Eye movements are indispensable for visual image stabilization during self-generated and passive head and body motion and for visual orientation. Eye muscles and neuronal control elements are evolutionarily conserved, with novel behavioral repertoires emerging during the evolution of frontal eyes and foveae. The precise execution of eye movements with different dynamics is ensured by morphologically diverse yet complementary sets of extraocular muscle fibers and associated motoneurons. Singly and multiply innervated muscle fibers are controlled by motoneuronal subpopulations with largely selective premotor inputs from task-specific ocular motor control centers. The morphological duality of the neuromuscular interface is matched by complementary biochemical and molecular features that collectively assign different physiological properties to the motor entities. In contrast, the functionality represents a continuum where most motor elements contribute to any type of eye movement, although within preferential dynamic ranges, suggesting that signal transmission and muscle contractions occur within bands of frequency-selective pathways.
As part of the neuronal cytoskeleton, neurofilaments are involved in maintaining cellular integrity. In the setting of ischemic stroke, the affection of the neurofilament network is considered to mediate the transition towards long-lasting tissue damage. Although peripheral levels of distinct neurofilament subunits are shown to correlate with the clinically observed severity of cerebral ischemia, neurofilaments have so far not been considered for neuroprotective approaches. Therefore, the present study systematically addresses ischemia-induced alterations of the neurofilament light (NF-L), medium (NF-M), and heavy (NF-H) subunits as well as of α-internexin (INA). For this purpose, we applied a multi-parametric approach including immunofluorescence labeling, western blotting, qRT-PCR and electron microscopy. Analyses comprised ischemia-affected tissue from three stroke models of middle cerebral artery occlusion (MCAO), including approaches of filament-based MCAO in mice, thromboembolic MCAO in rats, and electrosurgical MCAO in sheep, as well as human autoptic stroke tissue. As indicated by altered immunosignals, impairment of neurofilament subunits was consistently observed throughout the applied stroke models and in human tissue. Thereby, altered NF-L immunoreactivity was also found to reach penumbral areas, while protein analysis revealed consistent reductions for NF-L and INA in the ischemia-affected neocortex in mice. At the mRNA level, the ischemic neocortex and striatum exhibited reduced expressions of NF-L- and NF-H-associated genes, whereas an upregulation for Ina appeared in the striatum. Further, multiple fluorescence labeling of neurofilament proteins revealed spheroid and bead-like structural alterations in human and rodent tissue, correlating with a cellular edema and lost cytoskeletal order at the ultrastructural level. Thus, the consistent ischemia-induced affection of neurofilament subunits in animals and human tissue, as well as the involvement of potentially salvageable tissue qualify neurofilaments as promising targets for neuroprotective strategies. During ischemia formation, such approaches may focus on the maintenance of neurofilament integrity, and appear applicable as co-treatment to modern recanalizing strategies.
Background Choroidal vascular regulation is mediated by the autonomic nervous system in order to gain proper blood flow control. While the mechanisms behind this control are unknown, neuroregulatory peptides are involved in this process. To better understand choroidal function, we investigate the presence of urocortin-1 (UCN), a neuroregulatory peptide with vascular effects, in the human choroid and its possible intrinsic and extrinsic origin. Methods Human choroid and eye-related cranial ganglia (superior cervical ganglion- SCG, ciliary ganglion-CIL, pterygopalatine ganglion-PPG, trigeminal ganglion-TRI) were prepared for immunohistochemistry against UCN, protein–gene product 9.5 (PGP9.5), substance P (SP), tyrosine hydroxylase (TH) and vesicular acetylcholine transporter (VAChT). For documentation, confocal laser scanning microscopy was used. Results In choroidal stroma, UCN-immunoreactivity was present in nerve fibres, small cells and intrinsic choroidal neurons (ICN). Some UCN+ nerve fibres colocalised for VAChT, while others were VAChT. A similar situation was found with SP: some UCN+ nerve fibres showed colocalisation for SP, while others lacked SP. Colocalisation for UCN and TH was not observed. In eye-related cranial ganglia, only few cells in the SCG, PPG and TRI were UCN+, while many cells of the CIL displayed weak UCN immunoreactivity. Conclusion UCN is part of the choroidal innervation. UCN+/VAChT+ fibres could derive from the few cells of the PPG or cells of the CIL, if these indeed supply the choroid. UCN+/SP+ fibres might originate from ICN, or the few UCN+ cells detected in the TRI. Further studies are necessary to establish UCN function in the choroid and its implication for choroidal autonomic control.
