Hippocampal lesions impair non-navigational spatial memory in macaques.

Decades of studies robustly support a critical role for the hippocampus in spatial memory across a wide range of species. Hippocampal damage produces clear and consistent deficits in allocentric spatial memory that requires navigating through space in rodents, non-human primates, and humans. By contrast, damage to the hippocampus spares performance in most non-navigational spatial memory tasks-which can typically be resolved using egocentric cues. We previously found that transient inactivation of the hippocampus impairs performance in the Hamilton Search Task (HST), a self-ordered non-navigational spatial search task. A key question, however, still needs to be addressed. Acute, reversible inactivation of the hippocampus may have resulted in an impairment in the HST because this approach does not allow for neuroplastic compensation, may prevent the development of an alternative learning strategy, and/or may produce network-based effects that disrupt performance. We compared learning and performance on the HST in male rhesus macaques (six unoperated control animals and six animals that underwent excitotoxic lesions of the hippocampus). We found a significant impairment in animals with hippocampal lesions. While control animals improved in performance over the course of 45 days of training, performance in animals with hippocampal lesions remained at chance levels. The HST thus represents a sensitive assay for probing the integrity of the hippocampus in non-human primates. These data provide evidence demonstrating that the hippocampus is critical for this type of non-navigational spatial memory, and help to reconcile the many null findings previously reported.

Neurons in the monkey frontopolar cortex encode learning stage and goal during a fast learning task.

The frontopolar cortex (FPC) is, to date, one of the least understood regions of the prefrontal cortex. The current understanding of its function suggests that it plays a role in the control of exploratory behaviors by coordinating the activities of other prefrontal cortex areas involved in decision-making and exploiting actions based on their outcomes. Based on this hypothesis, FPC would drive fast-learning processes through a valuation of the different alternatives. In our study, we used a modified version of a well-known paradigm, the object-in-place (OIP) task, to test this hypothesis in electrophysiology. This paradigm is designed to maximize learning, enabling monkeys to learn in one trial, which is an ability specifically impaired after a lesion of the FPC. We showed that FPC neurons presented an extremely specific pattern of activity by representing the learning stage, exploration versus exploitation, and the goal of the action. However, our results do not support the hypothesis that neurons in the frontal pole compute an evaluation of different alternatives. Indeed, the position of the chosen target was strongly encoded at its acquisition, but the position of the unchosen target was not. Once learned, this representation was also found at the problem presentation, suggesting a monitoring activity of the synthetic goal preceding its acquisition. Our results highlight important features of FPC neurons in fast-learning processes without confirming their role in the disengagement of cognitive control from the current goals.

Distinct roles of monkey OFC-subcortical pathways in adaptive behavior.

To be the most successful, primates must adapt to changing environments and optimize their behavior by making the most beneficial choices. At the core of adaptive behavior is the orbitofrontal cortex (OFC) of the brain, which updates choice value through direct experience or knowledge-based inference. Here, we identify distinct neural circuitry underlying these two separate abilities. We designed two behavioral tasks in which macaque monkeys updated the values of certain items, either by directly experiencing changes in stimulus-reward associations, or by inferring the value of unexperienced items based on the task's rules. Chemogenetic silencing of bilateral OFC combined with mathematical model-fitting analysis revealed that monkey OFC is involved in updating item value based on both experience and inference. In vivo imaging of chemogenetic receptors by positron emission tomography allowed us to map projections from the OFC to the rostromedial caudate nucleus (rmCD) and the medial part of the mediodorsal thalamus (MDm). Chemogenetic silencing of the OFC-rmCD pathway impaired experience-based value updating, while silencing the OFC-MDm pathway impaired inference-based value updating. Our results thus demonstrate a dissociable contribution of distinct OFC projections to different behavioral strategies, and provide new insights into the neural basis of value-based adaptive decision-making in primates.

Greater hippocampal atrophy in developmental amnesia is associated with better recall and working memory performance.

