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Non-human primates, especially rhesus macaques, have been a dominant model to study sensorimotor control of the upper limbs. Indeed, human and macaques have similar hands and homologous neural circuits to mediate manual behavior. However, few studies have systematically and quantitatively compared the manual behaviors of the two species. Such comparison is critical for assessing the validity of using the macaque sensorimotor system as a model of its human counterpart. In this study, we systematically compared the prehensile behaviors of humans and rhesus macaques using an identical experimental setup. We found human and macaque prehension kinematics to be generally similar with a few subtle differences. While the structure of the preshaping postures is similar in humans and macaques, human postures are more object-specific and human joints are less intercorrelated. Conversely, monkeys demonstrate more stereotypical grasping behaviors that are common across all grasp conditions and more variability in their postures across repeated grasps of the same object. Despite these subtle differences in manual behavior between humans and monkeys, our results bolster the use of the macaque model to understand the neural mechanisms of manual dexterity in humans.New and newsworthyMacaques have been a dominant animal model to study the neural mechanisms of human dexterity because they exhibit complex manual behavior. We show that the kinematics of prehension – a critical dexterous behavior – are largely similar in humans and macaques. However, human preshaping postures are more object-specific and the movement of human digits are less correlated with each other. The thumb, index, and wrist are major driver of these interspecies differences.

The macaque middle temporal (MT) area is well known for its visual motion selectivity and relevance to motion perception, but the possibility of it also reflecting higher-level cognitive functions has largely been ignored. We tested for effects of task performance distinct from sensory encoding by manipulating subjects' temporal evidence-weighting strategy during a direction discrimination task while performing electrophysiological recordings from groups of MT neurons in rhesus macaques (one male, one female). This revealed multiple components of MT responses that were, surprisingly, not interpretable as behaviorally relevant modulations of motion encoding, or as bottom-up consequences of the readout of motion direction from MT. The time-varying motion-driven responses of MT were strongly affected by our strategic manipulation—but with time courses opposite the subjects' temporal weighting strategies. Furthermore, large choice-correlated signals were represented in population activity distinct from its motion responses, with multiple phases that lagged psychophysical readout and even continued after the stimulus (but which preceded motor responses). In summary, a novel experimental manipulation of strategy allowed us to control the time course of readout to challenge the correlation between sensory responses and choices, and population-level analyses of simultaneously recorded ensembles allowed us to identify strong signals that were so distinct from direction encoding that conventional, single-neuron-centric analyses could not have revealed or properly characterized them. Together, these approaches revealed multiple cognitive contributions to MT responses that are task related but not functionally relevant to encoding or decoding of motion for psychophysical direction discrimination, providing a new perspective on the assumed status of MT as a simple sensory area.SIGNIFICANCE STATEMENTThis study extends understanding of the middle temporal (MT) area beyond its representation of visual motion. Combining multineuron recordings, population-level analyses, and controlled manipulation of task strategy, we exposed signals that depended on changes in temporal weighting strategy, but did not manifest as feedforward effects on behavior. This was demonstrated by (1) an inverse relationship between temporal dynamics of behavioral readout and sensory encoding, (2) a choice-correlated signal that always lagged the stimulus time points most correlated with decisions, and (3) a distinct choice-correlated signal after the stimulus. These findings invite re-evaluation of MT for functions outside of its established sensory role and highlight the power of experimenter-controlled changes in temporal strategy, coupled with recording and analysis approaches that transcend the single-neuron perspective.

Natural scenes are characterized by diverse image statistics, including various parameters of the luminance histogram, outputs of Gabor-like filters, and pairwise correlations between the filter outputs of different positions, orientations, and scales (Potilla-Simoncelli statistics). Some of these statistics capture the response properties of visual neurons. However, it remains unclear to what extent such statistics can explain neural responses to natural scenes and how neurons that are tuned to these statistics are distributed across the cortex. By using two-photon calcium imaging and an encoding-model approach, we addressed these issues in macaque visual areas V1 and V4. For each imaged neuron, we constructed an encoding model to mimic its responses to naturalistic videos. By extracting Potilla-Simoncelli statistics through outputs of both filters and filter correlations, and by computing an optimally weighted sum of these outputs, the model successfully reproduced responses in a subpopulation of neurons. We evaluated the selectivities of these neurons by quantifying the contributions of each statistic to visual responses. Neurons whose responses were mainly determined by Gabor-like filter outputs (low-level statistics) were abundant at most imaging sites in V1. In V4, the relative contribution of higher-order statistics, such as cross-scale correlation, was increased, and the neuronal selectivities varied markedly across sites; many sites included numerous neurons sensitive to luminance histogram parameters and/or correlation statistics, whereas some sites were dominated by neurons responding to low-level statistics. The results indicate that natural scene analysis progresses from V1 to V4, and neurons sharing preferred image statistics are locally clustered in V4.

Sequence learning is a ubiquitous facet of human and animal cognition. Here, using a common sequence reproduction task, we investigated whether and how the ordinal and relational structures linking consecutive elements are acquired by human adults, children, and macaque monkeys. While children and monkeys exhibited significantly lower precision than adults for spatial location and temporal order information, only monkeys appeared to exceedingly focus on the first item. Most importantly, only humans, regardless of age, spontaneously extracted the spatial relations between consecutive items and used a chunking strategy to compress sequences in working memory. Monkeys did not detect such relational structures, even after extensive training. Monkey behavior was captured by a conjunctive coding model, whereas a chunk-based conjunctive model explained more variance in humans. These age- and species-related differences are indicative of developmental and evolutionary mechanisms of sequence encoding and may provide novel insights into the uniquely human cognitive capacities.SIGNIFICANCE STATEMENTSequence learning, the ability to encode the order of discrete elements and their relationships presented within a sequence, is a ubiquitous facet of cognition among humans and animals. By exploring sequence-processing abilities at different human developmental stages and in nonhuman primates, we found that only humans, regardless of age, spontaneously extracted the spatial relations between consecutive items and used an internal language to compress sequences in working memory. The findings provided insights into understanding the origins of sequence capabilities in humans and how they evolve through development to identify the unique aspects of human cognitive capacity, which includes the comprehension, learning, and production of sequences, and perhaps, above all, language processing.

Concurrent genetic neuromodulation and functional magnetic resonance imaging (fMRI) in primates has provided a valuable opportunity to assess the modified brain-wide operation in the resting state. However, its application to link the network operation with behavior still remains challenging. Here, we combined chemogenetic silencing of the primary somatosensory cortex (SI) with tactile fMRI and related behaviors in macaques. Focal chemogenetic silencing of functionally identified SI hand region impaired grasping behavior. The same silencing also attenuated hand stimulation-evoked fMRI signal at both the local silencing site and the anatomically and/or functionally connected downstream grasping network, suggesting altered network operation underlying the induced behavioral impairment. Furthermore, the hand region silencing unexpectedly disinhibited foot representation with accompanying behavioral hypersensitization. These results demonstrate that focal chemogenetic silencing with sensory fMRI in macaques unveils bidirectional network changes to generate multifaceted behavioral impairments, thereby opening a pivotal window toward elucidating the causal network operation underpinning higher brain functions in primates., 手と足の感覚は、実は脳の中でつながっていた --脳障害による活動変化の広がりを見ることで常識を覆す発見、脳機能・疾患機序の理解へ前進--. 京都大学プレスリリース. 2021-10-21.

The dorsal visual stream, the cortical circuit that in the primate brain is mainly dedicated to the visual control of actions, is split into two routes, a lateral and a medial one, both involved in coding different aspects of sensorimotor control of actions. The lateral route, named “lateral grasping network”, is mainly involved in the control of the distal part of prehension, namely grasping and manipulation. The medial route, named “reach-to-grasp network”, is involved in the control of the full deployment of prehension act, from the direction of arm movement to the shaping of the hand according to the object to be grasped. In macaque monkeys, the reach-to-grasp network (the target of this review) includes areas of the superior parietal lobule (SPL) that hosts visual and somatosensory neurons well suited to control goal-directed limb movements toward stationary as well as moving objects. After a brief summary of the neuronal functional properties of these areas, we will analyze their cortical and thalamic inputs thanks to retrograde neuronal tracers separately injected into the SPL areas V6, V6A, PEc, and PE. These areas receive visual and somatosensory information distributed in a caudorostral, visuosomatic trend, and some of them are directly connected with the dorsal premotor cortex. This review is particularly focused on the origin and type of visual information reaching the SPL, and on the functional role this information can play in guiding limb interaction with objects in structured and dynamic environments.

