Area MST and heading perception in macaque monkeys

The macaque medial superior temporal area (MST) is proposed to be specialized for analyzing complex 'optic flow' information. Such space-varying motion patterns provide a rich source of information about self motion, scene structure and object shape. We report the performance of rhesus macaques on a two-alternative 'heading' task, in which they reported whether horizontally varying, simulated trajectories were to left or right of center. Monkeys were sensitive to small heading angles; thresholds averaged 1.5-3 degrees. Heading estimates were stable in the face of changing stimulus location and smooth pursuit eye movements. In addition, we tested the role of area MST in heading judgements by electrically activating columns of neurons in this area while the monkeys performed the heading task. Activation of MST frequently affected performance, usually causing choice biases. These induced biases were often large and usually concordant with the preference of the neurons being activated. In addition, the induced biases were often larger in the presence of smooth pursuit eye movements. These results favor the hypothesis that MST is involved in recovering self-motion direction from optic flow cues and in the process by which heading perception is compensated for ongoing eye movements.     

Expression arrays for macaque monkeys

Non-human primates (NHPs) serve as excellent models for transplantation research. Gene expression profiling has been shown to be an important tool in understanding many aspects of transplantation. The many advantages of using expression arrays, and the unavailability of monkey specific arrays (until recently), has prompted some investigators to use human expression arrays with samples from rhesus macaques (Macaca mulatta). This review examines attempts to use human expression arrays with monkey samples and the recent development of monkey-specific expression arrays.     

Long-range clustered connections within extrastriate visual area V5/MT of the rhesus macaque

Visual area V5/MT in the rhesus macaque has a distinct functional organization, where neurons with specific preferences for direction of motion and binocular disparity are co-organized in columns or clusters. Here, we analyze the pattern of intrinsic connectivity within cortical area V5/MT in both parasagittal sections of the intact brain and tangential sections from flatmounted cortex using small injections of the retrograde tracer cholera toxin subunit b. Labeled cells were predominantly found in cortical layers 2, 3, and 6. Going along the cortical layers, labeled cells were concentrated in regularly spaced clusters. The clusters nearest to the injection site were approximately 2 mm from its center. In flatmounted cortex, along the dorsoventral axis of V5/MT, we identified further clusters of labeled cells up to 10 mm from the injection site. Quantitative analysis of parasagittal sections estimated average cluster spacing at 2.2 mm; in cortical flatmounts, spacing was 2.3 mm measured radially from the injection site. The results suggest a regular pattern of intrinsic connectivity within V5/MT, which is consistent with connectivity between sites with a common preference for both direction of motion and binocular depth. The long-range connections can potentially account for the large suppressive surrounds of V5/MT neurons.     

Frontal-temporal disconnection abolishes object discrimination learning set in macaque monkeys

Two previous studies have shown that frontal-temporal disconnection in monkeys, produced by unilateral ablation of frontal cortex in one hemisphere and of visual inferior temporal cortex in the opposite hemisphere is entirely without effect on visual object-reward association learning in concurrent discrimination tasks. This is a surprising finding in light of the severe impairments that follow frontal-temporal disconnection in many other tests of visual learning and memory, including delayed matching-to-sample and several conditional learning tasks. To explore the limits of this preserved object-reward association learning, we trained monkeys on visual object discrimination learning set (DLS) prior to frontal-temporal disconnection. As a result of training with single object-reward associations, the monkeys acquired a proficient learning set, evidenced by the rapid learning of new single object-reward association problems. This rapid learning was not affected by unilateral ablations of either inferior temporal cortex alone or frontal cortex alone but was severely impaired after final surgery to complete the disconnection. Moreover, each individual monkey now learned single object-reward association problems at the slow rate at which that individual had learned such problems before the formation of learning set. This result shows that frontal-temporal disconnection abolishes visual learning set.     

