[THE THALAMIC DOPAMINERGIC SYSTEM. A NOVEL SYSTEM IN THE PRIMATE BRAIN]. / EL SISTEMA DOPAMINÉRGICO DEL TÁLAMO. NUEVO SISTEMA DEL CEREBRO DE PRIMATES.

The human and macaque monkey thalamus receives an abundant dopamine innervation, as revealed by immunolabeling of axons for molecules specific for the dopaminergic phenotype. The distribution of the innervation is highly heterogeneous, with specific association, limbic and motor nuclei receiving the densest innervation. The origin of thalamic dopamine is multiple; it includes dopaminergic nuclei in the hypothalamus, periaqueductal gray, ventral mesencephalon and lateral parabrachial nucleus. This novel dopaminergic system, notably developed in the primate brain, is rudimentary in rodents. Studying the thalamic dopaminergic system in primates opens new avenues for understanding neurological and psychiatric conditions.

Differential modes of termination of amygdalothalamic and amygdalocortical projections in the monkey.

The amygdala complex participates in multiple systems having to do with affective processes. It has been implicated in human disorders of social and emotional behavior, such as autism. Of the interconnected functional networks, considerable research in rodents and primates has focused on connections between the amygdala and orbitofrontal cortex (OFC). The amygdala projects to OFC by both a direct amygdalocortical (AC) pathway and an indirect pathway through mediodorsal thalamus. In the rat, retrograde tracer experiments indicate that the AC and amygdalothalamic (AT) pathways originate from separate populations, and may therefore convey distinctive information, although the characteristics of these pathways remain unclear. To investigate this issue in monkeys we made anterograde tracer injections in the basolateral amygdala complex (BLC; n = 3). Three distinctive features were found preferentially associated with the AT or AC pathways. First, AT terminations are large (average diameter = 3.5 microm; range = 1.2-7.0 microm) and cluster around proximal dendrites, in contrast with small-bouton AC terminations. Second, AT terminations form small arbors (diameter approximately 0.1 mm), while AC are widely divergent (often >1.0 mm long). The AT terminations features are reminiscent of large bouton, "driver" corticothalamic terminations. Finally, AC but not AT terminations are positive for zinc (Zn), a neuromodulator associated with synaptic plasticity. From these results we suggest that AC and AT terminations originate from distinct populations in monkey as well as in rodent. Further work is necessary to determine the degree and manner of their segregation and how these subsystems interact within a broader connectivity network.

Efferent association pathways originating in the caudal prefrontal cortex in the macaque monkey.

The efferent association fibers from the caudal part of the prefrontal cortex to posterior cortical areas course via several pathways: the three components of the superior longitudinal fasciculus (SLF I, SLF II, and SLF III), the arcuate fasciculus (AF), the fronto-occipital fasciculus (FOF), the cingulate fasciculus (CING F), and the extreme capsule (Extm C). Fibers from area 8Av course via FOF and SLF II, merging in the white matter of the inferior parietal lobule (IPL) and terminating in the caudal intraparietal sulcus (IPS). A group of these fibers turns ventrally to terminate in the caudal superior temporal sulcus (STS). Fibers from the rostral part of area 8Ad course via FOF and SLF II to the IPS and IPL and via the AF to the caudal superior temporal gyrus and STS. Some fibers from the rostral part of area 8Ad are conveyed to the medial parieto-occipital region via FOF, to the STS via Extm C, and to the caudal cingulate gyrus via CING F. Fibers from area 8B travel via SLF I to the supplementary motor area and area 31 in the caudal dorsal cingulate region and via the CING F to cingulate areas 24 and 23 and the cingulate motor areas. Fibers from area 9/46d course via SLF I to the superior parietal lobule and medial parieto-occipital region, via SLF II to the IPL. Fibers from area 9/46v travel via SLF III to the rostral IPL and the frontoparietal opercular region and via the CING F to the cingulate gyrus.

Thalamo-cortical projections to the posterior parietal cortex in the monkey.

