Cortex Of Rhesus Monkeys Research Articles

Immature Neurons in the Temporal Cortex of the Aging Rhesus Monkey

Adult neurogenesis is known to occur in specific regions of the brain including the Subgranular Zone (SGZ) of the hippocampal dentate gyrus (DG) and the Subventricular Zone (SVZ) of the lateral ventricle. The new neurons originating in these regions have shown to be necessary for specific cognitive functions. However, it remains unknown if adult‐generated neurons exist in other regions of the brain and contribute to cognitive processes. A novel population of cells expressing the immature neuronal marker, Doublecortin (DCX) has been identified in regions previously termed ‘non‐neurogenic’ including the cortex of cats, guinea pig, non‐human primate, and human. DCX+ cells co‐localize with the proliferative marker Bromodeoxyuridine (BrdU) in the cortex, but only at very low levels, suggesting cortical DCX+ cells with an extended maturation period. Preliminary work in our lab has identified DCX+ cells in the temporal cortex of rhesus monkeys. Tissue from behaviorally characterized young and old monkeys given BrdU for 21 days is being analyzed to quantify DCX+ cells in the cortex and the proportion that co‐localize with BrdU. Our objective is to use Stereologic analysis to quantify age‐related changes and the impact on cognitive function. The characterization of this unique population of cells is necessary to further investigate their role in cortical plasticity and aging. (Supported by R01AG021133 and P01AG000001)

Dopaminergic Dysregulation in Prefrontal Cortex of Rhesus Monkeys Following Cocaine Self-Administration

Chronic cocaine administration regulates the expression of several proteins related to dopaminergic signaling and synaptic function in the mesocorticolimbic pathway, including the prefrontal cortex. Functional abnormalities in the prefrontal cortex are hypothesized to be due in part to the expression of proteins involved in dopamine signaling and plasticity. Adult male rhesus monkeys self-administered cocaine (i.v.) under limited (n = 4) and extended access conditions (n = 6). The abundance of surrogate markers of dopamine signaling and plasticity in the dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC), and anterior cingulate cortex (ACC) were examined: glycosylated and non-glycosylated forms of the dopamine transporter (efficiency of dopamine transport), tyrosine hydroxylase (TH; marker of dopamine synthesis) and phosphorylated TH at Serine 30 and 40 (markers of enzyme activity), extracellular signal-regulated kinase 1 and 2 (ERK1 and ERK 2), and phosphorylated ERK1 and ERK2 (phosphorylates TH Serine 31; markers of synaptic plasticity), and markers of synaptic integrity, spinophilin and post-synaptic density protein 95 (roles in dopamine signaling and response to cocaine). Extended cocaine access increased non-glycosylated and glycosylated DAT in DLPFC and OFC. While no differences in TH expression were observed between groups for any of the regions, extended access induced significant elevations in pTHSer31 in all regions. In addition, a slight but significant reduction in phosphorylated pTHSer40 was found in the DLPFC. Phosphorylated ERK2 was increased in all regions; however, pERK1 was decreased in ACC and OFC but increased in DLPFC. PSD-95 was increased in the OFC but not in DLPFC or ACC. Furthermore, extended cocaine self-administration elicited significant increases in spinophilin protein expression in all regions. Results from the study provide insight into the biochemical alterations occurring in primate prefrontal cortex.

A Strong Constraint to the Joint Processing of Pairs of Cortical Signals

An important question in neuroscience is how the activity from spatially distributed cortical representations is integrated and processed together. In this study, we used a new approach to investigate the integration of distributed cortical activity. We used microstimulation to directly activate pairs of sites in primary visual cortex of rhesus monkeys. The sites were activated either singly or jointly, and the monkeys were trained to behaviorally report detection of the activation of either cortical site. We compared the detection performance with predictions from two different mathematical models of signal combination. Our data show that, at cortical separations <1 mm, signal integration is well described as a linear combination (d' summation) of individual site activity. At larger separations, signal integration is better described as a maximum operation on the site signals. We compare our neurophysiological findings to existing psychophysical data and suggest the intriguing possibility that cortical activity originating at spatial separations greater than ∼1 mm is processed as if by parallel, independent circuits whose signals can be compared against each other but not summed. This in turn implies that there is a strong constraint to the kinds of computations the brain can perform with spatially distributed cortical activity.