Despite early-life bilateral hippocampal damage, developmental amnesic (DA) patients exhibit well-developed semantic memory, but severely impaired episodic retrieval. It is unclear, however, whether the residual hippocampus plays a role in encoding and/or retrieval of new information. Here, we report that in DA patients the extent of atrophy in CA-DG subregions and subicular complex is above 40% while the atrophy of the uncus is only moderate (-23%). Importantly, the perihippocampal cortices are unaffected. Paradoxically, patients' recall, Verbal IQ, Working Memory, and Processing Speed scores correlate negatively with the volume of the uncus. We propose that in DA patients, the uncus serves as "gatekeeper" providing signals that may inhibit compensatory mnemonic functions by the preserved surrounding cortical areas. Our findings highlight the role of uncus in recall, and document not only the extent, but also the limits of functional plasticity and circuit reorganization in the young brain after early bilateral hippocampal damage.

Neural correlates of category learning in monkey inferior temporal cortex.

We trained two monkeys implanted with multi-electrode arrays to categorize natural images of cats and dogs, in order to observe changes in neural activity related to category learning. We recorded neural activity from area TE, which is required for normal learning of visual categories based on perceptual similarity. Neural activity during a passive viewing task was compared pre- and post-training. After the category training, the accuracy of abstract category decoding improved. Specifically, the proportion of single units with category selectivity increased, and units sustained their category-specific responses for longer. Visual category learning thus appears to enhance category separability in area TE by driving changes in the stimulus selectivity of individual neurons and by recruiting more units to the active network.

Chemogenetic Disconnection between the Orbitofrontal Cortex and the Rostromedial Caudate Nucleus Disrupts Motivational Control of Goal-Directed Action.

The orbitofrontal cortex (OFC) and its major downstream target within the basal ganglia-the rostromedial caudate nucleus (rmCD)-are involved in reward-value processing and goal-directed behavior. However, a causal contribution of the pathway linking these two structures to goal-directed behavior has not been established. Using the chemogenetic technology of designer receptors exclusively activated by designer drugs with a crossed inactivation design, we functionally and reversibly disrupted interactions between the OFC and rmCD in two male macaque monkeys. We injected an adeno-associated virus vector expressing an inhibitory designer receptor, hM4Di, into the OFC and contralateral rmCD, the expression of which was visualized in vivo by positron emission tomography and confirmed by postmortem immunohistochemistry. Functional disconnection of the OFC and rmCD resulted in a significant and reproducible loss of sensitivity to the cued reward value for goal-directed action. This decreased sensitivity was most prominent when monkeys had accumulated a certain amount of reward. These results provide causal evidence that the interaction between the OFC and the rmCD is needed for motivational control of action on the basis of the relative reward value and internal drive. This finding extends the current understanding of the physiological basis of psychiatric disorders in which goal-directed behavior is affected, such as obsessive-compulsive disorder.SIGNIFICANCE STATEMENT In daily life, we routinely adjust the speed and accuracy of our actions on the basis of the value of expected reward. Abnormalities in these kinds of motivational adjustments might be related to behaviors seen in psychiatric disorders such as obsessive-compulsive disorder. In the current study, we show that the connection from the orbitofrontal cortex to the rostromedial caudate nucleus is essential for motivational control of action in monkeys. This finding expands our knowledge about how the primate brain controls motivation and behavior and provides a particular insight into disorders like obsessive-compulsive disorder in which altered connectivity between the orbitofrontal cortex and the striatum has been implicated.

Contributions of the Monkey Inferior Temporal Areas TE and TEO to Visual Categorization.

The ability to categorize images is thought to depend on neural processing within the ventral visual stream. Recently, we reported that after removal of architectonic area TE, the terminal region of the ventral stream, monkeys were still able to categorize images as cats or dogs moderately well. Here, we investigate the contribution of TEO, the architectonically defined region located one step earlier than area TE in the ventral stream. Bilateral removal of TEO caused only a mild impairment in categorization. However, combined TE + TEO removal was followed by a severe, long-lasting impairment in categorization. All of the monkeys tested, including those with combined TE + TEO removals, had normal low-level visual functions, such as visual acuity. These results support the conclusion that categorization based on visual similarity is processed in parallel in TE and TEO.

MRI monitoring of macaque monkeys in neuroscience: Case studies, resource and normative data comparisons.