In 1991, Felleman and Van Essen published their seminal study regarding hierarchical processing in the primate cerebral cortex. Their work encompassed a widescale analysis of connections reported through tracing between 35 regions in the macaque visual cortex, extending from cortical regions to the laminar level. In this work, we revisit laminar-level connectivity in the macaque brain using a whole-brain MRI-based approach. We use multi-modal ex-vivo MRI imaging of the macaque brain in both white and grey matter, which are then integrated via a simple model of laminar connectivity. This model uses a granularity-based approach to define a set of rules that expands cortical connections to the laminar level. Different fiber tracking routines are then examined in order to explore the ability of our model to infer laminar connectivity. The network of macaque cortical laminar connectivity resulting from the chosen routine is then validated in the visual cortex by comparison to findings from Felleman and Van Essen with an 83% accuracy level. By using a more comprehensive definition of the cortex that addresses its heterogenous laminar composition, we can explore a new avenue of structural connectivity on the laminar level.

An ordered relation of structure and function has been a cornerstone in thinking about brain organization. Like the brain itself, however, this is not straightforward and is confounded both by functional intricacy and structural plasticity (many routes to a given outcome). As a striking case of putative structure–function correlation, this mini-review focuses on the relatively well-characterized pattern of cytochrome oxidase (CO) blobs (aka “patches” or “puffs”) in the supragranular layers of macaque monkey visual cortex. The pattern is without doubt visually compelling, and the semi-dichotomous array of CO+ blobs and CO− interblobs is consistent with multiple studies reporting compartment-specific preferential connectivity and distinctive physiological response properties. Nevertheless, as briefly reviewed here, the finer anatomical organization of this system is surprisingly under-investigated, and the relation to functional aspects, therefore, unclear. Microcircuitry, cell type, and three-dimensional spatiotemporal level investigations of the CO+ CO− pattern are needed and may open new views to structure–function organization of visual cortex, and to phylogenetic and ontogenetic comparisons across nonhuman primates (NHP), and between NHP and humans.

In the current study, we examined the number, distribution, and aspects of the neurochemical identities of infracortical white matter neurons, also termed white matter interstitial cells (WMICs), in the brains of a southern lesser galago (Galago moholi), a black-capped squirrel monkey (Saimiri boliviensis boliviensis), and a crested macaque (Macaca nigra). Staining for neuronal nuclear marker (NeuN) revealed WMICs throughout the infracortical white matter, these cells being most dense close to inner cortical border, decreasing in density with depth in the white matter. Stereological analysis of NeuN-immunopositive cells revealed estimates of approximately 1.1, 10.8, and 37.7 million WMICs within the infracortical white matter of the galago, squirrel monkey, and crested macaque, respectively. The total numbers of WMICs form a distinct negative allometric relationship with brain mass and white matter volume when examined in a larger sample of primates where similar measures have been obtained. In all three primates studied, the highest densities of WMICs were in the white matter of the frontal lobe, with the occipital lobe having the lowest. Immunostaining revealed significant subpopulations of WMICs containing neuronal nitric oxide synthase (nNOS) and calretinin, with very few WMICs containing parvalbumin, and none containing calbindin. The nNOS and calretinin immunopositive WMICs represent approximately 21% of the total WMIC population; however, variances in the proportions of these neurochemical phenotypes were noted. Our results indicate that both the squirrel monkey and crested macaque might be informative animal models for the study of WMICs in neurodegenerative and psychiatric disorders in humans.

Theta-burst transcranial magnetic stimulation (TBS) has become a standard non-invasive technique to induce offline changes in cortical excitability in human volunteers. Yet, TBS suffers from a high variability across subjects. A better knowledge about how TBS affects neural activity in vivo could uncover its mechanisms of action and ultimately allow its mainstream use in basic science and clinical applications. To address this issue, we applied continuous TBS (cTBS, 300 pulses) in awake behaving rhesus monkeys and quantified its after-effects on neuronal recordings and behavior. Guided by anatomical MRI, we recorded single-cell activity in parietal area PFG during passive fixation of real-world objects. Overall, we observed a pronounced, long-lasting and highly reproducible reduction in neuronal excitability after cTBS in individual parietal neurons, with some neurons exhibiting periods of hyperexcitability during the recovery phase. We applied the same stimulation protocol during visually-guided grasping of objects, and observed a significant grasping impairment. These results provide the first experimental evidence on the effects of cTBS on single neurons in awake behaving monkeys.

Emerging appreciation for the hyperdirect pathway (HDP) as an important cortical glutamatergic input to the subthalamic nucleus (STN) has motivated a wide range of recent investigations on its role in motor control, as well as the mechanisms of subthalamic deep brain stimulation (DBS). However, the pathway anatomy and terminal arbor morphometry by which the HDP links cortical and subthalamic activity are incompletely understood. One critical hindrance to advancing understanding is the lack of anatomically detailed population models which can help explain how HDP pathway anatomy and neuronal biophysics give rise to spatiotemporal patterns of stimulus-response activity observed in vivo. Therefore, the goal of this study was to establish a population model of motor HDP axons through application of generative algorithms constrained by recent histology and imaging data. The products of this effort include a de novo macaque brain atlas, detailed statistical analysis of histological reconstructions of macaque motor HDP axons, and the generation of 10,000 morphometrically constrained synthetic motor HDP axons. The synthetic HDP axons exhibited a 3.8% mean error with respect to parametric distributions of the fiber target volume, total length, number of bifurcations, bifurcation angles, meander angles, and segment lengths measured in BDA-labeled HDP axon reconstructions. As such, this large population of synthetic motor HDP axons represents an anatomically based foundation for biophysical simulations that can be coupled to electrophysiological and/or behavioral measurements, with the goal of better understanding the role of the HDP in motor system activity.

Reward valuation in social contexts is by nature relative rather than absolute; it is made in reference to others. This socially relative reward valuation is based on our propensity to conduct comparisons and competitions between self and other. Exploring its neural substrate has been an active area of research in human neuroimaging. More recently, electrophysiological investigation of the macaque brain has enabled us to understand neural mechanisms underlying this valuation process at single-neuron and network levels. Here I show that shared neural networks centered at the medial prefrontal cortex and dopamine-related subcortical regions are involved in this process in humans and nonhuman primates. Thus, socially relative reward valuation is mediated by cortico-subcortically coordinated activity linking social and reward brain networks.

The pulvinar is the largest nucleus in the primate thalamus and has topographically organized connections with multiple cortical areas, thereby forming extensive cortico-pulvino-cortical input-output loops. Neurophysiological studies have suggested a role for these transthalamic pathways in regulating information transmission between cortical areas. However, evidence for a causal role of the pulvinar in regulating cortico-cortical interactions is sparse and it is not known whether pulvinar's influences on cortical networks are task-dependent or, alternatively, reflect more basic large-scale network properties that maintain functional connectivity across networks regardless of active task demands. In the current study, under passive viewing conditions, we conducted simultaneous electrophysiological recordings from ventral (area V4) and dorsal (lateral intraparietal area [LIP]) nodes of macaque visual system, while reversibly inactivating the dorsal part of the lateral pulvinar (dPL), which shares common anatomical connectivity with V4 and LIP, to probe a causal role of the pulvinar. Our results show a significant reduction in local field potential phase coherence between LIP and V4 in low frequencies (4-15 Hz) following muscimol injection into dPL. At the local level, no significant changes in firing rates or LFP power were observed in LIP or in V4 following dPL inactivation. Synchronization between pulvinar spikes and cortical LFP phase decreased in low frequencies (4-15 Hz) both in LIP and V4, while the low frequency synchronization between LIP spikes and pulvinar phase increased. These results indicate a causal role for pulvinar in synchronizing neural activity between interconnected cortical nodes of a large-scale network, even in the absence of an active task state.