Thalamo-cortical projections to the posterior parietal cortex (PPC) were investigated electrophysiologically in the monkey. Cortical field potentials evoked by the thalamic stimulation were recorded with electrodes chronically implanted on the cortical surface and at a 2.0-3.0 mm cortical depth in the PPC. The stimulation of the nucleus lateralis posterior (LP), nucleus ventralis posterior lateralis pars caudalis (VPLc), and nucleus pulvinaris lateralis (Pul.l) and medialis (Pul.m) induced surface-negative, depth-positive potentials in the PPC. The LP and VPLc projected mainly to the superior parietal lobule (SPL) and the anterior bank of the intraparietal sulcus (IPS), and the Pul.m mainly to the inferior parietal lobule (IPL) and the posterior bank of the IPS. The Pul.l had projections to all of the SPL, the IPL and both the banks. The significance of the projections is discussed in connection with motor functions.

Thalamocortical and intracortical connections of monkey cingulate motor areas.

Although there has been an increasing interest in motor functions of the cingulate motor areas, data concerning their input organization are still limited. To address this issue, the patterns of thalamic and cortical inputs to the rostral (CMAr), dorsal (CMAd), and ventral (CMAv) cingulate motor areas were investigated in the macaque monkey. Tracer injections were made into identified forelimb representations of these areas, and the distributions of retrogradely labeled neurons were analyzed in the thalamus and the frontal cortex. The cells of origin of thalamocortical projections to the CMAr were located mainly in the parvicellular division of the ventroanterior nucleus and the oral division of the ventrolateral nucleus (VLo). On the other hand, the thalamocortical neurons to the CMAd/CMAv were distributed predominantly in the VLo and the oral division of the ventroposterolateral nucleus-the caudal division of the ventrolateral nucleus. Additionally, many neurons in the intralaminar nuclear group were seen to project to the cingulate motor areas. Except for their well-developed interconnections, the corticocortical projections to the CMAr and CMAd/CMAv were also distinctively preferential. Major inputs to the CMAr arose from the presupplementary motor area and the dorsal premotor cortex, whereas inputs to the CMAd/CMAv originated not only from these areas but also from the supplementary motor area and the primary motor cortex. The present results indicate that the CMAr and the caudal cingulate motor area (involving both the CMAd and the CMAv) are characterized by distinct patterns of thalamocortical and intracortical connections, reflecting their functional differences.

Anatomical origins of the classical receptive field and modulatory surround field of single neurons in macaque visual cortical area V1.

From the analyses of our own and others' anatomical and physiological data for the macaque visual system, we arrive at a conclusion that three pathways can provide the V1 neuron with access to information from the visual field and affect its response. First, direct thalamic input can determine the size of the initial activating RF at high contrast. Second, lateral connections can enlarge the RF at low contrast by pooling information from larger regions of cortex that are otherwise ineffective when high contrast thalamic input is driving the cortical neuron. Thirdly, feedback from extrastriate cortex (possibly together with overlap or interdigitation of coactive lateral connectional fields within V1) can provide a large and stimulus specific surround modulatory field. The stimulus specificity of the interactions between the center and surround fields, may be due to the orderly, matching structure and different scales of intra-areal and feedback projection excitatory pathways. The observed activity changes of single recorded excitatory neurons could be a result of the relative weight of excitation on the excitatory neurons themselves and on local inhibitory interneurons that synapse on them. Inhibitory basket neurons, driven by the local excitatory neurons, could govern local interactions between cortical patches of different tuning properties, resulting in more distant changes in excitatory input in the laterally connected intra-areal neuronal pools.

Neurons associated with behavioral context errors in the primary and higher-order gustatory cortices in the monkey.

Cue responses of neurons in the taste-related cortex of Japanese macaque monkeys were studied during a NaCl-water discrimination GO-NOGO task, to compare the correct and incorrect responses. Most neurons produced a steady pattern of discharges in response to a given cue at both correct and incorrect responses, presumably responding to the physicochemical nature of the cue. Some neurons showed the discharge pattern for a certain cue changing to that for another cue at task error, presumably representing the subsequent behavioral reaction or behavioral context. These neurons were mainly located in the precentral operculum and orbitofrontal cortex, and rarely in the primary gustatory area, area G.