Information from Magnetic Resonance Imaging (MRI) is useful for diagnosis and treatment management of human neurological patients. MRI monitoring might also prove useful for non-human animals involved in neuroscience research provided that MRI is available and feasible and that there are no MRI contra-indications precluding scanning. However, MRI monitoring is not established in macaques and a resource is urgently needed that could grow with scientific community contributions. Here we show the utility and potential benefits of MRI-based monitoring in a few diverse cases with macaque monkeys. We also establish a PRIMatE MRI Monitoring (PRIME-MRM) resource within the PRIMatE Data Exchange (PRIME-DE) and quantitatively compare the cases to normative information drawn from MRI data from typical macaques in PRIME-DE. In the cases, the monkeys presented with no or mild/moderate clinical signs, were well otherwise and MRI scanning did not present a significant increase in welfare impact. Therefore, they were identified as suitable candidates for clinical investigation, MRI-based monitoring and treatment. For each case, we show MRI quantification of internal controls in relation to treatment steps and comparisons with normative data in typical monkeys drawn from PRIME-DE. We found that MRI assists in precise and early diagnosis of cerebral events and can be useful for visualising, treating and quantifying treatment response. The scientific community could now grow the PRIME-MRM resource with other cases and larger samples to further assess and increase the evidence base on the benefits of MRI monitoring of primates, complementing the animals' clinical monitoring and treatment regime.

Theta, but Not Gamma Oscillations in Area V4 Depend on Input from Primary Visual Cortex.

Theta (3-9 Hz) and gamma (30-100 Hz) oscillations have been observed at different levels along the hierarchy of cortical areas and across a wide set of cognitive tasks. In the visual system, the emergence of both rhythms in primary visual cortex (V1) and mid-level cortical areas V4 has been linked with variations in perceptual reaction times.1-5 Based on analytical methods to infer causality in neural activation patterns, it was concluded that gamma and theta oscillations might both reflect feedforward sensory processing from V1 to V4.6-10 Here, we report on experiments in macaque monkeys in which we experimentally assessed the presence of both oscillations in the neural activity recorded from multi-electrode arrays in V1 and V4 before and after a permanent V1 lesion. With intact cortex, theta and gamma oscillations could be reliably elicited in V1 and V4 when monkeys viewed a visual contour illusion and showed phase-to-amplitude coupling. Laminar analysis in V1 revealed that both theta and gamma oscillations occurred primarily in the supragranular layers, the cortical output compartment of V1. However, there was a clear dissociation between the two rhythms in V4 that became apparent when the major feedforward input to V4 was removed by lesioning V1: although V1 lesioning eliminated V4 theta, it had little effect on V4 gamma power except for delaying its emergence by >100 ms. These findings suggest that theta is more tightly associated with feedforward processing than gamma and pose limits on the proposed role of gamma as a feedforward mechanism.

Dimensionality, information and learning in prefrontal cortex.

Learning leads to changes in population patterns of neural activity. In this study we wanted to examine how these changes in patterns of activity affect the dimensionality of neural responses and information about choices. We addressed these questions by carrying out high channel count recordings in dorsal-lateral prefrontal cortex (dlPFC; 768 electrodes) while monkeys performed a two-armed bandit reinforcement learning task. The high channel count recordings allowed us to study population coding while monkeys learned choices between actions or objects. We found that the dimensionality of neural population activity was higher across blocks in which animals learned the values of novel pairs of objects, than across blocks in which they learned the values of actions. The increase in dimensionality with learning in object blocks was related to less shared information across blocks, and therefore patterns of neural activity that were less similar, when compared to learning in action blocks. Furthermore, these differences emerged with learning, and were not a simple function of the choice of a visual image or action. Therefore, learning the values of novel objects increases the dimensionality of neural representations in dlPFC.

Information-Limiting Correlations in Large Neural Populations.

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 STATEMENT Recent 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.

Colocalization of Tectal Inputs With Amygdala-Projecting Neurons in the Macaque Pulvinar.

Neuropsychological and neuroimaging studies have suggested the presence of a fast, subcortical route for the processing of emotionally-salient visual information in the primate brain. This putative pathway consists of the superior colliculus (SC), pulvinar and amygdala. While the presence of such a pathway has been confirmed in sub-primate species, it has yet to be documented in the primate brain using conventional anatomical methods. We injected retrograde tracers into the amygdala and anterograde tracers into the colliculus, and examined regions of colocalization of these signals within the pulvinar of the macaque. Anterograde tracers injected into the SC labeled axonal projections within the pulvinar, primarily within the oral, lateral and medial subdivisions. These axonal projections from the colliculus colocalized with cell bodies within the pulvinar that were labeled by retrograde tracer injected into the lateral amygdala. This zone of overlap was most notable in the medial portions of the medial (PM), oral (PO) and inferior pulvinar (PI), and was often densely concentrated in the vicinity of the brachium of the SC. These data provide an anatomical basis for the previously suggested pathway mediating fast processing of emotionally salient information.

