive of somatic dimensions. The protocols and regression equations established here provide a basis for reliable reconstruction of somatic dimension from catarrhine fossils and validate our ability to compare or combine results of studies based on population data of either hard or soft tissue proxies.

Pterion variation in the skulls of rhesus macaques from Cayo Santiago: Inheritance, development, and pathology.

The pterion is the sutural juncture of the frontal, parietal, sphenoidal, temporal, and zygomatic bones on the lateral aspect of the cranium. As a craniometric landmark, the pterion has a taxonomic valence, in addition to a common neurosurgical entry point in medicine. Variation in the articulation patterns at the pterion have been documented between primate species yet have a high degree of uniformity within species, suggesting a genetic control for this complex region of the skull. In this study, pterion pattern variation was investigated in 1627 Rhesus macaque crania of the Cayo Santiago colony. The colony's associated skeletal collections accompany known age, sex, and maternal lineages. Pterion pattern prevalence rates were tested against matrilines, as well as cranial shape, and cranial sutural fusion ages (including individuals with prematurely fused sutures). Five patterns were identified, the most prominent being the prevailing Old World Monkey frontotemporal (FT) articulation (83.4%). The relative frequency of those not exhibiting the FT pattern was found to vary considerably between matrilineal families (p = 0.037), ranging from 5.3% to 34.2%. Mothers with the non-FT pterion pattern were three times as likely to bear non-FT offspring. Cranial shape additionally varied with pterion type. Males exhibiting zygomaticotemporal (ZT) and sphenoparietal (SP) articulations possessed a relatively longer and narrower cranium than those with the default FT type (p = < 0.001). Cranial sutural fusion ages were not found to differ between pterion types, though all individuals with craniosynostosis (6; 0.38%) exhibited the FT type. The study provided strong evidence for a genetic source for pterion pattern as well as outlining a relatively novel relationship with cranial shape and sutural fusion ages. A unifying explanation may lie in those genes involved in both sutural and craniofacial development, or in the variation of brain growth processes channeling sutural articulation at the pterion. Both may be heritable and responsible for producing observed matrilineal differences in the pterion.

Generalising XTRACT tractography protocols across common macaque brain templates.

Non-human primates are extensively used in neuroscience research as models of the human brain, with the rhesus macaque being a prominent example. We have previously introduced a set of tractography protocols (XTRACT) for reconstructing 42 corresponding white matter (WM) bundles in the human and the macaque brain and have shown cross-species comparisons using such bundles as WM landmarks. Our original XTRACT protocols were developed using the F99 macaque brain template. However, additional macaque template brains are becoming increasingly common. Here, we generalise the XTRACT tractography protocol definitions across five macaque brain templates, including the F99, D99, INIA, Yerkes and NMT. We demonstrate equivalence of such protocols in two ways: (a) Firstly by comparing the bodies of the tracts derived using protocols defined across the different templates considered, (b) Secondly by comparing the projection patterns of the reconstructed tracts across the different templates in two cross-species (human-macaque) comparison tasks. The results confirm similarity of all predictions regardless of the macaque brain template used, providing direct evidence for the generalisability of these tractography protocols across the five considered templates.

Testing the reliability of the rearticulation of osteological primate pelves in comparative morphological studies.

The evolution of human pelvic form is primarily studied using disarticulated osteological material of living and fossil primates that need rearticulation to approximate anatomical position. To test whether this technique introduces errors that impact biological signals, virtual rearticulations of the pelvis in anatomical position from computed tomography scans were compared with rearticulated models from the same individuals for one female and one male of Homo sapiens, Pan troglodytes, Macaca mulatta, Lepilemur mustelinus, Galago senegalensis, and Nycticebus pygmaeus. "Cadaveric" pelvic bones were first analyzed in anatomical position, then the three bones were segmented individually, intentionally scattered, and "rearticulated" to test for rearticulation error. Three-dimensional landmarks and linear measurements were used to characterize the overall pelvis shape. Cadaveric and rearticulated pelves were not identical, but inter-specific and intra-specific shape differences were higher than the landmarking error in the cadaveric individuals and the landmarking/rearticulation error in the rearticulated pelves, demonstrating that the biological signal is stronger than the noise introduced by landmarking and rearticulation. The rearticulation process, however, underestimates the medio-lateral pelvic measurements in species with a substantial pubic gap (e.g., G. senegalensis, N. pygmaeus) possibly because the greater contribution of soft tissue to the pelvic girdle introduces higher uncertainty during rearticulation. Nevertheless, this discrepancy affects only the caudal-most part of the pelvis. This study demonstrates that the rearticulation of pelvic bones does not substantially affect the biological signal in comparative 3D morphological studies but suggests that anatomically connected pelves of species with wide pubic gaps should be preferentially included in these studies.