Zero-lag synchronous dynamics in triplets of interconnected cortical areas.

Oscillatory and synchronized activities involving widespread populations of neurons in neocortex are associated with the execution of complex sensorimotor tasks and have been proposed to participate in the 'binding' of sensory attributes during perceptual synthesis. How the brain constructs these coherent firing patterns remains largely unknown. Several mechanisms of intracortical synchronization have been considered, in particular mutual inhibition and reciprocal excitation. These mechanisms fail to account for the zero-lag correlations observed among areas located at different levels in the visual hierarchy because the asymmetric laminar organization of ascending and descending connections in this hierarchy would predict systematic inter-areal phase lags. Here we show through detailed computer simulations that, when triplets rather than pairs of reciprocally connected areas in a cortical hierarchy are considered, zero-lag synchronization emerges naturally from their three-way interactions. These simulations were motivated by the observation that most areas in the cat and macaque monkey visual cortex are organized in such triplets. Our results suggest that patterns of anatomical connections in the mammalian neocortex provide a structural basis for the multi-level synchronization of neuronal activity.

Cerebello-thalamo-cortical projections to the posterior parietal cortex in the macaque monkey.

The cerebello-thalamo-posterior parietal cortical projections were investigated electrophysiologically and morphologically in macaque monkeys. In anesthetized monkeys, electrical stimulation of every cerebellar nucleus evoked marked surface-positive, depth-negative (s-P, d-N) cortical field potentials in the superior parietal lobule and the cortical bank of the intraparietal sulcus, but no responses in the inferior parietal lobule. Tract-tracing experiments combining the anterograde method with the retrograde one indicated that the interposed and lateral cerebellar nuclei projected to the posterior parietal cortex mainly through the nucleus ventral lateralis caudalis of the thalamus. The significance of the projections is discussed in connection with cognitive functions.

Axon trajectories in local circuits of the primary motor cortex in the macaque monkey (Macaca fuscata).

The intrinsic trajectories and terminal arbors of two axons and one horizontal axon collateral within the primary motor cortex (M1) were studied in the macaque monkey using injections of biotinylated dextran amine (BDA) into the putative primary forelimb motor cortex, and two-dimensional (2-D) reconstruction of the individually labeled axons and collateral. (1) A long collateral of the main axon from a large pyramidal cell in layer Vb of the putative forelimb area on the anterior bank of the central sulcus coursed horizontally anteriorly for 3 mm and formed a terminal arbor in layer III of M1. (2) The main axon of a pyramidal cell in layer IIIa+b of the putative forelimb area on the precentral gyrus descended into the white matter and then entered the anterior bank of the central sulcus to form a terminal arbor in layers III and V. (3) The main axon of a pyramidal cell in layer IIIc of the putative forelimb area on the precentral gyrus descended and bifurcated in the white matter. One branch entered the anterior bank of the central sulcus to form a terminal field in layer VI. These results indicate that some local axons and horizontal axon collaterals arising from M1 reach their single targets within M1 to form single terminal fields.

Organization of inputs from cingulate motor areas to basal ganglia in macaque monkey.

The cingulate motor areas reside within regions lining the cingulate sulcus and are divided into rostral and caudal parts. Recent studies suggest that the rostral and caudal cingulate motor areas participate in distinct aspects of motor function: the former plays a role in higher-order cognitive control of movements, whereas the latter is more directly involved in their execution. Here, we investigated the organization of cingulate motor areas inputs to the basal ganglia in the macaque monkey. Identified forelimb representations of the rostral and caudal cingulate motor areas were injected with different anterograde tracers and the distribution patterns of labelled terminals were analysed in the striatum and the subthalamic nucleus. Corticostriatal inputs from the rostral and caudal cingulate motor areas were located within the rostral striatum, with the highest density in the striatal cell bridges and the ventrolateral portions of the putamen, respectively. There was no substantial overlap between these input zones. Similarly, a certain segregation of input zones from the rostral and caudal cingulate motor areas occurred along the mediolateral axis of the subthalamic nucleus. It has also been revealed that corticostriatal and corticosubthalamic input zones from the rostral cingulate motor area considerably overlapped those from the presupplementary motor area, while the input zones from the caudal cingulate motor area displayed a large overlap with those from the primary motor cortex. The present results indicate that a parallel design underlies motor information processing in the cortico-basal ganglia loop derived from the rostral and caudal cingulate motor areas.

