Larry F. Hoffman

MUSCARINIC ACETYLCHOLINE RECEPTOR SUBTYPE mRNAs IN THE HUMAN AND RAT VESTIBULAR PERIPHERY

The expression of the five muscarinic acetylcholine receptor (mAChR) subtypes (m1–m5) in the vestibular end‐organs and in the primary afferent vestibular ganglia of the human and rat was studied using RT‐PCR from the two tissue populations from both species. In the human, although all five mAChR subtypes were expressed in brain, only the m1, m2, and m5 mAChR subtypes were amplified from both the vestibular ganglia and the vestibular end‐organs, while in the rat, all five mAChR subtypes were expressed. These data suggest that the efferent cholinergic axo‐dendritic and axo‐somatic synapses have a muscarinic component and that there are pharmacologic implications for patients with vestibular dysfunction.

The measurement and manipulation of intralabyrinthine pressure in experimental endolymphatic hydrops

Three to four months after unilateral surgical ablation of the endolymphatic duct and sac, endolymphatic and perilymphatic pressures were measured in both the normal and hydropic ears of 11 guinea pigs. In normal ears, endolymphatic pressure always approximated perilymphatic pressure. Endolymphatic pressure exceeded perilymphatic pressure in all ears with hydrops, except one in which these pressures were equal. The effect of postural inversion on inner ear pressures were studied in both normal and hydropic inner ears. Normal ears showed endolymphatic and perilymphatic pressure to rise equally during this maneuver. In hydropic ears, the difference between endolymphatic and perilymphatic pressure was notably reduced from measurements obtained in the prone position. This study indicates that an alteration in pressure regulation within the inner ear may be important in the pathogenesis and manifestation of experimental endolymphatic hydrops in the guinea pig. Physiologic mechanisms and clinical implications of these results are described.

Distribution of high-conductance calcium-activated potassium channels in rat vestibular epithelia.

Voltage‐ and calcium‐activated potassium channels (BK) are important regulators of neuronal excitability. BK channels seem to be crucial for frequency tuning in nonmammalian vestibular and auditory hair cells. However, there are a paucity of data concerning BK expression in mammalian vestibular hair cells. We therefore investigated the localization of BK channels in mammalian vestibular hair cells, specifically in rat vestibular neuroepithelia. We find that only a subset of hair cells in the utricle and the crista ampullaris express BK channels. BK‐positive hair cells are located mainly in the medial striolar region of the utricle, where they constitute at most 12% of hair cells, and in the central zone of the horizontal crista. A majority of BK‐positive hair cells are encapsulated by a calretinin‐positive calyx defining them as type I cells. The remainder are either type I cells encapsulated by a calretinin‐negative calyx or type II hair cells. Surprisingly, the number of BK‐positive hair cells in the utricle peaks in juvenile rats and declines in early adulthood. BK channels were not found in vestibular afferent dendrites or somata. Our data indicate that BK channel expression in the mammalian vestibular system differs from the expression pattern in the mammalian auditory and the nonmammalian vestibular system. The molecular diversity of vestibular hair cells indicates a functional diversity that has not yet been fully characterized. The predominance of BK‐positive hair cells within the medial striola of juvenile animals suggests that they contribute to a scheme of highly lateralized coding of linear head movements during late development. J. Comp. Neurol. 517:134–145, 2009.

Dynamics and the single spike

Responses of vestibular primary afferent neurons to head rotation exhibit fractional-order dynamics. As a consequence, the head tends to be in a localized region of its state-space at spike times of a particular neuron during arbitrary head movements, and single spikes can be interpreted as state measurements. We are developing a model of neural computations underlying trajectory prediction and control tasks, based on this experimental observation. This is a step toward a formal neural calculus in which single spikes are modeled realistically as the operands of neural computation.

