Ocular dominance-dependent binocular combination of monocular neuronal responses in macaque V1.

Primates rely on two eyes to perceive depth, while maintaining stable vision when either one eye or both eyes are open. Although psychophysical and modeling studies have investigated how monocular signals are combined to form binocular vision, the underlying neuronal mechanisms, particularly in V1 where most neurons exhibit binocularity with varying eye preferences, remain poorly understood. Here, we used two-photon calcium imaging to compare the monocular and binocular responses of thousands of simultaneously recorded V1 superficial-layer neurons in three awake macaques. During monocular stimulation, neurons preferring the stimulated eye exhibited significantly stronger responses compared to those preferring both eyes. However, during binocular stimulation, the responses of neurons preferring either eye were suppressed on the average, while those preferring both eyes were enhanced, resulting in similar neuronal responses irrespective of their eye preferences, and an overall response level similar to that with monocular viewing. A neuronally realistic model of binocular combination, which incorporates ocular dominance-dependent divisive interocular inhibition and binocular summation, is proposed to account for these findings.

Agranular frontal cortical microcircuit underlying cognitive control in macaques.

The error-related negativity and an N2-component recorded over medial frontal cortex index core functions of cognitive control. While they are known to originate from agranular frontal areas, the underlying microcircuit mechanisms remain elusive. Most insights about microcircuit function have been derived from variations of the so-called canonical microcircuit model. These microcircuit architectures are based extensively on studies from granular sensory cortical areas in monkeys, cats, and rodents. However, evidence has shown striking cytoarchitectonic differences across species and differences in the functional relationships across cortical layers in agranular compared to granular sensory areas. In this minireview, we outline a tentative microcircuit model underlying cognitive control in the agranular frontal cortex of primates. The model incorporates the main GABAergic interneuron subclasses with specific laminar arrangements and target regions on pyramidal cells. We emphasize the role of layer 5 pyramidal cells in error and conflict detection. We offer several specific questions necessary for creating a specific intrinsic microcircuit model of the agranular frontal cortex.

Multiplicative joint coding in preparatory activity for reaching sequence in macaque motor cortex.

Although the motor cortex has been found to be modulated by sensory or cognitive sequences, the linkage between multiple movement elements and sequence-related responses is not yet understood. Here, we recorded neuronal activity from the motor cortex with implanted micro-electrode arrays and single electrodes while monkeys performed a double-reach task that was instructed by simultaneously presented memorized cues. We found that there existed a substantial multiplicative component jointly tuned to impending and subsequent reaches during preparation, then the coding mechanism transferred to an additive manner during execution. This multiplicative joint coding, which also spontaneously emerged in recurrent neural networks trained for double reach, enriches neural patterns for sequential movement, and might explain the linear readout of elemental movements.

Neural correlates of perceptual similarity masking in primate V1.

Visual detection is a fundamental natural task. Detection becomes more challenging as the similarity between the target and the background in which it is embedded increases, a phenomenon termed 'similarity masking'. To test the hypothesis that V1 contributes to similarity masking, we used voltage sensitive dye imaging (VSDI) to measure V1 population responses while macaque monkeys performed a detection task under varying levels of target-background similarity. Paradoxically, we find that during an initial transient phase, V1 responses to the target are enhanced, rather than suppressed, by target-background similarity. This effect reverses in the second phase of the response, so that in this phase V1 signals are positively correlated with the behavioral effect of similarity. Finally, we show that a simple model with delayed divisive normalization can qualitatively account for our findings. Overall, our results support the hypothesis that a nonlinear gain control mechanism in V1 contributes to perceptual similarity masking.

Neurotensin modulates ovarian vascular permeability via adherens junctions.