In primates, broad thorny retinal ganglion cells are highly sensitive to small, moving stimuli. They have tortuous, fine dendrites with many short, spine-like branches that occupy three contiguous strata in the middle of the inner plexiform layer. The neural circuits that generate their responses to moving stimuli are not well-understood, and that was the goal of this study. A connectome from central macaque retina was generated by serial block-face scanning electron microscopy, a broad thorny cell was reconstructed, and its synaptic inputs were analyzed. It received fewer than 2% of its inputs from both ON and OFF types of bipolar cells; the vast majority of its inputs were from amacrine cells. The presynaptic amacrine cells were reconstructed, and seven types were identified based on their characteristic morphology. Two types of narrow-field cells, knotty bistratified type 1 and wavy multistratified type 2, were identified. Two types of medium-field amacrine cells, ON starburst and spiny, were also presynaptic to the broad thorny cell. Three types of wide-field amacrine cells, wiry type 2, stellate wavy and semilunar type 2, also made synapses onto the broad thorny cell. Physiological experiments using a macaque retinal preparation in vitro confirmed that broad thorny cells received robust excitatory input from both the ON and the OFF pathways. Given the paucity of bipolar cell inputs, it is likely that amacrine cells provided much of the excitatory input, in addition to inhibitory input. This article is protected by copyright. All rights reserved.

The accurate processing of temporal information is of critical importance in everyday life. Yet, psychophysical studies in humans have shown that the perception of time is distorted around saccadic eye movements. The neural correlates of this misperception are still poorly understood. Behavioral and neural evidence suggest that it is tightly linked to other known perisaccadic modulations of visual perception. To further our understanding of how temporal processing is affected by saccades, we studied the representations of brief visual time intervals during fixation and saccades in area V4 of two awake macaques. We presented random sequences of vertical bar stimuli and extracted neural responses to double-pulse stimulation at varying interstimulus intervals. Our results show that temporal information about very brief intervals of as brief as 20 ms is reliably represented in the multiunit activity in area V4. Response latencies were not systematically modulated by the saccade. However, a general increase in perisaccadic activity altered the ratio of response amplitudes within stimulus pairs compared with fixation. In line with previous studies showing that the perception of brief time intervals is partly based on response levels, this may be seen as a possible correlate of the perisaccadic misperception of time.

Visual cues coming from the lower visual field (VF) play an important role in the visual guidance of upper and lower limb movements. A recently described region situated in the dorsomedial parietal cortex, area hPEc (Pitzalis et al. in NeuroImage 202:116092, 2019), might have a role in integrating visually derived information with somatomotor signals to guide limb interaction with the environment. In macaque, it has been demonstrated that PEc receives visual information mostly from the lower visual field but, to date, there has been no systematic investigation of VF preference in the newly defined human homologue of macaque area PEc (hPEc). Here we examined the VF preferences of hPEc while participants performed a visuomotor task implying spatially directed delayed eye-, hand- and foot-movements towards different spatial locations within the VF. By analyzing data as a function of the different target locations towards which upcoming movements were planned (and then executed), we observed the presence of asymmetry in the vertical dimension of VF in area hPEc, being this area more strongly activated by limb movements directed towards visual targets located in the lower compared to the upper VF. This result confirms the view, first advanced in macaque monkey, that PEc is involved in processing visual information to guide body interaction with the external environment, including locomotion. We also observed a contralateral dominance for the lower VF preference in the foot selective somatomotor cortex anterior to hPEc. This result might reflect the role of this cortex (which includes areas PE and S-I) in providing highly topographically organized signals, likely useful to achieve an appropriate foot posture during locomotion. Supplementary Information The online version contains supplementary material available at 10.1007/s00429-021-02254-3.

The spatial processing of color is important for visual perception. Double-opponent (DO) cells likely contribute to this processing by virtue of their spatially opponent and cone-opponent receptive fields (RFs). However, the representation of visual features by DO cells in the primary visual cortex of primates is unclear because the spatial structure of their RFs has not been fully characterized. To fill this gap, we mapped the RFs of DO cells in awake macaques with colorful, dynamic white noise patterns. The spatial RF of each neuron was fitted with a Gabor function and three versions of the difference of Gaussians (DoG) function. The Gabor function provided the more accurate description for most DO cells, a result that is incompatible with a center-surround RF organization. A nonconcentric version of the DoG function, in which the RFs have a circular center and a crescent-shaped surround, performed nearly as well as the Gabor model thus reconciling results from previous reports. For comparison, we also measured the RFs of simple cells. We found that the superiority of the Gabor fits over DoG fits was slightly more decisive for simple cells than for DO cells. The implications of these results on biological image processing and visual perception are discussed. NEW & NOTEWORTHY Double-opponent cells in macaque area V1 respond to spatial chromatic contrast in visual scenes. What information they carry is debated because their receptive field organization has not been characterized thoroughly. Using white noise analysis and statistical model comparisons, De and Horwitz show that many double-opponent receptive fields can be captured by either a Gabor model or a center-with-an-asymmetric-surround model but not by a difference of Gaussians model.

Perceptual decision-making is increasingly being understood to involve an interaction between bottom-up sensory-driven signals and top-down choice-driven signals, but how these signals interact to mediate perception is not well understood. The parieto-insular vestibular cortex (PIVC) is an area with prominent vestibular responsiveness, and previous work has shown that inactivating PIVC impairs vestibular heading judgments. To investigate the nature of PIVC's contribution to heading perception, we recorded extracellularly from PIVC neurons in two male rhesus macaques during a heading discrimination task, and compared findings with data from previous studies of dorsal medial superior temporal (MSTd) and ventral intraparietal (VIP) areas using identical stimuli. By computing partial correlations between neural responses, heading, and choice, we find that PIVC activity reflects a dynamically changing combination of sensory and choice signals. In addition, the sensory and choice signals are more balanced in PIVC, in contrast to the sensory dominance in MSTd and choice dominance in VIP. Interestingly, heading and choice signals in PIVC are negatively correlated during the middle portion of the stimulus epoch, reflecting a mismatch in the polarity of heading and choice signals. We anticipate that these results will help unravel the mechanisms of interaction between bottom-up sensory signals and top-down choice signals in perceptual decision-making, leading to more comprehensive models of self-motion perception.SIGNIFICANCE STATEMENTVestibular information is important for our perception of self-motion, and various cortical regions in primates show vestibular heading selectivity. Inactivation of the macaque vestibular cortex substantially impairs the precision of vestibular heading discrimination, more so than inactivation of other multisensory areas. Here, we record for the first time from the vestibular cortex while monkeys perform a forced-choice heading discrimination task, and we compare results with data collected previously from other multisensory cortical areas. We find that vestibular cortex activity reflects a dynamically changing combination of sensory and choice signals, with both similarities and notable differences with other multisensory areas.

In primates, the retinal ganglion cells contributing to high acuity spatial vision (midget cells and parasol cells), and blue-yellow color vision (small bistratified cells) are well understood. Many other ganglion cell types with large dendritic fields (named wide-field ganglion cells) have been identified, but their spatial density and distribution are largely unknown. Here we took advantage of the recently established molecular diversity of ganglion cells to study wide-field ganglion cell populations in three primate species. We used antibodies against the transcription factor Special AT-rich binding protein 2 (Satb2) to explore its expression in macaque (Macaca fascicularis, M. nemestrina), human and marmoset (Callithrix jacchus) retinas. In all three species, Satb2 cells make up a low proportion (1.5-4%) of the ganglion cell population, with a slight increase from central to peripheral retina. Intracellular dye injections revealed that in macaque and human retinas, the large majority (over 80%) of Satb2 cells are inner and outer stratifying large sparse cells. By contrast, in marmoset retina the majority (over 60%) of Satb2 expressing cells were broad thorny cells, with smaller proportions of recursive bistratified (putative direction-selective), large bistratified, and outer stratifying narrow thorny cells. Our findings imply that Satb2 expression has undergone rapid species specific adaptations during primate evolution, because expression is not conserved across Old World (macaque, human) and New World (marmoset) suborders.

