Paul J. May

The mammalian superior colliculus: laminar structure and connections.

The superior colliculus is a laminated midbrain structure that acts as one of the centers organizing gaze movements. This review will concentrate on sensory and motor inputs to the superior colliculus, on its internal circuitry, and on its connections with other brainstem gaze centers, as well as its extensive outputs to those structures with which it is reciprocally connected. This will be done in the context of its laminar arrangement. Specifically, the superficial layers receive direct retinal input, and are primarily visual sensory in nature. They project upon the visual thalamus and pretectum to influence visual perception. These visual layers also project upon the deeper layers, which are both multimodal, and premotor in nature. Thus, the deep layers receive input from both somatosensory and auditory sources, as well as from the basal ganglia and cerebellum. Sensory, association, and motor areas of cerebral cortex provide another major source of collicular input, particularly in more encephalized species. For example, visual sensory cortex terminates superficially, while the eye fields target the deeper layers. The deeper layers are themselves the source of a major projection by way of the predorsal bundle which contributes collicular target information to the brainstem structures containing gaze-related burst neurons, and the spinal cord and medullary reticular formation regions that produce head turning.

Cerebellotectal pathways in the macaque : implications for collicular generation of saccades

The cerebellum is thought to modulate saccadic activity in the primate in order to maintain targeting accuracy, and the cerebellotectal pathway has been posited to play a role in this modulation. However, anatomical descriptions of this pathway in primates are sketchy and conflicting. To determine whether the organization of the cerebellotectal projection in primates is similar to that found in other species, neuroanatomical tracer transport techniques were utilized in two species of macaque monkey to label cerebellotectal somata and fiber terminations. Two pathways were found. One, the fastigiotectal pathway, is derived from cells in the caudal fastigial nucleus and projects bilaterally to the rostral end of the intermediate gray layer. The other pathway is derived from cells in the posterior interposed nucleus and the adjacent posterior wing of the dentate nucleus, and it terminates contralaterally throughout the ventral half of the intermediate gray and the deep gray layers. Both of these pathways terminate within the layers of the superior colliculus containing premotor, saccade-related neurons, but the differences in the distribution of their terminals and cells of origin suggest that these two pathways have different functions. Furthermore, the pattern of connections of these two pathways indicates that they do not function as a traditional feedback circuit. We suggest that the cerebellotectal pathways may instead modulate collicular activity in a more complex manner. For example, it may provide signals necessary for corrective saccades or for maintaining spatial registry between the different sensory representations supplied to the superior colliculus and its presaccadic output, which is organized into a motor map.

Multimodal Coding of Three-Dimensional Rotation and Translation in Area MSTd: Comparison of Visual and Vestibular Selectivity

Recent studies have shown that most neurons in the dorsal medial superior temporal area (MSTd) signal the direction of self-translation (i.e., heading) in response to both optic flow and inertial motion. Much less is currently known about the response properties of MSTd neurons during self-rotation. We have characterized the three-dimensional tuning of MSTd neurons while monkeys passively fixated a central, head-fixed target. Rotational stimuli were either presented using a motion platform or simulated visually using optic flow. Nearly all MSTd cells were significantly tuned for the direction of rotation in the absence of optic flow, with more neurons preferring roll than pitch or yaw rotations. The preferred rotation axis in response to optic flow was generally the opposite of that during physical rotation. This result differs sharply from our findings for translational motion, where approximately half of MSTd neurons have congruent visual and vestibular preferences. By testing a subset of neurons with combined visual and vestibular stimulation, we also show that the contributions of visual and vestibular cues to MSTd responses depend on the relative reliabilities of the two stimulus modalities. Previous studies of MSTd responses to motion in darkness have assumed a vestibular origin for the activity observed. We have directly verified this assumption by recording from MSTd neurons after bilateral labyrinthectomy. Selectivity for physical rotation and translation stimuli was eliminated after labyrinthectomy, whereas selectivity to optic flow was unaffected. Overall, the lack of MSTd neurons with congruent rotation tuning for visual and vestibular stimuli suggests that MSTd does not integrate these signals to produce a robust perception of self-rotation. Vestibular rotation signals in MSTd may instead be used to compensate for the confounding effects of rotatory head movements on optic flow.

