The Neural Correlates of Spatial Disorientation in Head Direction Cells.

While the brain has evolved robust mechanisms to counter spatial disorientation, their neural underpinnings remain unknown. To explore these underpinnings, we monitored the activity of anterodorsal thalamic head direction (HD) cells in rats while they underwent unidirectional or bidirectional rotation at different speeds and under different conditions (light vs dark, freely-moving vs head-fixed). Under conditions that promoted disorientation, HD cells did not become quiescent but continued to fire, although their firing was no longer direction specific. Peak firing rates, burst frequency, and directionality all decreased linearly with rotation speed, consistent with previous experiments where rats were inverted or climbed walls/ceilings in zero gravity. However, access to visual landmarks spared the stability of preferred firing directions (PFDs), indicating that visual landmarks provide a stabilizing signal to the HD system while vestibular input likely maintains direction-specific firing. In addition, we found evidence that the HD system underestimated angular velocity at the beginning of head-fixed rotations, consistent with the finding that humans often underestimate rotations. When head-fixed rotations in the dark were terminated HD cells fired in bursts that matched the frequency of rotation. This postrotational bursting shared several striking similarities with postrotational "nystagmus" in the vestibulo-ocular system, consistent with the interpretation that the HD system receives input from a vestibular velocity storage mechanism that works to reduce spatial disorientation following rotation. Thus, the brain overcomes spatial disorientation through multisensory integration of different motor-sensory inputs.

On the absence or presence of 3D tuned head direction cells in rats: a review and rebuttal.

A major question in the field of spatial cognition is how animals represent three-dimensional (3D) space. Different results have been obtained across various species and may depend on whether the species inhabits a 3D environment or is terrestrial (land dwelling). The head direction (HD) cell system is an attractive candidate to study in terms of 3D representations. HD cells fire as a function of the animal's directional heading in the horizontal plane, independent of the animal's location and on-going behavior. Another issue concerns whether HD cells are tuned in 3D space or tuned to the 2D horizontal plane. Shinder and Taube (Shinder ME, Taube JS. J Neurophysiol 121: 4-37, 2019) addressed this issue by manipulating a rat's orientation in 3D space while monitoring responses from classic HD cells in the rat anterodorsal thalamus. They reported that HD cells did not display conjunctive firing with pitch or roll orientations. Direction-specific firing was primarily derived from horizontal semicircular canal information and that the gravity vector played an important role in influencing the cell's firing rate and its preferred firing direction. Laurens and Angelaki (Laurens J, Angelaki DE. J Neurophysiol 122: 1274-1287, 2019) challenged this view by performing a mathematical analysis on the Shinder and Taube data and concluded that they would not have seen 3D tuning based on their experimental approach. We provide a historical review of these issues followed by a summary of the experiments, which includes additional analyses. We then define what it means for a HD cell to be tuned in 3D and finish by rebutting the reanalyses performed by Laurens and Angelaki.

Three-dimensional tuning of head direction cells in rats.

Head direction (HD) cells fire when the animal faces that cell's preferred firing direction (PFD) in the horizontal plane. The PFD response when the animal is oriented outside the earth-horizontal plane could result from cells representing direction in the plane of locomotion or as a three-dimensional (3D), global-referenced direction anchored to gravity. To investigate these possibilities, anterodorsal thalamic HD cells were recorded from restrained rats while they were passively positioned in various 3D orientations. Cell responses were unaffected by pitch or roll up to ~90° from the horizontal plane. Firing was disrupted once the animal was oriented >90° away from the horizontal plane and during inversion. When rolling the animal around the earth-vertical axis, cells were active when the animal's ventral surface faced the cell's PFD. However, with the rat rolled 90° in an ear-down orientation, pitching the rat and rotating it around the vertical axis did not produce directionally tuned responses. Complex movements involving combinations of yaw-roll, but usually not yaw-pitch, resulted in reduced directional tuning even at the final upright orientation when the rat had full visual view of its environment and was pointing in the cell's PFD. Directional firing was restored when the rat's head was moved back-and-forth. There was limited evidence indicating that cells contained conjunctive firing with pitch or roll positions. These findings suggest that the brain's representation of directional heading is derived primarily from horizontal canal information and that the HD signal is a 3D gravity-referenced signal anchored to a direction in the horizontal plane. NEW & NOTEWORTHY This study monitored head direction cell responses from rats in three dimensions using a series of manipulations that involved yaw, pitch, roll, or a combination of these rotations. Results showed that head direction responses are consistent with the use of two reference frames simultaneously: one defined by the surrounding environment using primarily visual landmarks and a second defined by the earth's gravity vector.

Self-motion improves head direction cell tuning.

Head direction (HD) cells respond when an animal faces a particular direction in the environment and form the basis for the animal's perceived directional heading. When an animal moves through its environment, accurate updating of the HD signal is required to reflect the current heading, but the cells still maintain a representation of HD even when the animal is motionless. This finding suggests that the HD system holds its current state in the absence of input, a view that we tested by rotating a head-restrained rat in the presence of a prominent visual landmark and then stopping it suddenly when facing the cell's preferred firing direction (PFD). Firing rates were unchanged for the first 100 ms, but then progressively decreased over the next 4 s and stabilized at ∼42% of their initial values. When the rat was stopped facing away from the PFD, there was no initial effect of braking, but the firing rate then increased steadily over 4 s and plateaued at ∼14% of its peak firing rate, substantially above initial background firing rates. In experiment 2, the rat was serially placed facing one of eight equidistant directions over 360° and held there for 30 s. Compared with the cell's peak firing rate during a passive rotation session, firing rates were reduced (51%) for in-PFD directions and increased (∼300%) from background levels for off-PFD directions, values comparable to those observed in the braking protocol. These differential HD cell responses demonstrate the importance of self-motion to the HD signal integrity.