Neurotensin (NTS) is a 13-amino acid peptide which is highly expressed in the mammalian ovary in response to the luteinizing hormone surge. Antibody neutralization of NTS in the ovulatory follicle of the cynomolgus macaque impairs ovulation and induces follicular vascular dysregulation, with excessive pooling of red blood cells in the follicle antrum. We hypothesize that NTS is an essential intrafollicular regulator of vascular permeability. In the present study, follicle injection of the NTS receptor antagonist SR142948 also resulted in vascular dysregulation. To measure vascular permeability changes in vitro, primary macaque ovarian microvascular endothelial cells (mOMECs) were enriched from follicle aspirates and studied in vitro. When treated with NTS, permeability of mOMECs decreased. RNA sequencing (RNA-Seq) of mOMECs revealed high mRNA expression of the permeability-regulating adherens junction proteins N-cadherin (CDH2) and K-cadherin (CDH6). Immunofluorescent detection of CDH2 and CDH6 confirmed expression and localized these cadherins to the cell-cell boundaries, consistent with function as components of adherens junctions. mOMECs did not express detectable levels of the typical vascular endothelial cadherin, VE-cadherin (CDH5) as determined by RNA-Seq, qPCR, western blot, and immunofluorescence. Knockdown of CDH2 or CDH6 via siRNA abrogated the NTS effect on mOMEC permeability. Collectively, these data suggest that NTS plays an ovulation-critical role in vascular permeability maintenance, and that CDH2 and CDH6 are involved in the permeability modulating effect of NTS on the ovarian microvasculature. NTS can be added to a growing number of angiogenic regulators which are critical for successful ovulation.

Evolutionary and developmental specialization of foveal cell types in the marmoset.

In primates, high-acuity vision is mediated by the fovea, a small specialized central region of the retina. The fovea, unique to the anthropoid lineage among mammals, undergoes notable neuronal morphological changes during postnatal maturation. However, the extent of cellular similarity across anthropoid foveas and the molecular underpinnings of foveal maturation remain unclear. Here, we used high-throughput single-cell RNA sequencing to profile retinal cells of the common marmoset (Callithrix jacchus), an early divergent in anthropoid evolution from humans, apes, and macaques. We generated atlases of the marmoset fovea and peripheral retina for both neonates and adults. Our comparative analysis revealed that marmosets share almost all their foveal types with both humans and macaques, highlighting a conserved cellular structure among primate foveas. Furthermore, by tracing the developmental trajectory of cell types in the foveal and peripheral retina, we found distinct maturation paths for each. In-depth analysis of gene expression differences demonstrated that cone photoreceptors and Müller glia (MG), among others, show the greatest molecular divergence between these two regions. Utilizing single-cell ATAC-seq and gene-regulatory network inference, we uncovered distinct transcriptional regulations differentiating foveal cones from their peripheral counterparts. Further analysis of predicted ligand-receptor interactions suggested a potential role for MG in supporting the maturation of foveal cones. Together, these results provide valuable insights into foveal development, structure, and evolution.

Species -shared and -unique gyral peaks on human and macaque brains.

Cortical folding is an important feature of primate brains that plays a crucial role in various cognitive and behavioral processes. Extensive research has revealed both similarities and differences in folding morphology and brain function among primates including macaque and human. The folding morphology is the basis of brain function, making cross-species studies on folding morphology important for understanding brain function and species evolution. However, prior studies on cross-species folding morphology mainly focused on partial regions of the cortex instead of the entire brain. Previously, our research defined a whole-brain landmark based on folding morphology: the gyral peak. It was found to exist stably across individuals and ages in both human and macaque brains. Shared and unique gyral peaks in human and macaque are identified in this study, and their similarities and differences in spatial distribution, anatomical morphology, and functional connectivity were also dicussed.

Mpox virus Clade IIb infected Cynomolgus macaques via mimic natural infection routes closely resembled human mpox infection.

Generating an infectious non-human primate (NHP) model using a prevalent monkeypox virus (MPXV) strain has emerged as a crucial strategy for assessing the efficacy of vaccines and antiviral drugs against human MPXV infection. Here, we established an animal model by infecting cynomolgus macaques with the prevalent MPXV strain, WIBP-MPXV-001, and simulating its natural routes of infection. A comprehensive analysis and evaluation were conducted on three animals, including monitoring clinical symptoms, collecting hematology data, measuring viral loads, evaluating cellular and humoral immune responses, and examining histopathology. Our findings revealed that initial skin lesions appeared at the inoculation sites and subsequently spread to the limbs and back, and all infected animals exhibited bilateral inguinal lymphadenopathy, eventually leading to a self-limiting disease course. Viral DNA was detected in post-infection blood, nasal, throat, rectal and blister fluid swabs. These observations indicate that the NHP model accurately reflects critical clinical features observed in human MPXV infection. Notably, the animals displayed clinical symptoms and disease progression similar to those of humans, rather than a lethal outcome as observed in previous studies. Historically, MPXV was utilized as a surrogate model for smallpox. However, our study contributes to a better understanding of the dynamics of current MPXV infections while providing a potential infectious NHP model for further evaluation of vaccines and antiviral drugs against mpox infection. Furthermore, the challenge model closely mimics the primary natural routes of transmission for human MPXV infections. This approach enhances our understanding of the precise mechanisms underlying the interhuman transmission of MPXV.