CT anatomy and normal radiography of the skull of the Rhesus monkey (Macaca mulatta).

BACKGROUND: Considering the relationship between human morphology and physiology with the Rhesus monkey, this animal is the most prominent species of laboratory primate for human and animal health research. Moreover, sending Macaca mulatta monkey into space and simulating a living environment for humans shows the similarity of this animal's physiology with humans. OBJECTIVE: So far, no comprehensive study has been done on computed tomography (CT) scan and radiography of skulls in Rhesus monkeys. Therefore, providing accurate documents from the CT anatomy of the skull in these animals can help us to better understand normal conditions and diseases, and we can use a functional atlas of diagnostic imaging from the skull of this animal. METHODS: Ten mature monkeys weighing 6.5 kg were used for this project (five males and five females). A radiographic examination with standard views was performed during general anaesthesia. Then the monkeys were placed in a spherical CT scan during general anaesthesia with standard sternal recumbency. RESULTS: The frontal bone was seen as two parallel radiopaque lines coming forward and downward. The frontal sinus in the Rhesus monkey was not visible in both lateral and dorsoventral radiographs, which could indicate the degeneration of this sinus in this species. The number of teeth in an adult monkey was 32. Molar teeth had a bilophodont arrangement. CONCLUSIONS: The comparison between the size of the eye ball in human and Rhesus monkey, unlike other measured parameters, did not differ much, and this indicates that the volume ratio of the eye ball to the whole skull in Rhesus monkey is higher than that of humans.

Diffusion MRI and anatomic tracing in the same brain reveal common failure modes of tractography.

Anatomic tracing is recognized as a critical source of knowledge on brain circuitry that can be used to assess the accuracy of diffusion MRI (dMRI) tractography. However, most prior studies that have performed such assessments have used dMRI and tracer data from different brains and/or have been limited in the scope of dMRI analysis methods allowed by the data. In this work, we perform a quantitative, voxel-wise comparison of dMRI tractography and anatomic tracing data in the same macaque brain. An ex vivo dMRI acquisition with high angular resolution and high maximum b-value allows us to compare a range of q-space sampling, orientation reconstruction, and tractography strategies. The availability of tracing in the same brain allows us to localize the sources of tractography errors and to identify axonal configurations that lead to such errors consistently, across dMRI acquisition and analysis strategies. We find that these common failure modes involve geometries such as branching or turning, which cannot be modeled well by crossing fibers. We also find that the default thresholds that are commonly used in tractography correspond to rather conservative, low-sensitivity operating points. While deterministic tractography tends to have higher sensitivity than probabilistic tractography in that very conservative threshold regime, the latter outperforms the former as the threshold is relaxed to avoid missing true anatomical connections. On the other hand, the q-space sampling scheme and maximum b-value have less of an impact on accuracy. Finally, using scans from a set of additional macaque brains, we show that there is enough inter-individual variability to warrant caution when dMRI and tracer data come from different animals, as is often the case in the tractography validation literature. Taken together, our results provide insights on the limitations of current tractography methods and on the critical role that anatomic tracing can play in identifying potential avenues for improvement.

The Subcortical Atlas of the Rhesus Macaque (SARM) for neuroimaging.

