Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina.

High-acuity vision in primates, including humans, is mediated by a small central retinal region called the fovea. As more accessible organisms lack a fovea, its specialized function and its dysfunction in ocular diseases remain poorly understood. We used 165,000 single-cell RNA-seq profiles to generate comprehensive cellular taxonomies of macaque fovea and peripheral retina. More than 80% of >60 cell types match between the two regions but exhibit substantial differences in proportions and gene expression, some of which we relate to functional differences. Comparison of macaque retinal types with those of mice reveals that interneuron types are tightly conserved. In contrast, projection neuron types and programs diverge, despite exhibiting conserved transcription factor codes. Key macaque types are conserved in humans, allowing mapping of cell-type and region-specific expression of >190 genes associated with 7 human retinal diseases. Our work provides a framework for comparative single-cell analysis across tissue regions and species.

Evolution of the Human Nervous System Function, Structure, and Development.

The nervous system-in particular, the brain and its cognitive abilities-is among humans' most distinctive and impressive attributes. How the nervous system has changed in the human lineage and how it differs from that of closely related primates is not well understood. Here, we consider recent comparative analyses of extant species that are uncovering new evidence for evolutionary changes in the size and the number of neurons in the human nervous system, as well as the cellular and molecular reorganization of its neural circuits. We also discuss the developmental mechanisms and underlying genetic and molecular changes that generate these structural and functional differences. As relevant new information and tools materialize at an unprecedented pace, the field is now ripe for systematic and functionally relevant studies of the development and evolution of human nervous system specializations.

Specialized Networks for Social Cognition in the Primate Brain.

Primates have evolved diverse cognitive capabilities to navigate their complex social world. To understand how the brain implements critical social cognitive abilities, we describe functional specialization in the domains of face processing, social interaction understanding, and mental state attribution. Systems for face processing are specialized from the level of single cells to populations of neurons within brain regions to hierarchically organized networks that extract and represent abstract social information. Such functional specialization is not confined to the sensorimotor periphery but appears to be a pervasive theme of primate brain organization all the way to the apex regions of cortical hierarchies. Circuits processing social information are juxtaposed with parallel systems involved in processing nonsocial information, suggesting common computations applied to different domains. The emerging picture of the neural basis of social cognition is a set of distinct but interacting subnetworks involved in component processes such as face perception and social reasoning, traversing large parts of the primate brain.

The growth factor EPIREGULIN promotes basal progenitor cell proliferation in the developing neocortex.

Neocortex expansion during evolution is linked to higher numbers of neurons, which are thought to result from increased proliferative capacity and neurogenic potential of basal progenitor cells during development. Here, we show that EREG, encoding the growth factor EPIREGULIN, is expressed in the human developing neocortex and in gorilla cerebral organoids, but not in the mouse neocortex. Addition of EPIREGULIN to the mouse neocortex increases proliferation of basal progenitor cells, whereas EREG ablation in human cortical organoids reduces proliferation in the subventricular zone. Treatment of cortical organoids with EPIREGULIN promotes a further increase in proliferation of gorilla but not of human basal progenitor cells. EPIREGULIN competes with the epidermal growth factor (EGF) to promote proliferation, and inhibition of the EGF receptor abrogates the EPIREGULIN-mediated increase in basal progenitor cells. Finally, we identify putative cis-regulatory elements that may contribute to the observed inter-species differences in EREG expression. Our findings suggest that species-specific regulation of EPIREGULIN expression may contribute to the increased neocortex size of primates by providing a tunable pro-proliferative signal to basal progenitor cells in the subventricular zone.

Probing Computation in the Primate Visual System at Single-Cone Resolution.

Daylight vision begins when light activates cone photoreceptors in the retina, creating spatial patterns of neural activity. These cone signals are then combined and processed in downstream neural circuits, ultimately producing visual perception. Recent technical advances have made it possible to deliver visual stimuli to the retina that probe this processing by the visual system at its elementary resolution of individual cones. Physiological recordings from nonhuman primate retinas reveal the spatial organization of cone signals in retinal ganglion cells, including how signals from cones of different types are combined to support both spatial and color vision. Psychophysical experiments with human subjects characterize the visual sensations evoked by stimulating a single cone, including the perception of color. Future combined physiological and psychophysical experiments focusing on probing the elementary visual inputs are likely to clarify how neural processing generates our perception of the visual world.

