Reorganization of Corticospinal Projections after Prominent Recovery of Finger Dexterity from Partial Spinal Cord Injury in Macaque Monkeys.

We investigated morphologic changes in the corticospinal tract (CST) to understand the mechanism underlying recovery of hand function after lesion of the CST at the C4/C5 border in seven macaque monkeys. All monkeys exhibited prominent recovery of precision grip success ratio within a few months. The trajectories and terminals of CST from the contralesional (n = 4) and ipsilesional (n = 3) hand area of primary motor cortex (M1) were investigated at 5-29 months after the injury using an anterograde neural tracer, biotinylated dextran amine (BDA). Reorganization of the CST was assessed by counting the number of BDA-labeled axons and bouton-like swellings in the gray and white matters. Rostral to the lesion (at C3), the number of axon collaterals of the descending axons from both contralesional and ipsilesional M1 entering the ipsilesional and contralesional gray matter, respectively, were increased. Caudal to the lesion (at C8), axons originating from the contralesional M1, descending in the preserved gray matter around the lesion, and terminating in ipsilesional Laminae VI/VII and IX were observed. In addition, axons and terminals from the ipsilesional M1 increased in the ipsilesional Lamina IX after recrossing the midline, which were not observed in intact monkeys. Conversely, axons originating from the ipsilesional M1 and directed toward the contralesional Lamina VII decreased. These results suggest that multiple reorganizations of the corticospinal projections to spinal segments both rostral and caudal to the lesion originating from bilateral M1 underlie a prominent recovery in long-term after spinal cord injury.

Chemogenetic dissection of a prefrontal-hypothalamic circuit for socially subjective reward valuation in macaques.

The value of one's own reward is affected by the reward of others, serving as a source for envy. However, it is not known which neural circuits mediate such socially subjective value modulation. Here, we chemogenetically dissected the circuit from the medial prefrontal cortex (MPFC) to the lateral hypothalamus (LH) while male macaques were presented with visual stimuli that concurrently signaled the prospects of one's own and others' rewards. We found that functional disconnection between the MPFC and LH rendered animals significantly less susceptible to others' but not one's own reward prospects. In parallel with this behavioral change, inter-areal coordination, as indexed by coherence and Granger causality, decreased primarily in the delta and theta bands. These findings demonstrate that the MPFC-to-LH circuit plays a crucial role in carrying information about upcoming other-rewards for subjective reward valuation in social contexts.

Cognitive genomics of learning delay and low level of social performance monitoring in macaque.

Cognitive skills and the underlying neural architecture are under the influence of genetics. Cognitive genomics research explores the triadic relationship between genes, brain, and cognition, with its major strategy being genotype-driven. Here we show that an inverse strategy is feasible to identify novel candidate genes for particular neuro-cognitive phenotypes in macaques. Two monkeys, originally involved in separate psychological studies, exhibited learning delay and low levels of social performance monitoring. In one monkey, mirror neurons were fewer compared to controls and mu suppression was absent in the frontal cortex. The other monkey showed heightened visual responsiveness in both frontal cortex and dopamine-rich midbrain, with a lack of inter-areal synchronization. Exome analyses revealed that the two monkeys were most likely cousins and shared variants in MAP2, APOC1, and potentially HTR2C. This phenotype-driven strategy in cognitive genomics provides a useful means to clarify the genetic basis of phenotypic variation and develop macaque models of neuropsychiatric disorders.

Origin of Multisynaptic Corticospinal Pathway to Forelimb Segments in Macaques and Its Reorganization After Spinal Cord Injury.

Removal of the monosynaptic corticospinal pathway (CSP) terminating within the forelimb segments severely impairs manual dexterity. Functional recovery from the monosynaptic CSP lesion can be achieved through the remaining multisynaptic CSP toward the forelimb segments. In the present study, we applied retrograde transsynaptic labeling with rabies virus to a monkey model of spinal cord injury. By injecting the virus into the spinal forelimb segments immediately after the monosynaptic CSP lesion, we showed that the contralateral primary motor cortex (M1), especially its caudal and bank region (so-called "new" M1), was the principal origin of the CSP linking the motor cortex to the spinal forelimb segments disynaptically (disynaptic CSP). This forms a striking contrast to the architecture of the monosynaptic CSP that involves extensively other motor-related areas, together with M1. Next, the rabies injections were made at the recovery period of 3 months after the monosynaptic CSP lesion. The second-order labeled neurons were located in the ipsilateral as well as in the contralateral "new" M1. This indicates that the disynaptic CSP input from the ipsilateral "new" M1 is recruited during the motor recovery from the monosynaptic CSP lesion. Our results suggest that the disynaptic CSP is reorganized to connect the ipsilateral "new" M1 to the forelimb motoneurons for functional compensation after the monosynaptic CSP lesion.

