J. David Dickman

Asymmetric Localization of Vangl2 and Fz3 Indicate Novel Mechanisms for Planar Cell Polarity in Mammals

Planar cell polarity (PCP) is a process in which cells develop with uniform orientation within the plane of an epithelium. To begin to elucidate the mechanisms of PCP in vertebrates, the localization of the protein Vangl2 (Van Gogh-like) was determined during the development of the mammalian cochlea. Results indicate that Vangl2 becomes asymmetrically localized to specific cell–cell boundaries along the axis of polarization and that this asymmetry is lost in PCP mutants. In addition, PDZ2 (postsynaptic density/Discs large/zona occludens 1), PDZ3, and PDZ4 of the PCP protein Scrb1 (Scribble) are shown to bind to the C-terminal PDZ binding domain of Vangl2, suggesting that Scrb1 plays a direct role in asymmetric targeting of Vangl2. Finally, Fz3 (Frizzled), a newly demonstrated mediator of PCP, is also asymmetrically localized in a pattern that matches that of Vangl2. The presence and asymmetry of Fz3 at the membrane is shown to be dependent on Vangl2. This result suggests a role for Vangl2 in the targeting or anchoring of Fz3, a hypothesis strengthened by the existence of a physical interaction between the two proteins. Together, our data support the idea that protein asymmetry plays an important role in the development of PCP, but the colocalization and interaction of Fz3 and Vangl2 suggests that novel PCP mechanisms exist in vertebrates.

Neurons compute internal models of the physical laws of motion.

A critical step in self-motion perception and spatial awareness is the integration of motion cues from multiple sensory organs that individually do not provide an accurate representation of the physical world. One of the best-studied sensory ambiguities is found in visual processing, and arises because of the inherent uncertainty in detecting the motion direction of an untextured contour moving within a small aperture. A similar sensory ambiguity arises in identifying the actual motion associated with linear accelerations sensed by the otolith organs in the inner ear. These internal linear accelerometers respond identically during translational motion (for example, running forward) and gravitational accelerations experienced as we reorient the head relative to gravity (that is, head tilt). Using new stimulus combinations, we identify here cerebellar and brainstem motion-sensitive neurons that compute a solution to the inertial motion detection problem. We show that the firing rates of these populations of neurons reflect the computations necessary to construct an internal model representation of the physical equations of motion.

Purkinje Cells in Posterior Cerebellar Vermis Encode Motion in an Inertial Reference Frame

The ability to orient and navigate through the terrestrial environment represents a computational challenge common to all vertebrates. It arises because motion sensors in the inner ear, the otolith organs, and the semicircular canals transduce self-motion in an egocentric reference frame. As a result, vestibular afferent information reaching the brain is inappropriate for coding our own motion and orientation relative to the outside world. Here we show that cerebellar cortical neuron activity in vermal lobules 9 and 10 reflects the critical computations of transforming head-centered vestibular afferent information into earth-referenced self-motion and spatial orientation signals. Unlike vestibular and deep cerebellar nuclei neurons, where a mixture of responses was observed, Purkinje cells represent a homogeneous population that encodes inertial motion. They carry the earth-horizontal component of a spatially transformed and temporally integrated rotation signal from the semicircular canals, which is critical for computing head attitude, thus isolating inertial linear accelerations during navigation.

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.

Neural Correlates of a Magnetic Sense

Magnetic Sense Many species orient and navigate using aspects of Earths magnetic field. Magnetic receptors have been found in the eyes, ears, and bills of birds, but there has been no clear evidence of the neural mechanism by which magnetic signals are translated into direction. Recording from the brainstem within conscious pigeons, Wu and Dickman (p. 1054, published online 26 April; see the Perspective by Winklhofer) reveal the presence of neurons in the pigeons brain that encode the inclination angle and intensity of the geomagnetic field. Thus, pigeons—and perhaps other species—can develop an internal model of geopositional latitude to facilitate spatial orientation and navigation based on magnetoreception. Neurons in a pigeon’s brain encode the direction and intensity of the geomagnetic field. Many animals rely on Earth’s magnetic field for spatial orientation and navigation. However, how the brain receives and interprets magnetic field information is unknown. Support for the existence of magnetic receptors in the vertebrate retina, beak, nose, and inner ear has been proposed, and immediate gene expression markers have identified several brain regions activated by magnetic stimulation, but the central neural mechanisms underlying magnetoreception remain unknown. Here we describe neuronal responses in the pigeon’s brainstem that show how single cells encode magnetic field direction, intensity, and polarity; qualities that are necessary to derive an internal model representing directional heading and geosurface location. Our findings demonstrate that there is a neural substrate for a vertebrate magnetic sense.