Structural connections between cortical areas form an intricate network with a high degree of specificity. Many aspects of this complex network organization in the adult mammalian cortex are captured by an architectonic type principle, which relates structural connections to the architectonic differentiation of brain regions. In particular, the laminar patterns of projection origins are a prominent feature of structural connections that varies in a graded manner with the relative architectonic differentiation of connected areas in the adult brain. Here we show that the architectonic type principle is already apparent for the laminar origins of cortico-cortical projections in the immature cortex of the macaque monkey. We find that prenatal and neonatal laminar patterns correlate with cortical architectonic differentiation, and that the relation of laminar patterns to architectonic differences between connected areas is not substantially altered by the complete loss of visual input. Moreover, we find that the degree of change in laminar patterns that projections undergo during development varies in proportion to the relative architectonic differentiation of the connected areas. Hence, it appears that initial biases in laminar projection patterns become progressively strengthened by later developmental processes. These findings suggest that early neurogenetic processes during the formation of the brain are sufficient to establish the characteristic laminar projection patterns. This conclusion is in line with previously suggested mechanistic explanations underlying the emergence of the architectonic type principle and provides further constraints for exploring the fundamental factors that shape structural connectivity in the mammalian brain. Supplementary Information The online version contains supplementary material available at 10.1007/s00429-021-02219-6.

Saccades are stereotypic behaviors whose investigation improves our understanding of how primate brains implement precise motor control. Furthermore, saccades offer an important window into the cognitive and attentional state of the brain. Historically, saccade studies have largely relied on macaques. However, the cortical network giving rise to the saccadic command is difficult to study in macaques because relevant cortical areas lie in deep sulci and are difficult to access. Recently, a New World monkey. the marmoset, has garnered attention as an alternative to macaques because of advantages including its smooth cortical surface. However, adoption of the marmoset for oculomotor research has been limited due to a lack of in-depth descriptions of marmoset saccade kinematics and their ability to perform psychophysical tasks. Here, we directly compare free-viewing and visually guided behavior of marmoset, macaque, and human engaged in identical tasks under similar conditions. In the video free-viewing task, all species exhibited qualitatively similar saccade kinematics up to 25° in amplitude although with different parameters. Furthermore, the conventional bottom-up saliency model predicted gaze targets at similar rates for all species. We further verified their visually guided behavior by training them with step and gap saccade tasks. In the step paradigm, marmosets did not show shorter saccade reaction time for upward saccades whereas macaques and humans did. In the gap paradigm, all species showed similar gap effect and express saccades. Our results suggest that the marmoset can serve as a model for oculomotor, attentional, and cognitive research while we need to be aware of their difference from macaque or human.

Stroke is a leading cause of death and disability worldwide and survivors are frequently left with long-term disabilities that diminish their autonomy and result in the need for chronic care. There is an urgent need for the development of therapies that improve stroke recovery, as well as accurate and quantitative tools to measure function. Nonhuman primates closely resemble humans in neuroanatomy and upper limb function and may be crucial in randomized pre-clinical trials for testing the efficacy of stroke therapies. To test the feasibility of robotic assessment of motor function in a NHP model of stroke, two cynomolgus macaques were trained to perform a visually guided reaching task and were also assessed in a passive stretch task using the Kinarm robot. Strokes were then induced in these animals by transiently occluding the middle cerebral artery, and their motor performance on the same tasks was assessed after recovery. Relative to pre-stroke performance, post-stroke hand movements of the affected limb became slower and less accurate. Regression analyses revealed both recovered and compensatory movements to complete movements in different spatial directions. Lastly, we noted decreased range of motion in the elbow joint of the affected limb post-stroke associated with spasticity during passive stretch. Taken together, these studies highlight that sensorimotor deficits in reaching movements following stroke in cynomolgus macaques resemble those in human patients and validate the use of robotic assessment tools in a nonhuman primate model of stroke for identifying and characterizing such deficits.

Contains fulltext : 241277.pdf (Publisher’s version ) (Open Access) According to dual-process signal-detection (DPSD) theories, short- and long-term recognition memory draws upon both familiarity and recollection. It remains unclear how primate prefrontal cortex (PFC) contributes to these processes, but frequency-specific neuronal activities are considered to play a key role. In Experiment 1, nonhuman primate (NHP) local field potential (LFP) electrophysiological recordings in macaque left dorsolateral PFC (dlPFC) revealed performance-related differences in a low-beta frequency range during the sample presentation phase of a visual object recognition memory task. Experiment 2 employed a similar task in humans and targeted left dlPFC (and vertex as a control) with repetitive transcranial magnetic stimulation (rTMS) at 12.5 Hz during occasional sample presentations. This low-beta frequency rTMS to dlPFC decreased DPSD derived indices of recollection, but not familiarity, in subsequent memory tests of the targeted samples after short delays. The same number of rTMS pulses over the same total duration albeit at a random frequency had no effect on either recollection or familiarity. Neither stimulation protocols had any causal effect upon behaviour when targeted to the control site (vertex). In this study, our hypotheses for our human TMS study were derived from our observations in NHPs; this approach might inspire further translational research through investigation of homologous brain regions and tasks across species using similar neuroscientific methodologies to advance the neural mechanism of recognition memory in primates. 28 p.

Summary Inter-areal coherence between field potentials is a widespread phenomenon in cortex. Coherence has been hypothesized to reflect phase-synchronization between oscillators and flexibly gate communication according to behavioral and cognitive demands. We reveal an alternative mechanism where coherence is not the cause but the consequence of communication and naturally emerges because spiking activity in a sending area causes post-synaptic potentials both in the same and in other areas. Consequently, coherence depends in a lawful manner on power and phase-locking in the sender and connectivity. Changes in oscillatory power explained prominent changes in fronto-parietal and LGN-V1 coherence across behavioral conditions. Optogenetic experiments and excitatory-inhibitory network simulations identified afferent synaptic inputs rather than spiking entrainment as the principal determinant of coherence. These findings suggest that unique spectral profiles of different brain areas automatically give rise to large-scale coherence patterns that follow anatomical connectivity and continuously reconfigure as a function of behavior and cognition., Highlights • Synaptic projections from a sending to a receiving area explain long-range coherence • Inter-areal coherence can be predicted by power and connectivity • Power explains major changes in long-range coherence across behavioral states • Coherence emerges without spiking entrainment due to afferent synaptic inputs, Schneider et al. establish a mechanism for inter-areal coherence between field potentials, where it is the result and not the cause of communication. Consequently, coherence depends in a lawful manner on connectivity and power and does not require spiking entrainment. This mechanism explains behavior-related changes in fronto-parietal and LGN-V1 coherence.

In the macaque brain, projections from distant, interconnected cortical areas converge in specific zones of the striatum. For example, specific zones of the motor putamen are targets of projections from frontal motor, inferior parietal, and ventrolateral prefrontal hand-related areas and thus are integral part of the so-called “lateral grasping network.” In the present study, we analyzed the laminar distribution of corticostriatal neurons projecting to different parts of the motor putamen. Retrograde neural tracers were injected in different parts of the putamen in 3Macaca mulatta(one male) and the laminar distribution of the labeled corticostriatal neurons was analyzed quantitatively. In frontal motor areas and frontal operculum, where most labeled cells were located, almost everywhere the proportion of corticostriatal labeled neurons in layers III and/or VI was comparable or even stronger than in layer V. Furthermore, within these regions, the laminar distribution pattern of corticostriatal labeled neurons largely varied independently from their density and from the projecting area/sector, but likely according to the target striatal zone. Accordingly, the present data show that cortical areas may project in different ways to different striatal zones, which can be targets of specific combinations of signals originating from the various cortical layers of the areas of a given network. These observations extend current models of corticostriatal interactions, suggesting more complex modes of information processing in the basal ganglia for different motor and nonmotor functions and opening new questions on the architecture of the corticostriatal circuitry.SIGNIFICANCE STATEMENTProjections from the ipsilateral cerebral cortex are the major source of input to the striatum. Previous studies have provided evidence for distinct zones of the putamen specified by converging projections from specific sets of interconnected cortical areas. The present study shows that the distribution of corticostriatal neurons in the various layers of the primary motor and premotor areas varies depending on the target striatal zone. Accordingly, different striatal zones collect specific combinations of signals from the various cortical layers of their input areas, possibly differing in terms of coding, timing, and direction of information flow (e.g., feed-forward, or feed-back).