Live agent preference and social action monitoring in the macaque mid-superior temporal sulcus region.

Mentalizing, the ability to infer the mental states of others, is a cornerstone of adaptive social intelligence. While functional brain mapping of human mentalizing has progressed considerably, its evolutionary signature in nonhuman primates remains debated. The discovery that the middle part of the macaque superior temporal sulcus (mid-STS) region has a connectional fingerprint most similar to the human temporoparietal junction (TPJ)-a crucial node in the mentalizing network-raises the possibility that these cortical areas may also share basic functional properties associated with mentalizing. Here, we show that this is the case in aspects of a preference for live social interactions and in a theoretical framework of predictive coding. Macaque monkeys were trained to perform a turn-taking choice task with another real monkey partner sitting directly face-to-face or a filmed partner appearing in prerecorded videos. We found that about three-fourths of task-related mid-STS neurons exhibited agent-dependent activity, most responding selectively or preferentially to the partner's action. At the population level, activities of these partner-type neurons were significantly greater under live-partner compared to video-recorded-partner task conditions. Furthermore, a subset of the partner-type neurons responded proactively when predictions about the partner's action were violated. This prediction error coding was specific to the action domain; almost none of the neurons signaled error in the prediction of reward. The present findings highlight unique roles of the macaque mid-STS at the single-neuron level and further delineate its functional parallels with the human TPJ in social cognitive processes associated with mentalizing.

Morphological features of large layer V pyramidal neurons in cortical motor-related areas of macaque monkeys: analysis of basal dendrites.

In primates, large layer V pyramidal neurons located in the frontal motor-related areas send a variety of motor commands to the spinal cord, giving rise to the corticospinal tract, for execution of skilled motor behavior. However, little is known about the morphological diversity of such pyramidal neurons among the areas. Here we show that the structure of basal dendrites of the large layer V pyramidal neurons in the dorsal premotor cortex (PMd) is different from those in the other areas, including the primary motor cortex, the supplementary motor area, and the ventral premotor cortex. In the PMd, not only the complexity (arborization) of basal dendrites, i.e., total dendritic length and branching number, was poorly developed, but also the density of dendritic spines was so low, as compared to the other motor-related areas. Regarding the distribution of the three dendritic spine types identified, we found that thin-type (more immature) spines were prominent in the PMd in comparison with stubby- and mushroom-type (more mature) spines, while both thin- and stubby-type spines were in the other areas. The differential morphological features of basal dendrites might reflect distinct patterns of motor information processing within the large layer V pyramidal neurons in individual motor-related areas.

Subcortical encoding of agent-relevant associative signals for adaptive social behavior in the macaque.

Primates are group-living creatures that constantly face the challenges posed by complex social demands. To date, the cortical mechanisms underlying social information processing have been the major focus of attention. However, emerging evidence suggests that subcortical regions also mediate the collection and processing of information from other agents. Here, we review the literature supporting the hypothesis that behavioral variables important for decision-making, i.e., stimulus, action, and outcome, are associated with agent information (self and other) in subcortical regions, such as the amygdala, striatum, lateral hypothalamus, and dopaminergic midbrain nuclei. Such self-relevant and other-relevant associative signals are then integrated into a social utility signal, presumably at the level of midbrain dopamine neurons. This social utility signal allows decision makers to organize their optimal behavior in accordance with social demands. Determining how self-relevant and other-relevant signals might be altered in psychiatric and neurodevelopmental disorders will be fundamental to better understand how social behaviors are dysregulated in disease conditions.

A causal role for frontal cortico-cortical coordination in social action monitoring.

Decision-making via monitoring others' actions is a cornerstone of interpersonal exchanges. Although the ventral premotor cortex (PMv) and the medial prefrontal cortex (MPFC) are cortical nodes in social brain networks, the two areas are rarely concurrently active in neuroimaging, inviting the hypothesis that they are functionally independent. Here we show in macaques that the ability of the MPFC to monitor others' actions depends on input from the PMv. We found that delta-band coherence between the two areas emerged during action execution and action observation. Information flow especially in the delta band increased from the PMv to the MPFC as the biological nature of observed actions increased. Furthermore, selective blockade of the PMv-to-MPFC pathway using a double viral vector infection technique impaired the processing of observed, but not executed, actions. These findings demonstrate that coordinated activity in the PMv-to-MPFC pathway has a causal role in social action monitoring.

