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[Display omitted] • In utero exposure to VPA results in an increased risk of ASD in humans. • VPA exposure resulted in fewer neurons in vestibular nuclei and fewer CB puncta. • VPA exposure resulted in impaired performance on motor tasks. • VPA exposure resulted in delayed VEMPs and horizontal nystagmus. Autism spectrum disorder (ASD) is a neurodevelopmental disorder that includes several key neuropathological changes and behavioral impairments. In utero exposure to the anti-epileptic valproic acid (VPA) increases risk of an ASD diagnosis in human subjects and timed in utero exposure to VPA is a clinically relevant animal model of ASD. Many human subjects with ASD have cerebellar hypoplasia, fewer Purkinje cells, difficulties with balance, ophthalmic dysfunction and abnormal responses to vestibular stimulation and such vestibular difficulties are likely under reported in ASD. We have recently shown that animals exposed to VPA in utero have fewer neurons in their auditory brainstem, reduced axonal projections to the auditory midbrain and thalamus, reduced expression of the calcium binding protein calbindin (CB) in the brainstem and cerebellum, smaller and occasionally ectopic cerebellar Purkinje cells and ataxia on several motor tasks. Based on these findings, we hypothesized that in utero VPA exposure similarly impacts structure and function of the vestibular brainstem. We investigated this hypothesis using quantitative morphometric analyses, immunohistochemistry for CB, a battery of vestibular challenges, recording of vestibular-evoked myogenic potentials and spontaneous eye movements. Our results indicate that VPA exposure results in fewer neurons in the vestibular nuclei, fewer CB-positive puncta, difficulty on certain motor tasks, longer latency VEMPs and significantly more horizontal eye movements. These findings indicate that the vestibular nuclei are impacted by in utero VPA exposure and provide a basis for further study of vestibular circuits in human cases of ASD. [ABSTRACT FROM AUTHOR]

Abstract: Vestibular information is essential for the control of posture, balance, and eye movements. The vestibular nerve projects to the four nuclei of the vestibular nuclear complex (VNC), as well as to several additional brainstem nuclei and the cerebellum. We have found that expression of the calcium-binding proteins calretinin (CR) and calbindin (CB), and the synthetic enzyme for nitric oxide synthase (nNOS) define subdivisions of the medial vestibular nucleus (MVe) and the nucleus prepositus (PrH), in cat, monkey, and human. We have asked if the pattern of expression of nonphosphorylated neurofilament protein (NPNFP) might define additional subdivisions of these or other nuclei that participate in vestibular function. We studied the distribution of cells immunoreactive to NPNFP in the brainstems of 5 cats and one squirrel monkey. Labeled cells were scattered throughout the four nuclei of the VNC, as well as in PrH, the reticular formation (RF) and the external cuneate nucleus. We used double-label immunofluorescence to visualize the distribution of these cells relative to other neurochemically defined subdivisions. NPNFP cells were excluded from the CR and CB regions of the MVe. In PrH, NPNFP and nNOS were not colocalized. Cells in the lateral vestibular nucleus and RF colocalized NPNFP and a marker for glutamatergic neurons. We also found that the cholinergic cells and axons of cranial nerve nuclei 3, 4, 6, 7,10 and 12 colocalize NPNFP. The data suggest that NPNFP is expressed by a subset of glutamatergic projection neurons of the vestibular brainstem. NPNFP may be a marker for those cells that are especially vulnerable to the effects of normal aging, neurological disease or disruption of sensory input. [Copyright &y& Elsevier]

Abstract: The vestibulo-ocular reflex (VOR) exhibits motor learning that initially depends on synaptic plasticity in the cerebellar cortex. Learned decreases in VOR gain can be disrupted by rotation in darkness immediately following learning, but consolidate rapidly if the disruption stimulus is delayed. Disruption may simply reverse the synaptic changes that have recently occurred, or it may reflect new learning at other sites. The alternative to disruption, rapid consolidation, also may take place by altering the existing memory trace or may require changes at other locations. To test these possibilities, we induced decreases in the gain of the VOR in cats that wore miniaturizing goggles. Using a range of frequencies of rotation, we investigated the patterns of generalization for disruption and for rapid consolidation of the learned changes in gain. Learning was most effective at the particular frequencies that were used during training. However, disruption and rapid consolidation were not more effective at the rotation frequencies that were used during training. Instead, after consolidation, the memory retained the frequency tuning that had been established during the learning process. We conclude that disruption and rapid consolidation may not require new learning. [Copyright &y& Elsevier]

The present study was conducted to examine adaptive gain changes of vertical vestibulo-ocular reflex (VOR) after exposure to a vertical visual–vestibular mismatch in cats. The visual–vestibular mismatch was induced by oscillating the animals for an hour about an inter-aural axis at frequencies of 0.16 and 0.32 Hz with the peak velocity of 20°/s, coupled with either in-phase (“gain decrease” conditioning) or out-of-phase (“gain increase” conditioning) sinusoidal rotation of a random-dot pattern. Eye movements were measured with a magnetic search coil system. Before conditioning, vertical VOR showed up–down asymmetric responses. That is, upward slow phase eye velocity (SPV) in response to downward head rotation was significantly larger than downward SPV in response to upward head rotation. After adaptation to “gain increase” conditioning, VOR gain increased in both stimulus directions. The increase in VOR gain was significantly larger for upward SPV than for downward SPV. After adaptation to “gain decrease” conditioning, VOR gain decreased in both stimulus directions. The decrease in VOR gain was, however, significantly larger for downward SPV than for upward SPV. Our results indicate that VOR in the vertical plane adaptively changes but that the gain change shows a directional asymmetry. This asymmetry was dependent on the direction of the slip of visual image rather than the direction of head rotation, and the gain change was smaller when the retinal slip was generated downward. Possible explanations for the asymmetry are discussed on a physiological and anatomical basis. [Copyright &y& Elsevier]