Increased expression of CD38 on endothelial cells in SARS-CoV-2 infection in cynomolgus macaques.

SARS-CoV-2 infection causes activation of endothelial cells (ECs), leading to dysmorphology and dysfunction. To study the pathogenesis of endotheliopathy, the activation of ECs in lungs of cynomolgus macaques after SARS-CoV-2 infection and changes in nicotinamide adenine dinucleotide (NAD) metabolism in ECs were investigated, with a focus on the CD38 molecule, which degrades NAD in inflammatory responses after SARS-CoV-2 infection. Activation of ECs was seen from day 3 after SARS-CoV-2 infection in macaques, with increases of intravascular fibrin and NAD metabolism-associated enzymes including CD38. In vitro, upregulation of CD38 mRNA in human ECs was detected after interleukin 6 (IL-6) trans-signaling induction, which was increased in the infection. In the presence of IL-6 trans-signaling stimulation, however, CD38 mRNA silencing induced significant IL-6 mRNA upregulation in ECs and promoted EC apoptosis after stimulation. These results suggest that upregulation of CD38 in patients with COVID-19 has a protective role against IL-6 trans-signaling stimulation induced by SARS-CoV-2 infection.

Mixed probiotics reduce the severity of stress-induced depressive-like behaviors.

In recent years, the gut microbiome has gained significant attention in the spheres of research and public health. As a result, studies have increasingly explored the potential of probiotic dietary supplements as treatment interventions for conditions such as anxiety and depression. The present study examined the effect of mixed probiotics (Lacticaseibacillus rhamnosus and Enterococcus faecium) on inflammation, microbiome composition, and depressive-like behaviors in a macaque monkey model. The mixed probiotics effectively reduced the severity of depressive-like behaviors in macaque monkeys. Further, treatment with mixed probiotics gradually increased the abundance of beneficial bacteria in the gut, improving the balance of the gut microbiota. Additionally, macaques treated with the mixed probiotics showed decreased serum levels of inflammatory factors (P < 0.05), an increased rate of L-tryptophan metabolism (P < 0.05), and the restoration of 5-HT and 5-HTP levels (P < 0.05). Correlation analysis confirmed that Lacticaseibacillus and other beneficial bacteria exhibited a negative correlation with inflammation in the body (P < 0.05), and a positive correlation with tryptophan metabolism (P < 0.05). In conclusion, the mixed probiotics effectively restored intestinal homeostasis in macaques and enhanced tryptophan metabolism, ultimately alleviating inflammation and depressive-like behaviors.

Spontaneously emerging internal models of visual sequences combine abstract and event-specific information in the prefrontal cortex.

When exposed to sensory sequences, do macaque monkeys spontaneously form abstract internal models that generalize to novel experiences? Here, we show that neuronal populations in macaque ventrolateral prefrontal cortex jointly encode visual sequences by separate codes for the specific pictures presented and for their abstract sequential structure. We recorded prefrontal neurons while macaque monkeys passively viewed visual sequences and sequence mismatches in the local-global paradigm. Even without any overt task or response requirements, prefrontal populations spontaneously form representations of sequence structure, serial order, and image identity within distinct but superimposed neuronal subspaces. Representations of sequence structure rapidly update following single exposure to a mismatch sequence, while distinct populations represent mismatches for sequences of different complexity. Finally, those representations generalize across sequences following the same repetition structure but comprising different images. These results suggest that prefrontal populations spontaneously encode rich internal models of visual sequences reflecting both content-specific and abstract information.

A machine learning toolbox for the analysis of sharp-wave ripples reveals common waveform features across species.