Perceptual processing in the ventral visual stream requires area TE but not rhinal cortex.

There is an on-going debate over whether area TE, or the anatomically adjacent rhinal cortex, is the final stage of visual object processing. Both regions have been implicated in visual perception, but their involvement in non-perceptual functions, such as short-term memory, hinders clear-cut interpretation. Here, using a two-interval forced choice task without a short-term memory demand, we find that after bilateral removal of area TE, monkeys trained to categorize images based on perceptual similarity (morphs between dogs and cats), are, on the initial viewing, badly impaired when given a new set of images. They improve markedly with a small amount of practice but nonetheless remain moderately impaired indefinitely. The monkeys with bilateral removal of rhinal cortex are, under all conditions, indistinguishable from unoperated controls. We conclude that the final stage of the integration of visual perceptual information into object percepts in the ventral visual stream occurs in area TE.

Theta Rhythmic Neuronal Activity and Reaction Times Arising from Cortical Receptive Field Interactions during Distributed Attention.

Growing evidence suggests that distributed spatial attention may invoke theta (3-9 Hz) rhythmic sampling processes. The neuronal basis of such attentional sampling is, however, not fully understood. Here we show using array recordings in visual cortical area V4 of two awake macaques that presenting separate visual stimuli to the excitatory center and suppressive surround of neuronal receptive fields (RFs) elicits rhythmic multi-unit activity (MUA) at 3-6 Hz. This neuronal rhythm did not depend on small fixational eye movements. In the context of a distributed spatial attention task, during which the monkeys detected a spatially and temporally uncertain target, reaction times (RTs) exhibited similar rhythmic fluctuations. RTs were fast or slow depending on the target occurrence during high or low MUA, resulting in rhythmic MUA-RT cross-correlations at theta frequencies. These findings show that theta rhythmic neuronal activity can arise from competitive RF interactions and that this rhythm may result in rhythmic RTs potentially subserving attentional sampling.

Specialized Representations of Value in the Orbital and Ventrolateral Prefrontal Cortex: Desirability versus Availability of Outcomes.

Advantageous foraging choices benefit from an estimation of two aspects of a resource's value: its current desirability and availability. Both orbitofrontal and ventrolateral prefrontal areas contribute to updating these valuations, but their precise roles remain unclear. To explore their specializations, we trained macaque monkeys on two tasks: one required updating representations of a predicted outcome's desirability, as adjusted by selective satiation, and the other required updating representations of an outcome's availability, as indexed by its probability. We evaluated performance on both tasks in three groups of monkeys: unoperated controls and those with selective, fiber-sparing lesions of either the OFC or VLPFC. Representations that depend on the VLPFC but not the OFC play a necessary role in choices based on outcome availability; in contrast, representations that depend on the OFC but not the VLPFC play a necessary role in choices based on outcome desirability.

Thalamic connections of the core auditory cortex and rostral supratemporal plane in the macaque monkey.

In the primate auditory cortex, information flows serially in the mediolateral dimension from core, to belt, to parabelt. In the caudorostral dimension, stepwise serial projections convey information through the primary, rostral, and rostrotemporal (AI, R, and RT) core areas on the supratemporal plane, continuing to the rostrotemporal polar area (RTp) and adjacent auditory-related areas of the rostral superior temporal gyrus (STGr) and temporal pole. In addition to this cascade of corticocortical connections, the auditory cortex receives parallel thalamocortical projections from the medial geniculate nucleus (MGN). Previous studies have examined the projections from MGN to auditory cortex, but most have focused on the caudal core areas AI and R. In this study, we investigated the full extent of connections between MGN and AI, R, RT, RTp, and STGr using retrograde and anterograde anatomical tracers. Both AI and R received nearly 90% of their thalamic inputs from the ventral subdivision of the MGN (MGv; the primary/lemniscal auditory pathway). By contrast, RT received only ∼45% from MGv, and an equal share from the dorsal subdivision (MGd). Area RTp received ∼25% of its inputs from MGv, but received additional inputs from multisensory areas outside the MGN (30% in RTp vs. 1-5% in core areas). The MGN input to RTp distinguished this rostral extension of auditory cortex from the adjacent auditory-related cortex of the STGr, which received 80% of its thalamic input from multisensory nuclei (primarily medial pulvinar). Anterograde tracers identified complementary descending connections by which highly processed auditory information may modulate thalamocortical inputs.

