Distribution of cerebellothalamic and nigrothalamic projections in the dog: A double anterograde tracing study

The distribution of nigrothalamic and cerebellothalamic projections was investigated in the dog by a double labeling strategy combining the anterograde transport of wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) and tritiated amino acids. Following tritiated amino acid injections into the substantia nigra pars reticulata (SNr) and WGA-HRP injections into the contralateral cerebellar nuclei, we found that the nigrothalamic and cerebellothalamic afferents distribute to three main targets: the central portion of the ventral anterior nucleus (VA) and the ventral lateral nucleus (VL), the internal medullary lamina (IML) region, which includes the paralaminar VA, the mediodorsal nucleus (MD) and the central lateral nucleus (CL), and finally the ventromedial nucleus (VM). We observed three distribution patterns of labeled fibers: (a) Dense single label was observed in the central portion of VA following the SNr injections and in VL following the cerebellar nuclei injections. (b) A complementary pattern consisting of alternating foci of nigral and cerebellar label was found in the IML region. This pattern was also observed in the caudal intralaminar nuclei where cerebellar label predominated in the centrum medianum (CM), while the parafascicular nucleus (Pf) primarily contained nigral label. (c) An overlapping pattern of autoradiographic and WGA-HRP label was found in the lateral half of the VM. Overall, the distribution of nigrothalamic and cerebellothalamic projections was widespread throughout much of rostrocaudal thalamus. However, the pattern of projections varied along a continuum from lateral to medial thalamus. In lateral thalamus, nigral and cerebellar projections distributed to separate nuclei while in medial thalamus, the projection pattern changed to focal and complementary in the IML and overlapping in VM. Taken together, these thalamic projections may constitute crucial links in different functional channels involved in alerting and orienting mechanisms associated with motor behavior. Our findings also suggest that the organization of motor thalamic afferents in the dog shares similarities with the segregated and parallel circuitry characteristic of primates as well as with the overlapping and converging circuits of rodents and other carnivores.     

A description of the GABAergic neurons and axon terminals in the motor nuclei of the cat thalamus

The GABA neurons and their processes in the cat motor thalamic nuclei were identified and studied with glutamic acid decarboxylase (GAD) immunocytochemistry at both the light and electron microscopic levels. The three nuclei that comprise the motor thalamus, ventral anterior (VA), ventral medial (VM), and ventral lateral (VL), each displayed a characteristic distribution pattern of GAD-positive structures that was consistent with their afferent and intrinsic neuronal organization. All three thalamic nuclei displayed a population of small, GAD-positive cells the dendrites of which contained synaptic vesicles and participated in complex synaptic arrays such as serial synapses, triads, and glomeruli. Based on their ultrastructural features, these GAD-containing cells were identified as local circuit neurons. In contrast, the larger, GAD-negative cells were presumed to be the thalamocortical projection neurons. The axons of GAD-positive local circuit neurons could not be identified in these preparations. The number of GAD-positive dendrites in the neuropil was different for the three thalamic nuclei. In the VA and VM, the GAD-positive dendrites were numerous and formed symmetric synapses with dendrites of GAD-negative cells, mainly in association with corticothalamic boutons. Within VL, the GAD-containing dendrites were more numerous than in VA and VM and formed synapses at influential locations on presumed thalamocortical projection neurons, such as bases of primary dendrites, and bifurcation sites of primary and secondary dendrites. The VA and anterolateral VM nuclei that receive inhibitory GABAergic afferents from the entopeduncular nucleus and substantia nigra contained the highest concentration of large GAD-positive axon terminals. These boutons contained pleomorphic vesicles and numerous mitochondria and formed symmetric synapses and multiple puncta adherentes with dendrites and somata of presumed thalamocortical projection neurons. The size, ultrastructural features, and distribution of these GAD-positive boutons were similar to those features described for basal ganglia terminals in the motor thalamus of the cat. In addition, similar large-size GAD-positive boutons were observed in the medial VM, which receives basal ganglia afferents exclusively from the substantia nigra. The concentration of these terminals in medial VM along the dendrites of thalamocortical projection neurons was much less than that in VA and anterolateral VM. The VL nucleus which lacks basal ganglia input did not contain any large GAD-positive boutons.(ABSTRACT TRUNCATED AT 400 WORDS)     

Distribution of nigrothalamic projections in the dog.

