Pathways from the superior colliculus and the nucleus of the optic tract to the posterior parietal cortex in macaque monkeys: Functional frameworks for representation updating and online movement guidance.

The posterior parietal cortex (PPC) integrates multisensory and motor-related information for generating and updating body representations and movement plans. We used retrograde transneuronal transfer of rabies virus combined with a conventional tracer in macaque monkeys to identify direct and disynaptic pathways to the arm-related rostral medial intraparietal area (MIP), the ventral lateral intraparietal area (LIPv), belonging to the parietal eye field, and the pursuit-related lateral subdivision of the medial superior temporal area (MSTl). We found that these areas receive major disynaptic pathways via the thalamus from the nucleus of the optic tract (NOT) and the superior colliculus (SC), mainly ipsilaterally. NOT pathways, targeting MSTl most prominently, serve to process the sensory consequences of slow eye movements for which the NOT is the key sensorimotor interface. They potentially contribute to the directional asymmetry of the pursuit and optokinetic systems. MSTl and LIPv receive feedforward inputs from SC visual layers, which are potential correlates for fast detection of motion, perceptual saccadic suppression and visual spatial attention. MSTl is the target of efference copy pathways from saccade- and head-related compartments of SC motor layers and head-related reticulospinal neurons. They are potential sources of extraretinal signals related to eye and head movement in MSTl visual-tracking neurons. LIPv and rostral MIP receive efference copy pathways from all SC motor layers, providing online estimates of eye, head and arm movements. Our findings have important implications for understanding the role of the PPC in representation updating, internal models for online movement guidance, eye-hand coordination and optic ataxia.

Ascending vestibular pathways to parietal areas MIP and LIPv and efference copy inputs from the medial reticular formation: Functional frameworks for body representations updating and online movement guidance.

The posterior parietal cortex (PPC) serves as a sensorimotor interface by integrating multisensory signals with motor related information for generating and updating body representations and movement plans. Using retrograde transneuronal transfer of rabies virus combined with a conventional tracer, we identified direct and polysynaptic pathways to two PPC areas, the rostral medial intraparietal area (MIP) and the ventral part of the lateral intraparietal area (LIPv) in macaque monkeys. We found that rostral MIP and LIPv receive ascending vestibular pathways, and putative efference copy inputs disynaptically from the medullary medial reticular formation (MRF) where reticulospinal pathways to neck and arm motoneurons originate. LIPv receives minor disynaptic vestibular inputs, and substantial projections from the head movement-related rostral MRF, consistent with head gain modulation of LIPv activity and a role in planning gaze shifts. Rostral MIP is the target of prominent disynaptic pathways from reaching- and head movement-related MRF domains, and major ascending vestibular pathways trisynaptically from both labyrinths, explaining prominent vestibular responses and discrimination between active and passive movements demonstrated in rostral MIP and in the neighboring ventral intraparietal area, which are heavily interconnected. The findings that rostral MIP (belonging to the 'parietal reach region'), receives vestibular inputs as directly as classical vestibular areas, via a parallel channel, and efference copy signals pathways from MRF reticulospinal domains that belong to reach and head movement networks have important implications for the understanding of the role of the PPC in updating body representations and internal models for online guidance of movement.

The control of eye movements by the cerebellar nuclei: polysynaptic projections from the fastigial, interpositus posterior and dentate nuclei to lateral rectus motoneurons in primates.

