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1.  SPECIES-SPECIFIC DISTRIBUTIONS OF TYROSINE HYDROXYLASE-IMMUNOREACTIVE NEURONS IN THE PREFRONTAL CORTEX OF ANTHROPOID PRIMATES 
Neuroscience  2008;158(4):1551-1559.
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.
doi:10.1016/j.neuroscience.2008.10.058
PMCID: PMC2743909  PMID: 19041377
dopamine; area 9; area 32; human evolution
2.  Dopamine Innervation in the Thalamus: Monkey versus Rat 
Cerebral Cortex (New York, NY)  2008;19(2):424-434.
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.
doi:10.1093/cercor/bhn093
PMCID: PMC2638784  PMID: 18550594
dopamine; macaque; rat; species differences; thalamus
3.  Cortical Sulci Asymmetries in Chimpanzees and Macaques: A New Look at an Old Idea 
Neuroimage  2012;61(3):533-541.
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.
doi:10.1016/j.neuroimage.2012.03.082
PMCID: PMC3358493  PMID: 22504765
Chimpanzee; Brain asymmetry; Sulci morphology
4.  NEONATAL 6-HYDROXYDOPAMINE LESIONS OF THE FRONTAL CORTEX IN RATS: PERSISTING EFFECTS ON LOCOMOTOR ACTIVITY, LEARNING AND NICOTINE SELF-ADMINISTRATION 
Neuroscience  2008;154(3):885-897.
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.
doi:10.1016/j.neuroscience.2008.04.020
PMCID: PMC2581840  PMID: 18511204
6-OHDA; radial-arm maze; self-administration; dopamine; serotonin; nucleus accumbens; striatum
5.  Norepinephrinergic Afferents and Cytology of the Macaque Monkey Midline, Mediodorsal, and Intralaminar Thalamic Nuclei 
Brain structure & function  2008;212(6):465-479.
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.
doi:10.1007/s00429-008-0178-0
PMCID: PMC2649766  PMID: 18317800
dopamine-β hydroxylase; cingulate cortex; thalamus; locus coeruleus; stress; pain
6.  Distribution of vesicular monoamine transporter 2 protein in human brain: implications for brain imaging studies 
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.
doi:10.1038/jcbfm.2011.63
PMCID: PMC3208151  PMID: 21522164
cerebellum; occipital cortex; positron emission tomography; reference region; substantia nigra; vesicular monoamine transporter 2
7.  Lateral prefrontal cortex: architectonic and functional organization 
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.
doi:10.1098/rstb.2005.1631
PMCID: PMC1569489  PMID: 15937012
prefrontal cortex; frontal cortex; cytoarchitecture; monkey
8.  Axon sprouting in adult mouse spinal cord after motor cortex stroke 
Neuroscience letters  2008;450(2):191-195.
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.
doi:10.1016/j.neulet.2008.11.017
PMCID: PMC2793320  PMID: 19022347
stroke; axon sprouting; spinal cord; photothrombosis.
9.  Dopaminergic innervation of interneurons in the rat basolateral amygdala 
Neuroscience  2008;157(4):850-863.
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.
doi:10.1016/j.neuroscience.2008.09.043
PMCID: PMC2621110  PMID: 18948174
electron microscopy; immunocytochemistry; parvalbumin; calretinin
10.  Axonal Fiber Terminations Concentrate on Gyri 
Cerebral Cortex (New York, NY)  2011;22(12):2831-2839.
Convoluted cortical folding and neuronal wiring are 2 prominent attributes of the mammalian brain. However, the macroscale intrinsic relationship between these 2 general cross-species attributes, as well as the underlying principles that sculpt the architecture of the cerebral cortex, remains unclear. Here, we show that the axonal fibers connected to gyri are significantly denser than those connected to sulci. In human, chimpanzee, and macaque brains, a dominant fraction of axonal fibers were found to be connected to the gyri. This finding has been replicated in a range of mammalian brains via diffusion tensor imaging and high–angular resolution diffusion imaging. These results may have shed some lights on fundamental mechanisms for development and organization of the cerebral cortex, suggesting that axonal pushing is a mechanism of cortical folding.
doi:10.1093/cercor/bhr361
PMCID: PMC3491768  PMID: 22190432
cortical folding; diffusion tensor imaging; shape analysis
11.  Distinct Parietal and Temporal Pathways to the Homologues of Broca's Area in the Monkey 
PLoS Biology  2009;7(8):e1000170.