The distribution of nigrothalamic projections was studied in the dog by using the autoradiographic tracing method. On the basis of a systematic series of tritiated amino acid injections into different portions of the substantia nigra, we found that the rostral three-fourths of the substantia nigra pars reticulata (SNr) gives rise to widespread thalamic projections. The nigrothalamic label occupied a longitudinal band extending from rostral ventral anterior nucleus (VA) through to caudal mediodorsal nucleus (MD). In the dog, VA is histochemically identified as an acetylthiocholinesterase (AChE)-negative region and is distinct from the adjacent ventral lateral nuclei which stain positively for AChE. In rostral thalamus, the dense autoradiographic label was observed in rostral VA within the AchE-negative region lying alongside the mammillothalamic tract (MT). The adjacent AChE-positive ventral lateral nuclei did not contain autoradiographic label. In addition, homogeneously distributed silver grains were observed throughout the ventromedial nucleus (VM) bilaterally. More caudally, as the ventral lateral thalamic compartment emerges, label was also observed within the internal medullary lamina region, including the paralaminar portion of VA, the central lateral nucleus (CL), and the paralaminar portion of MD. Finally, in caudal thalamus, the central portion of MD, as well as the parafascicular nucleus (Pf), contained autoradiographic label. The overall nigrothalamic distribution observed in the dog was similar to the distribution of nigrothalamic projections in monkeys with one exception. Unlike that of primates, the distribution of nigral efferents is to the whole extent of VM in the dog as in other non-primate species. Overall, we found that nigral efferents primarily project to three main thalamic targets: the VA/MD region, VM, and the internal medullary lamina region, which includes dorsal CL and paralaminar VA and MD. We propose that these three nigrothalamic territories may constitute critical links subserving different functional channels.     

Organization of thalamostriatal terminals from the ventral motor nuclei in the macaque

This study examines the organization of thalamostriatal projections from ventral tier nuclei that relay basal ganglia output to the frontal cortex. Although previous thalamostriatal studies emphasize projections from the intralaminar nuclei, studies in primates show a substantial projection from the ventral anterior (VA) and ventral lateral (VL) nuclei. These nuclei make up the main efferent projection from the basal ganglia to frontal cortical areas, including primary motor, supplementary, premotor, and cingulate motor areas. Functionally related motor areas of the frontal cortex and VA/VL have convergent projections to specific regions of the dorsal striatum. The distribution of VA/VL terminals within the striatum is crucial to understanding their relationship to motor cortical afferents. We placed anterograde tracer injections into discrete VA/VL thalamic areas. VA/VL thalamostriatal projections terminate in broad, rostrocaudal regions of the dorsal striatum, corresponding to regions innervated by functionally related cortical motor areas. The pars oralis division of VL projects primarily to the dorsolateral, postcommissural putamen, whereas the parvicellular VA targets more medial and rostral putamen regions, and the magnocellular division of VA targets the dorsal head of the caudate nucleus. Whereas these results demonstrate a general functional topography, specific VA/VL projections overlap extensively, suggesting that functionally distinct VA/VL projections may also converge in dorsal striatal areas. Within striatal territories, VA/VL projections terminate in a patchy, nonhomogeneous manner, indicating another level of complexity. Moreover, terminal fields contain both terminal clusters and scattered, long, unbranched fibers with many varicosities. These fiber morphologies resemble those from the cortex and raise the possibility that VA/VL thalamostriatal projections neurons have divergent connectional features.     

Topographical organization of the thalamic afferent connections to the motor cortex in the cat

The topographical distribution of the cortical afferent connections to the different subdivisions of the motor cortex (MC) was studied in adult cats. The retrograde axonal transport of horseradish peroxidase technique was used. Small single injections of the enzyme were made in the entire MC, including the hidden regions in the depth of the sulcus cruciatus. The areal location and density of the subsequent thalamic neuronal labeling were evaluated in each case. Comparison of the results obtained in the various cases shows that the following: (1) The ventral anterior-ventral lateral complex is the principal thalamic source of afferents to the MC. (2) The ventral medial, dorsal medial, the different components of the posterior thalamic group (lateral, medial, and ventral posteroinferior and suprageniculate nuclei), and the intralaminar, lateral anterior, lateral intermediate, lateral medial, and anteromedial thalamic nuclei are also thalamic sites in which neural projections to the MC arise. (3) The thalamocortical projections to the MC are sequentially organized. The connections arising from the lateral part of the thalamus end in the region of area 4 that is situated medially in the superior lip of the sulcus cruciatus and in the posterior sigmoid gyrus. The projections originating in the most medial thalamic regions terminate in that region of area 6a beta which is located in the medial part of the inferior lip of the cruciate sulcus, and in the anterior sigmoid gyrus. Moreover, the ventral thalamic areas send connections to the most anteriorly located zones of the MC, while the most dorsal thalamic ones project to the most posteriorly located parts of the MC. (4) This shift in the thalamocortical connections is not restrained by cytoarchitectonic boundaries, either in the thalamus or in the cortex. (5) The populations of thalamocortical cells which project to neighboring MC subdivisions exhibit consistent overlapping among themselves. (6) These findings suggest, moreover, that the basal ganglia and the cerebellar projections to the MC through the thalamus are arranged in a number of parallel pathways, which may occasionally overlap.     