The study of sharp-wave ripples has advanced our understanding of memory function, and their alteration in neurological conditions such as epilepsy is considered a biomarker of dysfunction. Sharp-wave ripples exhibit diverse waveforms and properties that cannot be fully characterized by spectral methods alone. Here, we describe a toolbox of machine-learning models for automatic detection and analysis of these events. The machine-learning architectures, which resulted from a crowdsourced hackathon, are able to capture a wealth of ripple features recorded in the dorsal hippocampus of mice across awake and sleep conditions. When applied to data from the macaque hippocampus, these models are able to generalize detection and reveal shared properties across species. We hereby provide a user-friendly open-source toolbox for model use and extension, which can help to accelerate and standardize analysis of sharp-wave ripples, lowering the threshold for its adoption in biomedical applications.

Skipping without and with hurdles in bipedal macaque: global mechanics.

Macaques trained to perform bipedally used running gaits across a wide range of speeds. At higher speeds they preferred unilateral skipping (galloping). The same asymmetric stepping pattern was used while hurdling across two low obstacles placed at the distance of a stride within our experimental track. In bipedal macaques during skipping, we expected a differential use of the trailing and leading legs. The present study investigated global properties of the effective and virtual leg, the location of the virtual pivot point (VPP), and the energetics of the center of mass (CoM), with the aim of clarifying the differential leg operation during skipping in bipedal macaques. When skipping, macaques displayed minor double support and aerial phases during one stride. Asymmetric leg use was indicated by differences in leg kinematics. Axial damping and tangential leg work did not influence the indifferent peak ground reaction forces and impulses, but resulted in a lift of the CoM during contact of the leading leg. The aerial phase was largely due to the use of the double support. Hurdling amplified the differential leg operation. Here, higher ground reaction forces combined with increased double support provided the vertical impulse to overcome the hurdles. Following CoM dynamics during a stride, skipping and hurdling represented bouncing gaits. The elevation of the VPP of bipedal macaques resembled that of human walking and running in the trailing and leading phases, respectively. Because of anatomical restrictions, macaque unilateral skipping differs from that of humans, and may represent an intermediate gait between grounded and aerial running.

Neural circuits for retrospective and prospective introspection for the past, present and future in macaque monkeys and humans.

For animals, including humans, to have self-awareness, the ability to reflect on one's own perceptions and cognitions, which is known as metacognition, and an understanding of consistency of the self from the past to the present and into the future based on metacognition is essential. Through the mediation of self-consciousness, animals are thought to be able to proactively act to change their environment rather than passively responding to changes in their environment. However, it has not been known whether animals have self-awareness, and, if so, how it is implemented neurobiologically. In this review article, I introduce our studies examining the neural basis of metacognitive abilities for past, present, and future actions in macaque monkeys and humans, and explore the evolutionary origins of self-awareness.

Isolation of Diverse Simian Arteriviruses Causing Hemorrhagic Disease.

Genetically diverse simian arteriviruses (simarteriviruses) naturally infect geographically and phylogenetically diverse monkeys, and cross-species transmission and emergence are of considerable concern. Characterization of most simarteriviruses beyond sequence analysis has not been possible because the viruses fail to propagate in the laboratory. We attempted to isolate 4 simarteriviruses, Kibale red colobus virus 1, Pebjah virus, simian hemorrhagic fever virus, and Southwest baboon virus 1, by inoculating an immortalized grivet cell line (known to replicate simian hemorrhagic fever virus), primary macaque cells, macrophages derived from macaque induced pluripotent stem cells, and mice engrafted with macaque CD34+-enriched hematopoietic stem cells. The combined effort resulted in successful virus isolation; however, no single approach was successful for all 4 simarteriviruses. We describe several approaches that might be used to isolate additional simarteriviruses for phenotypic characterization. Our results will expedite laboratory studies of simarteriviruses to elucidate virus-host interactions, assess zoonotic risk, and develop medical countermeasures.

Differential functional organization of amygdala-medial prefrontal cortex networks in macaque and human.