Vestibular Signals in Primate Thalamus: Properties and Origins

Vestibular activation is found in diverse cortical areas. To characterize the pathways and types of signals supplied to cortex, we recorded responses to rotational and/or translational stimuli in the macaque thalamus. Few cells responded to rotation alone, with most showing convergence between semicircular canal and otolith signals. During sinusoidal rotation, thalamic responses lead head velocity by ∼30° on average at frequencies between 0.01–4 Hz. During translation, neurons encoded combinations of linear acceleration and velocity. In general, thalamic responses were similar to those recorded in the vestibular and cerebellar nuclei using identical testing paradigms, but differed from those of vestibular afferents. Thalamic responses represented a biased continuum: most cells more strongly encoded translation and fewer cells modulated primarily in response to net gravitoinertial acceleration. Responsive neurons were scattered within a large area that included regions of the ventral posterior and ventral lateral nuclei, and so were not restricted to the known vestibular nuclei projection zones. To determine the origins of these responses, a retrograde tracer was injected into a dorsolateral thalamic site where rotation/translation-sensitive cells were encountered. This injection labeled neurons in the rostral contralateral anterior interposed and fastigial nuclei, but did not label cells within the vestibular nuclei. Examination of thalamic terminations after tracer injections into the cerebellar and vestibular nuclei indicated that most vestibular responsive units fall within the thalamic terminal zones of these nuclei. Thus, vestibular signals, which are supplied to the thalamus from both vestibular and cerebellar nuclei, are positioned for distribution to widespread cortical areas.

THE EDINGER-WESTPHAL NUCLEUS: A HISTORICAL, STRUCTURAL AND FUNCTIONAL PERSPECTIVE ON A DICHOTOMOUS TERMINOLOGY

The eponymous term nucleus of Edinger‐Westphal (EW) has come to be used to describe two juxtaposed and somewhat intermingled cell groups of the midbrain that differ dramatically in their connectivity and neurochemistry. On one hand, the classically defined EW is the part of the oculomotor complex that is the source of the parasympathetic preganglionic motoneuron input to the ciliary ganglion (CG), through which it controls pupil constriction and lens accommodation. On the other hand, EW is applied to a population of centrally projecting neurons involved in sympathetic, consumptive, and stress‐related functions. This terminology problem arose because the name EW has historically been applied to the most prominent cell collection above or between the somatic oculomotor nuclei (III), an assumption based on the known location of the preganglionic motoneurons in monkeys. However, in many mammals, the nucleus designated as EW is not made up of cholinergic, preganglionic motoneurons supplying the CG and instead contains neurons using peptides, such as urocortin 1, with diverse central projections. As a result, the literature has become increasingly confusing. To resolve this problem, we suggest that the term EW be supplemented with terminology based on connectivity. Specifically, we recommend that 1) the cholinergic, preganglionic neurons supplying the CG be termed the Edinger‐Westphal preganglionic (EWpg) population and 2) the centrally projecting, peptidergic neurons be termed the Edinger‐Westphal centrally projecting (EWcp) population. The history of this nomenclature problem and the rationale for our solutions are discussed in this review. J. Comp. Neurol. 519:1413–1434, 2011.

Reciprocal connections between the zona incerta and the pretectum and superior colliculus of the cat

