In this study, we assessed the distribution of cortical neurons immunoreactive for tyrosine hydroxylase (TH) in prefrontal cortical regions of humans and nonhuman primate species. Immunohistochemical methods were used to visualize TH-immunoreactive (TH-ir) neurons in areas 9 (dorsolateral prefrontal cortex) and 32 (anterior paracingulate cortex). The study sample included humans, great apes (chimpanzee, bonobo, gorilla, orangutan), one lesser ape (siamang), and Old World monkeys (golden guenon, patas monkey, olive baboon, moor macaque, black and white colobus, and François' langur). The percentage of neurons within the cortex expressing TH was quantified using computer-assisted stereology. TH-ir neurons were present in layers V and VI and the subjacent white matter in each of the Old World monkey species, the siamang, and in humans. TH-ir cells were also occasionally observed in layer III of human, siamang, baboon, colobus, and François' langur cortex. Cortical cells expressing TH were notably absent in each of the great ape species. Quantitative analyses did not reveal a phylogenetic trend for percentage of TH-ir neurons in these cortical areas among species. Interestingly, humans and monkey species exhibited a bilaminar pattern of TH-ir axon distributions within prefrontal regions, with layers I-II and layers V-VI having the densest contingent of axons. In contrast, the great apes had a different pattern of laminar innervation, with a remarkably denser distribution of TH-ir axons within layer III. It is possible that the catecholaminergic afferent input to layer III in chimpanzees and other great apes covaries with loss of TH-ir cells within the cortical mantle.
dopamine; area 9; area 32; human evolution
We recently identified the thalamic dopaminergic system in the human and macaque monkey brains, and, based on earlier reports on the paucity of dopamine in the rat thalamus, hypothesized that this dopaminergic system was particularly developed in primates. Here we test this hypothesis using immunohistochemistry against the dopamine transporter (DAT) in adult macaque and rat brains. The extent and density of DAT-immunoreactive (-ir) axons were remarkably greater in the macaque dorsal thalamus, where the mediodorsal association nucleus and the ventral motor nuclei held the densest immunolabeling. In contrast, sparse DAT immunolabeling was present in the rat dorsal thalamus; it was mainly located in the mediodorsal, paraventricular, ventral medial, and ventral lateral nuclei. The reticular nucleus, zona incerta, and lateral habenular nucleus held numerous DAT-ir axons in both species. Ultrastructural analysis in the macaque mediodorsal nucleus revealed that thalamic interneurons are a main postsynaptic target of DAT-ir axons; this suggests that the marked expansion of the dopamine innervation in the primate in comparison to the rodent thalamus may be related to the presence of a sizable interneuron population in primates. We remark that it is important to be aware of brain species differences when using animal models of human brain disease.
dopamine; macaque; rat; species differences; thalamus
A comparison of the architecture of the human prefrontal cortex with that of the macaque monkey showed a very similar architectonic organization in these two primate species. There is no doubt that the prefrontal cortical areas of the human brain have undergone considerable development, but it is equally clear that the basic architectonic organization is the same in the two species. Thus, a comparative approach to the study of the functional organization of the primate prefrontal cortex is more likely to reveal the essential aspects of the various complex control processes that are the domain of frontal function. The lateral frontal cortex appears to be functionally organized along both a rostral–caudal axis and a dorsal–ventral axis. The most caudal frontal region, the motor region on the precentral gyrus, is involved in fine motor control and direct sensorimotor mappings, whereas the caudal lateral prefrontal region is involved in higher order control processes that regulate the selection among multiple competing responses and stimuli based on conditional operations. Further rostrally, the mid-lateral prefrontal region plays an even more abstract role in cognitive control. The mid-lateral prefrontal region is itself organized along a dorsal–ventral axis of organization, with the mid-dorsolateral prefrontal cortex being involved in the monitoring of information in working memory and the mid-ventrolateral prefrontal region being involved in active judgments on information held in posterior cortical association regions that are necessary for active retrieval and encoding of information.
prefrontal cortex; frontal cortex; cytoarchitecture; monkey
Functional and neuroanatomical asymmetries are an important characteristic of the human brain. The evolution of such specializations in the human cortex has provoked great interest in primate brain evolution. Most research on cortical sulci has revolved around linear measurements, which represent only one dimension of sulci organization. Here, we used a software program (BrainVISA) to quantify asymmetries in cortical depth and surface area from magnetic resonance images in a sample of 127 chimpanzees and 49 macaques. Population brain asymmetries were determined from 11 sulci in chimpanzees and seven sulci in macaques. Sulci were taken from the frontal, temporal, parietal, and occipital lobes. Population-level asymmetries were evident in chimpanzees for several sulci, including the fronto-orbital, superior precentral, and sylvian fissure sulci. The macaque population did not reveal significant population-level asymmetries, except for surface area of the superior temporal sulcus. The overall results are discussed within the context of the evolution of higher order cognition and motor functions.