The prefrontal cortex: from monkey to man.

The prefrontal cortex is so important to human beings that, if deprived of it, our behaviour is reduced to action-reactions and automatisms, with no ability to make deliberate decisions. Why does the prefrontal cortex hold such importance in humans? In answer, this review draws on the proximity between humans and other primates, which enables us, through comparative anatomical-functional analysis, to understand the cognitive functions we have in common and specify those that distinguish humans from their closest cousins. First, a focus on the lateral region of the prefrontal cortex illustrates the existence of a continuum between rhesus monkeys (the most studied primates in neuroscience) and humans for most of the major cognitive functions in which this region of the brain plays a central role. This continuum involves the presence of elementary mental operations in the rhesus monkey (e.g. working memory or response inhibition) that are constitutive of 'macro-functions' such as planning, problem-solving and even language production. Second, the human prefrontal cortex has developed dramatically compared to that of other primates. This increase seems to concern the most anterior part (the frontopolar cortex). In humans, the development of the most anterior prefrontal cortex is associated with three major and interrelated cognitive changes: (i) a greater working memory capacity, allowing for greater integration of past experiences and prospective futures; (ii) a greater capacity to link discontinuous or distant data, whether temporal or semantic; and (iii) a greater capacity for abstraction, allowing humans to classify knowledge in different ways, to engage in analogical reasoning or to acquire abstract values that give rise to our beliefs and morals. Together, these new skills enable us, among other things, to develop highly sophisticated social interactions based on language, enabling us to conceive beliefs and moral judgements and to conceptualize, create and extend our vision of our environment beyond what we can physically grasp. Finally, a model of the transition of prefrontal functions between humans and non-human primates concludes this review.

Smarter foragers do not forage smarter: a test of the diet hypothesis for brain expansion.

A leading hypothesis for the evolution of large brains in humans and other species is that a feedback loop exists whereby intelligent animals forage more efficiently, which results in increased energy intake that fuels the growth and maintenance of large brains. We test this hypothesis for the first time with high-resolution tracking data from four sympatric, frugivorous rainforest mammal species (42 individuals) and drone-based maps of their predominant feeding trees. We found no evidence that larger-brained primates had more efficient foraging paths than smaller brained procyonids. This refutes a key assumption of the fruit-diet hypothesis for brain evolution, suggesting that other factors such as temporal cognition, extractive foraging or sociality have been more important for brain evolution.

Behavioral thermoregulation in primates: A review of literature and future avenues.

Primates face severe challenges from climate change, with warming expected to increase animals' thermoregulatory demands. Primates have limited long-term options to cope with climate change, but possess a remarkable capacity for behavioral plasticity. This creates an urgency to better understand the behavioral mechanisms primates use to thermoregulate. While considerable information exists on primate behavioral thermoregulation, it is often scattered in the literature in a manner that is difficult to integrate. This review evaluates the status of the available literature on primate behavioral thermoregulation to facilitate future research. We surveyed peer-reviewed publications on primate thermoregulation for N = 17 behaviors across four thermoregulatory categories: activity budgeting, microhabitat use, body positioning, and evaporative cooling. We recorded data on the primate taxa evaluated, support for a thermoregulatory function, thermal variable assessed, and naturalistic/manipulative study conditions. Behavioral thermoregulation was pervasive across primates, with N = 721 cases of thermoregulatory behaviors identified across N = 284 published studies. Most genera were known to utilize multiple behaviors ( x ¯ = 4.5 ± 3.1 behaviors/genera). Activity budgeting behaviors were the most commonly encountered category in the literature (54.5% of cases), while evaporative cooling behaviors were the least represented (6.9% of cases). Behavioral thermoregulation studies were underrepresented for certain taxonomic groups, including lemurs, lorises, galagos, and Central/South American primates, and there were large within-taxa disparities in representation of genera. Support for a thermoregulatory function was consistently high across all behaviors, spanning both hot- and cold-avoidance strategies. This review reveals asymmetries in the current literature and avenues for future research. Increased knowledge of the impact thermoregulatory behaviors have on biologically relevant outcomes is needed to better assess primate responses to warming environments and develop early indicators of thermal stress.