Over the course of evolution, the amygdala (AMG) and medial frontal cortex (mPFC) network, involved in behavioral adaptation, underwent structural changes in the old-world monkey and human lineages. Yet, whether and how the functional organization of this network differs remains poorly understood. Using resting-state functional magnetic resonance imagery, we show that the functional connectivity (FC) between AMG nuclei and mPFC regions differs between humans and awake macaques. In humans, the AMG-mPFC FC displays U-shaped pattern along the corpus callosum: a positive FC with the ventromedial prefrontal (vmPFC) and anterior cingulate cortex (ACC), a negative FC with the anterior mid-cingulate cortex (MCC), and a positive FC with the posterior MCC. Conversely, in macaques, the negative FC shifted more ventrally at the junction between the vmPFC and the ACC. The functional organization divergence of AMG-mPFC network between humans and macaques might help understanding behavioral adaptation abilities differences in their respective socio-ecological niches.

Social network shrinking is explained by active and passive effects but not increasing selectivity with age in wild macaques.

Evidence of social disengagement, network narrowing and social selectivity with advancing age in several non-human animals challenges our understanding of the causes of social ageing. Natural animal populations are needed to test whether social ageing and selectivity occur under natural predation and extrinsic mortality pressures, and longitudinal studies are particularly valuable to disentangle the contribution of within-individual ageing from the demographic processes that shape social ageing at the population level. Data on wild Assamese macaques (Macaca assamensis) were collected between 2013 and 2020 at the Phu Khieo Wildlife Sanctuary, Thailand. We investigated the social behaviour of 61 adult females observed for 13 270 h to test several mechanistic hypotheses of social ageing and evaluated the consistency between patterns from mixed-longitudinal and within-individual analyses. With advancing age, females reduced the size of their social network, which could not be explained by an overall increase in the time spent alone, but by an age-related decline in mostly active, but also passive, behaviour, best demonstrated by within-individual analyses. A selective tendency to approach preferred partners was maintained into old age but did not increase. Our results contribute to our understanding of the driver of social ageing in natural animal populations and suggest that social disengagement and selectivity follow independent trajectories during ageing.

Visuo-frontal interactions during social learning in freely moving macaques.

Social interactions represent a ubiquitous aspect of our everyday life that we acquire by interpreting and responding to visual cues from conspecifics1. However, despite the general acceptance of this view, how visual information is used to guide the decision to cooperate is unknown. Here, we wirelessly recorded the spiking activity of populations of neurons in the visual and prefrontal cortex in conjunction with wireless recordings of oculomotor events while freely moving macaques engaged in social cooperation. As animals learned to cooperate, visual and executive areas refined the representation of social variables, such as the conspecific or reward, by distributing socially relevant information among neurons in each area. Decoding population activity showed that viewing social cues influences the decision to cooperate. Learning social events increased coordinated spiking between visual and prefrontal cortical neurons, which was associated with improved accuracy of neural populations to encode social cues and the decision to cooperate. These results indicate that the visual-frontal cortical network prioritizes relevant sensory information to facilitate learning social interactions while freely moving macaques interact in a naturalistic environment.

Sniffing behavior of semi free-ranging Barbary macaques (Macaca sylvanus).

Olfaction is one of the evolutionarily oldest senses and plays a fundamental role in foraging and social interactions across mammals. In primates, the role of olfaction is now well recognized, but better investigated in strepsirrhine and platyrrhine primates than in catarrhines. We observed the sniffing behavior of semi-free ranging Barbary macaques, Macaca sylvanus, at Affenberg Salem, Germany, to assess how frequently macaques sniff and in which contexts, and how sniffing is affected by sex and age. Focal observations of 24 males and 24 females aged 1-25 years showed that Barbary macaques sniffed, on average, 5.24 times per hour, with more than 80% of sniffs directed at food. Irrespective of the context, younger individuals sniffed more often than older ones. Females' sniffs were more often directed at food than male sniffs, while males sniffed more often than females in a social context. Sniffs at conspecifics occurred primarily in a sexual context, with 70% of social sniffs directed at female anogenital swellings performed by males. Of the observed 176 anogenital inspections, 51 involved sniffing of the swelling. Olfactory inspections were followed by copulation significantly less often than merely visual inspections, suggesting that anogenital odors may play a role in male mating decisions, but the role of olfaction in sexual interactions warrants further investigations. In sum, results show that Barbary macaques routinely use olfaction during feeding, but also in a socio-sexual context, corroborating the relevance of the olfactory sense in the lives of catarrhine primates.