Premotor circuits driving extraocular motoneurons and downstream motor outputs of cerebellar nuclei are well known. However, there is, as yet, no unequivocal account of cerebellar output pathways controlling eye movements in primates. Using retrograde transneuronal transfer of rabies virus from the lateral rectus (LR) eye muscle, we studied polysynaptic pathways to LR motoneurons in primates. Injections were placed either into the central or distal muscle portion, to identify innervation differences of LR motoneurons supplying singly innervated (SIFs) or multiply innervated muscle fibers (MIFs). We found that SIF motoneurons receive major cerebellar 'output channels' bilaterally, while oligosynaptic cerebellar innervation of MIF motoneurons is negligible and/or more indirect. Inputs originate from the fastigial nuclei di- and trisynaptically, and from a circumscribed rostral portion of the ventrolateral interpositus posterior and from the caudal pole of the dentate nuclei trisynaptically. While disynaptic cerebellar inputs to LR motoneurons stem exclusively from the caudal fastigial region involved in saccades, pursuit and convergence (via its projections to brainstem oculomotor populations), minor trisynaptic inputs from the rostral fastigial nucleus, which contributes to gaze shifts, may reflect access to vestibular and reticular eye-head control pathways. Trisynaptic inputs to LR motoneurons from the rostral ventrolateral interpositus posterior, involved in divergence (far-response), is likely mediated by projections to the supraoculomotor area, contributing to LR motoneuron activation during divergence. Trisynaptic inputs to LR motoneurons from the caudal dentate, which also innervates disynaptically the frontal and parietal eye fields, can be explained by its superior colliculus projections, and likely target saccade-related burst neurons.

Face-infringement space: the frame of reference of the ventral intraparietal area.

Experimental studies have shown that responses of ventral intraparietal area (VIP) neurons specialize in head movements and the environment near the head. VIP neurons respond to visual, auditory, and tactile stimuli, smooth pursuit eye movements, and passive and active movements of the head. This study demonstrates mathematical structure on a higher organizational level created within VIP by the integration of a complete set of variables covering face-infringement. Rather than positing dynamics in an a priori defined coordinate system such as those of physical space, we assemble neuronal receptive fields to find out what space of variables VIP neurons together cover. Section 1 presents a view of neurons as multidimensional mathematical objects. Each VIP neuron occupies or is responsive to a region in a sensorimotor phase space, thus unifying variables relevant to the disparate sensory modalities and movements. Convergence on one neuron joins variables functionally, as space and time are joined in relativistic physics to form a unified spacetime. The space of position and motion together forms a neuronal phase space, bridging neurophysiology and the physics of face-infringement. After a brief review of the experimental literature, the neuronal phase space natural to VIP is sequentially characterized, based on experimental data. Responses of neurons indicate variables that may serve as axes of neural reference frames, and neuronal responses have been so used in this study. The space of sensory and movement variables covered by VIP receptive fields joins visual and auditory space to body-bound sensory modalities: somatosensation and the inertial senses. This joining of allocentric and egocentric modalities is in keeping with the known relationship of the parietal lobe to the sense of self in space and to hemineglect, in both humans and monkeys. Following this inductive step, variables are formalized in terms of the mathematics of graph theory to deduce which combinations are complete as a multidimensional neural structure that provides the organism with a complete set of options regarding objects impacting the face, such as acceptance, pursuit, and avoidance. We consider four basic variable types: position and motion of the face and of an external object. Formalizing the four types of variables allows us to generalize to any sensory system and to determine the necessary and sufficient conditions for a neural center (for example, a cortical region) to provide a face-infringement space. We demonstrate that VIP includes at least one such face-infringement space.

Harmaline attenuates voltage--sensitive Ca(2+) currents in neurons of the inferior olive.

PURPOSE: Harmaline is one member of a class of tremorgenic harmala alkaloids that have been implicated in neuroprotective effects and neurodegenerative disorders. It has been reported to interact with several neurotransmitter receptors as well as ion exchangers and voltage-sensitive channels. One site of harmaline action in the brain is the inferior olive (IO). Either local or systemic harmaline injection has been reported to increase spiking rate and coherence in the inferior olive and this activation is thought to produce tremor and ataxia through inferior olivary neuron activation of target neurons in the cerebellum, but the cellular mechanism is not yet known. METHODS: Here, we have performed whole cell voltage-clamp and current clamp recordings from olivary neurons in brain slices derived from newborn rats. RESULTS: We found that both transient low-voltage activated (LVA) and sustained high voltage-activated (HVA) Ca(2+) currents are significantly attenuated by 0.125 - 0.25 mM harmaline applied to the bath and that this attenuation is partially reversible. In current clamp recordings, spike-afterhyperpolarization complexes were evoked by brief positive current injections. Harmaline produced a small attenuation of spike amplitude, but large spike broadening associated with attenuation of the fast and medium afterhyperpolarization. CONCLUSION: Our data suggest that one mode of olivary neuron activation by harmaline involves attenuation of both HVA and LVA Ca(2+) conductances and consequent attenuation of Ca(2+)-sensitive K(+) conductances resulting in spike broadening and attenuation of the afterhyperpolarization. Both of HVA and LVA attenuation also suggests a role to regulate intracelluar Ca(2+), thereby to protect neurons from apoptosis.