Architectonic subdivisions of the motor thalamus of owl monkeys: Nissl,acetylcholinesterase, and cytochrome oxidase patterns

As the first part of an investigation of the motor thalamus and its cortical connections in the owl monkey, a New World anthropoid primate, we studied thalamic architecture by using stains for Nissl, acetylcholinesterase (AChE), and cytochrome oxidase (CO), in order to identify subdivisions of the ventrolateral thalamic region as well as other nuclei with motor connections. Material was obtained from brains cut in the frontal, horizontal, and parasagittal planes. Our results indicate that the ventrolateral thalamic region (VL) of owl monkeys is a heterogeneous structure composed of several architectonic subdivisions that resemble divisions that have been described in macaques and other Old World anthropoids. All of these subdivisions are more readily distinguished in AChE than in Nissl or CO preparations. The anterior part of VL, VLa (VLo of Olszewski), is characterized by clusters of medium-sized, darkly stained neurons. VLa is also distinguished by AChE-positive cells embedded in a matrix of neurites as well as by a characteristic dark, irregular net of blood vessels. The posterior part of VL is rather uniform cytoarchitectonically and contains large, darkly stained, and sparsely distributed neurons. However, we were able to distinguish three subdivisions of posterior VL that closely correspond to structures described by Olszewski in macaques: a principal segment, VLp (VPLo of Olszewski), a medial segment, VLx (“area X” of Olszewski), and a dorsal segment, VLd (VLc and VLps of Olszewski). In AChE, VLd is much darker than the other divisions. The distinction between VLp and VLx, which together make up the largest part of VL, is less marked, although VLp is somewhat darker and more irregular in appearance in AChE than is VLx. © 1994 Wiley-Liss, Inc.     

Relations between the basal ganglia and the thalamus of the primate. New morphologic data. New physiopathologic interpretations

Considerable progress has been made over the last few years in our knowledge of the thalamus and basal ganglia and their relationships to the cerebral cortex. More detailed topographic studies in the macaque have demonstrated the separation, in the lateral region of the thalamus, between afferent cerebellar and basal ganglia territories. These territories fail to correlate with the subdivision between ventral and dorsal elements or the limits of a single cytoarchitectonic nucleus. The cerebellar territory corresponds to VIL (or VPLo) which projects towards the primary cortex, and to VIM (or area X) and DI (or VLc) which project towards premotor cortex. The nigral (and tectal) territory corresponds to VOM (or VAmc) and to some parts of the medial nucleus and projects mainly towards the oculomotor area, supplementary motor area and prefrontal cortex. In return, the oculomotor area and substantia nigra project towards the colliculus superior. Several thalamic nuclei constitute the pallidal territory: VOL (or VLo) projects mainly towards supplementary motor area, LPo (or VApc) and Do towards the prefrontal cortex. The median center, which receives afferents from pallidum and motor cortex, projects towards the striatum but also the motor cortex. The parafascicular nucleus projects towards the striatum and premotor cortex. It is still not possible to transpose data acquired in the macaque to man, but functional reinterpretations are possible. A system which involves the median pallidum, VOL and supplementary motor area could control motor initiative and flow of movement. A second system, involving the substantia nigra, colliculus superior, thalamic relay and oculomotor area could control posture. The pallidum and substantia nigra, anterior part of lateral mass, medial nucleus and prefrontal cortex could elaborate motor programmes.     

Study of projections from the entopeduncular nucleus to the thalamus of the rat

The entopeduncular nucleus (EP) is a major outflow nucleus of the basal ganglia and innervates the lateral habenula, parafascicular, pedunculopontine, ventrolateral (VL), ventromedial (VM), and mediodorsal thalamic nuclei. This study investigated the morphology of single axons of entopeduncular neurons projecting to the motor thalamus by placing small injections of dextran biotin into the EP and reconstructing drawings of single axons from serial sections. There were two populations of entopeduncular-thalamic projection axons: those that projected only to the motor thalamus (VL and VM) and those that projected to both the motor thalamus and other nuclei (e.g., the habenula). The neurochemistry of EP neurons projecting to the thalamus was investigated by injecting the retrograde tracer FluoroGold into the VL and VM thalamic nuclei to retrogradely fill entopeduncular projection neurons. These were subsequently immunohistochemically labeled for choline acetyl transferase, gamma-aminobutyric acid (GABA), and glutamate. Consistent with previous studies, significant proportions of these neurons were GABA immunoreactive. In addition, approximately half of the entopeduncular-thalamic projecting neurons were found to be cholinergic. This excitatory input is most likely derived from axons that branch as they pass through the motor thalamus to the lateral habenula.     