The insula of Reil revisited: multiarchitectonic organization in macaque monkeys

The insula of Reil represents a large cortical territory buried in the depth of the lateral sulcus and subdivided into 3 major cytoarchitectonic domains: agranular, dysgranular, and granular. The present study aimed at reinvestigating the architectonic organization of the monkey's insula using multiple immunohistochemical stainings (parvalbumin, PV; nonphosphorylated neurofilament protein, with SMI-32; acetylcholinesterase, AChE) in addition to Nissl and myelin. According to changes in density and laminar distributions of the neurochemical markers, several zones were defined and related to 8 cytoarchitectonic subdivisions (Ia1-Ia2/Id1-Id3/Ig1-Ig2/G). Comparison of the different patterns of staining on unfolded maps of the insula revealed: 1) parallel ventral to dorsal gradients of increasing myelin, PV- and AChE-containing fibers in middle layers, and of SMI-32 pyramidal neurons in supragranular layers, with merging of dorsal and ventral high-density bands in posterior insula, 2) definition of an insula "proper" restricted to two-thirds of the "morphological" insula (as bounded by the limiting sulcus) and characterized most notably by lower PV, and 3) the insula proper is bordered along its dorsal, posterodorsal, and posteroventral margin by a strip of cortex extending beyond the limits of the morphological insula and continuous architectonically with frontoparietal and temporal opercular areas related to gustatory, somatosensory, and auditory modalities.     

Serial memory strategies in macaque monkeys: behavioral and theoretical aspects

Serial memory is the ability to encode and retrieve a list of items in their correct temporal order. To study nonverbal strategies involved in serial memory, we trained four macaque monkeys on a novel delayed sequence-recall task and analysed the mechanisms underlying their performance in terms of a neural network model. Thirty fractal images, divided into 10 triplets, were presented repeatedly in fixed temporal order. On each trial the monkeys viewed three sequentially presented sample images, followed by a test stimulus consisting of the same triplet of images and a distractor image (chosen randomly from the remaining 27). The task was to touch the three images in their original order, avoiding the distractor. The monkeys' most common error was touching the distractor when it had the same ordinal position (in its own triplet) as the correct image. This finding suggests that monkeys naturally categorize images by their ordinal number. Additional, secondary strategies were eventually used to avoid distractor images. These include memory of the sample images (working memory) and associations between triplet members. Further direct evidence for ordinal number categorization was provided by a transfer of learning to untrained images of the same ordinal category, following reassignment of image categories within each triplet. We propose a generic three-tier neuronal framework that can explain the components and complex set of characteristics of the observed behavior. This framework, with its intermediate level representing ordinal categories, can also explain the transfer of learning following category reassignment.     

Age-related dendritic and spine changes in corticocortically projecting neurons in macaque monkeys

Alterations in neuronal morphology occur in primate cerebral cortex during normal aging, vary depending on the neuronal type, region and cortical layer, and have been related to memory and cognitive impairment. We analyzed how such changes affect a specific subpopulation of cortical neurons forming long corticocortical projections from the superior temporal cortex to prefrontal area 46. These neurons were identified by retrograde transport in young and old macaque monkeys. Dendritic arbors of retrogradely labeled neurons were visualized in brain slices by intracellular injection of Lucifer Yellow, and reconstructed three-dimensionally using computer-assisted morphometry. Total dendritic length, numbers of segments, numbers of spines, and spine density were analyzed in layer III pyramidal neurons forming the projection considered. Sholl analysis was used to determine potential age-related changes in dendritic complexity. We observed statistically significant age-related decreases in spine numbers and density on both apical and basal dendritic arbors in these projection neurons. On apical dendrites, changes in spine numbers occurred mainly on the proximal dendrites but spine density decreased uniformly among the different branch orders. On basal dendrites, spine numbers and density decreased preferentially on distal branches. Regressive dendritic changes were observed only in one particular portion of the apical dendrites, with the general dendritic morphology and extent otherwise unaffected by aging. In view of the fact that there is no neuronal loss in neocortex and hippocampus in old macaque monkeys, it is possible that the memory and cognitive decline known to occur in these animals is related to rather subtle changes in the morphological and molecular integrity of neurons subserving identifiable neocortical association circuits that play a critical role in cognition.     