Digitized neuroanatomical atlases that can be overlaid onto functional data are crucial for localizing brain structures and analyzing functional networks identified by neuroimaging techniques. To aid in functional and structural data analysis, we have created a comprehensive parcellation of the rhesus macaque subcortex using a high-resolution ex vivo structural imaging scan. This anatomical scan and its parcellation were warped to the updated NIMH Macaque Template (NMT v2), an in vivo population template, where the parcellation was refined to produce the Subcortical Atlas of the Rhesus Macaque (SARM) with 210 primary regions-of-interest (ROIs). The subcortical parcellation and nomenclature reflect those of the 4th edition of the Rhesus Monkey Brain in Stereotaxic Coordinates (Paxinos et al., in preparation), rather than proposing yet another novel atlas. The primary ROIs are organized across six spatial hierarchical scales from small, fine-grained ROIs to broader composites of multiple ROIs, making the SARM suitable for analysis at different resolutions and allowing broader labeling of functional signals when more accurate localization is not possible. As an example application of this atlas, we have included a functional localizer for the dorsal lateral geniculate (DLG) nucleus in three macaques using a visual flickering checkerboard stimulus, identifying and quantifying significant fMRI activation in this atlas region. The SARM has been made openly available to the neuroimaging community and can easily be used with common MRI data processing software, such as AFNI, where the atlas has been embedded into the software alongside cortical macaque atlases.

The forearm and hand musculature of semi-terrestrial rhesus macaques (Macaca mulatta) and arboreal gibbons (fam.Hylobatidae). Part II. Quantitative analysis.

Nonhuman primates have a highly diverse locomotor repertoire defined by an equally diverse hand use. Based on how primates use their hands during locomotion, we can distinguish between terrestrial and arboreal taxa. The 'arboreal' hand is likely adapted towards high wrist mobility and grasping, whereas the 'terrestrial' hand will show adaptations to loading. While the morphology of the forearm and hand bones have been studied extensively, functional adaptations in the forearm and hand musculature to locomotor behaviour have been documented only scarcely. In this paper, we investigate the forelimb musculature of the highly arboreal gibbons (including Hylobates lar,Hylobates pileatus,Nomascus leucogenys,Nomascus concolor and Symphalangus syndactylus) and compare this with the musculature of the semi-terrestrial rhesus macaques (Macaca mulatta). Anatomical data from previous dissections on knuckle-walking bonobos (Pan paniscus) and bipedal humans (Homo sapiens) are also included to further integrate the analyses in the scope of catarrhine hand adaptation. This study indicates that the overall configuration of the arm and hand musculature of these primates is very similar but there are some apparent differences in relative size which can be linked to differences in forelimb function and which might be related to their specific locomotor behaviour. In macaques, there is a large development of wrist deviators, wrist and digital flexors, and m. triceps brachii, as these muscles are important during the different phases of palmi- and digitigrade quadrupedal walking to stabilize the wrist and elbow. In addition, their m. flexor carpi ulnaris is the most important contributor to the total force-generating capacity of the wrist flexors and deviators, and is needed to counteract the adducting torque at the elbow joint during quadrupedal walking. Gibbons show a relatively high force-generating capacity in their forearm rotators, wrist and digital flexors, which are important muscles in brachiation to actively regulate forward movement of the body. The results also stress the importance of the digital flexors in bonobos, during climbing and clambering, and in humans, which is likely linked to our advanced manipulation skills.

Variability in the number of infraorbital foramina in rhesus macaques (Macaca mulatta) and cynomolgus macaques (Macaca fascicularis).

This study aimed to determine the number of infraorbital foramina in monkeys of the Papionini tribe. The authors performed a µCT analysis of the morphology of the infraorbital foramina. A total number of 52 simian skulls belonged to two macaque species: Macaca mulatta and Macaca fascicularis were used in the study. The number of infraorbital foramina was counted macroscopically and with the use of a magnifying glass. Next, the skull representing the most common morphological type was selected and scanned by micro-computed tomography (µCT). The Shapiro-Wilk normality test was used in the study. To compare the differences in the number of infraorbital foramen between species, sex and sides, the Mann-Whitney U test was applied. Three infraorbital foramina were present in most individuals from the test group. The Mann-Whitney test revealed no statistically significant difference between the number of foramina on the right- and left-hand side. Likewise, no statistically significant differences between the numbers of infraorbital foramina across sexes were observed. Volumetric reconstructions revealed the presence of separate infraorbital canals for each infraorbital foramen. Craniofacial innervation in macaques is formed by complex branching patterns of cranial nerves. Variability in the number of infraorbital foramina suggests a variable maxillary innervation pattern in these animals. Based on the analysis of volumetric projections, the presence of two labial branches and a single nasal branch of the infraorbital nerve is suggested. Detailed descriptions are supported by quantitative data and µCT evidence.