Representation of distinct reward variables for self and other in primate lateral hypothalamus.

The lateral hypothalamus (LH) has long been implicated in maintaining behavioral homeostasis essential for the survival of an individual. However, recent evidence suggests its more widespread roles in behavioral coordination, extending to the social domain. The neuronal and circuit mechanisms behind the LH processing of social information are unknown. Here, we show that the LH represents distinct reward variables for "self" and "other" and is causally involved in shaping socially motivated behavior. During a Pavlovian conditioning procedure incorporating ubiquitous social experiences where rewards to others affect one's motivation, LH cells encoded the subjective value of self-rewards, as well as the likelihood of self- or other-rewards. The other-reward coding was not a general consequence of other's existence, but a specific effect of other's reward availability. Coherent activity with and top-down information flow from the medial prefrontal cortex, a hub of social brain networks, contributed to signal encoding in the LH. Furthermore, deactivation of LH cells eliminated the motivational impact of other-rewards. These results indicate that the LH constitutes a subcortical node in social brain networks and shapes one's motivation by integrating cortically derived, agent-specific reward information.

Layer specificity of inputs from supplementary motor area and dorsal premotor cortex to primary motor cortex in macaque monkeys.

The primate frontal lobe processes diverse motor information in parallel through multiple motor-related areas. For example, the supplementary motor area (SMA) is mainly involved in internally-triggered movements, whereas the premotor cortex (PM) is highly responsible for externally-guided movements. The primary motor cortex (M1) deals with both aspects of movements to execute a single motor behavior. To elucidate how the cortical motor system is structured to process a variety of information, the laminar distribution patterns of signals were examined between SMA and M1, or PM and M1 in macaque monkeys by using dual anterograde tract-tracing. Dense terminal labeling was observed in layers 1 and upper 2/3 of M1 after one tracer injection into SMA, another tracer injection into the dorsal division of PM resulted in prominent labeling in the deeper portion of layer 2/3. Weaker labeling was also visible in layer 5 in both cases. On the other hand, inputs from M1 terminated in both the superficial and the deep layers of SMA and PM. The present data indicate that distinct types of motor information are arranged in M1 in a layer-specific fashion to be orchestrated through a microcircuit within M1.

Treatment With the Neutralizing Antibody Against Repulsive Guidance Molecule-a Promotes Recovery From Impaired Manual Dexterity in a Primate Model of Spinal Cord Injury.

Axons in the mature mammalian central nervous system have only a limited capacity to grow/regenerate after injury, and spontaneous recovery of motor functions is therefore not greatly expected in spinal cord injury (SCI). To promote functional recovery after SCI, it is critical that corticospinal tract (CST) fibers reconnect properly with target spinal neurons through enhanced axonal growth/regeneration. Here, we applied antibody treatment against repulsive guidance molecule-a (RGMa) to a monkey model of SCI. We found that inhibition of upregulated RGMa around the lesioned site in the cervical cord resulted in recovery from impaired manual dexterity by accentuated penetration of CST fibers into laminae VII and IX, where spinal interneurons and motoneurons are located, respectively. Furthermore, pharmacological inactivation following intracortical microstimulation revealed that the contralesional, but not the ipsilesional, primary motor cortex was crucially involved in functional recovery at a late stage in our SCI model. The present data indicate that treatment with the neutralizing antibody against RGMa after SCI is a potential target for achieving restored manual dexterity in primates.

Social reward monitoring and valuation in the macaque brain.

Behaviors are influenced by rewards to both oneself and others, but the neurons and neural connections that monitor and evaluate rewards in social contexts are unknown. To address this issue, we devised a social Pavlovian conditioning procedure for pairs of monkeys. Despite being constant in amount and probability, the subjective value of forthcoming self-rewards, as indexed by licking and choice behaviors, decreased as partner-reward probability increased. This value modulation was absent when the conspecific partner was replaced by a physical object. Medial prefrontal cortex neurons selectively monitored self-reward and partner-reward information, whereas midbrain dopaminergic neurons integrated this information into a subjective value. Recordings of local field potentials revealed that responses to reward-predictive stimuli in medial prefrontal cortex started before those in dopaminergic midbrain nuclei and that neural information flowed predominantly in a medial prefrontal cortex-to-midbrain direction. These findings delineate a dedicated pathway for subjective reward evaluation in social environments.