Premotor Ramping of Thalamic Neuronal Activity Is Modulated by Nigral Inputs and Contributes to Control the Timing of Action Release

The ventromedial (VM)/ventro-anterior-lateral (VAL) motor thalamus is a key junction within the brain circuits sustaining normal and pathologic motor control functions and decision-making. In this area of thalamus, on one hand, the inhibitory nigro-thalamic pathway provides a main output from the basal ganglia, and, on the other hand, motor thalamo-cortical loops are involved in the maintenance of ramping preparatory activity before goal-directed movements. To better understand the nigral impact on thalamic activity, we recorded electrophysiological responses from VM/VAL neurons while male and female mice were performing a delayed right/left decision licking task. Analysis of correct (corr) and error trials revealed that thalamic ramping activity was stronger for premature licks (impulsive action) and weaker for trials with no licks [omission (omi)] compared with correct trials. Suppressing ramping activity through optogenetic activation of nigral terminals in the motor thalamus during the delay epoch of the task led to a reduced probability of impulsive action and an increased amount of omissions trials. We propose a parsimonious model explaining our data and conclude that a thalamic ramping mechanism contributes to the control of proper timing of action release and that inhibitory nigral inputs are sufficient to interrupt this mechanism and modulate the amount of motor impulsivity in this task.SIGNIFICANCE STATEMENT Coordinated neural activity in motor circuits is essential for correct movement preparation and execution, and even slight imbalances in neural processing can lead to failure in behavioral tasks or motor disorders. Here we focused on how failure to regulate the control of activity balance in the motor thalamus can be implicated in impulsive action release or omissions to act, through an activity ramping mechanism that is required for proper action release. Using optogenetic activation of inhibitory basal ganglia terminals in motor thalamus we show that basal ganglia input is well positioned to control this ramping activity and determine the timing of action initiation.     

Complementary distribution of glutamatergic cerebellar and GABAergic basal ganglia afferents to the rat motor thalamic nuclei

Motor thalamic nuclei, ventral anterior (VA), ventral lateral (VL) and ventral medial (VM) nuclei, receive massive glutamatergic and GABAergic afferents from the cerebellum and basal ganglia, respectively. In the present study, these afferents were characterized with immunoreactivities for glutamic acid decarboxylase of 67 kDa (GAD67) and vesicular glutamate transporter (VGluT)2, and examined by combining immunocytochemistry with the anterograde axonal labeling and neuronal depletion methods in the rat brain. VGluT2 immunoreactivity was intense in the caudodorsal portion of the VA-VL, whereas GAD67 immunoreactivity was abundant in the VM and rostroventral portion of the VA-VL. The rostroventral VA-VL and VM contained two types of GAD67-immunopositive varicosities (large and small), but the caudodorsal VA-VL comprised small ones alone. VGluT2-immunopositive varicosities were much larger in the caudodorsal VA-VL than those in the rostroventral VA-VL and VM. When anterograde tracers were injected into the basal ganglia output nuclei, the vast majority of labeled axon varicosities were large and distributed in the rostroventral VA-VL and VM, showing immunoreactivity for GAD67, but not for VGluT2. Only the large GAD67-immunopositive varicosities were mostly abolished by kainic acid depletion of substantia nigra neurons. In contrast, large to giant axon varicosities derived from the deep cerebellar nuclei were distributed mostly in the caudodorsal VA-VL, displaying VGluT2 immunoreactivity. The VGluT2-positive varicosities disappeared from the core portion of the caudodorsal VA-VL by depletion of cerebellar nucleus neurons. Thus, complementary distributions of large VGluT2- and GAD67-positive terminals in the motor thalamic nuclei are considered to reflect glutamatergic cerebellar and GABAergic basal ganglia afferents, respectively.     