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.
Author Summary
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.
doi:10.1371/journal.pbio.1000170
PMCID: PMC2714989  PMID: 19668354
12.  Pyramidal Cells in Prefrontal Cortex of Primates: Marked Differences in Neuronal Structure Among Species 
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.
doi:10.3389/fnana.2011.00002
PMCID: PMC3039119  PMID: 21347276
macaque; baboon; human; guenon; spine; primate; cognition; connectivity
13.  Broca's Area Homologue in Chimpanzees (Pan troglodytes): Probabilistic Mapping, Asymmetry, and Comparison to Humans 
Cerebral Cortex (New York, NY)  2009;20(3):730-742.
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.
doi:10.1093/cercor/bhp138
PMCID: PMC2820707  PMID: 19620620
cytoarchitecture; evolution; great ape; handedness; stereology
14.  Transient Down-Regulation of Sound-Induced c-Fos Protein Expression in the Inferior Colliculus after Ablation of the Auditory Cortex 
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.
doi:10.3389/fnana.2010.00141
PMCID: PMC2981384  PMID: 21088696
rat; immediate early gene; homeostatic plasticity; auditory descending projection
15.  Both Noncoding and Protein-Coding RNAs Contribute to Gene Expression Evolution in the Primate Brain 
Despite striking differences in cognition and behavior between humans and our closest primate relatives, several studies have found little evidence for adaptive change in protein-coding regions of genes expressed primarily in the brain. Instead, changes in gene expression may underlie many cognitive and behavioral differences. Here, we used digital gene expression: tag profiling (here called Tag-Seq, also called DGE:tag profiling) to assess changes in global transcript abundance in the frontal cortex of the brains of 3 humans, 3 chimpanzees, and 3 rhesus macaques. A substantial fraction of transcripts we identified as differentially transcribed among species were not assayed in previous studies based on microarrays. Differentially expressed tags within coding regions are enriched for gene functions involved in synaptic transmission, transport, oxidative phosphorylation, and lipid metabolism. Importantly, because Tag-Seq technology provides strand-specific information about all polyadenlyated transcripts, we were able to assay expression in noncoding intragenic regions, including both sense and antisense noncoding transcripts (relative to nearby genes). We find that many noncoding transcripts are conserved in both location and expression level between species, suggesting a possible functional role. Lastly, we examined the overlap between differential gene expression and signatures of positive selection within putative promoter regions, a sign that these differences represent adaptations during human evolution. Comparative approaches may provide important insights into genes responsible for differences in cognitive functions between humans and nonhuman primates, as well as highlighting new candidate genes for studies investigating neurological disorders.
doi:10.1093/gbe/evq002
PMCID: PMC2839352  PMID: 20333225
gene expression; transcriptional evolution; Tag-Seq; noncoding RNA
16.  Comparative Anatomy of the Locus Coeruleus in Humans and Non-Human Primates 
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.