Coagulation biomarkers in healthy male Cynomolgus macaque monkeys (Macaca fascicularis)

We designed this study to define reference values of the cynomolgus monkey coagulation system, as the normal range of values has not been established. Measurement of coagulation function was determined by testing plasma samples from 30 healthy male cynomolgus monkeys. Prothrombin time (PT), PT activity, PT international normalized ratio (INR), activated prothrombin time (aPTT), antithrombin III activity, factor II, V, VII, VIII, IX, X, XI, and XII, protein C activity, protein S activity, and d‐dimer were measured using standardized techniques. Mean age and body weight were 69.5 ± 11.8 months and 5.3 ± 0.8 kg, respectively. The mean PT, PT activity, PT INR, aPTT, and antithrombin III activities were 11.72 seconds (95% CI = 10.55‐12.88), 143.4% (95% CI = 102.0‐184.9), 0.85 (95% CI = 0.74‐0.96), 28.2 seconds (95% CI = 23.24‐33.09), and 99.7% (95% CI = 79.2‐120.3), respectively. The mean activities of factors II, V, VII, VIII, IX, X, XI, and XII were 110.2% (95% CI = 88.8‐131.5), 134.1% (95% CI = 73.0‐195.2), 318.9% (95% CI = 185.0‐452.9) 160.2% (95% CI = 96.9‐261.3), 38.0% (95% CI = 20.9‐55.1), 85.7% (95% CI = 61.4‐110.0), 155.0% (95% CI = 81.4‐228.6), and 353.7% (95% CI = 246.7‐460.6), respectively. The mean activities of protein C and protein S were 195.7% (95% CI = 133.4‐258.0) and 122.7% (95% CI = 83.2‐162.3), respectively. The mean level of d‐dimer was 1.80 μg/mL (95% CI = 0.27‐3.33). Factors V (P = 0.008), IX (P = 0.002), and XI (P = 0.002), and protein S activity (P = 0.025) were positively correlated with age. Our study presented the baseline values of coagulation biomarkers of cynomolgus monkeys. Despite the similarity to previous published studies, more data are required to elucidate the age effect on coagulation biomarkers.     

Functional anatomy and interaction of fast and slow visual pathways in macaque monkeys

We measured the timing, areal distribution, and laminar profile of fast, wavelength-insensitive and slower, wavelength-sensitive responses in V1 and extrastriate areas, using laminar current-source density analysis in awake macaque monkeys. There were 3 main findings. 1) We confirmed previously reported significant ventral-dorsal stream latency lags at the level of V4 (V4 mean = 38.7 ms vs. middle temporal mean = 26.9 ms) and inferotemporal cortex (IT mean = 43.4 ms vs. dorsal bank of the superior temporal sulcus mean = 33.9 ms). 2) We found that wavelength-sensitive inputs in areas V1, V4, and IT lagged the wavelength-insensitive responses by significant margins; this lag increased over successive levels of the system. 3) We found that laminar activation profiles in V4 and IT were inconsistent with "feedforward" input through the ascending ventral cortical pathway; the likely alternative input routes include both lateral inputs from the dorsal stream and direct inputs from nonspecific thalamic neurons. These findings support a "Framing" Model of ventral stream visual processing in which rapidly conducted inputs, mediated by one or more accessory pathways, modulate the processing of more slowly conducted feedforward inputs.     

Non-uniformity of neocortex: areal heterogeneity of NADPH-diaphorase reactive neurons in adult macaque monkeys

We have examined the distribution of cortical neurons in adult monkey cortex which stain for nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d), an enzyme which is involved in the synthesis of nitric oxide. In order to compare distributions across areas we employed a cortical unit defined as the radial column, which refers to the volume of cortex below 1 mm(2) of cortical surface. Numbers of labeled neurons per radial column generate areal density measurements either for the full thickness of the cortex or for individual layers. Measurements were made in six cortical regions (areas V1, V2, STS, auditory cortex, area 4 and area 6). NADPH-d stains nonpyramidal neurons which can be divided into two major groups. Type 1 neurons have large soma diameters, stain densely for NADPH-d and show few morphological variations both within and across areas. Type 2 neurons have small somata and short processes, and can be subdivided on the basis of soma size into dense and light staining categories. Both subcategories of type 2 neurons show significant areal variations in size. In each cortical area the majority of type 1 neurons are located in the white matter. Areal densities of type 1 neurons are minimal in areas V1 and V2, and twice as dense in the frontal cortex. Pairwise comparisons of areal densities among the six areas examined show that in a radial column throughout the full thickness of cortex, areas differ significantly from each other in 12/15 comparisons. Consideration of individual layers shows significant differences in 13/15 comparisons. Type 2 neurons are exclusively located in the cortical gray matter, and in all areas are considerably more numerous than type 1 neurons. Area V1 is unique it that it has up to three times the areal density found in any other cortical area. With reference to published laminar cell density counts our results show that the percentage of labeled NADPH-d neurons in individual layers of area V1 are significantly higher than in the other areas. The laminar distributions of type 1 and type 2 neurons show that each area has a unique profile of NADPH-d expression. The modular or columnar organization of the cortex, also referred to as the radial column hypothesis, is important for understanding both the development and function of the cortex. The present results show that radial columns in individual cortical areas possess distinctive patterns of NADPH-d expression. This important degree of areal heterogeneity of NADPH-d neurons has far reaching implications for both the development and functions of neocortical areas.     