Optimal firing rate estimation

We define a measure for evaluating the quality of a predictive model of the behavior of a spiking neuron. This measure, information gain per spike (Is), indicates how much more information is provided by the model than if the prediction were made by specifying the neurons average firing rate over the same time period. We apply a maximum Is criterion to optimize the performance of Gaussian smoothing filters for estimating neural firing rates. With data from bullfrog vestibular semicircular canal neurons and data from simulated integrate-and-fire neurons, the optimal bandwidth for firing rate estimation is typically similar to the average firing rate. Precise timing and average rate models are limiting cases that perform poorly. We estimate that bullfrog semicircular canal sensory neurons transmit in the order of 1 bit of stimulus-related information per spike.

Morphologic and Quantitative Study of the Efferent Vestibular System in the Chinchilla: 3-D Reconstruction

An HRP study of the EVN has been performed. Three groups of somas have been identified: Those located in the proximity of the vestibular nuclei, those sandwiched between the facial genu and the IVth ventricle, and those in the RF, surrounding the abducens nucleus. The number of somas is greater in the contralateral brain-stem side. Axons could be followed through the midline, but could not be traced to a labelled soma. A 3-D reconstruction of the EVN within the brain stem is presented.

Intraotic administration of gentamicin : A new method to study ototoxicity in the crista ampullaris of the bullfrog

A new method of local gentamicin administration was tested in the bullfrog inner ear to achieve ototoxic‐induced hair cell destruction. Gelfoam pledgets soaked with known amounts of gentamicin were inserted into the perilymphatic cisterna of the bullfrog through a ventral surgical approach. A dose of 1.20 mg gentamicin, consistent with a perilymphatic concentration of 65 μg/ml, resulted in the desired ototoxic‐induced hair cell damage, that is, complete hair cell destruction with minimal disruption of other components of the sensory epithelium. This study demonstrates that this is a useful and simple method to investigate the process of vestibular ototoxicity and hair cell regeneration, including aspects of hair cell destruction and repair.

State-space receptive fields of semicircular canal afferent neurons in the bullfrog

Receptive fields are commonly used to describe spatial characteristics of sensory neuron responses. They can be extended to characterize temporal or dynamical aspects by mapping neural responses in dynamical state spaces. The state-space receptive field of a neuron is the probability distribution of the dynamical state of the stimulus-generating system conditioned upon the occurrence of a spike. We have computed state-space receptive fields for semicircular canal afferent neurons in the bullfrog (Rana catesbeiana). We recorded spike times during broad-band Gaussian noise rotational velocity stimuli, computed the frequency distribution of head states at spike times, and normalized these to obtain conditional pdfs for the state. These state-space receptive fields quantify what the brain can deduce about the dynamical state of the head when a single spike arrives from the periphery.

Vestibular and Optokinetic Function in the Normal Guinea Pig

Vestibular and optokinetic function was quantitatively studied in the normal guinea pig through investigation of the vestibulo-ocular reflex (VOR), optokinetic nystagmus (OKN), and the visual vestibulo-ocular reflex (VVOR) by means of sinusoidal stimulation with a computer-controlled rate table (VOR and VVOR) or an optokinetic drum. The VOR exhibited high-pass filter characteristics with steady state gain achieved at 0.125 Hz. The maximum gain was 0.55 at a velocity of 60°/s. The VOR was modeled by a transfer function with best fits obtained with an adaptation time constant of 12.5 seconds. The OKN showed low-pass filter characteristics with a decrease in gain for increase in stimulus amplitude. The maximum gain measured was 0.64. A fractional pole model provided a fit of these data. The VVOR exhibited a mean gain of between 0.6 and 0.7 across the stimulus bandwidth and peak velocities. A model based on a linear combination of the actual OKN and VOR gains provided an estimate of the VVOR gain.

A Model of Cerebellar Computations for Dynamical State Estimation

The cerebellum is a neural structure that is essential for agility in vertebrate movements. Its contribution to motor control appears to be due to a fundamental role in dynamical state estimation, which also underlies its role in various non-motor tasks. Single spikes in vestibular sensory neurons carry information about head state. We show how computations for optimal dynamical state estimation may be accomplished when signals are encoded in spikes. This provides a novel way to design dynamical state estimators, and a novel way to interpret the structure and function of the cerebellum.