Chimpanzee; Brain asymmetry; Sulci morphology
The most ubiquitous neuron in the cerebral cortex, the pyramidal cell, is characterized by markedly different dendritic structure among different cortical areas. The complex pyramidal cell phenotype in granular prefrontal cortex (gPFC) of higher primates endows specific biophysical properties and patterns of connectivity, which differ from those in other cortical regions. However, within the gPFC, data have been sampled from only a select few cortical areas. The gPFC of species such as human and macaque monkey includes more than 10 cortical areas. It remains unknown as to what degree pyramidal cell structure may vary among these cortical areas. Here we undertook a survey of pyramidal cells in the dorsolateral, medial, and orbital gPFC of cercopithecid primates. We found marked heterogeneity in pyramidal cell structure within and between these regions. Moreover, trends for gradients in neuronal complexity varied among species. As the structure of neurons determines their computational abilities, memory storage capacity and connectivity, we propose that these specializations in the pyramidal cell phenotype are an important determinant of species-specific executive cortical functions in primates.
macaque; baboon; human; guenon; spine; primate; cognition; connectivity
Dopaminergic innervation of the frontal cortex in adults is important for a variety of cognitive functions and behavioral control. However, the role of frontal cortical dopaminergic innervation for neurobehavioral development has received little attention. In the current study, rats were given dopaminergic lesions in the frontal cortex with local micro-infusions of 6-hydroxydopamine (6-OHDA) at one week of age. The long-term behavioral effects of neonatal frontal cortical 6-OHDA lesions were assessed in a series of tests of locomotor activity, spatial learning and memory, and intravenous (IV) nicotine self-administration. In addition, neurochemical indices were assessed with tissue homogenization and HPLC in the frontal cortex, striatum, and nucleus accumbens of neonatal and adult rats after neonatal 6-OHDA lesions. In neonatal rats, frontal 6-OHDA lesions as intended caused a significant reduction in frontal cortical dopamine without effects on frontal cortical serotonin and norepinephrine. The frontal cortical dopamine depletion increased serotonin and norepinephrine levels in the nucleus accumbens. Locomotor activity assessment during adulthood in the Figure-8 maze showed that lesioned male rats were hyperactive relative to sham lesioned males. Locomotor activity of female rats was not significantly affected by the neonatal frontal 6-OHDA lesion. Learning and memory in the radial-arm maze was also affected by neonatal frontal 6-OHDA lesions. There was a general trend toward impaired performance in early maze acquisition and a paradoxical improvement at the end of cognitive testing. Nicotine self-administration showed significant lesion × sex interactions. The sex difference in nicotine self-administration with females self-administering significantly more nicotine than males was reversed by neonatal 6-OHDA frontal cortical lesions. Neurochemical studies in adult rats showed that frontal cortical dopamine and DOPAC levels significantly correlated with nicotine self-administration in the 6-OHDA lesioned animals but not in the controls. Frontal cortical serotonin and 5HIAA showed inverse correlations with nicotine self-administration in the 6-OHDA lesioned animals but not in the controls. These results show that interfering with normal dopamine innervation of the frontal cortex during early postnatal development has persisting behavioral effects, which are sex-specific.
6-OHDA; radial-arm maze; self-administration; dopamine; serotonin; nucleus accumbens; striatum
The locus coeruleus (LC) is a dense cluster of neurons that projects axons throughout the neuroaxis and is located in the rostral pontine tegmentum extending from the level of the inferior colliculus to the motor nucleus of the trigeminal nerve. LC neurons are lost in the course of several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. In this study, we used Nissl staining and tyrosine hydroxylase (TH) immunoreactivity to compare the human LC with that of closely related primate species, including great and lesser apes, and macaque monkeys. TH catalyzes the initial and rate-limiting step in catecholamine biosynthesis. The number of TH-immunoreactive (TH-ir) neurons was estimated in each species using stereologic methods. In the LC of humans, the mean total number of TH-ir neurons was significantly higher compared to the other primates. Because the total number of TH-ir neurons in the LC was highly correlated with the species mean volume of the medulla oblongata, cerebellum, and neocortical gray matter, we conclude that much of the observed phylogenetic variation can be explained by anatomical scaling. Notably, the total number of LC neurons in humans was most closely predicted by the nonhuman allometric scaling relationship relative to medulla size, whereas the number of LC neurons in humans was considerably lower than predicted according to neocortex and cerebellum volume.