The horizontal rotatory vestibulo-ocular reflex (VOR) stabilizes gaze by moving the eyes at an angular velocity proportional to head velocity, and can accomplish this for a broad range of frequencies and amplitudes of head motion. Rotation at 5 Hz and above may be processed differently than lower frequencies by the VOR network. We recorded discharges and calculated spike densities of a small sample of vestibular neurons in alert cats during low-velocity rotation at frequencies up to 8 Hz. At high frequencies, we found both vestibular-only (V-only) and eye-movement-sensitive (EM) cells that generated asymmetric output signals. Asymmetry was primarily of the cutoff type, i.e., changes in spike density were smallest for rotation in the inhibitory direction. Most cells were identified as secondary neurons. The mean spike density was 23 sp/s, which was lower than previously reported in vestibular neurons of monkeys. A few neurons had very high sensitivities, associated with phase-locking, to rotation at high frequencies. In general, vestibular neurons carried a high-pass-filtered version of rotational signals. When synaptic inputs from the vestibular commissure were quantified, we found that the immediate change in probability of firing due to commissural vestibular input was inversely correlated with the degree of high-pass filtering. At high frequencies, increased asymmetry and phase-locking occurred in some neurons. A small number of neurons responded with increased probability of firing to both directions of rotation. Together, these observations suggest that high frequencies of rotation may be encoded differently than low frequencies by central vestibular neurons in alert animals. [Copyright &y& Elsevier]

The horizontal and vertical vestibulo ocular reflex (VOR) of head tilted (het) mutant mice was compared to C57BL/6 controls. Eye movements were recorded in darkness using a temporarily attached search coil. Contributions of semicircular canal versus otolith organ signals were investigated by providing a canal only (vertical axis) or canal plus otolith organ (horizontal axis) stimulus. In controls, rotations that stimulated only the canals (upright yaw and on tail roll) produced accurate VOR timing during middle frequency rotations at 0.5 Hz (gain 0.27, phase error 6°), and a phase advanced VOR during low frequency rotations at 0.05 Hz (0.05, 115°). In het mutant mice, these rotations produced a highly attenuated VOR response and phase errors at both 0.5 Hz (0.11, 42°) and 0.05 Hz (0.01, 36°). In controls, rotations that stimulated both the otolith organs and semicircular canals (upright roll and on tail yaw) produced higher VOR gains overall than were elicited during vertical axis rotations, with phase accurate VOR at both 0.5 Hz (0.52, 4°) and 0.05 Hz (0.34, 9°). In het mutant mice, these rotations produced a highly attenuated VOR response and phase errors at both 0.5 Hz (0.14, 51°) and 0.05 Hz (0.01, 43°). During constant velocity rotations about an earth horizontal axis, eye velocity bias and modulation were virtually absent in het mutant mice, while robust in controls. Control mice produced compensatory ocular deviations in response to static head tilt, but responses in het mice were weak and inconsistent. These results show that het mice not only lack all aspects of otolith mediated VOR, but also are deficient in canal mediated VOR. Because semicircular canals are normal in het mice, we conclude that central neurons of the canal VOR are dependent on otolith organ signals for normal performance. [Copyright &y& Elsevier]

• Light-optical and ultrastructural analysis of the mice trochlear nucleus after spaceflight. • Motoneurons dendrites of the trochlear nucleus reorganize orientation in microgravity. • Increased branching of dendrites contribute adaptation to reduced signaling. During spaceflight and immediately after it, adaptive neuroplastic changes occur in the sensorimotor structures of the central nervous system, which are associated with changes of mainly vestibular and visual signals. It is known that the movement of the eyeball in the vertical direction is carried out by muscles that are innervated by the trochlear nerve (CN IV) and the oculomotor nerve (CN III). To elucidate the cellular processes underlying the atypical vertical nystagmus that occurs under microgravity conditions, it seems necessary to study the state of these nuclei in animals in more detail after prolonged space flights. We carried out a qualitative and quantitative light-optical and ultrastructural analysis of the nuclei of the trochlear nerve in mice after a 30-day flight on the Bion-M1 biosatellite. As a result, it was shown that the dendrites of motoneurons in the nucleus of the trochlear nerve significantly reorganized their geometry and orientation under microgravity conditions. The number of dendritic branches was increased, possibly in order to amplify the reduced signal flow. To ensure such plastic changes, the number and size of mitochondria in the soma of motoneurons and in axons coming from the vestibular structures increased. Thus, the main role in the adaptation of the trochlear nucleus to microgravity conditions, apparently, belongs to the dendrites of motoneurons, which rearrange their structure and function to enhance the flow of sensory information. These results complement our knowledge of the causes of atypical nystagmus in microgravity. [ABSTRACT FROM AUTHOR]