Basal ganglia and thalamic input from neurons located within the ventral tier cell cluster region of the substantia nigra pars compacta in the rat

The most caudally located dopaminergic (DA) ventral tier neurons of the substantia nigra pars compacta (SNc) form typical cell clusters that are deeply embedded in the substantia nigra pars reticulata (SNr). Here we examine the efferent projections of 35 neurons located in the SNr region where these SNc cell clusters reside. The neuronal cell body was injected with biotinylated dextran amine so as to trace each complete axon in the sagittal or the coronal plane. Electrophysiological guidance guaranteed that the tracer was ejected among neurons displaying a typical SNc discharge pattern. Furthermore, double immunofluorescence and immunohistochemical labeling ensured that the tracer deposits were placed within the DA cell clusters. Three types of projection neurons occurred in the SNc ventral tier cell cluster region: type I neurons, projecting to basal ganglia; type II neurons, targeting both the basal ganglia and thalamus; and type III neurons, projecting only to the thalamus. The striatum was targeted by most of the type I and II neurons and the innervation reached both the striosome/subcallosal streak and matrix compartments. Many nigrostriatal fibers provided collaterals to the globus pallidus and, less frequently, to the subthalamic nucleus. At a thalamic level, type II and III neurons preferentially targeted the reticular, ventral posterolateral, and ventral medial nuclei. Our results reveal that the SNr region where DA ventral tier cell clusters reside harbors neurons projecting to the basal ganglia and/or the thalamus, thus suggesting that neurodegeneration of nigral neurons in Parkinson′s disease might affect various extrastriatal basal ganglia structures and multiple thalamic nuclei. J. Comp. Neurol. 518:1283–1300, 2010. © 2009 Wiley‐Liss, Inc.     

Thalamo-cortical connections of areas 3a and M1 in marmoset monkeys.

The present investigation is part of a broader effort to examine cortical areas that contribute to manual dexterity, reaching, and grasping. In this study we examine the thalamic connections of electrophysiologically defined regions in area 3a and architectonically defined primary motor cortex (M1). Our studies demonstrate that area 3a receives input from nuclei associated with the somatosensory system: the superior, inferior, and lateral divisions of the ventral posterior complex (VPs, VPi, and VPl, respectively). Surprisingly, area 3a receives the majority of its input from thalamic nuclei associated with the motor system, posterior division of the ventral lateral nucleus of the thalamus (VL), the mediodorsal nucleus (MD), and intralaminar nuclei including the central lateral nucleus (CL) and the centre median nucleus (CM). In addition, sparse but consistent projections to area 3a are from the anterior pulvinar (Pla). Projections from the thalamus to the cortex immediately rostral to area 3a, in the architectonically defined M1, are predominantly from VL, VA, CL, and MD. There is a conspicuous absence of inputs from the nuclei associated with processing somatic inputs (VP complex). Our results indicate that area 3a is much like a motor area, in part because of its substantial connections with motor nuclei of the thalamus and motor areas of the neocortex (Huffman et al. [2000] Soc. Neurosci. Abstr. 25:1116). The indirect input from the cerebellum and basal ganglia via the ventral lateral nucleus of the thalamus supports its role in proprioception. Furthermore, the presence of input from somatosensory thalamic nuclei suggests that it plays an important role in somatosensory and motor integration.     

Basal forebrain cholinergic and noncholinergic projections to the thalamus and brainstem in cats and monkeys

The projections of basal forebrain neurons to the thalamus and the brainstem were investigated in cats and primates by using retrograde transport techniques and choline acetyltransferase (ChAT) immunohistochemistry. In a first series of experiments, the lectin wheat germ-agglutinin conjugated with horseradish peroxidase (WGA-HRP) was injected into all major sensory, motor, intralaminar, and reticular (RE) thalamic nuclei of cats and into the mediodorsal (MD) and pulvinar-lateroposterior thalamic nuclei of macaque monkeys. In cats numerous neurons of the vertical and horizontal limbs of the diagonal band nucleus and the substantia innominata (SI), including its rostromedial portion termed the ventral pallidum (VP), were retrogradely labeled after WGA-HRP injections in the rostral pole of the RE complex, the MD, and anteroventral/anteromedial (AV/AM) thalamic nuclei. Fewer retrogradely labeled cells were observed in the same areas after injections in the ventromedial (VM) thalamic nucleus, and none or very few after other thalamic injections. After RE, MD, and AV/AM injections, 7-20% of all retrogradely labeled cells in the basal forebrain were also ChAT positive, while none of the retrogradely labeled neurons following VM injections displayed ChAT immunoreactivity. The basal forebrain projection to the MD nucleus was shown to arise principally from VP in both cats and macaque monkeys. In a second series of experiments performed in cats, injections of WGA-HRP in the brainstem peribrachial (PB) area comprising the pedunculopontine nucleus led to retrograde labeling of a moderate number of neurons in the lateral part of the VP, SI, and preoptic area (POA), only a few of which displayed ChAT immunoreactivity. In addition, a large number of retrogradely labeled cells were observed in the bed nuclei of the anterior commissure and stria terminalis after PB injections. In a third series of experiments, the use of the retrograde double-labeling method with fluorescent tracers in squirrel monkeys allowed us to identify a significant number of basal forebrain neurons sending axon collaterals to both the RE thalamic nucleus and PB brainstem area, while no double-labeled neurons were disclosed after injections confined to the ventral anterior/ventral lateral (VA/VL) thalamic nuclei and PB area or following injections in the cerebral cortex and PB area. Our findings reveal the existence of cholinergic and noncholinergic basal forebrain projections to the thalamus and the brainstem in both cats and macaque monkeys. We suggest that these projections may play a crucial role in the control of thalamic functions in mammals.     