doi:10.1002/cne.22249
PMCID: PMC2820586  PMID: 20127761
Locus coeruleus; non-human primates; hominids; tyrosine hydroxylase; stereology
17.  Humans and great apes share increased neocortical neuropeptide Y innervation compared to other haplorhine primates 
Neuropeptide Y (NPY) plays a role in a variety of basic physiological functions and has also been implicated in regulating cognition, including learning and memory. A decrease in neocortical NPY has been reported for Alzheimer's disease, schizophrenia, bipolar disorder, and depression, potentially contributing to associated cognitive deficits. The goal of the present analysis was to examine variation in neocortical NPY-immunoreactive axon and varicosity density among haplorhine primates (monkeys, apes, and humans). Stereologic methods were used to measure the ratios of NPY-expressing axon length density to total neuron density (ALv/Nv) and NPY-immunoreactive varicosity density to neuron density (Vv/Nv), as well as the mean varicosity spacing in neocortical areas 10, 24, 44, and 22 (Tpt) of humans, African great apes, New World monkeys, and Old World monkeys. Humans and great apes showed increased cortical NPY innervation relative to monkey species for ALv/Nv and Vv/Nv. Furthermore, humans and great apes displayed a conserved pattern of varicosity spacing across cortical areas and layers, with no differences between cortical layers or among cortical areas. These phylogenetic differences may be related to shared life history variables and may reflect specific cognitive abilities.
doi:10.3389/fnhum.2014.00101
PMCID: PMC3937817  PMID: 24616688
NPY; Broca's area; Wernicke's area; primate evolution
18.  Low Nigrostriatal Reserve for Motor Parkinsonism in Nonhuman Primates 
Experimental neurology  2012;237(2):355-362.
Objective
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.
Methods
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.
Results
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.
Conclusions
The nigral cell body and terminal field injury needed to produce parkinsonian motor manifestations may be much less than previously thought.
doi:10.1016/j.expneurol.2012.07.008
PMCID: PMC3443325  PMID: 22836146
Parkinsonism; MPTP; substantia nigra; dopamine
19.  Cortical Regulation of Dopamine Depletion-Induced Dendritic Spine Loss in Striatal Medium Spiny Neurons 
Neuroscience  2007;149(2):457-464.
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.
doi:10.1016/j.neuroscience.2007.06.044
PMCID: PMC2094700  PMID: 17888581
cortex; dendrite; glutamate; MPP+; Parkinson’s Disease; striatum
20.  Development of Cannabinoid 1 Receptor Protein and Messenger RNA in Monkey Dorsolateral Prefrontal Cortex 
Cerebral Cortex (New York, NY)  2009;20(5):1164-1174.
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.
doi:10.1093/cercor/bhp179
PMCID: PMC2852503  PMID: 19703937
cholecystokinin; GABA; interneurons; parvalbumin; schizophrenia
21.  The Organization of Dorsal Frontal Cortex in Humans and Macaques 
The Journal of Neuroscience  2013;33(30):12255-12274.
The human dorsal frontal cortex has been associated with the most sophisticated aspects of cognition, including those that are thought to be especially refined in humans. Here we used diffusion-weighted magnetic resonance imaging (DW-MRI) and functional MRI (fMRI) in humans and macaques to infer and compare the organization of dorsal frontal cortex in the two species. Using DW-MRI tractography-based parcellation, we identified 10 dorsal frontal regions lying between the human inferior frontal sulcus and cingulate cortex. Patterns of functional coupling between each area and the rest of the brain were then estimated with fMRI and compared with functional coupling patterns in macaques. Areas in human medial frontal cortex, including areas associated with high-level social cognitive processes such as theory of mind, showed a surprising degree of similarity in their functional coupling patterns with the frontal pole, medial prefrontal, and dorsal prefrontal convexity in the macaque. We failed to find evidence for “new” regions in human medial frontal cortex. On the lateral surface, comparison of functional coupling patterns suggested correspondences in anatomical organization distinct from those that are widely assumed. A human region sometimes referred to as lateral frontal pole more closely resembled area 46, rather than the frontal pole, of the macaque. Overall the pattern of results suggest important similarities in frontal cortex organization in humans and other primates, even in the case of regions thought to carry out uniquely human functions. The patterns of interspecies correspondences are not, however, always those that are widely assumed.