After damage to the primary visual cortex (V1), conscious vision is impaired. However, some patients can respond to visual stimuli presented in their lesion-affected visual field using residual visual pathways bypassing V1. This phenomenon is called “blindsight.” Many studies have tried to identify the brain regions responsible for blindsight, and the pulvinar and/or lateral geniculate nucleus (LGN) are suggested to play key roles as the thalamic relay of visual signals. However, there are critical problems regarding these preceding studies in that subjects with different sized lesions and periods of time after lesioning were investigated; furthermore, the ability of blindsight was assessed with different measures. In this study, we used double dissociation to clarify the roles of the pulvinar and LGN by pharmacological inactivation of each region and investigated the effects in a simple task with visually guided saccades (VGSs) using monkeys with a unilateral V1 lesion, by which nearly all of the contralesional visual field was affected. Inactivating either the ipsilesional pulvinar or LGN impaired VGS toward a visual stimulus in the affected field. In contrast, inactivation of the contralesional pulvinar had no clear effect, but inactivation of the contralesional LGN impaired VGS to the intact visual field. These results suggest that the pulvinar and LGN play key roles in performing the simple VGS task after V1 lesioning, and that the visuomotor functions of blindsight monkeys were supported by plastic changes in the visual pathway involving the pulvinar, which emerged after V1 lesioning.SIGNIFICANCE STATEMENTMany studies have been devoted to understanding the mechanism of mysterious symptom called “blindsight,” in which patients with damage to the primary visual cortex (V1) can respond to visual stimuli despite loss of visual awareness. However, there is still a debate on the thalamic relay of visual signals. In this study, to pin down the issue, we tried double dissociation in the same subjects (hemi-blindsight macaque monkeys) and clarified that the lateral geniculate nucleus (LGN) plays a major role in simple visually guided saccades in the intact state, while both pulvinar and LGN critically contribute after the V1 lesioning, suggesting that plasticity in the visual pathway involving the pulvinar underlies the blindsight.

Databases of consistent, directed- and weighted inter-areal connectivity for mouse, macaque and marmoset monkeys have recently become available and begun to be used to build structural and dynamical models. A structural hierarchy can be defined based by laminar patterns of cortical connections. A large-scale dynamical model of the macaque cortex endowed with a laminar structure accounts for empirically observed frequency-modulated interplay between bottom-up and top-down processes. Signal propagation in the model with spiking neurons displays a threshold of stimulus amplitude for the activity to gain access to the prefrontal cortex, reminiscent of the ignition phenomenon associated with conscious perception. These two examples illustrate how connectomics inform structurally based dynamic models of multi-regional brain systems. Theory raises novel questions for future anatomical and physiological empirical research, in a back-and-forth collaboration between experimentalists and theorists. Directed- and weighted inter-areal cortical connectivity matrices of macaque, marmoset and mouse exhibit similarities as well as marked differences. The new connectomic data provide quantitative information for structural and dynamical modeling of multi-regional cortical circuit providing insight to the global cortical function. Quantification of cortical hierarchy guides investigations of interplay between bottom-up and top-down information processes.

Objects constitute the fundamental currency of our consciousness: they are the things that we perceive, remember and think about. One of the most important objects for a primate is a face. Research on the macaque face patch system in recent years has given us a remarkable window into the detailed processes underlying object recognition. Here, we review the macaque face patch system, including its anatomical organization, coding principles, role in behaviour and interactions with other brain regions. We highlight not only how it constitutes an archetypal object recognition system but also how it may provide a key to understanding mechanisms for higher cognitive function.

The genus Macaca is an ideal model for investigating the biological basis of primate social behavior from an evolutionary perspective. A significant amount of behavioral diversity has been reported among the macaque species, but little is known about the neural substrates that support this variation. The present study compared neural cell density and serotonergic innervation of the amygdala among four macaque species using histological and immunohistochemical methods. The species examined included rhesus (Macaca mulatta), Japanese (M. fuscata), pigtailed (M. nemestrina), and moor macaques (M. maura). We anticipated that the more aggressive rhesus and Japanese macaques would have lower serotonergic innervation within the amygdala compared to the more affiliative pigtailed and moor macaques. In contrast to our prediction, pigtailed macaques had higher serotonergic innervation than Japanese and moor macaques in the basal and central amygdala nuclei when controlling for neuron density. Our analysis of neural cell populations revealed that Japanese macaques possess significantly higher neuron and glia densities relative to the other three species, however we observed no glia-to-neuron ratio differences among species. The results of this study revealed serotonergic innervation and cell density differences among closely related macaque species, which may play a role in modulating subtle differences in emotional processing and species-typical social styles.

Disparity-defined 3D shape is processed in both the ventral and the dorsal visual stream. The network of cortical areas that is activated during the processing of disparity-defined 3D shape includes, in addition to parietal and premotor areas, three clearly distinct regions in inferotemporal cortex (ITC). To investigate the connectivity of the latter regions, we combined electrical stimulation with fMRI in male macaque monkeys. Electrical stimulation of each of the 3D-structure nodes in ITC mainly elicited increased fMRI activations in the other 3D-structure nodes and more variably in other parts of ventral visual cortex. Importantly, no increased activation was found in parietal areas, nor in PFC, whereas microstimulation in posterior parietal cortex did activate the ITC. Our results indicate that 3D-structure nodes in ITC form a strongly interconnected network, receiving input from parietal areas implicated in 3D-structure processing.SIGNIFICANCE STATEMENTPrevious studies combining electrical microstimulation with functional imaging showed an interconnected set of regions in the ventral stream processing faces or bodies, but is has been unclear whether the same is true for other visual categories. Here the authors show that there is a connected system of stereo-selective regions in inferotemporal cortex, receiving input from parietal areas in the dorsal stream.

An animal's choice behavior is shaped by the outcome feedback from selected actions in a trial-and-error approach. Tonically active neurons (TANs), presumed cholinergic interneurons in the striatum, are thought to be involved in the learning and performance of reward-directed behaviors, but it remains unclear how TANs are involved in shaping reward-directed choice behaviors based on the outcome feedback. To this end, we recorded activity of TANs from the dorsal striatum of two macaque monkeys (Macaca fuscata; 1 male, 1 female) while they performed a multi-step choice task to obtain multiple rewards. In this task, the monkeys first searched for a rewarding target from among three alternatives in a trial-and-error manner and then earned additional rewards by repeatedly choosing the rewarded target. We found that a considerable proportion of TANs selectively responded to either the reward or the no-reward outcome feedback during the trial-and-error search, but these feedback responses were not observed during repeat trials. Moreover, the feedback responses of TANs were similarly observed in any search trials, without distinctions regarding the predicted probability of rewards and the location of chosen targets. Unambiguously, TANs detected reward and no-reward feedback specifically when the monkeys performed trial-and-error searches, in which the monkeys were learning the value of the targets and adjusting their subsequent choice behavior based on the reward and no-reward feedback. These results suggest that striatal cholinergic interneurons signal outcome feedback specifically during search behavior, in circumstances where the choice outcomes cannot be predicted with certainty by the animals.