Locus coeruleus; non-human primates; hominids; tyrosine hydroxylase; stereology
Nigrostriatal reserve refers to the threshold of neuronal injury to dopaminergic cell bodies and their terminal fields required to produce parkinsonian motor deficits. Inferential studies have estimated striatal dopamine reserve to be at least 70%. Knowledge of this threshold is critical for planning interventions to prevent symptom onset or reverse nigrostriatal injury sufficient to restore function in people with Parkinson disease. In this study, we determine the nigrostriatal reserve in a non-human primate model that mimics the motor manifestations of Parkinson disease.
Fifteen macaque monkeys received unilateral randomized doses of the selective dopaminergic neuronal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We compared blinded validated ratings of parkinsonism to in vitro measures of striatal dopamine and unbiased stereologic counts of nigral neurons after tyrosine hydroxylase immunostaining.
The percent of residual cell counts in lesioned nigra correlated linearly with the parkinsonism score at 2 months (r = −0.87, p <0.0001). The parkinsonism score at 2 months correlated linearly with the percent residual striatal dopamine (r = −0.77, p = 0.016) followed by a flooring effect once nigral cell loss exceeded 50%. A reduction of about 14 to 23% of nigral neuron counts or 14 to 37% of striatal dopamine was sufficient to induce mild parkinsonism.
The nigral cell body and terminal field injury needed to produce parkinsonian motor manifestations may be much less than previously thought.
Parkinsonism; MPTP; substantia nigra; dopamine
Vesicular glutamate transporters reuptake glutamate into synaptic vesicles at excitatory synapses. Vesicular glutamate transporter 2 (VGLUT2) is localized in the cortical terminals of neuronal somas located in the main sensory nuclei of the thalamus. Thus, immunolabeling of cortex with antibodies to VGLUT2 can reveal geniculostriate terminal distributions in species in which connectivity cannot be studied with tract-tracing techniques, permitting broader comparative studies of cortical specializations. Here, we used VGLUT2 immunohistochemistry to compare the organization of geniculostriate afferents in primary visual cortex in hominid primates (humans, chimpanzees, orangutan), Old World monkeys (rhesus macaques, vervets), and New World monkeys (squirrel monkeys). The New World and Old World monkeys had a broad, dense band of terminal-like labeling in cortical layer 4C, a narrow band of labeling in layer 4A, and additional labeling in layers 2/3 and 6, consistent with results from conventional tract-tracing studies in these species. By contrast, although the hominid primates had a prominent layer 4C band, labeling of layer 4A was sparse or absent. Label was also present in layers 2/3 and 6, although labeling of layer 6 in hominids was weaker and possibly more individually variable than in Old World and New World monkeys. These findings are consistent with previous observations from cytochrome oxidase histochemistry and a very small number of connectivity studies, suggesting that the projection from the parvocellular layers of the lateral geniculate nucleus to layer 4A were strongly reduced or eliminated in humans and apes following their evolutionary divergence from the other anthropoid primates.
Vesicular glutamate transporter; Area 17; Primary visual cortex; Architectonics; Primate; Human; Blobs; Evolution; Chimpanzees
An unprecedented detailed analysis of ventrolateral frontal cortical circuitry in Broca's area of the non-human primate brain clarifies the functional pathways permitting interaction between posterior cortical areas and the anterior language zone, providing important clues about the evolution of language.