Caspase Inhibitors Promote Vestibular Hair Cell Survival and Function after Aminoglycoside Treatment In Vivo

The sensory hair cells of the inner ear undergo apoptosis after acoustic trauma or aminoglycoside antibiotic treatment, causing permanent auditory and vestibular deficits in humans. Previous studies have demonstrated a role for caspase activation in hair cell death and ototoxic injury that can be reduced by concurrent treatment with caspase inhibitors in vitro. In this study, we examined the protective effects of caspase inhibition on hair cell death in vivo after systemic injections of aminoglycosides. In one series of experiments, chickens were implanted with osmotic pumps that administrated the pan-caspase inhibitor z-Val-Ala-Asp(Ome)-fluoromethylketone (zVAD) into inner ear fluids. One day after the surgery, the animals received a 5 d course of treatment with streptomycin, a vestibulotoxic aminoglycoside. Direct infusion of zVAD into the vestibule significantly increased hair cell survival after streptomycin treatment. A second series of experiments determined whether rescued hair cells could function as sensory receptors. Animals treated with streptomycin displayed vestibular system impairment as measured by a greatly reduced vestibulo-ocular response (VOR). In contrast, animals that received concurrent systemic administration of zVAD with streptomycin had both significantly greater hair cell survival and significantly increased VOR responses, as compared with animals treated with streptomycin alone. These findings suggest that inhibiting the activation of caspases promotes the survival of hair cells and protects against vestibular function deficits after aminoglycoside treatment.

Magnetoreception in an avian brain in part mediated by inner ear lagena

Many animals use the Earths geomagnetic field for orientation and navigation, but the neural mechanisms underlying that ability remain enigmatic. Support for at least two avian magnetoreceptors exists, including magnetically activated photochemicals in the retina and ferrimagnetic particles in the beak. The possibility of a third magnetoreceptor in the inner ear lagena organs has been suggested. The brain must process magnetic receptor information to derive constructs representing directional heading and geosurface location. Here, we used the c-Fos transcription factor, a marker for activated neurons, to discover where in the brain computations related to a specific set of magnetic field stimulations occur. We found that neural activations in discrete brain loci known to be involved in orientation, spatial memory, and navigation may constitute a major magnetoreception pathway in birds. We also found, through ablation studies, that much of the observed pathway appears to receive magnetic information from the pigeon lagena receptor organs.

Sensory Convergence Solves a Motion Ambiguity Problem

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.

Spatial tuning and dynamics of vestibular semicircular canal afferents in rhesus monkeys

Rotational head motion in vertebrates is detected by the three semicircular canals of the vestibular system whose innervating primary afferent fibers encode movement information in specific head planes. In order to further investigate the nature of vestibular central processing of rotational motion in rhesus monkeys, it was first necessary to quantify afferent information coding in this species. Extracellular recordings were performed to determine the spatial and dynamic properties of semicircular canal afferents to rotational motion in awake rhesus monkeys. We found that the afferents innervating specific semicircular canals had maximum sensitivity vectors that were mutually orthogonal. Similar to other species, afferent response dynamics varied, with regular firing afferents having increased long time constants (t1), decreased cupula velocity time constants (tv), and decreased fractional order dynamic operator values (sk) as compared to irregular firing afferents.

Computation of egomotion in the macaque cerebellar vermis.

The nodulus and uvula (lobules X and IX of the vermis) receive mossy fibers from both vestibular afferents and vestibular nuclei neurons and are thought to play a role in spatial orientation. Their properties relate to a sensory ambiguity of the vestibular periphery: otolith afferents respond identically to translational (inertial) accelerations and changes in orientation relative to gravity. Based on theoretical and behavioral evidence, this sensory ambiguity is resolved using rotational cues from the semicircular canals. Recordings from the cerebellar cortex have identified a neural correlate of the brains ability to resolve this ambiguity in the simple spike activities of nodulus/uvula Purkinje cells. This computation, which likely involves the cerebellar circuitry and its reciprocal connections with the vestibular nuclei, results from a remarkable convergence of spatially- and temporally-aligned otolith-driven and semicircular canal-driven signals. Such convergence requires a spatio-temporal transformation of head-centered canal-driven signals into an estimate of head reorientation relative to gravity. This signal must then be subtracted from the otolith-driven estimate of net acceleration to compute inertial motion. At present, Purkinje cells in the nodulus/uvula appear to encode the output of this computation. However, how the required spatio-temporal matching takes place within the cerebellar circuitry and what role complex spikes play in spatial orientation and disorientation remains unknown. In addition, the role of visual cues in driving and/or modifying simple and complex spike activity, a process potentially critical for long-term adaptation, constitutes another important direction for future studies.