Lost sensations, such as touch, could be restored by microstimulation (MiSt) along the sensory neural substrate. Such neuroprosthetic sensory information can be used as feedback from an invasive brain-machine interface (BMI) to control a robotic arm/hand, such that tactile and proprioceptive feedback from the sensorized robotic arm/hand is directly given to the BMI user. Microstimulation in the human somatosensory thalamus (Vc) has been shown to produce somatosensory perceptions. However, until recently, systematic methods for using thalamic stimulation to evoke naturalistic touch perceptions were lacking. We have recently presented rigorous methods for determining a mapping between ventral posterior lateral thalamus (VPL) MiSt, and neural responses in the somatosensory cortex (S1), in a rodent model (Choi et al., 2016; Choi and Francis, 2018). Our technique minimizes the difference between S1 neural responses induced by natural sensory stimuli and those generated via VPL MiSt. Our goal is to develop systems that know what neural response a given MiSt will produce and possibly allow the development of natural “sensation.” To date, our optimization has been conducted in the rodent model and simulations. Here, we present data from simple non-optimized thalamic MiSt during peri-operative experiments, where we used MiSt in the VPL of macaques, which have a somatosensory system more like humans, as compared to our previous rat work (Li et al., 2014; Choi et al., 2016). We implanted arrays of microelectrodes across the hand area of the macaque S1 cortex as well as in the VPL. Multi and single-unit recordings were used to compare cortical responses to natural touch and thalamic MiSt in the anesthetized state. Post-stimulus time histograms were highly correlated between the VPL MiSt and natural touch modalities, adding support to the use of VPL MiSt toward producing a somatosensory neuroprosthesis in humans.

Color perception relies on comparisons between adjacent lights, but how the brain performs these comparisons is poorly understood. To elucidate the underlying mechanisms, we recorded spiking responses of individual V1 neurons in macaque monkeys to pairs of stimuli within the classical receptive field (RF). We estimated the spatial-chromatic RF of each neuron and then presented customized colored edges using a closed-loop technique. We found that many double-opponent (DO) cells, which have spatially and chromatically opponent RFs, responded to chromatic contrast as a weighted sum, akin to how other V1 neurons responded to luminance contrast. Yet other neurons integrated chromatic signals nonlinearly, confirming that linear signal integration is not an obligate property of V1 neurons. The functional similarity of cone-opponent DO cells and cone non-opponent simple cells suggests that these two groups may share a common underlying circuitry, promotes the construction of image-computable models for full-color image representation, and sheds new light on V1 complex cells.

Inhibitory control, the ability to override an inappropriate prepotent response, is crucial in many aspects of everyday life. However, the various paradigms designed to measure inhibitory control often suffer from a lack of systematic validation and have yielded mixed results. Thus the nature of this ability remains unclear, is it a general construct or a family of distinct sub-components? Therefore, the aim of this study was first to demonstrate the content validity and the temporal repeatability of a battery of inhibitory control tasks. Then we wanted to assess the contextual consistency of performances between these tasks to better understand the structure of inhibitory control. We tested 21 rhesus macaques (Macaca mulatta, 12 males, nine females) in a battery of touchscreen tasks assessing three main components of inhibitory control: inhibition of a distraction (using a Distraction task), inhibition of an impulsive action (using a Go/No-go task) and inhibition of a cognitive set (using a Reversal learning task). All tasks were reliable and effective at measuring the inhibition of a prepotent response. However, while there was consistency of performance between the inhibition of a distraction and the inhibition of an action, representing a response-driven basic form of inhibition, this was not found for the inhibition of a cognitive set. We argue that the inhibition of a cognitive set is a more cognitively demanding form of inhibition. This study gives a new insight in the multifaceted structure of inhibitory control and highlights the importance of a systematic validation of cognitive tasks in animal cognition.

Macaque ventral intraparietal area (VIP) in the fundus of the intraparietal sulcus has been implicated in a diverse range of sensorimotor and cognitive functions such as motion processing, multisensory integration, processing of head peripersonal space, defensive behavior, and numerosity coding. Here, we exhaustively review macaque VIP function, cytoarchitectonics, and anatomical connectivity and integrate it with human studies that have attempted to identify a potential human VIP homologue. We show that human VIP research has consistently identified three, rather than one, bilateral parietal areas that each appear to subsume some, but not all, of the macaque area’s functionality. Available evidence suggests that this human “VIP complex” has evolved as an expansion of the macaque area, but that some precursory specialization within macaque VIP has been previously overlooked. The three human areas are dominated, roughly, by coding the head or self in the environment, visual heading direction, and the peripersonal environment around the head, respectively. A unifying functional principle may be best described as prediction in space and time, linking VIP to state estimation as a key parietal sensorimotor function. VIP’s expansive differentiation of head and self-related processing may have been key in the emergence of human bodily self-consciousness.

Cortico-cortical networks involved in motor control have been well defined in the macaque using a range of invasive techniques. The advent of neuroimaging has enabled non-invasive study of these large-scale functionally specialized networks in the human brain; however, assessing its accuracy in reproducing genuine anatomy is more challenging. We set out to assess the similarities and differences between connections of macaque motor control networks defined using axonal tracing and those reproduced using structural and functional connectivity techniques. We processed a cohort of macaques scanned in vivo that were made available by the open access PRIME-DE resource, to evaluate connectivity using diffusion imaging tractography and resting state functional connectivity (rs-FC). Sectors of the lateral grasping and exploratory oculomotor networks were defined anatomically on structural images, and connections were reproduced using different structural and functional approaches (probabilistic and deterministic whole-brain and seed-based tractography; group template and native space functional connectivity analysis). The results showed that parieto-frontal connections were best reproduced using both structural and functional connectivity techniques. Tractography showed lower sensitivity but better specificity in reproducing connections identified by tracer data. Functional connectivity analysis performed in native space had higher sensitivity but lower specificity and was better at identifying connections between intrasulcal ROIs than group-level analysis. Connections of AIP were most consistently reproduced, although those connected with prefrontal sectors were not identified. We finally compared diffusion MR modelling with histology based on an injection in AIP and speculate on anatomical bases for the observed false negatives. Our results highlight the utility of precise ex vivo techniques to support the accuracy of neuroimaging in reproducing connections, which is relevant also for human studies. Electronic supplementary material The online version of this article (10.1007/s00429-020-02142-2) contains supplementary material, which is available to authorized users.

When we move the features of our face, or turn our head, we communicate changes in our internal state to the people around us. How this information is encoded and used by an observer's brain is poorly understood. We investigated this issue using a functional MRI adaptation paradigm in awake male macaques. Among face-selective patches of the superior temporal sulcus (STS), we found a double dissociation of areas processing facial expression and those processing head orientation. The face-selective patches in the STS fundus were most sensitive to facial expression, as was the amygdala, whereas those on the lower, lateral edge of the sulcus were most sensitive to head orientation. The results of this study reveal a new dimension of functional organization, with face-selective patches segregating within the STS. The findings thus force a rethinking of the role of the face-processing system in representing subject-directed actions and supporting social cognition.SIGNIFICANCE STATEMENTWhen we are interacting with another person, we make inferences about their emotional state based on visual signals. For example, when a person's facial expression changes, we are given information about their feelings. While primates are thought to have specialized cortical mechanisms for analyzing the identity of faces, less is known about how these mechanisms unpack transient signals, like expression, that can change from one moment to the next. Here, using an fMRI adaptation paradigm, we demonstrate that while the identity of a face is held constant, there are separate mechanisms in the macaque brain for processing transient changes in the face's expression and orientation. These findings shed new light on the function of the face-processing system during social exchanges.

We investigated the visuotopic organization of macaque posterior parietal cortex (PPC) by combining functional imaging (fMRI) and wide-field retinotopic mapping in two macaque monkeys. Whole brain blood-oxygen-level-dependent (BOLD) signal was recorded while monkeys maintained central fixation during the presentation of large rotating wedges and expending/contracting annulus of a “shaking” fruit basket, designed to maximize the recruitment of PPC neurons. Results of the surface-based population receptive field (pRF) analysis reveal a new cluster of four visuotopic areas at the confluence of the parieto-occipital and intra-parietal sulci, in a location previously defined histologically and anatomically as the posterior intra-parietal (PIP) region. This PIP cluster groups together two recently described areas (CIP1/2) laterally and two newly identified ones (PIP1/2) medially, whose foveal representations merge in the fundus of the intra-parietal sulcus. The cluster shares borders with other visuotopic areas: V3d posteriorly, V3A/DP laterally, V6/V6A medially and LIP anteriorly. Together, these results show that monkey PPC is endowed with a dense set of visuotopic areas, as its human counterpart. The fact that fMRI and wide-field stimulation allows a functional parsing of monkey PPC offers a new framework for studying functional homologies with human PPC. Electronic supplementary material The online version of this article (10.1007/s00429-020-02134-2) contains supplementary material, which is available to authorized users.