The homologues of the two distinct architectonic areas 44 and 45 that constitute the anterior language zone (Broca's region) in the human ventrolateral frontal lobe were recently established in the macaque monkey. Although we know that the inferior parietal lobule and the lateral temporal cortical region project to the ventrolateral frontal cortex, we do not know which of the several cortical areas found in those regions project to the homologues of Broca's region in the macaque monkey and by means of which white matter pathways. We have used the autoradiographic method, which permits the establishment of the cortical area from which axons originate (i.e., the site of injection), the precise course of the axons in the white matter, and their termination within particular cortical areas, to examine the parietal and temporal connections to area 44 and the two subdivisions of area 45 (i.e., areas 45A and 45B). The results demonstrated a ventral temporo-frontal stream of fibers that originate from various auditory, multisensory, and visual association cortical areas in the intermediate superolateral temporal region. These axons course via the extreme capsule and target most strongly area 45 with a more modest termination in area 44. By contrast, a dorsal stream of axons that originate from various cortical areas in the inferior parietal lobule and the adjacent caudal superior temporal sulcus was found to target both areas 44 and 45. These axons course in the superior longitudinal fasciculus, with some axons originating from the ventral inferior parietal lobule and the adjacent superior temporal sulcus arching and forming a simple arcuate fasciculus. The cortex of the most rostral part of the inferior parietal lobule is preferentially linked with the ventral premotor cortex (ventral area 6) that controls the orofacial musculature. The cortex of the intermediate part of the inferior parietal lobule is linked with both areas 44 and 45. These findings demonstrate the posterior parietal and temporal connections of the ventrolateral frontal areas, which, in the left hemisphere of the human brain, were adapted for various aspects of language production. These precursor circuits that are found in the nonlinguistic, nonhuman, primate brain also exist in the human brain. The possible reasons why these areas were adapted for language use in the human brain are discussed. The results throw new light on the prelinguistic precursor circuitry of Broca's region and help understand functional interactions between Broca's ventrolateral frontal region and posterior parietal and temporal association areas.
Two distinct cortical areas in the frontal lobe of the human brain, known as Broca's region, are involved with language production. This region has also been shown to exist in nonhuman primates. In this study, we explored the precise neural connectivity of Broca's region in macaque monkeys using the autoradiographic method to achieve a level of detail impossible in the human brain. We identified two major streams of connections feeding into Broca's area: a ventral stream from the temporal region, which includes areas processing auditory, multisensory, and visual information and a dorsal stream originating from the inferior parietal lobule and the adjacent superior temporal sulcus. Our detailed connectivity analysis illuminates the pathways via which posterior cortical areas can interact functionally with Broca's region, in addition to contributing to an understanding of the evolution of language. We suggest that a fundamental function of Broca's region is to retrieve information in a controlled strategic way from posterior cortical regions and to translate this information into action. This fundamental function was adapted during evolution of the left hemisphere of the human brain to serve language.
Adolescent cannabis use is associated with an increased risk of schizophrenia and with impairments in cognitive processes reliant on the circuitry of the dorsolateral prefrontal cortex (DLPFC). Additionally, maternal cannabis use is associated with cognitive dysfunction in offspring. The effects of cannabis are mediated by the cannabinoid 1 receptor (CB1R), which is present in high density in the primate DLPFC. In order to determine how developmental changes in CB1Rs might render DLPFC circuitry vulnerable to cannabis exposure, we examined the density and innervation patterns of CB1R-immunoreactive (IR) axons and the expression of CB1R mRNA in the DLPFC from 81 macaque monkeys, ranging in age from embryonic 82 days to 18 years. Overall CB1R immunoreactivity in the gray matter robustly increased during the perinatal period and achieved adult levels by 1 week postnatal. However, laminar analyses revealed that CB1R-IR axon density significantly decreased with age in layers 1–2 but significantly increased in layer 4, especially during adolescence. In contrast, CB1R mRNA levels were highest 1 week postnatal, declined over the next 2 months, and then remained unchanged into adulthood. These findings provide a potential substrate for discrete, age-dependent effects of cannabis exposure on the maturation of primate DLPFC circuitry.