The goal of the present experiments was to examine the relationships of the zona incerta with two structures associated with visuomotor behavior, the superior colliculus and pretectum. The experiments were carried out in the cat, a species commonly used in studies of visuomotor integration, and utilized wheat germ agglutinin horseradish peroxidase and biocytin as retrograde and anterograde neuronal tracers. Retrograde axonal transport demonstrated that most cells in the ventral subdivision of the zona incerta project to the superior colliculus. Anterograde tracers demonstrated that the incertotectal terminal field is most dense in the intermediate gray layer, which is the primary source of the descending pathway from the superior colliculus to brainstem gaze centers. Further experiments showed that scattered cells within the intermediate gray layer give rise to a reciprocal pathway that terminates in both the dorsal and ventral subdivisions of the zona incerta. The distribution of both labeled incertotectal cells and tectoincertal terminals extends dorsolateral to the zona incerta proper, between the reticular thalamic nucleus and the external medullary lamina. Electron microscopic examination of labeled tectoincertal terminals demonstrated that they contain mainly spherical vesicles and have slightly asymmetric to symmetric synaptic densities. Labeled terminals were observed contacting labeled cells in the zona incerta, suggesting that the reciprocal pathway may be monosynaptic. The zona incerta is also reciprocally interconnected with the pretectum. The anterior pretectal nucleus provides a dense projection to the ventral part of the zona incerta and receives a sparse reciprocal projection. The posterior pretectal nucleus and nucleus of the optic tract may also project to the zona incerta. The pretectoincertal fibers form terminals that contain primarily spherical vesicles and make distinctly asymmetric synaptic contacts. In summary, these results indicate that the deep layers of the superior colliculus, which are important for controlling saccades, are the target of a projection from the ventral subdivision of the zona incerta. Like the substantia nigra, the zona incerta may play a permissive role in the tectal initiation of saccadic eye movements. The incertotectal terminal field in the cat is less dense than that observed previously in the rat, suggesting species differences in the development of this pathway. An additional finding of this study is that one of the main sources of input to these incertotectal cells is the anterior pretectal nucleus. This pretectal incertal tectal pathway is likely to play a role in the guidance of tectally initiated saccades by somatosensory stimuli.

A direct projection from superior colliculus to substantia nigra pars compacta in the cat.

Dopaminergic neurons exhibit a short-latency, phasic response to unexpected, biologically salient stimuli. The midbrain superior colliculus also is sensitive to such stimuli, exhibits sensory responses with latencies reliably less than those of dopaminergic neurons, and, in rat, has been shown to send direct projections to regions of the substantia nigra and ventral tegmental area containing dopaminergic neurons (e.g. pars compacta). Recent electrophysiological and electrochemical evidence also suggests that tectonigral connections may be critical for relaying short-latency (<100 ms) visual information to midbrain dopaminergic neurons. By investigating the tectonigral projection in the cat, the present study sought to establish whether this pathway is a specialization of the rodent, or whether it may be a more general feature of mammalian neuroanatomy. Anterogradely and retrogradely transported anatomical tracers were injected into the superior colliculus and substantia nigra pars compacta, respectively, of adult cats. In the anterograde experiments, abundant fibers and terminals labeled with either biotinylated dextran amine or Phaseolus vulgaris leucoagglutinin were seen in close association with tyrosine hydroxylase-positive (dopaminergic) somata and processes in substantia nigra pars compacta and the ventral tegmental area. In the retrograde experiments, injections of biotinylated dextran amine into substantia nigra produced significant retrograde labeling of tectonigral neurons of origin in the intermediate and deep layers of the ipsilateral superior colliculus. Approximately half of these biotinylated dextran amine-labeled neurons were, in each case, shown to be immunopositive for the calcium binding proteins, parvalbumin or calbindin. Significantly, virtually no retrogradely labeled neurons were found either in the superficial layers of the superior colliculus or among the large tecto-reticulospinal output neurons. Taken in conjunction with recent data in the rat, the results of this study suggest that the tectonigral projection may be a common feature of mammalian midbrain architecture. As such, it may represent an additional route by which short-latency sensory information can influence basal ganglia function.