Express saccades are rapid saccadic eye movements that can accurately redirect gaze to behaviorally relevant stimuli in the visual environment. This behavior can be commonly observed when the fixation spot disappears at a consistent, short interval before a target spot appears at a repeated location. While seemingly automatic, whether cognitive control can govern express saccade production has not been investigated. Here we report the production and manipulation of express saccades under unfavorable conditions in a saccade countermanding task necessitating cognitive control. To perform this task, we trained two monkeys to fixate a central spot and, following a variable amount of time, saccade to a target stimulus at one of two fixed locations (no-stop trials) presented simultaneously with the disappearance of the fixation dot. On a minority of trials, the fixation point reappeared instructing the monkeys to cancel their planned saccade to the peripheral target (stop-signal trials). Monkeys earned fluid reward for generating saccades to targets on no-stop trials and for maintaining fixation on stop-signal trials. Monkeys and humans adapt to the stop-signal trials by increasing saccade latencies. However, in two macaque monkeys we observed a significant fraction of trials with saccade latencies < 100 ms, resulting in a bimodal distribution of saccadic latencies. Target timing derived from regularities of the fixation interval (foreperiod) was used by some monkeys in some sessions to adapt regular but not express saccade latencies. Furthermore, simulations revealed by varying express saccade production, monkeys could maximize the opportunity for reward. To determine whether monkeys exploited this opportunity, reward contingencies for express saccade were changed. When unrewarded, significantly fewer express saccades were produced. This was confirmed in two other monkeys. This study highlights an unexpected manifestation of cognitive control through release of very short latency responses.

Human visual function degrades with age. Previous studies of visual perception have shown that aged people have worse performance in the coding of orientation information. However, the neuronal mechanism still remains elusive. In this study, we performed in vivo extracellular single-unit recording in the primary visual cortex of senescent and young monkeys, and we used the Chernoff distance to quantify the encoded information of neurons for fine and coarse orientation difference. Our results showed that the Chernoff distance for fine orientation difference in senescent monkeys is significantly smaller than that in young monkeys. In contrast, the Chernoff distance for the coarse coding was comparable in young and old groups. Meanwhile, increased spontaneous response and maximum evoked response was also observed. Further investigation of neuronal correlation showed higher noise and signal correlations in aging monkeys than that in young monkeys. These correlation changes predicted a detrimental effect on the efficiency of population coding of orientation information. Taken together, our results suggest that the information coding efficiency of orientation information is impaired during aging and might account for the degradation of performance in human fine orientation discrimination task.

Rhesus macaques are widely used as animal models for studies of the nervous system; however, it is unknown whether the alterations in the protein profile of the brain during aging are conserved between humans and rhesus macaques. In this study, temporal cortex samples from old and young humans (84 vs. 34 years, respectively) or rhesus macaques (20 vs. 6 years, respectively) were subjected to tandem mass tag-labeled proteomic analysis followed by bioinformatic analysis. A total of 3861 homologous pairs of proteins were identified during the aging process. The conservatively upregulated proteins (n = 190) were involved mainly in extracellular matrix (ECM), focal adhesion and coagulation; while, the conservatively downregulated proteins (n = 56) were enriched in ribosome. Network analysis showed that these conservatively regulated proteins interacted with each other with respect to protein synthesis and cytoskeleton-ECM connection. Many proteins in the focal adhesion, blood clotting, complement and coagulation, and cytoplasmic ribosomal protein pathways were regulated in the same direction in human and macaque; while, proteins involved in oligodendrocyte specification and differentiation pathways were downregulated during human aging, and many proteins in the electron transport chain pathway showed differences in the altered expression profiles. Data are available via ProteomeXchange with identifier PXD013597. Our findings suggest similarities in some changes in brain protein profiles during aging both in humans and macaques, although other changes are unique to only one of these species.

Pupil diameter determines how much light hits the retina and, thus, how much information is available for visual processing. This is regulated by a brainstem reflex pathway. Here, we investigate whether this pathway is under the control of internal models about the environment. This would allow adjusting pupil dynamics to environmental statistics to augment information transmission. We present image sequences containing internal temporal structure to humans of either sex and male macaque monkeys. We then measure whether the pupil tracks this temporal structure not only at the rate of luminance variations, but also at the rate of statistics not available from luminance information alone. We find entrainment to environmental statistics in both species. This entrainment directly affects visual processing by increasing sensitivity at the environmentally relevant temporal frequency. Thus, pupil dynamics are matched to the temporal structure of the environment to optimize perception, in line with an active sensing account. SIGNIFICANCE STATEMENT When light hits the retina, the pupil reflexively constricts. This determines how much light and thus how much information is available for visual processing. We show that the rate at which the pupil constricts and dilates is matched to the temporal structure of our visual environment, although this information is not directly contained in the light variations that usually trigger reflexive pupil constrictions. Adjusting pupil diameter in accordance with environmental regularities optimizes information transmission at ecologically relevant temporal frequencies. We show that this is the case in humans and macaque monkeys, suggesting that the reflex pathways that regulate pupil diameter are under some degree of cognitive control across primate species.

The entorhinal cortex is the main gateway for interactions between the neocortex and the hippocampus. Distinct regions, layers and cells of the hippocampal formation exhibit different profiles of structural and molecular maturation during postnatal development. Here, we provide estimates of neuron number, neuronal soma size, and volume of the different layers and subdivisions of the monkey entorhinal cortex (Eo, Er, Elr, Ei, Elc, Ec, Ecl) during postnatal development. We found different developmental changes in neuronal soma size and volume of distinct layers in different subdivisions, but no changes in neuron number. Layers I and II developed early in most subdivisions. Layer III exhibited early maturation in Ec and Ecl, a two-step/early maturation in Ei and a late maturation in Er. Layers V and VI exhibited an early maturation in Ec and Ecl, a two-step and early maturation in Ei, and a late maturation in Er. Neuronal soma size increased transiently at six months of age and decreased thereafter to reach adult size, except in layer II of Ei, and layers II and III of Ec and Ecl. These findings support the theory that different hippocampal circuits exhibit distinct developmental profiles, which may subserve the emergence of different hippocampus-dependent memory processes. We discuss how the early maturation of the caudal entorhinal cortex may contribute to path integration and basic allocentric spatial processing, whereas the late maturation of the rostral entorhinal cortex may contribute to the increased precision of allocentric spatial representations and the temporal integration of individual items into episodic memories.

Understanding the neural code requires understanding how populations of neurons code information. Theoretical models predict that information may be limited by correlated noise in large neural populations. Nevertheless, analyses based on tens of neurons have failed to find evidence of saturation. Moreover, some studies have shown that noise correlations can be very small, and therefore may not affect information coding. To determine whether information-limiting correlations exist, we implanted eight Utah arrays in prefrontal cortex (PFC; area 46) of two male macaque monkeys, recording >500 neurons simultaneously. We estimated information in PFC about saccades as a function of ensemble size. Noise correlations were, on average, small (∼10−3). However, information scaled strongly sublinearly with ensemble size. After shuffling trials, destroying noise correlations, information was a linear function of ensemble size. Thus, we provide evidence for the existence of information-limiting noise correlations in large populations of PFC neurons.SIGNIFICANCE STATEMENTRecent theoretical work has shown that even small correlations can limit information if they are “differential correlations,” which are difficult to measure directly. However, they can be detected through decoding analyses on recordings from a large number of neurons over a large number of trials. We have achieved both by collecting neural activity in dorsal-lateral prefrontal cortex of macaques using eight microelectrode arrays (768 electrodes), from which we were able to compute accurate information estimates. We show, for the first time, strong evidence for information-limiting correlations. Despite pairwise correlations being small (on the order of 10−3), they affect information coding in populations on the order of 100 s of neurons.