Proprioceptive pathways to posterior parietal areas MIP and LIPv from the dorsal column nuclei and the postcentral somatosensory cortex.

The posterior parietal cortex (PPC) serves as an interface between sensory and motor cortices by integrating multisensory signals with motor-related information. Sensorimotor transformation of somatosensory signals is crucial for the generation and updating of body representations and movement plans. Using retrograde transneuronal transfer of rabies virus in combination with a conventional tracer, we identified direct and polysynaptic somatosensory pathways to two posterior parietal areas, the ventral lateral intraparietal area (LIPv) and the rostral part of the medial intraparietal area (MIP) in macaque monkeys. In addition to direct projections from somatosensory areas 2v and 3a, respectively, we found that LIPv and MIP receive disynaptic inputs from the dorsal column nuclei as directly as these somatosensory areas, via a parallel channel. LIPv is the target of minor neck muscle-related projections from the cuneate (Cu) and the external cuneate nuclei (ECu), and direct projections from area 2v, that likely carry kinesthetic/vestibular/optokinetic-related signals. In contrast, MIP receives major arm and shoulder proprioceptive inputs disynaptically from the rostral Cu and ECu, and trisynaptically (via area 3a) from caudal portions of these nuclei. These findings have important implications for the understanding of the influence of proprioceptive information on movement control operations of the PPC and the formation of body representations. They also contribute to explain the specific deficits of proprioceptive guidance of movement associated to optic ataxia.

Comparative anatomy of the locus coeruleus in humans and nonhuman 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.

Cerebellar inputs to intraparietal cortex areas LIP and MIP: functional frameworks for adaptive control of eye movements, reaching, and arm/eye/head movement coordination.

Using retrograde transneuronal transfer of rabies virus in combination with a conventional tracer (cholera toxin B), we studied simultaneously direct (thalamocortical) and polysynaptic inputs to the ventral lateral intraparietal area (LIPv) and the medial intraparietal area (MIP) in nonhuman primates. We found that these areas receive major disynaptic inputs from specific portions of the cerebellar nuclei, the ventral dentate (D), and ventrolateral interpositus posterior (IP). Area LIPv receives inputs from oculomotor domains of the caudal D and IP. Area MIP is the target of projections from the ventral D (mainly middle third), and gaze- and arm-related domains of IP involved in reaching and arm/eye/head coordination. We also showed that cerebellar cortical "output channels" to MIP predominantly stem from posterior cerebellar areas (paramedian lobe/Crus II posterior, dorsal paraflocculus) that have the required connectivity for adaptive control of visual and proprioceptive guidance of reaching, arm/eye/head coordination, and prism adaptation. These findings provide important insight about the interplay between the posterior parietal cortex and the cerebellum regarding visuospatial adaptation mechanisms and visual and proprioceptive guidance of movement. They also have potential implications for clinical approaches to optic ataxia and neglect rehabilitation.

Posterior parietal cortex areas MIP and LIPv receive eye position and velocity inputs via ascending preposito-thalamo-cortical pathways.