Dynamic Suppression of Average Facial Structure Shapes Neural Tuning in Three Macaque Face Patches.

The visual perception of identity in humans and other primates is thought to draw upon cortical areas specialized for the analysis of facial structure. A prominent theory of face recognition holds that the brain computes and stores average facial structure, which it then uses to efficiently determine individual identity, though the neural mechanisms underlying this process are controversial. Here, we demonstrate that the dynamic suppression of average facial structure plays a prominent role in the responses of neurons in three fMRI-defined face patches of the macaque. Using photorealistic face stimuli that systematically varied in identity level according to a psychophysically based face space, we found that single units in the AF, AM, and ML face patches exhibited robust tuning around average facial structure. This tuning emerged after the initial excitatory response to the face and was expressed as the selective suppression of sustained responses to low-identity faces. The coincidence of this suppression with increased spike timing synchrony across the population suggests a mechanism of active inhibition underlying this effect. Control experiments confirmed that the diminished responses to low-identity faces were not due to short-term adaptation processes. We propose that the brain's neural suppression of average facial structure facilitates recognition by promoting the extraction of distinctive facial characteristics and suppressing redundant or irrelevant responses across the population.

PREEMACS: Pipeline for preprocessing and extraction of the macaque brain surface.

Accurate extraction of the cortical brain surface is critical for cortical thickness estimation and a key element to perform multimodal imaging analysis, where different metrics are integrated and compared in a common space. While brain surface extraction has become widespread practice in human studies, several challenges unique to neuroimaging of non-human primates (NHP) have hindered its adoption for the study of macaques. Although, some of these difficulties can be addressed at the acquisition stage, several common artifacts can be minimized through image preprocessing. Likewise, there are several image analysis pipelines for human MRIs, but very few automated methods for extraction of cortical surfaces have been reported for NHPs and none have been tested on data from diverse sources. We present PREEMACS, a pipeline that standardizes the preprocessing of structural MRI images (T1- and T2-weighted) and carries out an automatic surface extraction of the macaque brain. Building upon and extending pre-existing tools, the first module performs volume orientation, image cropping, intensity non-uniformity correction, and volume averaging, before skull-stripping through a convolutional neural network. The second module performs quality control using an adaptation of MRIqc method to extract objective quality metrics that are then used to determine the likelihood of accurate brain surface estimation. The third and final module estimates the white matter (wm) and pial surfaces from the T1-weighted volume (T1w) using an NHP customized version of FreeSurfer aided by the T2-weighted volumes (T2w). To evaluate the generalizability of PREEMACS, we tested the pipeline using 57 T1w/T2w NHP volumes acquired at 11 different sites from the PRIME-DE public dataset. Results showed an accurate and robust automatic brain surface extraction from images that passed the quality control segment of our pipeline. This work offers a robust, efficient and generalizable pipeline for the automatic standardization of MRI surface analysis on NHP.

Histological assessment of optogenetic tools to study fronto-visual and fronto-parietal cortical networks in the rhesus macaque.

Optogenetics offers unprecedented possibilities to investigate cortical networks. Yet, the number of successful optogenetic applications in non-human primates is still low, and the consequences of opsin expression in the primate brain are not well documented. We assessed histologically if we can target cerebrocortical networks with three common optogenetic constructs (AAV2/5-CaMKIIα-eNpHR3.0-mCherry, -ChR2-eYFP, -C1V1-mCherry). The frontal eye field or the dorsal premotor area of rhesus macaques were virally injected, and the resulting transduction spread, expression specificity, and opsin trafficking into axons projecting to parietal and visual areas were examined. After variable periods (2-24 months), expression was robust for all constructs at the injection sites. The CaMKIIα promoter driven-expression was predominant, but not exclusive, in excitatory neurons. In the case of eNpHR3.0-mCherry and ChR2-eYFP, opsins were present in axonal projections to target areas, in which sparse, retrogradely transduced neurons could also be found. Finally, the intracellular distribution of opsins differed: ChR2-eYFP had almost exclusive membrane localization, while eNpHR3.0-mCherry and C1V1-mCherry showed additional intracellular accumulations, which might affect neuronal survival in the long-term. Results indicate that all three constructs can be used for local neuronal modulation, but axonal stimulation and long-term use require additional considerations of construct selection and verification.