Position of spinothalamic tract axons in upper cervical spinal cord of monkeys.

Percutaneous upper cervical cordotomy continues to be performed on patients suffering from several types of severe chronic pain. It is believed that the operation is effective because it cuts the spinothalamic tract (STT), a primary pathway carrying nociceptive information from the spinal cord to the brain in humans. In recent years, there has been controversy regarding the location of STT axons within the spinal cord. The aim of this study was to determine the locations of STT axons within the spinal cord white matter of C2 segment in monkeys using methods of antidromic activation. Twenty lumbar STT cells were isolated. Eleven were classified as wide dynamic range neurons, six as high-threshold cells, and three as low-threshold cells. Eleven STT neurons were recorded in the deep dorsal horn and nine in superficial dorsal horn. The axons of the examined neurons were located at antidromic low-threshold points (<30 microA) within the contralateral lateral funiculus of C2. All low-threshold points were located ventral to the denticulate ligament, within the lateral half of the ventral lateral funiculus (VLF). None were found in the dorsal half of the lateral funiculus. The present findings support our previous suggestion that STT axons migrate ventrally as they ascend the length of the spinal cord. Also, the present findings indicate that surgical cordotomies that interrupt the VLF in C2 likely disrupt the entire lumbar STT.

Subcortical projections of area 25 (subgenual cortex) of the macaque monkey.

In several species, including primates, stimulation studies indicate that the infralimbic cortex, the most caudal part of the ventromedial prefrontal cortex, functions as a visceral motor region. In addition, recent positron emission tomography studies implicate the subgenual region in depression and mania. To determine the subcortical projections of this region in primates, injections of Phaseolus vulgaris leukoagglutinin, biotinylated dextran amine, or rhodamine-labeled dextran amine were placed in area 25 in three monkeys. In contrast to the efferents from area 25 previously described in the rat, there were no projections to autonomic effector regions, such as the nucleus of the solitary tract, magnocellular neurosecretory cell groups in the hypothalamus, ventrolateral medulla, or intermediolateral column of the spinal cord. However, projections were shown to a number of structures with probable roles in autonomic function and direct connections to some of the abovementioned autonomic effector regions, including bed nucleus of the stria terminalis, perifornical and anterior hypothalamus, periaqueductal gray, and lateral parabrachial nucleus. In addition, there were projections to several forebrain structures that receive projections from other components of the medial prefrontal network including the medial part of the caudate nucleus, lateral septum, midline and mediodorsal thalamic nuclei, the lateral parvocellular part of the basal accessory amygdaloid nucleus, and the magnocellular part of the basal amygdaloid. None of the injections resulted in labeling in the medulla. These connections support the idea of a role for cortical area 25 in emotional and autonomic responses, albeit less direct than that described in rodents.

Three-dimensional morphology and distribution of pallidal axons projecting to both the lateral region of the thalamus and the central complex in primates.

This study presents a three-dimensional analysis of pallido-thalamic axons and axonal endings in the monkey (Macaca mulatta and M. irus). Injections of the anterograde tracer biocytin were made in the dorsal, associative region of the medial pallidum. Numerous axonal endings were observed within the pallidal territory of the lateral region of the thalamus and the central complex. Individual axons were reconstructed from serial sections and traced in three dimensions. Two axons made a collateral branch in the ventral part of the lateral region and ended in the central complex. In the pallidal territory of the lateral region, axons divided several times before ending in different parts of the territory in a 'bunch', a characteristic dense terminal arborization. Axonal endings in the central complex were differently organized. Our data show that associative medial pallidal information is distributed throughout the pallidal territory of the lateral region and the pars media of the central complex by means of individual axons with numerous branches and axonal endings specific to each of the two targets.