Neuronal activity encoding eye position and gaze signals participates in updating the spatial representations found in the posterior parietal cortex and is necessary for spatial accuracy in goal-directed movements. Using retrograde transneuronal transfer of rabies virus in combination with a conventional tracer, we studied direct and polysynaptic inputs to the ventral lateral intraparietal area (LIPv) and medial intraparietal area (MIP) in non-human primates, to identify possible sources of eye position and gaze signals. We found that these areas receive disynaptic inputs from the brainstem horizontal eye position integrator network (nucleus prepositus hypoglossi, PH) via the central lateral and ventral lateral thalamic nuclei. Our findings provide the first demonstration that inputs from the horizontal eye position integrator reach cortical areas. We found important topographical differences between PH populations targeting MIP and LIPv that likely reflect transmission of different types of eye movement signals. LIPv receives projections from the ipsilateral rostral PH, which may transmit ipsilateral eye position signals. In addition to inputs from the rostral PH, MIP receives strong projections from the contralateral caudal PH, which may contribute to both eye position and velocity signals. Unlike the horizontal integrator, we found that the vertical eye position integrator network, the interstitial nucleus of Cajal, does not project to these posterior parietal areas, in keeping with findings that the thalamic nuclei targeting LIPv and MIP receive almost exclusively horizontal oculomotor signals.

Horizontal eye movement networks in primates as revealed by retrograde transneuronal transfer of rabies virus: differences in monosynaptic input to "slow" and "fast" abducens motoneurons.

The sources of monosynaptic input to "fast" and "slow" abducens motoneurons (MNs) were revealed in primates by retrograde transneuronal tracing with rabies virus after injection either into the distal or central portions of the lateral rectus (LR) muscle, containing, respectively, "en grappe" endplates innervating slow muscle fibers or "en plaque" motor endplates innervating fast fibers. Rabies uptake involved exclusively motor endplates within the injected portion of the muscle. At 2.5 days after injections, remarkable differences of innervation of slow and fast MNs were demonstrated. Premotor connectivity of slow MNs, revealed here for the first time, involves mainly the supraoculomotor area, central mesencephalic reticular formation, and portions of medial vestibular and prepositus hypoglossi nuclei carrying eye position and smooth pursuit signals. Results suggest that slow MNs are involved exclusively in slow eye movements (vergence and possibly smooth pursuit), muscle length stabilization and gaze holding (fixation), and rule out their participation in fast eye movements (saccades, vestibulo-ocular reflex). By contrast, all known monosynaptic pathways to LR MNs innervate fast MNs, showing their participation in the entire horizontal eye movements repertoire. Hitherto unknown monosynaptic connections were also revealed, such as those derived from the central mesencephalic reticular formation and vertical eye movements pathways (Y group, interstitial nucleus of Cajal, rostral interstitial nucleus of the medial longitudinal fasciculus). The different connectivity of fast and slow MNs parallel differences in properties of muscle fibers that they innervate, suggesting that muscle fibers properties, rather than being self-determined, are the result of differences of their premotor innervation.

Discrimination between active and passive head movements by macaque ventral and medial intraparietal cortex neurons.

An important prerequisite for effective motor action is the discrimination between active and passive body movements. Passive movements often require immediate reflexes, whereas active movements may demand suppression of the latter. The vestibular system maintains correct body and head posture in space through reflexes. Since vestibular inputs have been reported to be largely suppressed in the vestibular nuclei during active head movements, we investigated whether head movement-related signals in the primate parietal cortex, a brain region involved in self-motion perception, could support both reflex functions and self-movement behaviour. We employed a paradigm that made available direct comparison of neuronal discharge under active and passive movement conditions. In this study, we demonstrate that a population of intraparietal (VIP (ventral) and MIP (medial)) cortex neurons change their preferred directions during horizontal head rotations depending on whether animals have performed active movements, or if they were moved passively. In other neurons no such change occurred. A combination of these signals would provide differential information about the active or passive nature of an ongoing movement. Moreover, some neurons' responses clearly anticipated the upcoming active head movement, providing a possible basis for vestibular-related reflex suppression. Intraparietal vestibular neurons thus distinguish between active and passive head movements, and their responses differ substantially from those reported in brainstem vestibular neurons, regarding strength, timing, and direction selectivity. We suggest that the contextual firing characteristics of these neurons have far-reaching implications for the suppression of reflex movements during active movement, and for the representation of space during self-movement.

Vestibular signals of posterior parietal cortex neurons during active and passive head movements in macaque monkeys.