The forearm and hand musculature of semi-terrestrial rhesus macaques (Macaca mulatta) and arboreal gibbons (Fam. Hylobatidae). Part I. Description and comparison of the muscle configuration.

Primates live in very diverse environments and, as a consequence, show an equally diverse locomotor behaviour. During locomotion, the primate hand interacts with the superstrate and/or substrate and will therefore probably show adaptive signals linked with this locomotor behaviour. Whereas the morphology of the forearm and hand bones have been studied extensively, the functional adaptations in the hand musculature have been documented only scarcely. To evaluate whether there are potential adaptations in forelimb musculature to locomotor behaviour, we investigated the forearm and hand musculature of the highly arboreal gibbons (including Hylobates lar, Hylobates pileatus, Nomascus leucogenys, Nomascus concolor, Symphalangus syndactylus) and compared this with the musculature of the semi-terrestrial rhesus macaques (Macaca mulatta) by performing complete and detailed dissections on a sample of 15 unembalmed specimens. We found that the overall configuration of the upper arm and hand musculature is highly comparable between arboreal gibbons and semi-terrestrial macaques, and follows the general primate condition. Most of the identified differences in muscle configuration are located in the forearm. In macaques, a prominent m. epitrochleoanconeus is present, which potentially helps to extend the forearm and/or stabilize the elbow joint during quadrupedal walking. The m. flexor carpi radialis shows a more radial insertion in gibbons, which might be advantageous during brachiation, as it can aid radial deviation. The fingers of macaques are controlled in pairs by the m. extensor digiti secondi et tertii proprius and the m. extensor digiti quarti et quinti proprius-a similar organization can also be found in their flexors-which might aid in efficient positioning of the hand and fingers on uneven substrates during quadrupedal walking. In contrast, extension of the little finger in gibbons is controlled by a separate m. extensor digiti minimi, whereas digits 2 to 4 are extended by the m. extensor digitorum brevis, suggesting that simultaneous extension of digits 2-4 in gibbons might be important when reaching or grasping an overhead support during brachiation. In conclusion, the overall configuration of the forelimb and hand musculature is very similar in gibbons and macaques, with some peculiarities which can be linked to differences in forelimb function and which might be related to the specific locomotor behaviour of each group.

Dawn of the Visible Monkey: Segmentation of the Rhesus Monkey for 2D and 3D Applications.

BACKGROUND: To properly utilize the sectioned images in a Visible Monkey dataset, it is essential to segment the images into distinct structures. This segmentation allows the sectioned images to be compiled into two-dimensional or three-dimensional software packages to facilitate anatomy and radiology education, and allows them to be used in experiments involving electromagnetic radiation. The purpose of the present study was to demonstrate the potential of the sectioned images using the segmented images. METHODS: Using sectioned images of a monkey's entire body, 167 structures were segmented using Adobe Photoshop. The segmented images and sectioned images were packaged into the browsing software. Surface models were made from the segmented images using Mimics. Volume models were made from the sectioned images and segmented images using MRIcroGL. RESULTS: In total, 839 segmented images of 167 structures in the entire body of a monkey were produced at 0.5-mm intervals (pixel size, 0.024 mm; resolution, 8,688 × 5,792; color depth, 24-bit color; BMP format). Using the browsing software, the sectioned images and segmented images were able to be observed continuously and magnified along with the names of the structures. The surface models of PDF file were able to be handled freely using Adobe Reader. In the surface models, the space information of all segmented structures was able to be identified using Sim4Life. On MRIcroGL, the volume model was able to be browsed and sectioned at any angle with real color. CONCLUSION: Browsing software, surface models, and volume models are able to be produced based on the segmentation of the sectioned images. These will be helpful for students and researchers studying monkey anatomy and radiology, as well as for biophysicists examining the effects of electromagnetic radiation.

Rhesus Macaque Brain Developmental Trajectory: A Longitudinal Analysis Using Tensor-Based Structural Morphometry and Diffusion Tensor Imaging.