Probing Beat Perception with Event-Related Potentials (ERPs) in Human Adults, Newborns, and Nonhuman Primates.

The aim of this chapter is to give an overview of how the perception of rhythmic temporal regularity such as a regular beat in music can be studied in human adults, human newborns, and nonhuman primates using event-related brain potentials (ERPs). First, we discuss different aspects of temporal structure in general, and musical rhythm in particular, and we discuss the possible mechanisms underlying the perception of regularity (e.g., a beat) in rhythm. Additionally, we highlight the importance of dissociating beat perception from the perception of other types of structure in rhythm, such as predictable sequences of temporal intervals, ordinal structure, and rhythmic grouping. In the second section of the chapter, we start with a discussion of auditory ERPs elicited by infrequent and frequent sounds: ERP responses to regularity violations, such as mismatch negativity (MMN), N2b, and P3, as well as early sensory responses to sounds, such as P1 and N1, have been shown to be instrumental in probing beat perception. Subsequently, we discuss how beat perception can be probed by comparing ERP responses to sounds in regular and irregular sequences, and by comparing ERP responses to sounds in different metrical positions in a rhythm, such as on and off the beat or on strong and weak beats. Finally, we will discuss previous research that has used the aforementioned ERPs and paradigms to study beat perception in human adults, human newborns, and nonhuman primates. In doing so, we consider the possible pitfalls and prospects of the technique, as well as future perspectives.

An image-computable model of how endogenous and exogenous attention differentially alter visual perception.

Attention alters perception across the visual field. Typically, endogenous (voluntary) and exogenous (involuntary) attention similarly improve performance in many visual tasks, but they have differential effects in some tasks. Extant models of visual attention assume that the effects of these two types of attention are identical and consequently do not explain differences between them. Here, we develop a model of spatial resolution and attention that distinguishes between endogenous and exogenous attention. We focus on texture-based segmentation as a model system because it has revealed a clear dissociation between both attention types. For a texture for which performance peaks at parafoveal locations, endogenous attention improves performance across eccentricity, whereas exogenous attention improves performance where the resolution is low (peripheral locations) but impairs it where the resolution is high (foveal locations) for the scale of the texture. Our model emulates sensory encoding to segment figures from their background and predict behavioral performance. To explain attentional effects, endogenous and exogenous attention require separate operating regimes across visual detail (spatial frequency). Our model reproduces behavioral performance across several experiments and simultaneously resolves three unexplained phenomena: 1) the parafoveal advantage in segmentation, 2) the uniform improvements across eccentricity by endogenous attention, and 3) the peripheral improvements and foveal impairments by exogenous attention. Overall, we unveil a computational dissociation between each attention type and provide a generalizable framework for predicting their effects on perception across the visual field.

Effects of social environments on male primate HPG and HPA axis developmental programming.

Developmental plasticity is particularly important for humans and other primates because of our extended period of growth and maturation, during which our phenotypes adaptively respond to environmental cues. The hypothalamus-pituitary-gonadal (HPG) and hypothalamus-pituitary-adrenal (HPA) axes are likely to be principal targets of developmental "programming" given their roles in coordinating fitness-relevant aspects of the phenotype, including sexual development, adult reproductive and social strategies, and internal responses to the external environment. In social animals, including humans, the social environment is believed to be an important source of cues to which these axes may adaptively respond. The effects of early social environments on the HPA axis have been widely studied in humans, and to some extent, in other primates, but there are still major gaps in knowledge specifically relating to males. There has also been relatively little research examining the role that social environments play in developmental programming of the HPG axis or the HPA/HPG interface, and what does exist disproportionately focuses on females. These topics are likely understudied in males in part due to the difficulty of identifying developmental milestones in males relative to females and the general quiescence of the HPG axis prior to maturation. However, there are clear indicators that early life social environments matter for both sexes. In this review, we examine what is known about the impact of social environments on HPG and HPA axis programming during male development in humans and nonhuman primates, including the role that epigenetic mechanisms may play in this programming. We conclude by highlighting important next steps in this research area.