The laminar distribution of macaque tectobulbar and tectospinal neurons

The superior colliculus exerts its most direct influence over orienting movements, and saccades in particular, via its descending projections to the brain stem and spinal cord. However, while there is detailed physiological data concerning the generation of saccade-related activity in the primate superior colliculus, there is relatively little data on the detailed connectivity of this structure in primates. Consequently, retrograde transport techniques were utilized to determine the locations of the cells of origin of these descending pathways in macaque monkeys. Tectal cells that projected to the ipsilateral pontine reticular formation were mainly found in the deep gray layer and occasionally in the intermediate gray layer. Tectal cells that projected to the contralateral pontine reticular formation were predominantly located in the intermediate gray layer. The contralaterally projecting population could be subdivided into two groups. The cells in upper sublamina of the intermediate gray layer project primarily to the saccade-related regions of the paramedian reticular formation. Cells in the lower sublamina project primarily to more lateral regions of the pontine reticular formation and to the spinal cord. We conclude that the primate colliculus is provided with at least three descending output channels, which are likely to differ in their connections and functions. Specifically, it seems likely that the lower portion of the intermediate gray layer may be specialized to subserve combined head and eye orienting movements, while the upper sublamina subserves saccades.

Agmatine Crosses the Blood‐Brain Barrier

Abstract: The question of whether agmatine crosses the blood‐brain barrier has not been directly addressed, even though peripheral injection of this compound has produced behavioral responses in drug withdrawal, antidepressant, and anti‐anxiety paradigms. Two models were used in this investigation. In the first, mice were injected intraperitoneally (i.p.) with agmatine (10, 50, or 300 mg/kg body weight) or arginine (600 mg/kg). After 1 or 3 hours, the animals were killed under gas anesthesia by perfusing their brains with ice‐cold saline, and whole‐brain agmatine was measured by HPLC. In parallel studies, a rhesus monkey was injected under gas anesthesia either intravenously (i.v.) with agmatine (30 mg/kg) or arginine (150 mg/kg), or intracerebroventricularly (i.c.v.) with agmatine (0.3 mg/kg i.c.v.). At varying times thereafter, cisterna magna cerebrospinal fluid (CSF) and blood plasma were collected and analyzed for agmatine levels. A rise in mouse brain agmatine was apparent after doses of 50 and 300 mg/kg i.p. Monkey CSF agmatine peaked in parallel with plasma agmatine 15 minutes following intravenous (i.v.) agmatine injection and at one sixth the level of the plasma peak. Monkey CSF agmatine peaked 43 minutes after i.v. arginine injection. The ventricular injection of agmatine resulted in a threefold sustained rise in blood plasma agmatine for at least 24 hours after injection. Therefore, agmatine and its precursor, arginine, cross the blood‐brain barrier. CSF agmatine may be newly synthesized from peripherally injected arginine.

Tectonigral Projections in the Primate: A Pathway for Pre-Attentive Sensory Input to Midbrain Dopaminergic Neurons

Much of the evidence linking the short‐latency phasic signaling of midbrain dopaminergic neurons with reward‐prediction errors used in learning and habit formation comes from recording the visual responses of monkey dopaminergic neurons. However, the information encoded by dopaminergic neuron activity is constrained by the qualities of the afferent visual signals made available to these cells. Recent evidence from rats and cats indicates the primary source of this visual input originates subcortically, via a direct tectonigral projection. The present anatomical study sought to establish whether a direct tectonigral projection is a significant feature of the primate brain. Injections of anterograde tracers into the superior colliculus of macaque monkeys labelled terminal arbors throughout the substantia nigra, with the densest terminations in the dorsal tier. Labelled boutons were found in close association (possibly indicative of synaptic contact) with ventral midbrain neurons staining positively for the dopaminergic marker tyrosine hydroxylase. Injections of retrograde tracer confined to the macaque substantia nigra retrogradely labelled small‐ to medium‐sized neurons in the intermediate and deep layers of the superior colliculus. Together, these data indicate that a direct tectonigral projection is also a feature of the monkey brain, and therefore likely to have been conserved throughout mammalian evolution. Insofar as the superior colliculus is configured to detect unpredicted, biologically salient, sensory events, it may be safer to regard the phasic responses of midbrain dopaminergic neurons as ‘sensory prediction errors’ rather than ‘reward prediction errors’, in which case dopamine‐based theories of reinforcement learning will require revision.