How do the basal ganglia and cerebellum gain access to the cortical motor areas?

We have used retrograde transport of wheat germ agglutinin conjugated to horseradish peroxidase to examine the origin of the thalamic input to the two premotor areas with the densest projections to the motor cortex. These are: arcuate premotor area (APA) and the supplementary motor area (SMA). Retrograde transport demonstrated that the two premotor areas and the motor cortex each receive thalamic input from separate, cytoarchitectonically well-defined subdivisions of the ventrolateral thalamus. According to the nomenclature of Olszewski (1952), input to the APA originates largely from area X; input to the SMA originates largely from the pars oralis subdivision of the nucleus ventralis lateralis (VLo); and that to the motor cortex is largely from the pars oralis subdivision of the nucleus ventralis posterior lateralis (VPLo). These observations, when combined with prior studies on the termination of various subcortical efferents in the thalamus, lead to the following scheme of projections: rostral portions of the deep cerebellar nuclei project to motor cortex via VPLo, caudal portions of the deep cerebellar nuclei project to the APA via area X; and the globus pallidus projects to the SMA via VLo. Thus each thalamocortical pathway is associated with a distinct subcortical input.     

The primate mediodorsal (MD) nucleus and its projection to the frontal lobe

The frontal lobe projections of the mediodorsal (MD) nucleus of the thalamus were examined in rhesus monkey by transport of retrograde markers injected into one of nine cytoarchitectonic regions (Walker's areas 6, 8A, 9, 10, 11, 12, 13, 46, and Brodmann's area 4) located in the rostral third of the cerebrum. Each area of prefrontal, premotor, or motor cortex injected was found to receive a topographically unique thalamic input from clusters of cells in specific subdivisions within MD. All of the prefrontal areas examined also receive topographically organized inputs from other thalamic nuclei including, most prominently, the ventral anterior (VA) and medial pulvinar nuclei. Conversely, and in agreement with previous findings, MD projects to areas of the frontal lobe beyond the traditional borders of prefrontal cortex, such as the anterior cingulate and supplementary motor cortex. The topography of thalamocortical neurons revealed in coronal sections through VA, MD, and pulvinar is circumferential. In the medial part of MD, for example, thalamocortical neurons shift from a dorsal to a ventral position for cortical targets lying medial to lateral along the ventral surface of the lobe; neurons in the lateral MD move from a ventral to a dorsal position, for cortical areas situated lateral to medial on the convexity of the hemisphere. The aggregate evidence for topographic specificity is supported further by experiments in which different fluorescent dyes were placed in multiple areas of the frontal lobe in each of three cases. The results show that very few, if any, thalamic neurons project to more than one area of cortex. The widespread cortical targets of MD neurons together with evidence for multiple thalamic inputs to prefrontal areas support a revision of the classical hodological definition of prefrontal cortex as the exclusive cortical recipient of MD projections. Rather, the prefrontal cortex is defined by multiple specific relationships with the thalamus.     

Thalamic relay nuclei for cerebellar and certain related fiber systems in the cat.

Anterograde labeling techniques were used to define the terminal distributions in the thalamus of afferents arising in the deep cerebellar nuclei, entopeduncular nucleus and substantia nigra. Anterograde and retrograde labeling methods were then used to determine the extent of the cortical projections of the cerebellar relay nuclei. The cerebellar projection to the contralateral ventral nuclei of the thalamus terminates in a zone which is separate from that receiving pallido- and nigrothalamic fibers. None of the zones of termination of these fiber systems corresponds to commonly recognized cytoarchitectonic divisions. Instead, they include parts of the ventroanterior (VA), ventrolateral (VL) and principal ventromedial (VMp) nuclei. Some cells within the zone of termination of cerebellar afferents project to parietal cortex (areas 5 and 7). A further, distinct group of cells in this zone projects to motor cortex (area 4). But projections to area 4 also arise from small groups of cells: (a) in the zone receiving nigro- and pallidothalamic fibers; (b) in the part of VL, distinct from the cerebellar terminal zone, in which spinothalamic fibers terminate. Cerebellar, nigral, and entopeduncular fibers also terminate in the intralaminar nuclei. These projections are far greater in extent than those arising in the spinal cord. Some parts of the intralaminar nuclei are dominated by a particular afferent system, while others show substantial overlap of the terminal zone of several afferent systems.     