Cytology, architecture, development, and connections of the primate striatum: Hints for human pathology.

Degeneration of neurons and circuits across the striatum shows stereotyped time-course and spatial topography patterns that are distinct for Huntington's disease, Parkinson's disease, or the Tauopathies. These patterns of neurodegeneration in humans have not yet been systematically related to developmental, connectional, cellular, and chemical factors studied in human and non-human primates, that may underlie potential differences in selective vulnerability across striatal sectors. Relating primate anatomy to human pathology could provide new venues for identifying molecular, cellular, and connectional factors linked to the degeneration of striatal neurons and circuits. This review describes and summarizes several developmental, cellular, structural, and connectional features of the primate striatum in relation to patterns of neurodegeneration in the striatum of humans and of non-human primate models. We review (1) the types of neurons in the primate striatum, (2) the cyto-, myelo-, and chemoarchitecture of the primate striatum, (3) the developmental origin of the striatum in light of modern patterning studies, (4) the organization of corticostriatal projections in relation to cortical types, and (5) the topography and time-course of neuron loss, glial reaction, and protein aggregation induced by neurodegenerative diseases in humans and in non-human primate models across striatal sectors and their corresponding cortical areas. We summarize current knowledge about key aspects of primate striatal anatomy and human pathology and indicate knowledge gaps that should be addressed in future studies. We aim to identify factors for selective vulnerability to neurodegeneration of striatal neurons and circuits and obtain hints that could help elucidate striatal pathology in humans.

Hippocampal spatial view cells for memory and navigation, and their underlying connectivity in humans.

Hippocampal and parahippocampal gyrus spatial view neurons in primates respond to the spatial location being looked at. The representation is allocentric, in that the responses are to locations "out there" in the world, and are relatively invariant with respect to retinal position, eye position, head direction, and the place where the individual is located. The underlying connectivity in humans is from ventromedial visual cortical regions to the parahippocampal scene area, leading to the theory that spatial view cells are formed by combinations of overlapping feature inputs self-organized based on their closeness in space. Thus, although spatial view cells represent "where" for episodic memory and navigation, they are formed by ventral visual stream feature inputs in the parahippocampal gyrus in what is the parahippocampal scene area. A second "where" driver of spatial view cells are parietal inputs, which it is proposed provide the idiothetic update for spatial view cells, used for memory recall and navigation when the spatial view details are obscured. Inferior temporal object "what" inputs and orbitofrontal cortex reward inputs connect to the human hippocampal system, and in macaques can be associated in the hippocampus with spatial view cell "where" representations to implement episodic memory. Hippocampal spatial view cells also provide a basis for navigation to a series of viewed landmarks, with the orbitofrontal cortex reward inputs to the hippocampus providing the goals for navigation, which can then be implemented by hippocampal connectivity in humans to parietal cortex regions involved in visuomotor actions in space. The presence of foveate vision and the highly developed temporal lobe for object and scene processing in primates including humans provide a basis for hippocampal spatial view cells to be key to understanding episodic memory in the primate and human hippocampus, and the roles of this system in primate including human navigation.

Allocentric information represented by self-referenced spatial coding in the primate medial temporal lobe.