Development of social systems neuroscience using macaques.

This paper reviews the literature on social neuroscience studies using macaques in the hope of encouraging as many researchers as possible to participate in this field of research and thereby accelerate the system-level understanding of social cognition and behavior. We describe how different parts of the primate brain are engaged in different aspects of social information processing, with particular emphasis on the use of experimental paradigms involving more than one monkey in laboratory settings. The description begins with how individual neurons are used for evaluating socially relevant information, such as the identity, face, and focus of attention of others in various social contexts. A description of the neural bases of social reward processing and social action monitoring follows. Finally, we provide several perspectives on novel experimental strategies to help clarify the nature of interacting brains under more socially and ecologically plausible conditions.

Performance monitoring in the medial frontal cortex and related neural networks: From monitoring self actions to understanding others' actions.

Action is a key channel for interacting with the outer world. As such, the ability to monitor actions and their consequences - regardless as to whether they are self-generated or other-generated - is of crucial importance for adaptive behavior. The medial frontal cortex (MFC) has long been studied as a critical node for performance monitoring in nonsocial contexts. Accumulating evidence suggests that the MFC is involved in a wide range of functions necessary for one's own performance monitoring, including error detection, and monitoring and resolving response conflicts. Recent studies, however, have also pointed to the importance of the MFC in performance monitoring under social conditions, ranging from monitoring and understanding others' actions to reading others' mental states, such as their beliefs and intentions (i.e., mentalizing). Here we review the functional roles of the MFC and related neural networks in performance monitoring in both nonsocial and social contexts, with an emphasis on the emerging field of a social systems neuroscience approach using macaque monkeys as a model system. Future work should determine the way in which the MFC exerts its monitoring function via interactions with other brain regions, such as the superior temporal sulcus in the mentalizing system and the ventral premotor cortex in the mirror system.

Ongoing Alpha Activity in V1 Regulates Visually Driven Spiking Responses.

The interlaminar connections in the primate primary visual cortex (V1) are well described, as is the presence of ongoing alpha-range (7-14 Hz) fluctuations in this area. Less well understood is how these interlaminar connections and ongoing fluctuations contribute to the regulation of visual spiking responses. Here, we investigate the relationship between alpha fluctuations and spiking responses to visual stimuli across cortical layers. Using laminar probes in macaque V1, we show that neural firing couples with the phase of alpha fluctuations, and that magnitude of this coupling is particularly pronounced during visual stimulation. The strongest modulation of spiking activity was observed in layers 2/3. Alpha-spike coupling and current source density analysis pointed to an infragranular origin of the alpha fluctuations. Taken together, these results indicate that ongoing infragranular alpha-range fluctuations in V1 play a role in regulating columnar visual activity.

A Primary Role for Nucleus Accumbens and Related Limbic Network in Vocal Tics.

Inappropriate vocal expressions, e.g., vocal tics in Tourette syndrome, severely impact quality of life. Neural mechanisms underlying vocal tics remain unexplored because no established animal model representing the condition exists. We report that unilateral disinhibition of the nucleus accumbens (NAc) generates vocal tics in monkeys. Whole-brain PET imaging identified prominent, bilateral limbic cortico-subcortical activation. Local field potentials (LFPs) developed abnormal spikes in the NAc and the anterior cingulate cortex (ACC). Vocalization could occur without obvious LFP spikes, however, when phase-phase coupling of alpha oscillations were accentuated between the NAc, ACC, and the primary motor cortex. These findings contrasted with myoclonic motor tics induced by disinhibition of the dorsolateral putamen, where PET activity was confined to the ipsilateral sensorimotor system and LFP spikes always preceded motor tics. We propose that vocal tics emerge as a consequence of dysrhythmic alpha coupling between critical nodes in the limbic and motor networks. VIDEO ABSTRACT.

Supranormal orientation selectivity of visual neurons in orientation-restricted animals.

