Because of their close relationship with humans, non-human apes (chimpanzees, bonobos, gorillas, orangutans, and gibbons, including siamangs) are of great scientific interest. The goal of understanding their complex behavior would be greatly advanced by the ability to perform video-based pose tracking. Tracking, however, requires high-quality annotated datasets of ape photographs. Here we present OpenApePose, a new public dataset of 71,868 photographs, annotated with 16 body landmarks of six ape species in naturalistic contexts. We show that a standard deep net (HRNet-W48) trained on ape photos can reliably track out-of-sample ape photos better than networks trained on monkeys (specifically, the OpenMonkeyPose dataset) and on humans (COCO) can. This trained network can track apes almost as well as the other networks can track their respective taxa, and models trained without one of the six ape species can track the held-out species better than the monkey and human models can. Ultimately, the results of our analyses highlight the importance of large, specialized databases for animal tracking systems and confirm the utility of our new ape database.

This study examined the role of male pubertal maturation on physical growth and development of neurocircuits that regulate stress, emotional and cognitive control using a translational nonhuman primate model. We collected longitudinal data from male macaques between pre- and peri-puberty, including measures of physical growth, pubertal maturation (testicular volume, blood testosterone -T- concentrations) and brain structural and resting-state functional MRI scans to examine developmental changes in amygdala (AMY), hippocampus (HIPPO), prefrontal cortex (PFC), as well as functional connectivity (FC) between those regions. Physical growth and pubertal measures increased from pre- to peri-puberty. The indexes of pubertal maturation -testicular size and T- were correlated at peri-puberty, but not at pre-puberty (23 months). Our findings also showed ICV, AMY, HIPPO and total PFC volumetric growth, but with region-specific changes in PFC. Surprisingly, FC in these neural circuits only showed developmental changes from pre- to peri-puberty for HIPPO-orbitofrontal FC. Finally, testicular size was a better predictor of brain structural maturation than T levels -suggesting gonadal hormones-independent mechanisms-, whereas T was a strong predictor of functional connectivity development. We expect that these neural circuits will show more drastic pubertal-dependent maturation, including stronger associations with pubertal measures later, during and after male puberty.

The current study examined the long-term effects of neonatal amygdala (Neo-A) lesions on brain corticotropin-releasing factor (CRF) systems and hypothalamic-pituitary-adrenal (HPA) axis function of male and female prepubertal rhesus monkeys. At 12-months-old, CSF levels of CRF were measured and HPA axis activity was characterized by examining diurnal cortisol rhythm and response to pharmacological challenges. Compared with controls, Neo-A animals showed higher cortisol secretion throughout the day, and Neo-A females also showed higher CRF levels. Hypersecretion of basal cortisol, in conjunction with blunted pituitary-adrenal responses to CRF challenge, suggest HPA axis hyperactivity caused by increased CRF hypothalamic drive leading to downregulation of pituitary CRF receptors in Neo-A animals. This interpretation is supported by the increased CRF CSF levels, suggesting that Neo-A damage resulted in central CRF systems overactivity. Neo-A animals also exhibited enhanced glucocorticoid negative feedback, as reflected by an exaggerated cortisol suppression following dexamethasone administration, indicating an additional effect on glucocorticoid receptor (GR) function. Together these data demonstrate that early amygdala damage alters the typical development of the primate HPA axis resulting in increased rather than decreased activity, presumably via alterations in central CRF and GR systems in neural structures that control its activity. Thus, in contrast to evidence that the amygdala stimulates both CRF and HPA axis systems in the adult, our data suggest an opposite, inhibitory role of the amygdala on the HPA axis during early development, which fits with emerging literature on "developmental switches" in amygdala function and connectivity with other brain areas.