Architectonic subdivisions of the inferior pulvinar in New World and Old World monkeys.

Architectonic subdivisions of the inferior pulvinar (PI) complex were delineated in New World owl and squirrel monkeys and Old World macaque monkeys. Brain sections were processed for Nissl substance, myelin, cytochrome oxidase (CO), acetylcholinesterase (AChE), calbindin-D28K (Cb), or with the monoclonal antibody Cat-301. In all three primates, we identified the posterior nucleus (PIp) and the medial nucleus (PIm) of previous reports, and divided the previously recognized central nucleus (PIc) into two subdivisions, medial (PIcM) and lateral (PIcL). Each nucleus had several features that allowed it to be readily distinguished. (1) PIp was dark in Cb, and moderately dark in AChE and CO preparations. (2) PIm was Cb light, and AChE and CO dark. (3) PIcM was Cb dark, and AChE and CO light. (4) PIcL was Cb moderate with a scattering of dark neurons, and moderately dark for AChE and CO. (5) In sections processed for Cat-301, PIm in macaque monkeys and PIcM and PIp in squirrel monkeys stained darkly, while little staining was apparent in owl monkeys. The results allowed subdivisions of the inferior pulvinar to be more clearly defined, homologized, and compared across taxa. All monkeys appear to have the same four subdivisions of the PI, although properties vary.

Compartmental organization of layer IVA in human primary visual cortex.

Immunostaining for three neuronal proteins, nonphosphorylated neurofilament protein (with antibody SMI-32), calbindin, and parvalbumin, was used to examine the organization of layer IV in human primary visual cortex (area 17 or V1) specifically to determine whether, similar to the case in macaque V1, layer IVA is present and is divided into neurochemically distinct compartments. All three proteins are expressed by neurons that are unevenly distributed in layer IV of human V1; immunostaining for each protein includes a thin band corresponding to layer IVA of classic cytoarchitectonic studies. In this band, nonphosphorylated neurofilament protein immunoreactivity is present in relatively broad clusters of pyramidal cell somata and dendrites that appear as upwardly protruding parts of intense immunostaining in layer IVB, whereas immunoreactivity for calbindin and parvalbumin exists in somata of nonpyramidal neurons and in thin, dense clusters of punctate profiles. In tangential sections through layer IVA, the three proteins are seen in distinct compartments. Calbindin- and parvalbumin-immunostained neurons make up a thinly walled honeycomb or lattice, whereas neurons immunostained for nonphosphorylated neurofilament protein occupy the central lacunae. Direct comparison shows that neurons immunostained for calbindin occupy regions in layer IVA complementary to those immunostained for nonphosphorylated neurofilament protein. These data demonstrate a basic similarity in the organization of layer IV in macaques and humans. Layer IVA specifically is organized into complementary and neurochemically distinct compartments, including what appears to be a geniculocortically innervated and parvicellular-driven lattice and the interstitial lacunae formed by the periodic, upward protrusion of magnocellular-dominated layer IVB neurons.

Extent of intracortical arborization of thalamocortical axons as a determinant of representational plasticity in monkey somatic sensory cortex.