cholecystokinin; GABA; interneurons; parvalbumin; schizophrenia
The midline and intralaminar thalamic nuclei (MITN), locus coeruleus (LC) and cingulate cortex contain nociceptive neurons. The MITN that project to cingulate cortex have a prominent innervation by norepinephrinergic axons primarily originating from the LC. The hypothesis explored in this study is that MITN neurons that project to cingulate cortex receive a disproportionately high LC input that may modulate nociceptive afferent flow into the forebrain. Ten cynomolgus monkeys were evaluated for dopamine-β hydroxylase (DBH) immunohistochemistry and, nuclei with moderate or high DBH activity were analyzed for intermediate neurofilament proteins, calbindin, and calretinin. Sections of all but DBH were thionin counterstained to assure precise localization in the mediodorsal and MITN and cytoarchitecture was analyzed with neuron-specific nuclear binding protein. Moderate-high levels of DBH-immunoreactive (ir) axons were generally associated with high densities of CB-ir and CR-ir neurons and low levels of neurofilament proteins. The paraventricular, superior centrolateral, limitans and central nuclei had relatively high and evenly distributed DBH, the magnocellular mediodorsal and paracentral nuclei had moderate DBH-ir, and other nuclei had an even and low level of activity. Some nuclei also have heterogeneities in DBH-ir that raised questions of functional segregation. The anterior multiformis part of the mediodorsal nucleus but not middle and caudal levels had high DBH activity. The posterior parafascicular nucleus (Pf) was heterogeneous with the lateral part having little DBH activity, while its medial division had most DBH-ir axons and its multiformis part had only a small number. These findings suggest that the LC may regulate nociceptive processing in the thalamus. The well established role of cingulate cortex in premotor functions and the projections of Pf and other MITN to the limbic striatum suggests a specific role in mediating motor outflow for the LC-innervated nuclei of the MITN.
dopamine-β hydroxylase; cingulate cortex; thalamus; locus coeruleus; stress; pain
The choice of reference region in positron emission tomography (PET) human brain imaging of the vesicular monoamine transporter 2 (VMAT2), a marker of striatal dopamine innervation, has been arbitrary, with cerebellar, whole cerebral, frontal, or occipital cortices used. To establish whether levels of VMAT2 are in fact low in these cortical areas, we measured VMAT2 protein distribution by quantitative immunoblotting in autopsied normal human brain (n=6). Four or five species of VMAT2 immunoreactivity (75, 55, 52, 45, 35 kDa) were detected, which were all markedly reduced in intensity in nigrostriatal regions of patients with parkinsonian conditions versus matched controls (n=9 to 10 each). Using the intact VMAT2 immunoreactivity, cerebellar and cerebral neocortices had levels of the transporter >100-fold lower than the VMAT2-rich striatum and with no significant differences among the cortical regions. We conclude that human cerebellar and cerebral cortices contain negligible VMAT2 protein versus the striatum and, in this respect, all satisfy a criterion for a useful reference region for VMAT2 imaging. The slightly lower PET signal for VMAT2 binding in occipital (the currently preferred reference region) versus cerebellar cortex might not therefore be explained by differences in VMAT2 protein itself but possibly by other imaging variables, for example, partial volume effects.
cerebellum; occipital cortex; positron emission tomography; reference region; substantia nigra; vesicular monoamine transporter 2
Neural changes that occurred during human evolution to support language are poorly understood. As a basis of comparison to humans, we used design-based stereological methods to estimate volumes, total neuron numbers, and neuron densities in Brodmann's areas 44 and 45 in both cerebral hemispheres of 12 chimpanzees (Pan troglodytes), one of our species’ closest living relatives. We found that the degree of interindividual variation in the topographic location and quantitative cytoarchitecture of areas 44 and 45 in chimpanzees was comparable to that seen in humans from previous studies. However, in contrast to the documented asymmetries in humans, we did not find significant population-level hemispheric asymmetry for any measures of areas 44 and 45 in chimpanzees. Furthermore, there was no relationship between asymmetries of stereological data and magnetic resonance imaging–based measures of inferior frontal gyrus morphology or hand preference on 2 different behavioral tasks. These findings suggest that Broca's area in the left hemisphere expanded in relative size during human evolution, possibly as an adaptation for our species’ language abilities.
cytoarchitecture; evolution; great ape; handedness; stereology
Functional reorganization of brain cortical areas occurs following stroke in humans, and many instances of this plasticity are associated with recovery of function. Rodent studies have shown that following a cortical stroke, neurons in uninjured areas of the brain are capable of sprouting new axons into areas previously innervated by injured cortex. The pattern and extent of structural plasticity depend on the species, experimental model, and lesion localization. In this study, we examined the pattern of axon sprouting in spinal cord after a localized lesion which selectively targeted the primary motor cortex in adult mice. We subjected mice to a stereotaxic-guided photothrombotic stroke of the left motor cortex, followed 2 weeks later by an injection of the neuronal tracer biotinylated dextran amine (BDA) into the uninjured right motor cortex. BDA-positive axons originating from the uninjured motor cortex were increased in the gray matter of the right cervical spinal cord in stroke mice, compared to sham control mice. These results show that axon sprouting can occur in the spinal cord of adult wild-type mice after a localized stroke in motor cortex.
stroke; axon sprouting; spinal cord; photothrombosis.
