No abstract

According to Einstein's equivalence principle, inertial accelerations during translational motion are physically indistinguishable from gravitational accelerations experienced during tilting movements. Nevertheless, despite ambiguous sensory representation of motion in primary otolith afferents, primate oculomotor responses are appropriately compensatory for the correct translational component of the head movement. The neural computational strategies used by the brain to discriminate the two and to reliably detect translational motion were investigated in the primate vestibulo-ocular system. The experimental protocols consisted of either lateral translations, roll tilts, or combined translation-tilt paradigms. Results using both steady-state sinusoidal and transient motion profiles in darkness or near target viewing demonstrated that semicircular canal signals are necessary sensory cues for the discrimination between different sources of linear acceleration. When the semicircular canals were inactivated, horizontal eye movements (appropriate for translational motion) could no longer be correlated with head translation. Instead, translational eye movements totally reflected the erroneous primary otolith afferent signals and were correlated with the resultant acceleration, regardless of whether it resulted from translation or tilt. Therefore, at least for frequencies in which the vestibulo-ocular reflex is important for gaze stabilization (>0.1 Hz), the oculomotor system discriminates between head translation and tilt primarily by sensory integration mechanisms rather than frequency segregation of otolith afferent information. Nonlinear neural computational schemes are proposed in which not only linear acceleration information from the otolith receptors but also angular velocity signals from the semicircular canals are simultaneously used by the brain to correctly estimate the source of linear acceleration and to elicit appropriate oculomotor responses.

Radiation therapy for head and neck cancers causes salivary gland dysfunction leading to permanent xerostomia. Limited progress in the discovery of new therapeutic strategies is attributed to the lack of in vitro models that mimic salivary gland function and allow high-throughput drug screening. We address this limitation by combining engineered extracellular matrices with microbubble (MB) array technology to develop functional tissue mimetics for mouse and human salivary glands. We demonstrate that mouse and human salivary tissues encapsulated within matrix metalloproteinase-degradable poly(ethylene glycol) hydrogels formed in MB arrays are viable, express key salivary gland markers, and exhibit polarized localization of functional proteins. The salivary gland mimetics (SGm) respond to calcium signaling agonists and secrete salivary proteins. SGm were then used to evaluate radiosensitivity and mitigation of radiation damage using a radioprotective compound. Altogether, SGm exhibit phenotypic and functional parameters of salivary glands, and provide an enabling technology for high-content/throughput drug testing.

Our inner ear is equipped with a set of linear accelerometers, the otolith organs, that sense the inertial accelerations experienced during self-motion. However, as Einstein pointed out nearly a century ago, this signal would by itself be insufficient to detect our real movement, because gravity, another form of linear acceleration, and self-motion are sensed identically by otolith afferents. To deal with this ambiguity, it was proposed that neural populations in the pons and midline cerebellum compute an independent, internal estimate of gravity using signals arising from the vestibular rotation sensors, the semicircular canals. This hypothesis, regarding a causal relationship between firing rates and postulated sensory contributions to inertial motion estimation, has been directly tested here by recording neural activities before and after inactivation of the semicircular canals. We show that, unlike cells in normal animals, the gravity component of neural responses was nearly absent in canal-inactivated animals. We conclude that, through integration of temporally matched, multimodal information, neurons derive the mathematical signals predicted by the equations describing the physics of the outside world.

The central projections of the utricular and saccular nerve in macaques were examined using transganglionic labeling of vestibular afferent neurons. In these experiments, biotinylated dextran amine was injected directly into the saccular or utricular neuroepithelium of fascicularis (Macaca fascicularis) or rhesus (Macaca mulatta) monkeys. Two to 5 weeks later, the animals were killed and the peripheral vestibular sensory organs, brainstem, and cerebellum were collected for analysis. The principal brainstem areas of saccular nerve termination were lateral, particularly the spinal vestibular nucleus, the lateral portion of the superior vestibular nucleus, ventral nucleus y, the external cuneate nucleus, and cell group l. The principal cerebellar projection was to the uvula with a less dense projection to the nodulus. Principle brainstem areas of termination of the utricular nerve were the lateral/dorsal medial vestibular nucleus, ventral and lateral portions of the superior vestibular nucleus, and rostral portion of the spinal vestibular nucleus. In the cerebellum, a strong projection was observed to the nodulus and weak projections were present in the flocculus, ventral paraflocculus, bilateral fastigial nuclei, and uvula. Although there is extensive overlap of saccular and utricular projections, saccular inputs to the lateral portions of the vestibular nuclear complex suggest that saccular afferents contribute to the vestibulospinal system. In contrast, the utricular nerve projects more rostrally into areas of known concentration of vestibulo-ocular related cells. Although sparse, the projections of the utricle to the flocculus/ventral paraflocculus suggest a potential convergence with floccular projection inputs from the vestibular brainstem that have been implicated in vestibulo-ocular motor learning.