Although the most notable clinical symptoms of Huntington's disease (HD) are motor disturbances and brain atrophy, other symptoms include cognitive dysfunction, emotional and hormonal dysregulation. Emotional dysregulation (irritability, anger/aggression, and anxiety) and increased inflammation are early emerging symptoms which can be detected decades before the onset of motor symptoms in HD patients. Despite the advances in understanding the genetic causes of HD there is still no cure or preventative treatment. Thus, to better understand the pathogenesis of HD and develop effective treatments, a holistic understanding of HD is needed, as well as animal models that replicate the full spectrum of HD symptoms. The current study examined the emotional, hormonal, and gene expression responses to an acute stressor of adult male transgenic HD rhesus monkeys (n = 2) as compared to wild-type controls (n = 2). Results revealed that HD monkeys expressed increased anxiety and irritability/aggression as compared to controls. Reactive cortisol response to the stressor was similar between groups. However, HD monkeys exhibited increased pro-inflammatory cytokines and higher induction of immune pathway genes as compared to controls. Overall, results reveal that HD monkeys exhibit these early emerging symptoms of HD and may be an effective animal model to facilitate the development of new therapeutics for HD patients.

Designer receptors exclusively activated by designer drugs (DREADDs) are extensively used to modulate neuronal activity in rodents, but their use in primates remains limited. An essential need that remains is the demonstration that DREADDs are efficiently expressed on the plasma membrane of primate neurons. To address this issue, electron microscopy immunogold was used to determine the subcellular localization of the AAV vector-induced DREADDs hM4Di and hM3Dq fused to different tags in various brain areas of rhesus monkeys and mice. When hM4Di was fused to mCherry, the immunogold labelling was mostly confined to the intracellular space, and poorly expressed at the plasma membrane in monkey dendrites. In contrast, the hM4Di-mCherry labelling was mostly localized to the dendritic plasma membrane in mouse neurons, suggesting species differences in the plasma membrane expression of these exogenous proteins. The lack of hM4Di plasma membrane expression may limit the functional effects of systemic administration of DREADD-actuators in monkey neurons. Removing the mCherry and fusing of hM4Di with the haemagglutinin (HA) tag resulted in strong neuronal plasma membrane immunogold labelling in both monkeys and mice neurons. Finally, hM3Dq-mCherry was expressed mostly at the plasma membrane in monkey neurons, indicating that the fusion of mCherry with hM3Dq does not hamper membrane incorporation of this specific DREADD. Our results suggest that the pattern of ultrastructural expression of DREADDs in monkey neurons depends on the DREADD/tag combination. Therefore, a preliminary characterization of plasma membrane expression of specific DREADD/tag combinations is recommended when using chemogenetic approaches in primates.

Manipulation of neuronal activity during the early postnatal period in monkeys has been largely limited to permanent lesion studies, which can be impacted by developmental plasticity leading to reorganization and compensation from other brain structures that can interfere with the interpretations of results. Chemogenetic tools, such as DREADDs (designer receptors exclusively activated by designer drugs), can transiently and reversibly activate or inactivate brain structures, avoiding the pitfalls of permanent lesions to better address important developmental neuroscience questions. We demonstrate that inhibitory DREADDs in the amygdala can be used to manipulate socioemotional behavior in infant monkeys. Two infant rhesus monkeys (1 male, 1 female) received AAV5-hSyn-HA-hM4Di-IRES-mCitrine injections bilaterally in the amygdala at 9 months of age. DREADD activation after systemic administration of either clozapine-N-oxide or low-dose clozapine resulted in decreased freezing and anxiety on the human intruder paradigm and changed the looking patterns on a socioemotional attention eye-tracking task, compared with vehicle administration. The DREADD-induced behaviors were reminiscent of, but not identical to, those seen after permanent amygdala lesions in infant monkeys, such that neonatal lesions produce a more extensive array of behavioral changes in response to the human intruder task that were not seen with DREADD-evoked inhibition of this region. Our results may help support the notion that the more extensive behavior changes seen after early lesions are manifested from brain reorganization that occur after permanent damage. The current study provides a proof of principle that DREADDs can be used in young infant monkeys to transiently and reversibly manipulate behavior.