Visual exploration is related to activity in the hippocampus (HC) and/or extended medial temporal lobe system (MTL), is influenced by stored memories, and is altered in amnesic cases. An extensive set of polysynaptic connections exists both within and between the HC and oculomotor systems such that investigating how HC responses ultimately influence neural activity in the oculomotor system, and the timing by which such neural modulation could occur, is not trivial. We leveraged TheVirtualBrain, a software platform for large-scale network simulations, to model the functional dynamics that govern the interactions between the two systems in the macaque cortex. Evoked responses following the stimulation of the MTL and some, but not all, subfields of the HC resulted in observable responses in oculomotor regions, including the frontal eye fields, within the time of a gaze fixation. Modeled lesions to some MTL regions slowed the dissipation of HC signal to oculomotor regions, whereas HC lesions generally did not affect the rapid MTL activity propagation to oculomotor regions. These findings provide a framework for investigating how information represented by the HC/MTL may influence the oculomotor system during a fixation and predict how HC lesions may affect visual exploration., Author Summary No major account of oculomotor (eye movement) guidance considers the influence of the hippocampus (HC) and broader medial temporal lobe (MTL) system, yet it is clear that information is exchanged between the two systems. Prior experience influences current viewing, and cases of amnesia due to compromised HC/MTL function show specific alterations in viewing behavior. By modeling large-scale network dynamics, we show that stimulation of subregions of the HC, and of the MTL, rapidly results in observable responses in oculomotor control regions, and that HC/MTL lesions alter signal propagation. These findings suggest that information from memory may readily guide visual exploration, and call for a reconsideration of the neural circuitry involved in oculomotor guidance.

We use sequences of saccadic eye movements to continually explore our visual environments. Previous behavioral studies have established that saccades in a sequence may be programmed in parallel by the oculomotor system. In this study, we tested the neural correlates of parallel programming of saccade sequences in the frontal eye field (FEF), using single-unit electrophysiological recordings from macaques performing a sequential saccade task. It is known that FEF visual neurons instantiate target selection whereas FEF movement neurons undertake saccade preparation, where the activity corresponding to a saccade vector gradually ramps up. The question of whether FEF movement neurons are involved in concurrent processing of saccade plans is as yet unresolved. In the present study, we show that, when a peripheral target is foveated after a sequence of two saccades, presaccadic activity of FEF movement neurons for the second saccade can be activated while the first is still underway. Moreover, the onset of movement activity varied parametrically with the behaviorally measured time available for parallel programming. Although at central fixation coactivated FEF movement activity may vectorially encode the retinotopic location of the second target with respect to the fixation point or the remapped location of the second target, with respect to the first our evidence suggests the possibility of early encoding of the remapped second saccade vector. Taken together, the results indicate that movement neurons, although located terminally in the FEF visual-motor spectrum, can accomplish concurrent processing of multiple saccade plans, leading to rapid execution of saccade sequences. NEW & NOTEWORTHY The execution of purposeful sequences underlies much of goal-directed behavior. How different brain areas accomplish sequencing is poorly understood. Using a modified double-step task to generate a rapid sequence of two saccades, we demonstrate that downstream movement neurons in the frontal eye field (FEF), a prefrontal oculomotor area, allow for coactivation of the first and second movement plans that constitute the sequence. These results provide fundamental insights into the neural control of action sequencing.

Response properties of MT neurons are often studied with “bikinetic” plaid stimuli, which consist of two superimposed sine wave gratings moving in different directions. Oculomotor studies using “unikinetic plaids” in which only one of the two superimposed gratings moves suggest that the eyes first move reflexively in the direction of the moving grating and only later converge on the perceived direction of the moving pattern. MT has been implicated as the source of visual signals that drives these responses. We wanted to know whether stationary gratings, which have little effect on MT cells when presented alone, would influence MT responses when paired with a moving grating. We recorded extracellularly from neurons in area MT and measured responses to stationary and moving gratings, and to their sums: bikinetic and unikinetic plaids. As expected, stationary gratings presented alone had a very modest influence on the activity of MT neurons. Responses to moving gratings and bikinetic plaids were similar to those previously reported and revealed cells selective for the motion of plaid patterns and of their components (pattern and component cells). When these neurons were probed with unikinetic plaids, pattern cells shifted their direction preferences in a way that revealed the influence of the static grating. Component cell preferences shifted little or not at all. These results support the notion that pattern-selective neurons in area MT integrate component motions that differ widely in speed, and that they do so in a way that is consistent with an intersection-of-constraints model. NEW & NOTEWORTHY Human perceptual and eye movement responses to moving gratings are influenced by adding a second, static grating to create a “unikinetic” plaid. Cells in MT do not respond to static gratings, but those gratings still influence the direction selectivity of some MT cells. The cells influenced by static gratings are those tuned for the motion of global patterns, but not those tuned only for the individual components of moving targets.

Most single units recorded from macaque secondary visual cortex (V2) respond with higher firing rates to synthetic texture images containing “naturalistic” higher-order statistics than to spectrally matched “noise” images lacking these statistics. In contrast, few single units in V1 show this property. We explored how the strength and dynamics of response vary across the different layers of visual cortex by recording multiunit (defined as high-frequency power in the local field potential) and gamma-band activity evoked by brief presentations of naturalistic and noise images in V1 and V2 of anesthetized macaque monkeys of both sexes. As previously reported, recordings in V2 showed consistently stronger responses to naturalistic texture than to spectrally matched noise. In contrast to single-unit recordings, V1 multiunit activity showed a preference for images with naturalistic statistics, and in gamma-band activity this preference was comparable across V1 and V2. Sensitivity to naturalistic image structure was strongest in the supragranular and infragranular layers of V1, but weak in granular layers, suggesting that it might reflect feedback from V2. Response timing was consistent with this idea. Visual responses appeared first in V1, followed by V2. Sensitivity to naturalistic texture emerged first in V2, followed by the supragranular and infragranular layers of V1, and finally in the granular layers of V1. Our results demonstrate laminar differences in the encoding of higher-order statistics of natural texture, and suggest that this sensitivity first arises in V2 and is fed back to modulate activity in V1.SIGNIFICANCE STATEMENTThe circuit mechanisms responsible for visual representations of intermediate complexity are largely unknown. We used a well validated set of synthetic texture stimuli to probe the temporal and laminar profile of sensitivity to the higher-order statistical structure of natural images. We found that this sensitivity emerges first and most strongly in V2 but soon after in V1. However, sensitivity in V1 is higher in the laminae (extragranular) and recording modalities (local field potential) most likely affected by V2 connections, suggesting a feedback origin. Our results show how sensitivity to naturalistic image structure emerges across time and circuitry in the early visual cortex.

Continuing investigations of corticostriatal connections in rodents emphasize an intricate architecture where striatal projections originate from different combinations of cortical layers, include an inhibitory component, and form terminal arborizations which are cell-type dependent, extensive, or compact. Here, we report that in macaque monkeys, deep and superficial cortical white matter neurons (WMNs), peri-claustral WMNs, and the claustrum proper project to the putamen. WMNs retrogradely labeled by injections in the putamen (four injections in three macaques) were widely distributed, up to 10 mm antero-posterior from the injection site, mainly dorsal to the putamen in the external capsule, and below the premotor cortex. Striatally projecting labeled WMNs (WMNsST) were heterogeneous in size and shape, including a small GABAergic component. We compared the number of WMNsST with labeled claustral and cortical neurons and also estimated their proportion in relation to total WMNs. Since some WMNsST were located adjoining the claustrum, we wanted to compare results for density and distribution of striatally projecting claustral neurons (ClaST). ClaST neurons were morphologically heterogeneous and mainly located in the dorsal and anterior claustrum, in regions known to project to frontal, motor, and cingulate cortical areas. The ratio of ClaST to WMNsST was about 4:1 averaged across the four injections. These results provide new specifics on the connectional networks of WMNs in nonhuman primates, and delineate additional loops in the corticostriatal architecture, consisting of interconnections across cortex, claustralstriatal and striatally projecting WMNs.