The basolateral nuclear complex of the amygdala (BLC) receives a dense dopaminergic innervation that plays a critical role in the formation of emotional memory. Dopamine has been shown to influence the activity of BLC GABAergic interneurons, which differentially control the activity of pyramidal cells. However, little is known about how dopaminergic inputs interface with different interneuronal subpopulations in this region. To address this question, dual-labeling immunohistochemical techniques were used at the light and electron microscopic levels to examine inputs from tyrosine hydroxylase-immunoreactive (TH+) dopaminergic terminals to two different interneuronal populations in the rat basolateral nucleus labeled using antibodies to parvalbumin (PV) or calretinin (CR). The basolateral nucleus exhibited a dense innervation by TH+ axons. Partial serial section reconstruction of TH+ terminals found that at least 43–50% of these terminals formed synaptic junctions in the basolateral nucleus. All of the synapses examined were symmetrical. In both TH/PV and TH/CR preparations the main targets of TH+ terminals were spines and distal dendrites of unlabeled cells. In sections dual-labeled for TH/PV 59% of the contacts of TH+ terminals with PV+ neurons were synapses, whereas in sections dual-labeled for TH/CR only 13% of the contacts of TH+ terminals with CR+ cells were synapses. In separate preparations examined in complete serial sections for TH+ basket-like innervation of PV+ perikarya, most (76.2%) of TH+ terminal contacts with PV+ perikarya were synapses. These findings suggest that PV+ interneurons, but not CR+ interneurons, are prominent synaptic targets of dopaminergic terminals in the BLC.
electron microscopy; immunocytochemistry; parvalbumin; calretinin
The proximate cause of Parkinson’s Disease is striatal dopamine depletion. Although no overt toxicity to striatal neurons has been reported in Parkinson’s Disease, one of the consequences of striatal dopamine loss is a decrease in the number of dendritic spines on striatal medium spiny neurons (MSNs). Dendrites of these neurons receive cortical glutamatergic inputs onto the dendritic spine head and dopaminergic inputs from the substantia nigra onto the spine neck. This synaptic arrangement suggests that dopamine gates corticostriatal glutamatergic drive onto spines. Using triple organotypic slice cultures comprised of ventral mesencephalon, striatum, and cortex, we examined the role of the cortex in dopamine depletion-induced dendritic spine loss in MSNs. The striatal dopamine innervation was lesioned by treatment of the cultures with the dopaminergic neurotoxin MPP+ or by removing the mesencephalon. Both MPP+ and mesencephalic ablation decreased MSN dendritic spine density. Analysis of spine morphology revealed that thin spines were preferentially lost after dopamine depletion. Removal of the cortex completely prevented dopamine depletion-induced spine loss. These data indicate that the dendritic remodeling of MSNs seen in parkinsonism occurs secondary to increases in corticostriatal glutamatergic drive, and suggest that modulation of cortical activity may be a useful therapeutic strategy in Parkinson’s Disease.
cortex; dendrite; glutamate; MPP+; Parkinson’s Disease; striatum
Brodmann areas 6, 44, and 45 in the ventrolateral frontal cortex of the left hemisphere of the human brain constitute the anterior language production zone. The anatomic connectivity of these areas with parietal and temporal cortical regions was recently examined in an autoradiographic tract-tracing study in the macaque monkey. Studies suggest strong correspondence between human resting state functional connectivity (RSFC) based on functional magnetic resonance imaging data and experimentally demonstrated anatomical connections in non-human primates. Accordingly, we hypothesized that areas 6, 44 and 45 of the human brain would exhibit patterns of RSFC consistent with patterns of anatomical connectivity observed in the macaque. In a primary analysis, we examined the RSFC associated with regions-of-interest placed in ventrolateral frontal areas 6, 44 and 45, on the basis of local sulcal and gyral anatomy. We validated the results of the primary hypothesis-driven analysis with a data-driven partitioning of ventrolateral frontal cortex into regions exhibiting distinct RSFC patterns, using a spectral clustering algorithm. The RSFC of ventrolateral frontal areas 6, 44 and 45 was consistent with patterns of anatomical connectivity shown in the macaque. We observed a striking dissociation between RSFC for the ventral part of area 6 that is involved in orofacial motor control and RSFC associated with Broca’s region (areas 44 and 45). These findings indicate rich and differential RSFC patterns for the ventrolateral frontal areas controlling language production, consistent with known anatomical connectivity in the macaque brain, and suggest conservation of connectivity during the evolution of the primate brain.