doi:10.1523/JNEUROSCI.5108-12.2013
PMCID: PMC3744647  PMID: 23884933
22.  Dopaminergic innervation of the human subventricular zone: a comparison between Huntington’s chorea and Parkinson’s disease 
The subventricular zone retains its neurogenic capacity throughout life and, as such, is often considered a potential source for endogenous repair in neurodegenerative disorders. Because dopamine is believed to stimulate adult neurogenesis, we looked for possible variations in the dopaminergic innervation of the subventricular zone between cases of Huntington’s chorea and Parkinson’s diseases. Antibodies against tyrosine hydroxylase (TH) and proliferating cell nuclear antigen (PCNA) were used as specific markers of dopaminergic axons and cell proliferating activity, respectively. The immunohistochemical approach was applied to postmortem tissue from 2 Parkinson’s disease cases, 4 Huntington’s disease cases, along with age-matched controls. The immunostaining was revealed with either diaminobenzidine or fluorescent-conjugated secondary antibodies. Optical density measurements were made along the entire dorso-ventral extent of the caudate nucleus. An intense TH+ zone was detected along the ventricular border of the caudate nucleus in Huntington’s disease cases, but not in patients with Parkinson’s disease or age-matched controls. This thin (287±38 μm) paraventricular zone was composed of numerous small and densely packed dopamine axon varicosities and overlapped the deep layers of the subventricular zone. Its immunoreactivity was 47±8% more intense than that of adjacent striatal areas. The dopamine innervation of the subventricular zone is strikingly massive in Huntington’s chorea compared to Parkinson’s disease, a finding that concurs with the marked increase in neurogenesis noted in the subventricular zone of Huntington’s disease patients. This finding suggests that dopamine plays a crucial role in mechanisms designed to compensate for the massive striatal neuronal losses that occur in Huntington’s disease.
PMCID: PMC3783834  PMID: 24093085
Stem cells; adult neurogenesis; basal ganglia; Parkinson’s disease; Huntington’s chorea; subventricular zone; neurodegenerative disorders; human striatum
23.  Evidence for Ape and Human Specializations in Geniculostriate Projections from VGLUT2 Immunohistochemistry 
Brain, behavior and evolution  2012;80(3):210-221.
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.
doi:10.1159/000341135
PMCID: PMC3503454  PMID: 22889767
Vesicular glutamate transporter; Area 17; Primary visual cortex; Architectonics; Primate; Human; Blobs; Evolution; Chimpanzees
24.  Dopaminergic neurons in the brain and dopaminergic innervation of the albumen gland in mated and virgin helisoma duryi (mollusca: pulmonata) 
BMC Physiology  2001;1:9.
Background
Dopamine was shown to stimulate the perivitelline fluid secretion by the albumen gland. Even though the albumen gland has been shown to contain catecholaminergic fibers and its innervation has been studied, the type of catecholamines, distribution of fibers and the precise source of this neural innervation has not yet been deduced. This study was designed to address these issues and examine the correlation between dopamine concentration and the sexual status of snails.
Results
Dopaminergic neurons were found in all ganglia except the pleural and right parietal, and their axons in all ganglia and major nerves of the brain. In the albumen gland dopaminergic axons formed a nerve tract in the central region, and a uniform net in other areas. Neuronal cell bodies were present in the vicinity of the axons. Dopamine was a major catecholamine in the brain and the albumen gland. No significant difference in dopamine quantity was found when the brain and the albumen gland of randomly mating, virgin and first time mated snails were compared.
Conclusions
Our results represent the first detailed studies regarding the catecholamine innervation and quantitation of neurotransmitters in the albumen gland. In this study we localized catecholaminergic neurons and axons in the albumen gland and the brain, identified these neurons and axons as dopaminergic, reported monoamines present in the albumen gland and the brain, and compared the dopamine content in the brain and the albumen gland of randomly mating, virgin and first time mated snails.
PMCID: PMC37538  PMID: 11513757
25.  Communicative Signaling Activates ‘Broca’s’ Homolog in Chimpanzees 
Current biology : CB  2008;18(5):343-348.
Summary
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.
doi:10.1016/j.cub.2008.01.049
PMCID: PMC2665181  PMID: 18308569

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