Zika virus (ZIKV) infection has a profound impact on the fetal nervous system. The postnatal period is also a time of rapid brain growth, and it is important to understand the potential neurobehavioral consequences of ZIKV infection during infancy. Here we show that postnatal ZIKV infection in a rhesus macaque model resulted in long-term behavioral, motor, and cognitive changes, including increased emotional reactivity, decreased social contact, loss of balance, and deficits in visual recognition memory at one year of age. Structural and functional MRI showed that ZIKV-infected infant rhesus macaques had persistent enlargement of lateral ventricles, smaller volumes and altered functional connectivity between brain areas important for socioemotional behavior, cognitive, and motor function (e.g. amygdala, hippocampus, cerebellum). Neuropathological changes corresponded with neuroimaging results and were consistent with the behavioral and memory deficits. Overall, this study demonstrates that postnatal ZIKV infection in this model may have long-lasting neurodevelopmental consequences.

Due to its low invasiveness and controllability, chemogenetic approaches offer a highly attractive option to modulate neuronal activity in basic research and future clinical applications. Chemogenetics have revolutionized neuroscience research by facilitating manipulations of selective brain circuits. To date, however, the large majority of these studies have been conducted in rodent models, while the wide application of chemogenetics in nonhuman primates (NHPs) is yet to occur. Still, important progress has been achieved in the use of chemogenetics in NHP studies in the last few years. Here we review the studies that have been published using chemogenetics in NHPs and discuss the current limitations of the technique to its more widespread use in NHPs and possible ways to overcome them.

The current study examined the long-term effects of neonatal amygdala lesions on emotional and hypothalamic-pituitary-adrenal (HPA) axis reactivity to an acute stressor in rhesus monkeys. Rhesus monkeys received either bilateral MRI-guided ibotenic acid amygdala (Neo-Aibo; n = 6) or sham (Neo-C; n = 7) lesions between 7–14 days of age. Emotional reactivity was assessed using the Human Intruder paradigm at 2 months, 4.5 months, and 6–8 years of age, whereas stress neuroendocrine response was only assessed in adulthood (6–8 years). The modulation of defensive and emotional behaviors based on the gaze direction of the intruder emerged between 2–4 months of age in surrogate-peer reared sham-operated infant monkeys, as already shown for mother-reared infants. Although neonatal amygdala lesions did not impair the ability to exhibit defensive and emotional behaviors, it altered the modulation of these responses based on the intruder’s gaze direction. The changes in emotional reactivity after neonatal amygdala lesions emerged in infancy and persisted throughout adulthood when they were associated with a reduction of basal cortisol levels and a blunted cortisol response to the stressor. These changes are reminiscent of those found after adult-onset amygdala lesions, demonstrating little functional compensation following early amygdala damage.

With the ultimate goal of developing a more representative animal model of Alzheimer's disease (AD), two female amyloid-β-(Aβ) precursor protein-transgenic (APPtg) rhesus monkeys were generated by lentiviral transduction of the APP gene into rhesus oocytes, followed by in vitro fertilization and embryo transfer. The APP-transgene included the AD-associated Swedish K670N/M671L and Indiana V717F mutations (APPSWE/IND) regulated by the human polyubiquitin-C promoter. Overexpression of APP was confirmed in lymphocytes and brain tissue. Upon sacrifice at 10 years of age, one of the monkeys had developed Aβ plaques and cerebral Aβ-amyloid angiopathy in the occipital, parietal, and caudal temporal neocortices. The induction of Aβ deposition more than a decade prior to its usual emergence in the rhesus monkey supports the feasibility of creating a transgenic nonhuman primate model for mechanistic analyses and preclinical testing of treatments for Alzheimer's disease and cerebrovascular amyloidosis.