High channel count single-unit recordings from nonhuman primate frontal cortex.

BACKGROUND: Single unit recording in behaving nonhuman primates is widely used to study the primate central nervous system. However, certain questions cannot be addressed without recording large numbers of neurons simultaneously. Multiple 96-electrode probes can be implanted at one time, but certain problems must be overcome to make this approach practical. NEW METHOD: We describe a series of innovations and practical guidance for implanting and recording from 8 arrays of 96 electrodes (768 electrodes) in the frontal cortex of Macaca mulatta. The methods include an individualized 3D-printed connector mounting platform, sequencing of assembly and surgical steps to minimize surgery time, and interventions to protect electrical connections of the implant. RESULTS: The methodology is robust and was successful in our hands on the first attempt. On average, we were able to isolate hundreds (535.7 and 806.9 in two animals) of high quality units in each session during one month of recording. COMPARISON WITH EXISTING METHODS: To the best of our knowledge, this technique at least doubles the number of Blackrock arrays that have been successfully implanted in single animals. Although each technological component was pre-existing at the time we developed these methods, their amalgamation to solve the problem of high channel count recording is novel. CONCLUSIONS: The implantation of large numbers of electrodes opens new research possibilities. Refinements could lead to even greater capacity.

Intrinsic Connections of the Core Auditory Cortical Regions and Rostral Supratemporal Plane in the Macaque Monkey.

In the ventral stream of the primate auditory cortex, cortico-cortical projections emanate from the primary auditory cortex (AI) along 2 principal axes: one mediolateral, the other caudorostral. Connections in the mediolateral direction from core, to belt, to parabelt, have been well described, but less is known about the flow of information along the supratemporal plane (STP) in the caudorostral dimension. Neuroanatomical tracers were injected throughout the caudorostral extent of the auditory core and rostral STP by direct visualization of the cortical surface. Auditory cortical areas were distinguished by SMI-32 immunostaining for neurofilament, in addition to established cytoarchitectonic criteria. The results describe a pathway comprising step-wise projections from AI through the rostral and rostrotemporal fields of the core (R and RT), continuing to the recently identified rostrotemporal polar field (RTp) and the dorsal temporal pole. Each area was strongly and reciprocally connected with the areas immediately caudal and rostral to it, though deviations from strictly serial connectivity were observed. In RTp, inputs converged from core, belt, parabelt, and the auditory thalamus, as well as higher order cortical regions. The results support a rostrally directed flow of auditory information with complex and recurrent connections, similar to the ventral stream of macaque visual cortex.

Correlated activity of cortical neurons survives extensive removal of feedforward sensory input.

A fundamental property of brain function is that the spiking activity of cortical neurons is variable and that some of this variability is correlated between neurons. Correlated activity not due to the stimulus arises from shared input but the neuronal circuit mechanisms that result in these noise correlations are not fully understood. Here we tested in the visual system if correlated variability in mid-level area V4 of visual cortex is altered following extensive lesions of primary visual cortex (V1). To this end we recorded longitudinally the neuronal correlations in area V4 of two behaving macaque monkeys before and after a V1 lesion while the monkeys fixated a grey screen. We found that the correlations of neuronal activity survived the lesions in both monkeys. In one monkey, the correlation of multi-unit spiking signals was strongly increased in the first week post-lesion, while in the second monkey, correlated activity was slightly increased, but not greater than some week-by-week fluctuations observed. The typical drop-off of inter-neuronal correlations with cortical distance was preserved after the lesion. Therefore, as V4 noise correlations remain without feedforward input from V1, these results suggest instead that local and/or feedback input seem to be necessary for correlated activity.