Selective effects of aging on simple and complex cells in primary visual cortex of rhesus monkeys

The visual system is hierarchically organized between and within areas. Previous studies have found that aging affects different visual areas in a progressive manner, e.g. more degradation occurs in the primary visual cortex (V1) than in the dorsal lateral geniculate nucleus (dLGN), and more in the secondary visual (V2) and middle temporal (MT) visual areas than in V1. In view of these findings, we hypothesize that higher levels within the visual information hierarchy are affected more severely by aging. Hierarchies exist not only between visual areas but also within areas (e.g. V1, has a simple to complex cell hierarchy). We expected that a similar pattern of ageing effects should be found within a given visual area. To study this question, primary visual cortex is a good candidate because there is good evidence for the simple to complex cell hierarchy. In this paper, we applied single unit recording techniques to study the visual response properties of V1 simple and complex cells in young and old monkeys in vivo. We found that the orientation and direction selectivity of complex cells were significantly degraded in old monkeys, while those of simple cells were relatively spared from the effects of aging. These findings are consistent with the hypothesis that higher hierarchical levels in the visual system, both between and within areas, may be affected more severely by aging.

Differential representation of auditory categories between cell classes in primate auditory cortex

A comprehensive understanding of the neural mechanisms of cognitive function requires an understanding of how neural representations are transformed across different scales of neural organization: from within local microcircuits to across different brain areas. However, the neural transformations within the local microcircuits are poorly understood. Particularly, the role that two main cell classes of neurons in cortical microcircuits (i.e. pyramidal neurons and interneurons) have in auditory behaviour and cognition remains unknown. In this study, we tested the hypothesis that pyramidal cells and interneurons in the auditory cortex play a differential role in auditory categorization. To test this hypothesis, we recorded single-unit activity from the auditory cortex of rhesus monkeys while they categorized speech sounds. Based on the spike-waveform shape, a neuron was classified as either a narrow-spiking putative interneuron or a broad-spiking putative pyramidal neuron. We found that putative interneurons and pyramidal neurons in the auditory cortex differentially coded category information: interneurons were more selective for auditory categories than pyramidal neurons. These differences between cell classes may be an essential property of the neural computations underlying auditory categorization within the microcircuitry of the auditory cortex.

Visuomotor Coordination and Motor Representation by Human Temporal Lobe Neurons

The division of cortical visual processing into distinct dorsal and ventral streams is a key concept in primate neuroscience [Goodale, M. A., & Milner, A. D. Separate visual pathways for perception and action. Trends in Neurosciences, 15, 20-25, 1992; Steele, G., Weller, R., & Cusick, C. Cortical connections of the caudal subdivision of the dorsolateral area (V4) in monkeys. Journal of Comparative Neurology, 306, 495-520, 1991]. The ventral stream is usually characterized as a "What" pathway, whereas the dorsal stream is implied in mediating spatial perception ("Where") and visually guided actions ("How"). A subpathway emerging from the dorsal stream and projecting to the medial-temporal lobe has been identified [Kravitz, D. J., Saleem, K. S., Baker, C. I., & Mishkin, M. A new neural framework for visuospatial processing. Nature Reviews Neuroscience, 12, 217-230, 2011; Cavada, C., & Goldman-Raiuc, P. S. Posterior parietal cortex in rhesus monkey: I. Parcellation of areas based on distinctive limbic and sensory cortico-cortical connections. Journal of Comparative Neurology, 287, 393-421, 1989]. The current article studies the coordination of visual information typically associated with the dorsal stream ("Where"), with planned movements, focusing on the temporal lobe. We recorded extracellular activity from 565 cells in the human medial-temporal and frontal lobes while 13 patients performed cued hand movements with visual feedback (visuomotor task), without feedback (motor task), or observed visual feedback without motor movement (visual-only task). We discovered two different neural populations in the human medial-temporal lobe. One consists of motor-like neurons representing hand position, speed or acceleration during the motor task but not during the visuomotor or visual tasks. The other is specific to the parahippocampal gyrus (an area known to process visual motion [Gur, M., & Snodderly, D. M. Direction selectivity in V1 of alert monkeys: Evidence for parallel pathways for motion processing. Journal of Physiology, 585, 383-400, 2007; Sato, N., & Nakamura, K. Visual response properties of neurons in the parahippocampal cortex of monkeys. Journal of Neurophysiology, 90, 876-886, 2003]) and encodes speed, acceleration, or direction of hand movements, but only during the visuomotor task: neither during visual-only nor during motor tasks. These findings suggest a functional basis for the anatomical subpathway between the dorsal stream and the medial-temporal lobe. Similar to the recent expansion of the motor control process into the sensory cortex [Matyas, F., Sreenivasan, V., Marbach, F., Wacongne, C., Barsy, B., Mateo, C., et al. Motor control by sensory cortex. Science, 330, 1240-1243, 2010], our findings render the human medial-temporal lobe an important junction in the process of planning and execution of motor acts whether internally or externally (visually) driven. Thus, the medial-temporal lobe might serve as an integration node between the two processing streams. Our findings thus shed new light on the brain mechanisms underlying visuomotor coordination which is a crucial capacity for everyday survival, whether it is identifying and picking up food, sliding a key into a lock, driving a vehicle, or escaping a predator.