Altered sensory experience in early life often leads to remarkable adaptations so that humans and animals can make the best use of the available information in a particular environment. By restricting visual input to a limited range of orientations in young animals, this investigation shows that stimulus selectivity, e.g., the sharpness of tuning of single neurons in the primary visual cortex, is modified to match a particular environment. Specifically, neurons tuned to an experienced orientation in orientation-restricted animals show sharper orientation tuning than neurons in normal animals, whereas the opposite was true for neurons tuned to non-experienced orientations. This sharpened tuning appears to be due to elongated receptive fields. Our results demonstrate that restricted sensory experiences can sculpt the supranormal functions of single neurons tailored for a particular environment. The above findings, in addition to the minimal population response to orientations close to the experienced one, agree with the predictions of a sparse coding hypothesis in which information is represented efficiently by a small number of activated neurons. This suggests that early brain areas adopt an efficient strategy for coding information even when animals are raised in a severely limited visual environment where sensory inputs have an unnatural statistical structure.

Reorganization of corticospinal tract fibers after spinal cord injury in adult macaques.

Previous studies have shown that sprouting of corticospinal tract (CST) fibers after spinal cord injury (SCI) contributes to recovery of motor functions. However, the neuroanatomical mechanism underlying the functional recovery through sprouting CST fibers remains unclear. Here we investigated the pattern of reorganization of CST fibers below the lesion site after SCI in adult macaques. Unilateral lesions were made at the level between the C7 and the C8 segment. The extent of spontaneous recovery of manual dexterity was assessed with a reaching/grasping task. The impaired dexterous manual movements were gradually recovered after SCI. When anterograde tract tracing with biotinylated dextran amine was performed to identify the intraspinal reinnervation of sprouting CST fibers, it was found that the laminar distribution of CST fibers was changed. The sprouting CST fibers extended preferentially into lamia IX where the spinal motor neuron pool was located, to innervate the motor neurons directly. Instead, few, if any, CST fibers were distributed in the dorsal laminae. The present results indicate that CST fibers below the lesion site after SCI in macaques are reorganized in conjunction with the recovery of dexterous manual movements.

Microcircuitry of agranular frontal cortex: contrasting laminar connectivity between occipital and frontal areas.

Neocortex is striking in its laminar architecture. Tracer studies have uncovered anatomical connectivity among laminae, but the functional connectivity between laminar compartments is still largely unknown. Such functional connectivity can be discerned through spontaneous neural correlations during rest. Previous work demonstrated a robust pattern of mesoscopic resting-state connectivity in macaque primary visual cortex (V1) through interlaminar cross-frequency coupling. Here we investigated whether this pattern generalizes to other cortical areas by comparing resting-state laminar connectivity between V1 and the supplementary eye field (SEF), a frontal area lacking a granular layer 4 (L4). Local field potentials (LFPs) were recorded with linear microelectrode arrays from all laminae of granular V1 and agranular SEF while monkeys rested in darkness. We found substantial differences in the relationship between the amplitude of gamma-band (>30 Hz) LFP and the phase of alpha-band (7-14 Hz) LFP between these areas. In V1, gamma amplitudes in L2/3 and L5 were coupled with alpha-band LFP phase in L5, as previously described. In contrast, in SEF phase-amplitude coupling was prominent within L3 and much weaker across layers. These results suggest that laminar interactions in agranular SEF are unlike those in granular V1. Thus the intrinsic functional connectivity of the cortical microcircuit does not seem to generalize across cortical areas.

Dorsal area 46 is a major target of disynaptic projections from the medial temporal lobe.

The medial temporal lobe (MTL) is responsible for various mnemonic functions, such as association/conjunction memory. The lateral prefrontal cortex (LPFC) also plays crucial roles in mnemonic functions and memory-based cognitive behaviors, for example, decision-making. Therefore, it is considered that the MTL and LPFC connect with each other and cooperate for the control of cognitive behaviors. However, there exist very weak, if any, direct inputs from the MTL to the LPFC. Employing retrograde transsynaptic transport of rabies virus, we investigated the organization of disynaptic bottom-up pathways connecting the MTL and the inferotemporal cortex to the LPFC in macaques. Three days after rabies injections into dorsal area 46, a large number of labeled neurons were observed in the MTL, such as the hippocampal formation (including the entorhinal cortex), the perirhinal cortex, and the parahippocampal cortex. In contrast, a majority of the labeled neurons were located in the inferotemporal cortex following rabies injections into ventral area 46 and lateral area 12. Rabies injections into lateral area 9/area 8B labeled only a small number of neurons in the MTL and the inferotemporal cortex. The present results indicate that, among the LPFC, dorsal area 46 is the main target of disynaptic inputs from the MTL.