fMRI; resting state; inferior frontal gyrus; language; clustering
The macaque visual cortex contains more than 30 different functional visual areas, yet surprisingly little is known about the underlying organizational principles that structure its components into a complete ‘visual’ unit. A recent model of visual cortical organization in humans suggests that visual field maps are organized as clusters. Clusters minimize axonal connections between individual field maps that represent common visual percepts, with different clusters thought to carry out different functions. Experimental support for this hypothesis, however, is lacking in macaques, leaving open the question of whether it is unique to humans or a more general model for primate vision. Here we show, using high-resolution BOLD fMRI data in the awake monkey at 7 Tesla, that area MT/V5 and its neighbors are organized as a cluster with a common foveal representation and a circular eccentricity map. This novel view on the functional topography of area MT/V5 and satellites indicates that field map clusters are evolutionarily preserved and may be a fundamental organizational principle of the old world primate visual cortex.
extrastriate cortex; MT/V5; Macaque; retinotopy; fMRI; 7T
Brain asymmetries, particularly asymmetries within regions associated with language, have been suggested as a key difference between humans and our nearest ancestors. These regions include the planum temporale (PT) - the bank of tissue that lies posterior to Heschl’s gyrus and encompasses Wernicke’s area, an important brain region involved in language and speech in the human brain. In the human brain, both the surface area and grey matter volume of the PT is larger in the left compared to right hemisphere, particularly among right-handed individuals. Here we compared the grey matter volume and asymmetry of the PT in chimpanzees and three other species of nonhuman primate in two Genera including vervet monkeys (Chlorocebus aethiops sabaeus), rhesus macaques (Macaca mulatta) and bonnet macaques (Macaca radiata). We show that the three monkey species do not show population-level asymmetries in this region whereas the chimpanzees do, suggesting that the evolutionary brain development that gave rise to PT asymmetry occurred after our split with the monkey species, but before our split with the chimpanzees.
nonhuman primates; planum temporale; brain asymmetry; laterality; language evolution
We tested whether lesions of the excitatory glutamatergic projection from the auditory cortex (AC) to the inferior colliculus (IC) induce plastic changes in neurons of this nucleus. Changes in neuronal activation in the IC deprived unilaterally of the cortico-collicular projection were assessed by quantitative c-Fos immunocytochemistry. Densitometry and stereology measures of sound-induced c-Fos immunoreactivity in the IC showed diminished labeling at 1, 15, 90, and 180 days after lesions to the AC suggesting protein down-regulation, at least up to 15 days post-lesion. Between 15 and 90 days after the lesion, c-Fos labeling recovers, approaching control values at 180 days. Thus, glutamatergic excitation from the cortex maintains sound-induced activity in neurons of the IC. Subdivisions of this nucleus receiving a higher density of cortical innervation such as the dorsal cortex showed greater changes in c-Fos immunoreactivity, suggesting that the anatomical strength of the projection correlates with effect strength. Therefore, after damage of the corticofugal projection, neurons of the IC down-regulate and further recover sound-induced c-Fos protein expression. This may be part of cellular mechanisms aimed at balancing or adapting neuronal responses to altered synaptic inputs.
rat; immediate early gene; homeostatic plasticity; auditory descending projection
All non-human primates communicate with conspecifics using vocalizations, a system involving both the production and perception of species-specific vocal signals. Much of the work on the neural basis of primate vocal communication in cortex has focused on the sensory processing of vocalizations, while relatively little data are available for vocal production. Earlier physiological studies in squirrel monkeys had shed doubts on the involvement of primate cortex in vocal behaviors. The aim of the present study was to identify areas of common marmoset (Callithrix jacchus) cortex that are potentially involved in vocal communication. In this study, we quantified cFos expression in three areas of marmoset cortex – frontal, temporal (auditory), and medial temporal – under various vocal conditions. Specifically, we examined cFos expression in these cortical areas during the sensory, motor (vocal production), and sensory–motor components of vocal communication. Our results showed an increase in cFos expression in ventrolateral prefrontal cortex as well as the medial and lateral belt areas of auditory cortex in the vocal perception condition. In contrast, subjects in the vocal production condition resulted in increased cFos expression only in dorsal premotor cortex. During the sensory–motor condition (antiphonal calling), subjects exhibited cFos expression in each of the above areas, as well as increased expression in perirhinal cortex. Overall, these results suggest that various cortical areas outside primary auditory cortex are involved in primate vocal communication. These findings pave the way for further physiological studies of the neural basis of primate vocal communication.