Functional Split between Parietal and Entorhinal Cortices in the Rat

Posterior parietal cortex (PPC) and medial entorhinal cortex (MEC) are important elements of the neural circuit for space, but whether representations in these areas are controlled by the same factors is unknown. We recorded single units simultaneously in PPC and MEC of freely foraging rats and found that a subset of PPC cells are tuned to specific modes of movement irrespective of the animals' location or heading, whereas grid cells in MEC expressed static spatial maps. The behavioral correlates of PPC cells switched completely when the same animals ran in a spatially structured maze or when they ran similar stereotypic sequences in an open arena. Representations in PPC were similar in identical mazes in different rooms where grid cells completely realigned their firing fields. The data suggest that representations in PPC are determined by the organization of actions while cells in MEC are driven by spatial inputs.

S4‐02‐06: Gene therapy utilizing growth factors

Brain-derived neurotrophic factor (BDNF) potently prevents the death and stimulates the function of cortical neurons in several rodent and primate models of Alzheimer's disease (AD). We previously reported that BDNF administration to the entorhinal cortex improved hippocampal-dependent learning and memory, enhanced synaptic function, and reduced neuronal loss (Nagahara et al., Nature Medicine 2009). Effects were observed in both the entorhinal cortex and hippocampus. We are now assessing the safety and toxicity of adeno-associated virus serotype 2 (AAV2) BDNF gene delivery at escalating doses in rodent and primate models. As part of potential clinical translation, it is essential to develop methods to accurately target AAV2-BDNF vector delivery to the entorhinal cortex. We have developed a “real-time” magnetic resonance imaging delivery system that enables accurate identification of vector infusion sites in the entorhinal cortex in rhesus monkeys, and that monitors spread of vector in each subjects at the time of active infusion. This system may be essential both in this AAV2-BDNF infusion program, and in other gene delivery programs targeting AD and other neurodegenerative brain disorders. Young rhesus monkeys underwent delivery of BDNF-AAV2 into the entorhinal cortex with the Clearpoint system (Surgivision) that uses a MRI-compatible head mounted frame (Smartframe), cannula system, and software to establish the cannula trajectory based real-time MRI. Using the real-time MRI, convection-enhanced delivery of BDNF-AAV2 mixed with 1mM gadoteridol (MRI contrast agent) into the entorhinal cortex is monitored during the infusion procedure. 1 month following vector delivery, monkeys are perfused and the brain is examined to confirm delivery of the BDNF-AAV2 to the targeted region. Real-time MRI during the infusion procedure allowed accurate targeting of BDNF-AAV2 to the entorhinal cortex. Comparison of BDNF immunolabeling in brain tissue and MR images of the vector infusion during surgery confirmed that real-time MRI accurately reflects targeting and spread of BDNF-AAV2. BDNF-AAV2 transduced only neurons, resulting in accurate vector delivery to the intended cellular targets. These findings demonstrate that real-time MRI during the infusion procedure can enable accurate targeting of gene delivery into entorhinal cortex of non-human primates. This represents a feasible method to deliver vectors into specific brain regions with 0.5 mm accuracy. The use of this system can allow accurate delivery of vector into this brain region in AD.