The posterior parietal cortex may function as an interface between sensory and motor cortices and thus could be involved in the formation of motor plans as well as abstract representations of space. We have recorded from neurons in the intraparietal sulcus, namely, the ventral and medial intraparietal areas (VIP and MIP, respectively), and analyzed their head-movement-related signals in relation to passive and active movements. To generate active head movements, we made the animals track a moving fixation spot in the horizontal plane under head-free conditions. When under certain circumstances the animals were tracking the fixation spot almost exclusively via head movements, a clear correlation between neuronal firing rate and head movement could be established. Furthermore, a newly employed paradigm, the "replay method," made available direct comparison of neuronal firing behavior under active and passive movement conditions. In such case, the animals were allowed to make spontaneous head movements in darkness. Subsequently, the heads were fixed and the previously recorded active head-movement profile was reproduced by a turntable as passive stimulation. Neuronal responses ranged from total extinction of the vestibular signal during active movement to presence of activity only during active movement. Furthermore, in approximately one-third of the neurons, a change of vestibular on-direction depending on active versus passive movement mode was observed, that is, type I neurons became type II neurons, etc. We suggest that the role of parietal vestibular neurons has to be sought in sensory space representation rather than reflex behavior and motor control contexts.

Vestibular response kinematics in posterior parietal cortex neurons of macaque monkeys.

Perception of extrapersonal space is a fundamental requirement for accurate interaction with the environment and moving in it. Parietal cortical areas are thought to play an important role in this function. A significant sensory input to this area arrives from the vestibular system. We quantified neuronal responses in the ventral intraparietal area and the medial intraparietal area of awake head-fixed macaque monkeys during classical vestibular sinusoidal stimulation protocols and with a newly developed random vestibular testing paradigm. The goal was to study more specifically the signal content of parietal vestibular neurons with respect to head movement kinematics. Traditional sinusoidal stimulation analysis revealed that about one-third of the neurons responded in phase with either head position or head acceleration, besides classical head velocity tuning. Random vestibular stimulation revealed more complex signal profiles in the majority of neurons, although quantification of the kinematic variables that drove the neurons most effectively led to similar results to phase shift analysis. Thus, a majority of cells was principally driven by head velocity, and a minority by either acceleration or position. Nevertheless, random stimulation also revealed the simultaneous presence of all three kinematic response parameters (i.e. velocity, position and acceleration) in a majority of neurons. A minority of cells coded only two kinematic variables, i.e. head velocity coupled with either acceleration or position. Neurons coding only one kinematic variable were not found. We hereby demonstrate for the first time that central vestibular neurons carry several head movement kinematic variables simultaneously.

Heading encoding in the macaque ventral intraparietal area (VIP).

We recorded neuronal responses to optic flow stimuli in the ventral intraparietal area (VIP) of two awake macaque monkeys. According to previous studies on optic flow responses in monkey extrastriate cortex we used different stimulus classes: frontoparallel motion, radial stimuli (expansion and contraction) and rotational stimuli (clockwise and counter-clockwise). Seventy-five percent of the cells showed statistically significant responses to one or more of these optic flow stimuli. Shifting the location of the singularity of the optic flow stimuli within the visual field led to a response modulation in almost all cases. For the majority of neurons, this modulatory influence could be approximated in a statistically significant manner by a two-dimensional linear regression. Gradient directions, derived from the regression parameters and indicating the direction of the steepest increase in the responses, were uniformly distributed. At the population level, an unbiased average response for the stimuli with different focus locations was observed. By applying a population code, termed 'isofrequency encoding', we demonstrate the capability of the recorded neuronal ensemble to retrieve the focus location from its population discharge. Responses to expansion and contraction stimuli cannot be predicted based on quantitative data on a neuron's frontoparallel preferred stimulus direction and the location and size of its receptive field. These results, taken together with data on polymodal motion responses in this area, suggest an involvement of area VIP in the analysis and the encoding of heading.

Visual-vestibular interactive responses in the macaque ventral intraparietal area (VIP).