The typical developmental trajectory of brain structure among nonhuman primates (NHPs) remains poorly understood. In this study, we characterized the normative trajectory of developmental change among a cohort of rhesus monkeys (n = 28), ranging in age from 2 to 22 months, using structural MRI datasets that were longitudinally acquired every 3-4 months. We hypothesized that NHP-specific transient intracranial volume decreases reported during late infancy would be part of the typical developmental process, which is driven by volumetric contraction of gray matter in primary functional areas. To this end, we performed multiscale analyses from the whole brain to voxel level, characterizing regional heterogeneity, hemispheric asymmetry, and sexual dimorphism in developmental patterns. The longitudinal trajectory of brain development was explained by three different regional volumetric growth patterns (exponentially decreasing, undulating, and linearly increasing), which resulted in developmental brain volume curves with transient brain volumetric decreases. White matter (WM) fractional anisotropy increased with age, corresponding to WM volume increases, while mean diffusivity (MD) showed biphasic patterns. The longitudinal trajectory of brain development in young rhesus monkeys follows typical maturation patterns seen in humans, but regional volumetric and MD changes are more dynamic in rhesus monkeys compared with humans, with marked decreases followed by "rebound-like" increases.

Social subordination alters estradiol-induced changes in cortico-limbic brain volumes in adult female rhesus monkeys.

Women have a higher risk of developing stress-related disorders compared to men and the experience of a stressful life event is a potent risk-factor. The rodent literature suggests that chronic exposure to stressors as well as 17ß-estradiol (E2) can result in alterations in neuronal structure in corticolimbic brain regions, however the translation of these data to humans is limited by the nature of the stressor experienced and issues of brain homology. To address these limitations, we used a well-validated rhesus monkey model of social subordination to examine effects of E2 treatment on subordinate (high stress) and dominant (low stress) female brain structure, including regional gray matter and white matter volumes using structural magnetic resonance imaging. Our results show that one month of E2 treatment in ovariectomized females, compared to control (no) treatment, decreased frontal cortex gray matter volume regardless of social status. In contrast, in the cingulate cortex, an area associated with stress-induced emotional processing, E2 decreased grey matter volume in subordinates but increased it in dominant females. Together these data suggest that physiologically relevant levels of E2 alter cortical gray matter volumes in females after only one month of treatment and interact with chronic social stress to modulate these effects on brain structure.

Preliminary study on fine structures of subcortical nuclei in rhesus monkeys by ex vivo 9.4 T MRI.

Changes in fine structures of the brain over a life span can have robust effects on neural activity and brain function, which both play crucial roles in neurodegenerative diseases. Clinically, however, low-resolution MRI only provides limited information about fine brain structures. Here, using high-resolution 9.4 T MRI, we established a set of structural images and explored the fine structures of the claustrum, hippocampus, amygdala complex, and subregions of the amygdala complex (BLA, including lateral, basal, and accessory basal subnuclei) in rhesus macaque (Macaca mulatta) brains. Based on these high-resolution images, we were able to discriminate the subregional boundaries accurately and, at the same time, obtain the volume of each brain nuclei. Thus, advanced high-resolution 9.4 T MRI not only provides a new strategy for early diagnosis of neurodegenerative diseases, but also provides the ability to observe fine structural changes in the brain across a life span.

Transcriptomic and open chromatin atlas of high-resolution anatomical regions in the rhesus macaque brain.

The rhesus macaque is a prime model animal in neuroscience. A comprehensive transcriptomic and open chromatin atlas of the rhesus macaque brain is key to a deeper understanding of the brain. Here we characterize the transcriptome of 416 brain samples from 52 regions of 8 rhesus macaque brains. We identify gene modules associated with specific brain regions like the cerebral cortex, pituitary, and thalamus. In addition, we discover 9703 novel intergenic transcripts, including 1701 coding transcripts and 2845 lncRNAs. Most of the novel transcripts are only expressed in specific brain regions or cortical regions of specific individuals. We further survey the open chromatin regions in the hippocampal CA1 and several cerebral cortical regions of the rhesus macaque brain using ATAC-seq, revealing CA1- and cortex-specific open chromatin regions. Our results add to the growing body of knowledge regarding the baseline transcriptomic and open chromatin profiles in the brain of the rhesus macaque.