Neural correlates of cognitive control of reaching movements in the dorsal premotor cortex of rhesus monkeys

Canceling a pending movement is a hallmark of voluntary behavioral control because it allows us to quickly adapt to unattended changes either in the external environment or in our thoughts. The countermanding paradigm allows the study of inhibitory processes of motor acts by requiring the subject to withhold planned movements in response to an infrequent stop-signal. At present the neural processes underlying the inhibitory control of arm movements are mostly unknown. We recorded the activity of single units in the rostral and caudal portion of the dorsal premotor cortex (PMd) of monkeys trained in a countermanding reaching task. We found that among neurons with a movement-preparatory activity, about one-third exhibit a modulation before the behavioral estimate of the time it takes to cancel a planned movement. Hence these neurons exhibit a pattern of activity suggesting that PMd plays a critical role in the brain networks involved in the control of arm movement initiation and suppression.

The representation of perceptual similarity between shapes in the inferotemporal cortex of rhesus monkeys

The representation of perceptual similarity between shapes in the inferotemporal cortex of rhesus monkeys

A conceptual cortical surface atlas.

Volumetric, slice-based, 3-D atlases are invaluable tools for understanding complex cortical convolutions. We present a simple scheme to convert a slice-based atlas to a conceptual surface atlas that is easier to visualize and understand. The key idea is to unfold each slice into a one-dimensional vector, and concatenate a succession of these vectors – while maintaining as much spatial contiguity as possible – into a 2-D matrix. We illustrate our methodology using a coronal slice-based atlas of the Rhesus Monkey cortex. The conceptual surface-based atlases provide a useful complement to slice-based atlases for the purposes of indexing and browsing.

Differences in DNA Methylation Patterns and Expression of the CCRK Gene in Human and Nonhuman Primate Cortices

Changes in DNA methylation patterns during embryo development and differentiation processes are linked to the transcriptional plasticity of our genome. However, little is known about the evolutionary conservation of DNA methylation patterns and the evolutionary impact of epigenetic differences between closely related species. Here we compared the methylation patterns of CpG islands (CGIs) in the promoter regions of seven genes in humans and chimpanzees. We identified a block of CpGs in the cell cycle-related kinase (CCRK) gene that is more methylated in the adult human cortex than in the chimpanzee cortex and, in addition, it exhibits considerable intraspecific variation both in humans and chimpanzees. The species-specifically methylated region (SMR) lies between the almost completely methylated 5' region and the completely demethylated 3' region of the presumed CCRK CGI promoter. It is part of an Alu-Sg1 repeat that has been integrated into the promoter region in a common ancestor of humans and New World monkeys. This SMR is relatively hypomethylated in the rhesus monkey cortex and more or less completely methylated in the baboon cortex, indicating extraordinary methylation dynamics during primate evolution. The mRNA expression level of CCRK has also changed during the course of primate evolution. CCRK is expressed at much higher levels in human and baboon cortices, which display an average SMR methylation of 70% and 100%, respectively, than in chimpanzee and rhesus macaque cortices with an average SMR methylation of 35% and 40%, respectively. The observed evolutionary dynamics suggests a possibility that CCRK has been important for evolution of the primate brain.

Roles of Platelet-Derived Growth Factor-B Expression in the Ventral Horn and Motor Cortex in the Spinal Cord–Hemisected Rhesus Monkey