immediate early gene expression; common marmoset; vocal communication; frontal cortex; auditory cortex; medial temporal cortex
We previously reported that secreted phosphoprotein 1 (SPP1) mRNA is expressed in neurons whose axons form the corticospinal tract (CST) of the rhesus macaque, but not in the corresponding neurons of the marmoset and rat. This suggests that SPP1 expression is involved in the functional or structural specialization of highly developed corticospinal systems in certain primate species. To further examine this hypothesis, we evaluated the expression of SPP1 mRNA in the motor cortex from three viewpoints: species differences, postnatal development, and functional/structural changes of the CST after a lesion of the lateral CST (l-CST) at the mid-cervical level. The density of SPP1-positive neurons in layer V of the primary motor cortex (M1) was much greater in species with highly developed corticospinal systems (i.e., rhesus macaque, capuchin monkey, and humans) than in those with less developed corticospinal systems (i.e., squirrel monkey, marmoset, and rat). SPP1-positive neurons in the macaque monkey M1 increased logarithmically in layer V during postnatal development, following a time course consistent with the increase in conduction velocity of the CST. After an l-CST lesion, SPP1-positive neurons increased in layer V of the ventral premotor cortex, in which compensatory changes in CST function/structure may occur, which positively correlated with the extent of finger dexterity recovery. These results further support the concept that the expression of SPP1 may reflect functional or structural specialization of highly developed corticospinal systems in certain primate species.
Studies in monkeys show clear anatomical and functional distinctions among networks connecting with subregions within the prefrontal cortex. Three such networks are centered on lateral orbitofrontal cortex, medial frontal and cingulate cortex, and lateral prefrontal cortex and all have been identified with distinct cognitive roles. Although these areas differ in a number of their cortical connections, some of the first anatomical evidence for these networks came from tracer studies demonstrating their distinct patterns of connectivity with the mediodorsal (MD) nucleus of the thalamus. Here, we present evidence for a similar topography of MD thalamus prefrontal connections, using non-invasive imaging and diffusion tractography (DWI–DT) in human and macaque. DWI–DT suggested that there was a high probability of interconnection between medial MD and lateral orbitofrontal cortex, between caudodorsal MD and medial frontal/cingulate cortex, and between lateral MD and lateral prefrontal cortex, in both species. Within the lateral prefrontal cortex a dorsolateral region (the principal sulcus in the macaque and middle frontal gyrus in the human) was found to have a high probability of interconnection with the MD region between the regions with a high probability of interconnection with other parts of the lateral prefrontal cortex and with the lateral orbitofrontal cortex. In addition to suggesting that the thalamic connectivity in the macaque is a good guide to human prefrontal cortex, and therefore that there are likely to be similarities in the cognitive roles played by the prefrontal areas in both species, the present results are also the first to provide insight into the topography of projections of an individual thalamic nucleus in the human brain.
Anatomy; DTI; Human; Macaque; Thalamus
Broca’s area, a cerebral cortical area located in the inferior frontal gyrus (IFG) of the human brain, has been identified as one of several critical regions associated with the motor planning and execution of language. Anatomically, Broca’s area is most often larger in the left hemisphere, and functional imaging studies in humans indicate significant left-lateralized patterns of activation during language-related tasks [1–3]. If, and to what extent, nonhuman primates, particularly chimpanzees, possess a homologous region that is involved in the production of their own communicative signals remains unknown. Here, we show that portions of the IFG as well as other cortical and subcortical regions in chimpanzees are active during the production of communicative signals. These findings are the first to provide direct evidence of the neuroanatomical structures associated with the production of communicative behaviors in chimpanzees. Significant activation in the left IFG in conjunction with other cortical and subcortical brain areas during the production of communicative signals in chimpanzees suggests that the neurological substrates underlying language production in the human brain may have been present in the common ancestor of humans and chimpanzees.