For living organisms, the ability to acquire information regarding the external space around them is critical for future actions. While the information must be stored in an allocentric frame to facilitate its use in various spatial contexts, each case of use requires the information to be represented in a particular self-referenced frame. Previous studies have explored neural substrates responsible for the linkage between self-referenced and allocentric spatial representations based on findings in rodents. However, the behaviors of rodents are different from those of primates in several aspects; for example, rodents mainly explore their environments through locomotion, while primates use eye movements. In this review, we discuss the brain mechanisms responsible for the linkage in nonhuman primates. Based on recent physiological studies, we propose that two types of neural substrates link the first-person perspective with allocentric coding. The first is the view-center background signal, which represents an image of the background surrounding the current position of fixation on the retina. This perceptual signal is transmitted from the ventral visual pathway to the hippocampus (HPC) via the perirhinal cortex and parahippocampal cortex. Because images that share the same objective-position in the environment tend to appear similar when seen from different self-positions, the view-center background signals are easily associated with one another in the formation of allocentric position coding and storage. The second type of neural substrate is the HPC neurons' dynamic activity that translates the stored location memory to the first-person perspective depending on the current spatial context.

Rapid evolution of the primate larynx?

Tissue vibrations in the larynx produce most sounds that comprise vocal communication in mammals. Larynx morphology is thus predicted to be a key target for selection, particularly in species with highly developed vocal communication systems. Here, we present a novel database of digitally modeled scanned larynges from 55 different mammalian species, representing a wide range of body sizes in the primate and carnivoran orders. Using phylogenetic comparative methods, we demonstrate that the primate larynx has evolved more rapidly than the carnivoran larynx, resulting in a pattern of larger size and increased deviation from expected allometry with body size. These results imply fundamental differences between primates and carnivorans in the balance of selective forces that constrain larynx size and highlight an evolutionary flexibility in primates that may help explain why we have developed complex and diverse uses of the vocal organ for communication.

The fire of evolution: energy expenditure and ecology in primates and other endotherms.

Total energy expenditure (TEE) represents the total energy allocated to growth, reproduction and body maintenance, as well as the energy expended on physical activity. Early experimental work in animal energetics focused on the costs of specific tasks (basal metabolic rate, locomotion, reproduction), while determination of TEE was limited to estimates from activity budgets or measurements of subjects confined to metabolic chambers. Advances in recent decades have enabled measures of TEE in free-living animals, challenging traditional additive approaches to understanding animal energy budgets. Variation in lifestyle and activity level can impact individuals' TEE on short time scales, but interspecific differences in TEE are largely shaped by evolution. Here, we review work on energy expenditure across the animal kingdom, with a particular focus on endotherms, and examine recent advances in primate energetics. Relative to other placental mammals, primates have low TEE, which may drive their slow pace of life and be an evolved response to the challenges presented by their ecologies and environments. TEE variation among hominoid primates appears to reflect adaptive shifts in energy throughput and allocation in response to ecological pressures. As the taxonomic breadth and depth of TEE data expand, we will be able to test additional hypotheses about how energy budgets are shaped by environmental pressures and explore the more proximal mechanisms that drive intra-specific variation in energy expenditure.

Pump the brakes! The hindlimbs of three-toed sloths decelerate and support suspensory locomotion.

Modern tree sloths are one of few mammalian taxa for which quadrupedal suspension is obligatory. Sloth limb musculature is specialized for slow velocity, large force contractions that stabilize their body below branches and conserve energy during locomotion. However, it is unknown whether two- and three-toed sloths converge in their use of limb kinetics and if these patterns are comparable to how primates perform arboreal suspensory locomotion. This study addressed this need by collecting limb loading data in three-toed sloths (Bradypus variegatus; N=5) during suspensory walking. Sloths performed locomotor trials at their preferred speed on an instrumented beam apparatus with a force platform as the central supporting segment. Peak forces and impulses of the forelimb and hindlimb were recorded and analyzed in three dimensions. The hindlimbs of B. variegatus apply large braking forces greater in magnitude than peak forces generated by the forelimbs in propulsion, a pattern consistent with that observed in two-toed sloths. However, B. variegatus exhibits hindlimb-biased body weight support in vertical peak forces and impulse, with appreciable laterally directed forces in each limb pair, both of which vary from limb loading distributions in two-toed sloths. Moreover, body weight distribution between limb pairs is opposite to that employed by primates during quadrupedal suspension. Thus, there appear to be multiple strategies for achieving suspensory locomotion in arboreal mammals. These differences may be attributable to anatomical variation or phylogenetic position, but as of yet an explanation remains unknown. Future EMG analyses are expected to provide insight into how specific hindlimb muscle groups contribute to braking forces and stabilizing the center of mass of sloths during suspension.