Neuronal responses in rostral trigeminal brain-stem nuclei of macaque monkeys after chronic trigeminal tractotomy

Unilateral trigeminal tractotomy was carried out at the level of the obex, just rostral to the subnucleus caudalis, in five young adult Macaca fascicularis monkeys. The animals had been trained previously to perform a behavioral shock avoidance task in response to electrical stimulation of dental pulp and facial skin. Tractotomy produced an elevation in the stimulus strength which elicited escape behavior when facial skin was stimulated but not when the tooth pulp was stimulated. Unit activity, evoked by electrical stimulation of the tooth pulp and facial skin as well as innocuous and noxious mechanical stimulation of orofacial regions, was recorded from neurons in the trigeminal main sensory nucleus and the subnuclei oralis and interpolaris of the spinal nucleus 8 to 12 weeks after tractotomy. Primary afferent input to these nuclei is unaffected by the tractotomy which is located more caudally. The tractotomy interrupts primary afferent input into the trigeminal nucleus caudalis and also intranuclear connections between caudalis and the more rostral nuclei. Forty-one units contralateral and 47 ipsilateral to the tractotomy were studied. Thirty-six of the units responded only to low-threshold mechanical or electrical stimulation of orofacial zones, 46 were responsive to innocuous mechanical and electrical stimulation of orofacial zones and also to electrical stimulation of the dental pulp. Six units responded only to dental pulp stimulation. No statistically significant differences between the populations of neurons ipsilateral and contralateral to the tractotomies were found relating to the size or location of the peripheral receptive fields, latencies, thresholds, mean firing densities, or responsiveness to the various forms of stimulation. The behavioral results suggest that trigeminal relay neurons rostral to the obex are able to signal dental pain sensation, and the physiological studies confirm that the firing of such neurons is unaffected by tractotomy. The physiological studies demonstrate that the firing patterns of relay neurons activated by natural and electrical cutaneous facial stimuli and which are located in trigeminal brain-stem nuclei rostral to the obex are also not affected by tractotomy. The cutaneous facial analgesia observed after tractotomy thus appears to be due to deafferentation of relay neurons in trigeminal nucleus caudalis rather than to alterations in coding patterns in rostrally located trigeminal neurons due to interruption of the intratrigeminal pathway between the caudal and rostral nuclear groups.     

Histological effects of intraputaminal infusion of glial cell line-derived neurotrophic factor in Parkinson disease model macaque monkeys

Glial cell line-derived neurotrophic factor (GDNF) is a potent neuroprotection and regeneration molecule for dopamine neurons in the substantia nigra. A recent clinical study showed that intraputaminal infusions of GDNF restored the striatal dopaminergic function, resulting in improvement in patients with Parkinson disease. To investigate the efficacy and the safety of this treatment, the histological changes associated with intraputaminal GDNF infusions were investigated in non-human primate models of Parkinson disease. Two types of Parkinson disease model were constructed: unilateral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) into the internal carotid artery to induce hemiparkinsonism and intermittent systemic injection to induce Parkinson disease. GDNF (50 microg) was infused into the putamen on the day of the first MPTP treatment and 4 weeks later. The monkey brains were examined by immunohistochemistry 2-4 weeks after the second GDNF infusion. Losses of the nigral dopamine neurons were mild (30-50% loss) on the side of GDNF infusion, and moderate (approximately 70% loss) on the side of vehicle infusion in the Parkinson disease model. The dopamine fibers were thick and dense in the striatum around the GDNF infusion sites. Both GDNF- and vehicle-treated monkeys of the hemiparkinsonian model showed severe decrease of dopamine neurons to 10% of the intact side. Although reactive astrocytes proliferated around the GDNF infusion sites, the densities of striatal neurons involving GABAergic and cholinergic neurons were not affected. Intraputaminal infusions of GDNF have beneficial effects in parkinsonian monkeys, but dose control is required according to the severity of the disease. The specificity for dopamine neurons is quite high and there are no serious histological changes.     