Abstract We studied eye movements and brainstem pathology in 2 patients with slow vertical saccades and autopsy‐proven amyotrophic lateral sclerosis (ALS). In both patients, the main ocular motor finding was supranuclear vertical gaze impairment with slow vertical saccades. The second patient had difficulty opening his eyes on command, with preserved spontaneous eyelid opening. Postmortem examination in both patients demonstrated cell loss in the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) and substantia nigra, along with histopathological findings consistent with ALS. The extent of the pathological changes in the riMLF corelated well with the degree of functional impairment as reflected in the slow vertical saccades. We suggest that motor neuron disease with early involvement of vertical saccades represents a distinct clinicopathological entity.
Motoneurons of extraocular muscles are controlled by different premotor pathways, whose selective damage may cause directionally selective eye movement disorders. The fact that clinical disorders can affect only one direction, e.g., isolated up-/downgaze palsy or up-/downbeat nystagmus, indicates that up- and downgaze pathways are organized separately. Recent work in monkey revealed that a subpopulation of premotor neurons of the vertical eye movement system contains the calcium-binding protein calretinin (CR). With combined tract-tracing and immunofluorescence, the motoneurons of vertically pulling eye muscles in monkey were investigated for the presence of CR-positive afferent terminals. In the oculomotor nucleus, CR was specifically found in punctate profiles contacting superior rectus and inferior oblique motoneurons, as well as levator palpebrae motoneurons, all of which participate in upward eye movements. Double-immunofluorescence labeling revealed that CR-positive terminals lacked the γ-aminobutyric acid (GABA)-synthesizing enzyme glutamate decarboxylase, which is present in inhibitory afferents to all motoneurons mediating vertical eye movements. Therefore, CR-containing afferents are considered to be excitatory. In conclusion, a strong CR input is confined to motoneurons mediating upgaze, which derive from premotor pathways mediating saccades and smooth pursuit, but not from secondary vestibulo-ocular neurons in the magnocellular part of the medial vestibular nucleus. The functional significance of CR in these connections is unclear, but it may serve as a useful marker to locate upgaze pathways in the human brain.
Palisade endings (PEs), which are unique to the eye muscles, are associated with multiply innervated muscle fibers. They lie at the myotendinous junctions and form a cap around the muscle fiber tip. They are found in all animals investigated so far, but their function is not known. Recently, we demonstrated that cell bodies of PEs and tendon organs lie around the periphery of the oculomotor nucleus in the C‐ and S‐groups. A morphological analysis of these peripheral neurons revealed the existence of different populations within the C‐group. We propose that a small group of round or spindle‐shaped cells gives rise to PEs, and another group of multipolar neurons provide the multiple motor endings. If PEs have a sensory function, then their cell body location close to motor neurons would be in an ideal location to control tension in extraocular muscles; in the case of the C‐group, its proximity to the preganglionic neurons of the Edinger–Westphal nucleus would permit its participation in the near response. Despite their unusual properties, PEs may have a sensory function.
The spatio-temporal convergent (STC) response occurs in central vestibular cells when dynamic and static inputs are activated. The functional significance of STC behavior is not fully understood. Whether STC is a property of some specific central vestibular neurons, or whether it is a response that can be induced in any neuron at some frequencies is unknown. It is also unknown how the change in orientation of otolith polarization vector (orientation adaptation) affects STC behavior. A new complex model, that includes inputs with regular and irregular discharges from both canal and otolith afferents, was applied to experimental data to determine how many convergent inputs are sufficient to explain the STC behavior as a function of frequency and orientation adaptation. The canal-otolith and otolith-only neurons were recorded in the vestibular nuclei of three monkeys. About 42% (11/26 canal-otolith and 3/7 otolith-only) neurons showed typical STC responses at least at one frequency before orientation adaptation. After orientation adaptation in side-down head position for 2 h, some canal-otolith and otolith-only neurons altered their STC responses. Thus, STC is a property of weights of the regular and irregular vestibular afferent inputs to central vestibular neurons which appear and/or disappear based on stimulus frequency and orientation adaptation. This indicates that STC properties are more common for central vestibular neurons than previously assumed. While gravity-dependent adaptation is also critically dependent on stimulus frequency and orientation adaptation, we propose that STC behavior is also linked to the neural network responsible for localized contextual learning during gravity-dependent adaptation.