Opportunities and limitations of genetically modified nonhuman primate models for neuroscience research.

The recently developed new genome-editing technologies, such as the CRISPR/Cas system, have opened the door for generating genetically modified nonhuman primate (NHP) models for basic neuroscience and brain disorders research. The complex circuit formation and experience-dependent refinement of the human brain are very difficult to model in vitro, and thus require use of in vivo whole-animal models. For many neurodevelopmental and psychiatric disorders, abnormal circuit formation and refinement might be at the center of their pathophysiology. Importantly, many of the critical circuits and regional cell populations implicated in higher human cognitive function and in many psychiatric disorders are not present in lower mammalian brains, while these analogous areas are replicated in NHP brains. Indeed, neuropsychiatric disorders represent a tremendous health and economic burden globally. The emerging field of genetically modified NHP models has the potential to transform our study of higher brain function and dramatically facilitate the development of effective treatment for human brain disorders. In this paper, we discuss the importance of developing such models, the infrastructure and training needed to maximize the impact of such models, and ethical standards required for using these models.

Fingerprint ridges allow primates to regulate grip.

Fingerprints are unique to primates and koalas but what advantages do these features of our hands and feet provide us compared with the smooth pads of carnivorans, e.g., feline or ursine species? It has been argued that the epidermal ridges on finger pads decrease friction when in contact with smooth surfaces, promote interlocking with rough surfaces, channel excess water, prevent blistering, and enhance tactile sensitivity. Here, we found that they were at the origin of a moisture-regulating mechanism, which ensures an optimal hydration of the keratin layer of the skin for maximizing the friction and reducing the probability of catastrophic slip due to the hydrodynamic formation of a fluid layer. When in contact with impermeable surfaces, the occlusion of the sweat from the pores in the ridges promotes plasticization of the skin, dramatically increasing friction. Occlusion and external moisture could cause an excess of water that would defeat the natural hydration balance. However, we have demonstrated using femtosecond laser-based polarization-tunable terahertz wave spectroscopic imaging and infrared optical coherence tomography that the moisture regulation may be explained by a combination of a microfluidic capillary evaporation mechanism and a sweat pore blocking mechanism. This results in maintaining an optimal amount of moisture in the furrows that maximizes the friction irrespective of whether a finger pad is initially wet or dry. Thus, abundant low-flow sweat glands and epidermal furrows have provided primates with the evolutionary advantage in dry and wet conditions of manipulative and locomotive abilities not available to other animals.

Relationships between correlated spikes, oxygen and LFP in the resting-state primate.

Resting-state functional MRI (rsfMRI) provides a view of human brain organization based on correlation patterns of blood oxygen level dependent (BOLD) signals recorded across the whole brain. The neural basis of resting-state BOLD fluctuations and their correlation remains poorly understood. We simultaneously recorded oxygen level, spikes, and local field potential (LFP) at multiple sites in awake, resting monkeys. Following a spike, the average local oxygen and LFP voltage responses each resemble a task-driven BOLD response, with LFP preceding oxygen by 0.5 s. Between sites, features of the long-range correlation patterns of oxygen, LFP, and spikes are similar to features seen in rsfMRI. Most of the variance shared between sites lies in the infraslow frequency band (0.01-0.1 Hz) and in the infraslow envelope of higher-frequency bands (e.g. gamma LFP). While gamma LFP and infraslow LFP are both strong correlates of local oxygen, infraslow LFP explains significantly more of the variance shared between correlated oxygen signals than any other electrophysiological signal. Together these findings are consistent with a causal relationship between infraslow LFP and long-range oxygen correlations in the resting state.