The extent of intracortical arborization of individual thalamocortical axons in area 3b of the somatic sensory cortex and the degree of overlap in the cortical projections of relay cells in the ventral posterior nucleus of the thalamus were examined in macaque monkeys. Paired intracortical deposits of Fast blue (FB) and Diamidino yellow (DY) separated by 100-1500 microns were made by inserting crystals of dye into the tracks of tungsten microelectrodes used to record receptive field data on area 3b cells. Each injection gave retrograde labeling of one or more clusters of cells extending in elongated anteroposterior arrays through the ventral posterior medial (VPM) or ventral posterior lateral (VPL) nucleus. Double-labeled cells were only found when the distance between the centers of the dye deposits was less than 600 microns. With interdeposit distances greater than 600 microns, most clusters of retrogradely labeled cells had a majority of cells labeled by FB or DY. However, even with interdeposit distances of 1-1.5 mm the labeled clusters also contained significant numbers of cells labeled with the other dye. These results and an accompanying regression analysis indicate that the extent of intracortical arborization of single thalamocortical axons in area 3b is no greater than 600 microns. However, adjoining cells in the same part of the thalamic body representation can project to cortical targets as discrepant as 1.5 mm. It is proposed that the fine grain of the cortical representation depends upon inputs from the majority population of each thalamic cell cluster.(ABSTRACT TRUNCATED AT 250 WORDS)

Spatial distribution of thalamic projections to the supplementary motor area and the primary motor cortex: a retrograde multiple labeling study in the macaque monkey.

The exact knowledge on spatial organization of information sources from the thalamus to the supplementary motor area (SMA) and to the primary motor cortex (MI) has not been established. We investigated the distribution of thalamocortical neurons projecting to forelimb representations of the SMA and the MI using a multiple retrograde labeling technique in the monkey. The forelimb area of the SMA, and the distal and proximal forelimb areas of the MI were identified by electrophysiological techniques of intracortical microstimulation and single neuron recording. Injections were made into these three representations with three different dyes in the same animal (horseradish peroxidase conjugated to wheat germ agglutinin, diamidino yellow, and fast blue), and the thalamic neurons were retrogradely labeled. Injections into the SMA densely labeled thalamic neurons in nuclei ventralis lateralis pars oralis (VLo), ventralis lateralis pars medialis (VLm) and ventralis lateralis pars caudalis (VLc), but not in nucleus ventralis posterior lateralis pars oralis (VPLo). Injections into the MI labeled thalamic neurons primarily in VLo, VLc, and VPLo. We found that the distribution of projection neurons to the three areas was largely separate in the thalamus. However, in the middle part of VLo, and in a limited portion of VLc, thalamic neurons projecting to the SMA partially overlapped with those to the distal forelimb area of the MI. They overlapped little with those to the proximal forelimb area of the MI. We noted no overlap between the distributions of thalamic projection neurons to the distal and proximal forelimb areas of the MI. These findings suggest that the SMA and MI receive separate information from the thalamus, while sharing minor sources of common inputs.

Central complex of the primate thalamus: a quantitative analysis of neuronal morphology.

Neuronal morphology was analyzed in the central complex (centre median-parafascicular complex) of macaques and humans. Cell bodies were described from Nissl material. Golgi-impregnated dendritic arborizations were reconstructed from serial sections and digitized in three dimensions by computer-assisted microscopy. The central complex was subdivided into three parts on the basis of cytoarchitectonic and hodological criteria: pars parafascicularis (medial), pars media (intermediate), and pars paralateralis (lateral). The mean cross-sectional areas of cell bodies were identical (181 microns2) in the three parts in macaques. In humans they were larger in the pars parafascicularis (304 microns2) than in the other parts (248 and 240 microns2). Small local circuit neurons were found throughout the complex. Large projection neurons differed statistically in the three parts. In macaques, pars parafascicularis neurons had few dendritic stems and tips (3-11) and a short total dendritic length (2,000 microns). Pars paralateralis neurons had more ramified (5-60) and longer (5,800 microns) dendrites. They bore numerous axonlike processes. Pars media neurons had intermediate characteristics (5-19; 2,400 microns). In humans, pars parafascicular neurons had similar topological characteristics (3-12) but longer dendrites (3,000 microns) than in the monkey. Pars paralateralis neurons had more branched (6-71) and longer (9,000 microns) dendrites, with more numerous axonlike processes. Pars media neurons also had intermediate characteristics (4-25; 3,800 microns). The present study supports a tripartite subdivision of the primate central complex and demonstrates significant interspecies differences.