It is well known that platelet-derived growth factor-B (PDGF-B), a member of the neurotrophic factor family, is involved in normal physiological conditions, pathological changes, and neuroregulation following lesions. But the roles of endogenous PDGF-B in neuroregulation following spinal cord injury are far from being well known, especially in primates. This study explored the role of PDGF-B in the spinal cord and motor cortex in rhesus monkeys subjected to cord hemisection. Evaluation of the hindlimb motor function and the cortical somatosensory evoked potentials (CSEP) demonstrated a significant partial recovery from 30 days post-operation (dpo) to 90 dpo. Immunostaining revealed PDGF-B expression in neurons and scattered macrophages in the spinal cord. The number of PDGF-B immunoreactive neurons in the ventral horn of the spinal cord decreased significantly at the injury site at 14 dpo, followed by a rapid increase that surpassed the numbers in the control group at 30 dpo, and remained at these levels until 90 dpo. The protein levels of PDGF-B and platelet-derived growth factor receptor-beta (PDGFR-beta) as assessed by Western blot, as well as the mRNA levels of PDGF-B as assessed by RT-PCR demonstrated a tendency similar to that seen with immunohistochemistry. PDGF-B antibody administration effectively decreased locomotor function in the hindlimbs, especially on the injured side. No PDGF-B immunoreactive cells were detected in the motor cortex. Taken together, the present findings indicate that intrinsic PDGF-B expressed in the spinal cord may play an essential role in neuroregulation in primates following cord hemisection.

The neuroglial population in the primary visual cortex of the aging rhesus monkey

The effects of age on neuroglial cells have been examined in the primary visual cortices of rhesus monkeys that had been behaviorally tested. The assessment of changes in the neuroglial populations was made on the basis of the frequency of occurrence of profiles of neuroglial cells in semithick sections of osmicated tissue stained with toluidine blue. No changes were found in the numbers of astrocytes and microglial cells with age, but the numbers of oligodendrocytes increased by about 50%. The myelinated nerve bundles at the level of layer 4 were also examined by electron microscopy to assess the effects of age on the nerve fibers. The numbers of nerve fiber profiles showing age-related alterations in their myelin sheaths increase with age. There was also an age-related increase in the frequency of profiles of nerve fibers sectioned through paranodes, indicating that shorter lengths of myelin are being produced by remyelination. These changes in sheaths both correlate significantly with the frequency of oligodendrocyte profiles, suggesting that with age additional oligodendrocytes are required to remyelinate nerve fibers whose sheaths have broken down, probably by death of the original parent oligodendroglial cell. Also the most cognitively impaired monkeys had the greatest numbers of oligodendrocytes, but this is probably a secondary correlation, reflecting the fact that altered myelin slows down the rate of conduction along nerve fibers, which leads to cognitive decline.

Mental Simulation of Action in the Service of Action Perception

We used the quantitative 14C-deoxyglucose method to map the activity pattern throughout the frontal cortex of rhesus monkeys, which either grasped a three-dimensional object or observed the same grasping movements executed by a human. We found that virtually the same frontal cortical networks were recruited for the generation and the perception of action, including the primary motor cortex (MI/F1), premotor cortical areas (F2, F5, and F6), the primary (SI) and supplementary (SSA) somatosensory cortex, medial cortical areas (8m and 9m), and the anterior cingulate. The overlapping networks for action execution and action observation support the notion that mental simulation of action could underlie the perception of others' actions. We suggest that the premotor and the somatotopic MI/F1 activations induced by action observation reflect motor grasp of the observed action, whereas the somatotopic SI and the SSA activations reflect recruitment of learned sensory-motor associations enabling perceptual understanding of the anticipated somatosensory feedback. We also found that the premotor activations were stronger for action observation, in contrast to the primary somatosensory-motor ones, which were stronger for action execution, and that activations induced by observation were bilateral, whereas those induced by execution were contralateral to the moving forelimb. We suggest that these differences in intensity and lateralization of activations between the executive and the perceptual networks help attribute the action to the correct agent, i.e., to the "self" during action execution and to the "other" during action observation. Accordingly, the "sense of agency" could be articulated within the core components of the circuitry supporting action execution/observation.

Amperometric measures of age-related changes in glutamate regulation in the cortex of rhesus monkeys