Neural circuits and functional organization of the striatum

The basal ganglia and motor thalamic nuclei are functionally and anatomically divided into the sensorimotor, supplementary motor, premotor, associative and limbic territories. There exist both primary segregated basal ganglia-thalamocortical loops and convergence of functionally related information from different cortical areas onto these cortical basal gaglia-thalamocortical loops. The basal ganglia-thalamocortical loop arising from the sensorimotor area, supplementary motor area (SMA), premotor area and cingulate motor area provides distinct segregated subloops through the functionally distict stritial, pallidal and thalamic regions with partial overlap. The subthalamic nucleus (STN) is also topographically organized. The ventrolateral part of the caudal 2/3 levels of the medial pallidal segment (GPi) projects to the primary motor area via the oral part of the ventral lateral thalamic nucleus (VLo) (Voa, Vop by Hassler's nomenclature). The thalamic relay nuclei of the GPi projection to SMA are identified in the transitional zoe of the VApc (parvicellular part of the anterior ventral nucleus)-VLo and in the rostromedical part of the VLo. The thalamic nuclei relaying the cingulate subloop are not yet clearly defined. The supplementary motor subloop appears to be divided into the pre-SMA and SMA proper subloops. The premotor area is also divided into the dorsal premotor area subloop and the ventral premotor area subloop. It is suggested that the limbic loop consists of a number of subloops in the monkey as indicated by Haber et al. [67] and in rats [64]. We review here the microcircuitry of the striatum, as well as the convergence and integration between the functionally segregated loops. Finally, we discuss the functional implications of stritial connections.

     

Thalamic connections of the primary motor cortex (M1) of owl monkeys

To determine the relative contributions of transthalamic cerebellar and pallidal projections to the primary motor cortex (M1) of owl monkeys, we examined the thalamic labeling resulting from injections of fluorescent tracers and wheatgerm agglutinin/horseradish peroxidase conjugate (WGA-HRP) into regions of M1 identified by intracortical microstimulation. Injections were placed in the major somatotopic divisions of M1 (the hindlimb, trunk, forelimb, and face representations) and in the caudal and rostral M1 subareas. In most cases, we injected several differentiable tracers into different parts of M1. Our results indicate that the strongest connections of M1 are with subdivisions of the ventral lateral thalamus (VL); other connections are mainly with intralaminar nuclei (the central lateral, paracentral, and center median nuclei) and the reticular nucleus. Most projections are reciprocal and topographically organized. M1 is strongly connected with the principal (VLp), medial (VLx), and anterior (VLa) subdivisions of the VL complex but has at most weak connections with the dorsal division (VLd). Each of the major somatotopic divisions of M1 is connected with an anteroposteriorly elongated territory within the VL complex. The connections are somatotopically organized such that the M1 hindlimb representation is connected with a band of cells in the lateral and anterior portions of the VL complex (spanning VLa and VLp), whereas the trunk, forelimb, and face representations are connected with successively more medially and posteriorly situated cell bands (spanning VLa, VLp, and VLx). There is some degree of overlap between the somatotopic territories within VL, although the absence of double-labeled cells in cases with injections of adjacent somatotopic divisions of M1 suggests that individual thalamic neurons project to single somatotopic regions. In addition to somatotopic differences, the connections of the caudal and rostral subdivisions of M1 differ to some extent. Caudal M1 is connected most strongly with VLp, a target of cerebellar projections, but it is also connected with VLa, which receives pallidal inputs. In complementary fashion, rostral M1 is most strongly connected with VLa, but it is also connected with VLp. VLx, a target of cerebellar projections, has significant connections with both caudal and rostral M1. These results indicate that all parts of M1 are influenced by both the cerebellum and globus pallidus in owl monkeys, as has been suggested in some recent studies of macaque monkeys. © 1994 Wiley-Liss, Inc.     