Neuronal responses in visual area V2 (V2) of macaque monkeys with strabismic amblyopia

Amblyopia, a developmental disorder of spatial vision, is thought to result from a cascade of cortical deficits over several processing stages beginning at the primary visual cortex (V1). However, beyond V1, little is known about how cortical development limits the visual performance of amblyopic primates. We quantitatively analyzed the monocular and binocular responses of V1 and V2 neurons in a group of strabismic monkeys exhibiting varying depths of amblyopia. Unlike in V1, the relative effectiveness of the affected eye to drive V2 neurons was drastically reduced in the amblyopic monkeys. The spatial resolution and the orientation bias of V2, but not V1, neurons were subnormal for the affected eyes. Binocular suppression was robust in both cortical areas, and the magnitude of suppression in individual monkeys was correlated with the depth of their amblyopia. These results suggest that the reduced functional connections beyond V1 and the subnormal spatial filter properties of V2 neurons might have substantially limited the sensitivity of the amblyopic eyes and that interocular suppression was likely to have played a key role in the observed alterations of V2 responses and the emergence of amblyopia.     

Differences in cortical serotonergic innervation among humans, chimpanzees, and macaque monkeys: a comparative study

In this study, we assess the possibility that the evolution of human intellectual capacities was supported by changes in the supply of serotonin to the frontal cortex. To this end, quantitative comparative analyses were performed among humans, chimpanzees, and macaques. Immunohistochemical methods were used to visualize serotonin transporter-immunoreactive (SERT-ir) axons within the cerebral cortex. Areas 9 and 32 were chosen for evaluation due to their roles in working memory and theory of mind, respectively. Primary motor cortex was also evaluated because it is not associated with higher cognitive functions. The findings revealed that humans do not display a quantitative increase in serotonin innervation. However, the results indicated region- and layer-specific differences among species in serotonergic innervation pattern. Compared with macaques, humans and chimpanzees together displayed a greater density of SERT-ir axons relative to neuron density in layers V/VI. This change was detected in cortical areas 9 and 32, but not in primary motor cortex. Further, morphological specializations, coils of axons, were observed in humans and chimpanzees that were absent in macaques. These features may represent a greater capacity for cortical plasticity exclusive to hominoids. Taken together, these results indicate a significant reorganization of cortical serotonergic transmission in humans and chimpanzees.     

Laminar distribution of neurons projecting from area V1 to V2 in macaque and squirrel monkeys.

The present study reevaluates the sublaminar distribution and cellular morphology of neurons projecting from area V1 to V2. Observations are based on retrogradely transported HRP, Phaseolus vulgaris leucoagglutinin (PHA-L), or biocytin after injections made in area V2 of three squirrel monkeys and eight macaques. With material prepared in the coronal or horizontal tissue planes, it is clear that projection neurons in V1, in both species, are concentrated in layer 4B and in a single band (150-250 microns wide) restricted to the upper subdivision of layer 3 (layer 3A). There are also labeled neurons, but fewer in number, in layers 3B and 4A, and occasionally in layers 2 and 5. Golgi-like labeling from PHA-L or biocytin confirmed that most of the projection neurons in layer 3A are pyramidal. As reported for several other corticocortical systems, these pyramidal neurons differ in soma size, soma shape, and dendritic geometry. These results emphasize the complex organization of layer 3, and the distributed nature of efferent projections from area V1. Given the selective connectivity of vertical interlaminar networks, these results specifically suggest that information transmitted to area V2 from neurons in layer 3A reflects more highly processed, convergent input than that originating from either layer 3B or 4B.     