Self-motion detection requires the interaction of a number of sensory systems for correct perceptual interpretation of a given movement and an eventual motor response. Parietal cortical areas are thought to play an important role in this function, and we have thus studied the encoding of multimodal signals and their spatiotemporal interactions in the ventral intraparietal area of macaque monkeys. Thereby, we have identified for the first time the presence of vestibular sensory input to this area and described its interaction with somatosensory and visual signals, via extracellular single-cell recordings in awake head-fixed animals. Visual responses were driven by large field stimuli that simulated either backward or forward self-motion (contraction or expansion stimuli, respectively), or movement in the frontoparallel plane (visual increments moving simultaneously in the same direction). While the dominant sensory modality in most neurons was visual, about one third of all recorded neurons responded to horizontal rotation. These vestibular responses were typically in phase with head velocity, but in some cases they could signal acceleration or even showed integration to position. The associated visual responses were always codirectional with the vestibular on-direction, i.e. noncomplementary. Somatosensory responses were in register with the visual preferred direction, either in the same or in the opposite direction, thus signalling translation or rotation in the horizontal plane. These results, taken together with data on responses to optic flow stimuli obtained in a parallel study, strongly suggest an involvement of area VIP in the analysis and the encoding of self-motion.

Density gradients of trans-synaptically labeled collicular neurons after injections of rabies virus in the lateral rectus muscle of the rhesus monkey.

We evaluated the two-dimensional distribution of superior colliculus (SC) neurons visualized after retrograde transneuronal transport of rabies virus injected into the lateral rectus muscle of rhesus monkeys to test whether the density of projection neurons might play a role in the spatiotemporal transformation and vector decomposition. If this were the case, the number of horizontal eye movement-related SC neurons should increase with their distance from the rostral pole of the SC and decrease with their distance from the representation of the horizontal meridian. Labeled neurons of the intermediate SC layers were counted inside a 1-mm-wide band that matched the horizontal meridian of the collicular motor map. Local areal densities were plotted against distance from the rostral SC pole. At 2.5 days after inoculation, there was no labeling in the SC. At 3 days, moderate labeling appeared on both sides, mostly in the intermediate layers. At 3.5 days, cell numbers substantially increased and the laminar distribution changed as cells appeared in the superficial SC layers. At 3 days, rostrocaudal density profiles were unimodal, with peaks at locations near 50 degrees (contralateral SC) and 25-30 degrees (ipsilateral SC) horizontal eccentricity. At 3.5 days, distributions were bimodal due to the appearance of a second high-density region near the rostral pole of the SC. The distribution of SC neurons influencing the abducens nucleus, thus, was nonuniform. Caudal sites contained more neurons, but the experimentally observed density gradients were shallower than the theoretically predicted ones that would be necessary to fully account for the spatiotemporal transformation. Similarly, we studied the distributions of cell densities in the intermediate SC layers along an isoamplitude line (representing saccades of equal amplitudes but different directions). Consistent with theoretical estimates of the density gradients required for vector decomposition, we found that the concentrations of labeled cells were highest in the vicinity of the horizontal meridian but their decrease toward the periphery of the motor map was steeper than predicted. We conclude that SC cell density gradients cannot fully account for the spatiotemporal transformation and vector decomposition in the absence of an additional mechanism such as the previously demonstrated (Grantyn et al., [1997] Soc. Neurosci. Abstr. 23:1295; Moschovakis et al., [1998] J. Neurosci. 18:10219-10229) locus-dependent weighting of the strength of efferent projections to the saccade generators.

Mapping the oculomotor system: the power of transneuronal labelling with rabies virus.

Neuronal networks underlying and related to horizontal eye movements were visualized by retrograde transneuronal tracing with rabies virus from the left medial rectus muscle in guinea pigs. Time-sequenced labelling revealed distinct circuitries involved in particular oculomotor functions, i.e. vestibulo-ocular reflex and saccade generation (brainstem circuitry), adaptive plasticity (cerebellar modules) and possibly motivation and navigation (limbic, hippocampal and cortical structures). Our results provide a first comprehensive road map of the oculomotor system that is unsurpassed by any previous tracing study. We report a number of unexpected findings that illustrate a much vaster and more complicated network for the control of the relatively simple horizontal eye movements than had been envisioned previously.