l-glutamate (glutamate) is the principal excitatory neurotransmitter of the central nervous system and is involved in altered neural function during aging and in neurodegenerative diseases. Relatively little is known about the mechanisms of glutamate signaling in the primate brain, in part, because there is an absence of a method capable of rapidly measuring glutamate in either a non-clinical or a clinical setting. We have addressed this paucity of information by measuring extracellular glutamate at 1 Hz in the pre-motor and motor cortices of young, middle-aged, and aged monkeys using a minimally invasive amperometric recording method. In the motor cortex, mean resting glutamate levels were five times higher in the aged group compared to the young group while the pre-motor cortex showed an increasing trend in resting glutamate levels that was not statistically significant. In addition, we measured rapid, phasic glutamate release after local pressure-ejection of nanoliter volumes of either isotonic 70 mM potassium (to stimulate glutamate release) or 1 mM glutamate (to study glutamate uptake) into the pre-motor and motor cortex. In the pre-motor cortex, we measured reproducible glutamate uptake signals that had a significantly decreased (47%) rate of glutamate uptake in aged animals compared to young animals. However, following a 70 mM potassium delivery, we did not observe any consistent changes in evoked release between young versus aged animals. Using these non-clinical microelectrodes to measure glutamate signaling in the brain, our results support the hypothesis that the glutamatergic system undergoes reorganization with aging of the central nervous system.

Looming Biases in Monkey Auditory Cortex

Looming signals (signals that indicate the rapid approach of objects) are behaviorally relevant signals for all animals. Accordingly, studies in primates (including humans) reveal attentional biases for detecting and responding to looming versus receding signals in both the auditory and visual domains. We investigated the neural representation of these dynamic signals in the lateral belt auditory cortex of rhesus monkeys. By recording local field potential and multiunit spiking activity while the subjects were presented with auditory looming and receding signals, we show here that auditory cortical activity was biased in magnitude toward looming versus receding stimuli. This directional preference was not attributable to the absolute intensity of the sounds nor can it be attributed to simple adaptation, because white noise stimuli with identical amplitude envelopes did not elicit the same pattern of responses. This asymmetrical representation of looming versus receding sounds in the lateral belt auditory cortex suggests that it is an important node in the neural network correlate of looming perception.

Exploring the extent and function of higher-order auditory cortex in rhesus monkeys

Just as cortical visual processing continues far beyond the boundaries of early visual areas, so too does cortical auditory processing continue far beyond the limits of early auditory areas. In passively listening rhesus monkeys examined with metabolic mapping techniques, cortical areas reactive to auditory stimulation were found to include the entire length of the superior temporal gyrus (STG) as well as several other regions within the temporal, parietal, and frontal lobes. Comparison of these widespread activations with those from an analogous study in vision supports the notion that audition, like vision, is served by several cortical processing streams, each specialized for analyzing a different aspect of sensory input, such as stimulus quality, location, or motion. Exploration with different classes of acoustic stimuli demonstrated that most portions of STG show greater activation on the right than on the left regardless of stimulus class. However, there is a striking shift to left-hemisphere “dominance” during passive listening to species-specific vocalizations, though this reverse asymmetry is observed only in the region of temporal pole. The mechanism for this left temporal pole “dominance” appears to be suppression of the right temporal pole by the left hemisphere, as demonstrated by a comparison of the results in normal monkeys with those in split-brain monkeys.

Quantitative analysis of corticospinal projection from digit area of motor cortex of rhesus monkey

Quantitative analysis of corticospinal projection from digit area of motor cortex of rhesus monkey

Primate Area MST-l Is Involved in the Generation of Goal-Directed Eye and Hand Movements

The contributions of the middle superior temporal area (MST) in the posterior parietal cortex of rhesus monkeys to the generation of smooth-pursuit eye movements as well as the contributions to motion perception are well established. Here, we present the first experimental evidence that this area also contributes to the generation of goal-directed hand movements toward a moving target. This evidence is based on the outcome of intracortical microstimulation experiments and transient lesions by small injections of muscimol at identified sites within the lateral part of area MST (MST-l). When microstimulation was applied during the execution of smooth-pursuit eye movements, postsaccadic eye velocity in the direction of the preferred direction of the stimulated site increased significantly (in 93 of 136 sites tested). When microstimulation was applied during a hand movement trial, the hand movement was displaced significantly in the same direction (in 28 of 39 sites tested). When we lesioned area MST-l transiently by injections of muscimol, steady-state eye velocity was exclusively reduced for ipsiversive smooth-pursuit eye movements. In contrast, hand movements were displaced toward the contralateral side, irrespective of the direction of the moving target. Our results provide evidence that area MST-l is involved in the processing of moving targets and plays a role in the execution of smooth-pursuit eye movements as well as visually guided hand movements.