Topographic and laminar maturation of striate cortex in early postnatal marmoset monkeys, as revealed by neurofilament immunohistochemistry

The maturation of pyramidal neurons in the primary visual cortex (V1) of marmoset monkeys was investigated using an antibody (SMI-32) to non-phosphorylated neurofilament protein (NNF). Analysis of animals aged between birth and postnatal day 91 (PD 91, which corresponds approximately to the peak of synaptogenesis in this species) revealed discrete changes in both the laminar and the areal distribution of NNF. At PD 0, the upper part of layer 6 contained darkly labelled neurons and associated neuropil, including axons. In this layer a centroperipheral gradient, with more labelled cells in the foveal representation, was apparent at PD 0. This topographic gradient gradually disappeared, and by PD 91 a similar density of labelled layer 6 cells was observed throughout V1. Labelled cells were not apparent in layer 3C until PD 7, and were not distributed according to a topographic gradient. Labelled cells were first observed in layer 3B(alpha) at PD 28, when they formed a centroperipheral gradient similar to that seen in layer 6. This gradient was still evident in an adult animal. These results demonstrate an inside-out profile of postnatal cortical development, with the topographic pattern of maturation of V1 mimicking the centroperipheral gradient of maturation in the retina.     

Maps of complex motion selectivity in the superior temporal cortex of the alert macaque monkey: a double-label 2-deoxyglucose study

The superior temporal sulcus (STS) of the macaque monkey contains multiple visual areas. Many neurons within these regions respond selectively to motion direction and to more complex motion patterns, such as expansion, contraction and rotation. Single-unit recording and optical recording studies in MT/MST suggest that cells with similar tuning properties are clustered into columns extending through multiple cortical layers. In this study, we used a double-label 2-deoxyglucose technique in awake, behaving macaque monkeys to clarify this functional organization. This technique allowed us to label, in a single animal, two populations of neurons responding to two different visual stimuli. In one monkey we compared expansion with contraction; in a second monkey we compared expansion with clockwise rotation. Within the STS we found a patchy arrangement of cortical columns with alternating stimulus selectivity: columns of neurons preferring expansion versus contraction were more widely separated than those selective for expansion versus rotation. This mosaic of interdigitating columns on the floor and posterior bank of the STS included area MT and some neighboring regions of cortex, perhaps including area MST.      

Spinal degenerative disk disease (DDD) in female macaque monkeys: epidemiology and comparison with women.

Spinal degenerative disk disease (DDD) in a radiographic, cross-sectional sample of 192 female macaque monkeys, approximately 5-30 years old, is described. The presence and extent of disk space narrowing (DSN) and anterior osteophytosis were assessed with reference to age, average lifetime body mass. and distribution within the thoracolumbar spine. Age was a strong correlate of disk narrowing and osteophytosis, with early signs appearing at equivalent ages in both species and increasing in prevalence thereafter. Macaques showed a far greater prevalence of DDD, especially in the oldest age group, than has been reported in the human data. Body mass was associated with disk narrowing in the macaque, but not with osteophytosis. The two species differed little in the pattern of distribution of DDD along the spine. Our results suggest that bipedality is not the singular, or even the most important, biomechanical factor in the development of human DDD. Rather, others shared postural regimes, e.g., sitting, may be responsible for the onset and progression of DDD in both species. The macaque model could substantially add to the understanding and, potentially, treatment of this oftentimes debilitating condition.     

Radial growth and function of the forearm after excision of the radial head. A study of growing macaque monkeys

In five immature macaque monkeys, the right radial head was excised and the left forearm served as a control. Growth of each radius, ulna, and proximal and distal physis was followed for eight years. Total radial growth was slightly less on the side that was operated on than it was on the control side. After excision of the radial head, 95 per cent of radial growth came from the distal physis, compared with 71 per cent on the control side. A regenerated radial head, which had an irregular surface of fibrocartilaginous tissue, accounted for the remainder of growth on the side that had been operated on. Incongruous contact of articular surfaces resulted in degenerative changes in the capitellum. The arms that had been operated on were left with a flexion contracture that was an average of 12 degrees greater than that of the normal elbows, and they had a carrying angle that was an average of 6 degrees greater than that on the normal side. The arc of pronation and supination was decreased for the forearms that had been operated on, but motion of the wrist was unaffected. In our study, excision of the radial head in growing monkeys resulted in minimum radial shortening, slight deformity of the elbow, and moderate impairment of rotation of the forearm.