Thalamic input to inferior area 6 and area 4 in the macaque monkey

Recent cytoarchitectonic, histochemical, and hodological studies in primates have shown that area 6 is formed by three main sectors: the supplementary motor area, superior area 6, which lies medial to the spur of the arcuate sulcus, and inferior area 6, which is located lateral to it. Inferior area 6 has been further subdivided into two histochemical areas: area F5, located along the inferior limb of the arcuate sulcus, and area F4, located between area F5 and area 4 (area F1). The present study traced the thalamocortical projections of inferior area 6 and the adjacent part of area 4 by injecting small amounts of WGA-HRP in specific sectors of the agranular frontal cortex. Our data showed that each histochemical area receives a large projection from one nucleus of the ventrolateral thalamus (motor thalamus) and additional projections from other nuclei of this thalamic sector. Area F5 receives a large projection from area X of Olszewski ('52) and additional projections from the caudal part of the nucleus ventralis posterior lateralis, pars oralis (VPLo), and the nucleus ventralis lateralis, pars caudalis (VLc) (VPLo-VLc complex). Area F4 receives a large projection from the nucleus ventralis lateralis, pars oralis (VLo), and additional projections from area X and the VPLo-VLc complex. The rostral part of area F1 is innervated chiefly by VLo, plus smaller contributions from rostral VPLo and the VPLo-VLc complex. The caudal part of F1 receives its greatest input from VPLo, with a small contribution from VLo. In addition, each histochemical area receives projections originating from the intralaminar thalamic nuclei, the posterior thalamus, and--for area F4 and area F5--also from the nucleus medialis dorsalis (MD). Analysis of the physiological properties of the various histochemical areas in relation to their main thalamic input showed that those cortical fields in which distal movements are predominant (area F5, caudal part of area F1) are innervated chiefly by area X and VPLo, whereas those cortical fields in which proximal movements are predominant receive their main input from VLo. Because VPLo and area X are targets of cerebellothalamic pathways, whereas VLo receives a pallidal input, we propose that the cortical fields in which distal movements are most heavily represented are mainly under the influence of the cerebellum, whereas the cortical fields in which proximal movements are most heavily represented are mainly under the influence of the basal ganglia.     

Contralateral pallidothalamic and pallidotegmental projections in primates: an anterograde and retrograde labeling study.

Unilateral injections of the anterograde tracer Phaseolus vulgaris-leucoagglutinin (PHA-L) in the internal segment of the pallidum (GPi) of the squirrel monkey (Saimiri sciureus) led to anterograde labeling of fibers ipsilaterally in the following thalamic nuclei: ventral anterior (VA), ventral lateral (VL), centromedian (CM), and lateral habenula (Hbl). The labeled fibers reached these ipsilateral thalamic nuclei by coursing along or through the ansa lenticularis, the lenticular and thalamic fasciculi, and the Forel's fields. They arborized profusely in VA/VL nuclei where they displayed small glomerule-like formations. Numerous labeled fibers also occurred in the CM. Most of them were long, varicose and gave rise to shorter fibers that formed a dense terminal field covering a large portion of the CM. A small but dense terminal field composed of delicate fibers and extremely fine terminals was noted in the Hbl. A large contingent of labeled fibers were seen to cross the midline, principally at the rostral pole of the CM and in the supramammillary decussation, to reach the contralateral thalamus where they arborized profusely in the VA/VL and CM nuclei, but not in the Hbl. The patterns of termination of these contralateral pallidothalamic fibers were strikingly similar to those observed ipsilaterally. Other anterogradely labeled fibers were also noted bilaterally in the pedunculopontine nucleus (TPP) and ipsilaterally in the external segment of the pallidum (GPe) and in the putamen. Complementary, double-labeling, retrograde studies involving the injection of nuclear yellow in the VA/VL and CM nuclei and Fast blue in the TPP, confirmed the existence of contralateral pallidothalamic and pallidotegmental projections. The number of retrogradely labeled cells in the contralateral GPi amounted approximately to 10-20% that in the ipsilateral GPi. These experiments further indicated that contralaterally projecting pallidothalamic neurons exhibited a high degree of axonal collateralization, the majority of its neurons projecting also to the contralateral TPP. Cells retrogradely labeled with the tracer injected into the thalamus were also encountered bilaterally in the thalamic reticular nucleus. Taken together, the results of these anterograde and retrograde investigations indicate that the contralateral pallidothalamic projection involves a relatively small population of GPi neurons, but that these neurons arborize extensively in their contralateral thalamic targets. Furthermore, the presence of retrogradely labeled cells in the ipsi- and contralateral reticular thalamic nucleus indicates that the VA/VL and CM nuclei, which receive a massive input from the GPi, are under the bilateral influence of this perithalamic nucleus. Such contralateral projections could play a major role in the subcortical organization of the bilateral aspect of normal basal ganglia function.(ABSTRACT TRUNCATED AT 400 WORDS)