Sensory convergence in the parieto-insular vestibular cortex.

Vestibular signals are pervasive throughout the central nervous system, including the cortex, where they likely play different roles than they do in the better studied brainstem. Little is known about the parieto-insular vestibular cortex (PIVC), an area of the cortex with prominent vestibular inputs. Neural activity was recorded in the PIVC of rhesus macaques during combinations of head, body, and visual target rotations. Activity of many PIVC neurons was correlated with the motion of the head in space (vestibular), the twist of the neck (proprioceptive), and the motion of a visual target, but was not associated with eye movement. PIVC neurons responded most commonly to more than one stimulus, and responses to combined movements could often be approximated by a combination of the individual sensitivities to head, neck, and target motion. The pattern of visual, vestibular, and somatic sensitivities on PIVC neurons displayed a continuous range, with some cells strongly responding to one or two of the stimulus modalities while other cells responded to any type of motion equivalently. The PIVC contains multisensory convergence of self-motion cues with external visual object motion information, such that neurons do not represent a specific transformation of any one sensory input. Instead, the PIVC neuron population may define the movement of head, body, and external visual objects in space and relative to one another. This comparison of self and external movement is consistent with insular cortex functions related to monitoring and explains many disparate findings of previous studies.

Active and passive movement are encoded equally by head direction cells in the anterodorsal thalamus.

The head direction (HD) system is composed of cells that represent the direction in which the animal's head is facing. Each HD cell responds optimally when the head is pointing in a particular, or preferred, direction. Although vestibular system input is necessary to generate the directional signal, motor/proprioceptive inputs can also influence HD cell responses. Previous studies comparing active and passive movement have reported significant suppression of the HD signal during passive restraint. However, in each of these studies there was considerable variability across cells, and the animal's head was never completely fixed. To address these issues, we developed a passive restraint system that more fully prevented head and body movement. HD cell responses in the anterodorsal thalamus (ADN) were evaluated during active and passive movement with this new system. Contrary to previous reports, HD cell responses were not affected by passive restraint. Both head-fixed and hand-held restraint failed to produce significant inhibition of the active HD cell response. Furthermore, direction-specific firing was maintained regardless of 1) the animal's previous experience with restraint, 2) whether it was tested in the light or dark, or 3) the position of the animal relative to the axis of rotation. The maintenance of a stable directional signal without appropriate motor, proprioceptive, or visual input indicates that vestibular input is necessary and sufficient for the generation of the HD signal. Motor and proprioceptive influences may therefore be important for the control of the preferred firing direction of HD cells, but not the generation of the signal itself.

Both visual and idiothetic cues contribute to head direction cell stability during navigation along complex routes.

Successful navigation requires a constantly updated neural representation of directional heading, which is conveyed by head direction (HD) cells. The HD signal is predominantly controlled by visual landmarks, but when familiar landmarks are unavailable, self-motion cues are able to control the HD signal via path integration. Previous studies of the relationship between HD cell activity and path integration have been limited to two or more arenas located in the same room, a drawback for interpretation because the same visual cues may have been perceptible across arenas. To address this issue, we tested the relationship between HD cell activity and path integration by recording HD cells while rats navigated within a 14-unit T-maze and in a multiroom maze that consisted of unique arenas that were located in different rooms but connected by a passageway. In the 14-unit T-maze, the HD signal remained relatively stable between the start and goal boxes, with the preferred firing directions usually shifting <45° during maze traversal. In the multiroom maze in light, the preferred firing directions also remained relatively constant between rooms, but with greater variability than in the 14-unit maze. In darkness, HD cell preferred firing directions showed marginally more variability between rooms than in the lighted condition. Overall, the results indicate that self-motion cues are capable of maintaining the HD cell signal in the absence of familiar visual cues, although there are limits to its accuracy. In addition, visual information, even when unfamiliar, can increase the precision of directional perception.

Differentiating ascending vestibular pathways to the cortex involved in spatial cognition.

Vestibular information is an important factor in maintaining accurate spatial awareness. Yet, each of the cortical areas involved in processing vestibular information has unique functionality. Further, the anatomical pathways that provide vestibular input for cognitive processes are also distinct. This review outlines some of the current understanding of vestibular pathways contributing to the perception of self-motion in the cortex. The vestibulo-thalamic pathway is associated with self-motion cues for updating motor behaviors, spatial representations, and self versus object motion distinctions. The mammillo-tegmental pathway supplies vestibular input to create a cognitive representation of head direction. Self-motion and head direction information then converge to define self-location. By outlining the functional anatomy of the vestibular cortical pathways, a multi-sensory and multi-faceted view of vestibular related spatial awareness emerges.

Asymmetric gene expression in the brain during acute compensation to unilateral vestibular labyrinthectomy in the Mongolian gerbil.

Commercial microarrays were used to identify transcriptome expression within vestibular related brain regions (vestibular brainstem and cerebellum, and caudotemporal cortical regions) during the acute period of recovery following unilateral surgical vestibular labyrinth ablation in the gerbil. As a representative model of vestibular compensation, vestibular lesions in the gerbil produced activation in a common set of genes related to vestibular compensation. The total RNA was prepared and amplified using Affymetrix Gene Chip probes from the Rat U34 Neurobiology and R230, and Mouse M430 gene sets, resulting in GCRMA summarized data from S+AA software. Matched rat and mouse genes from gerbil hybridization produced good interspecies synteny. Multiple gene target trends supported global increases in neuron excitability throughout the vestibular brainstem and cerebellum. We focused further on gene expression with anatomically asymmetric activation relative to the lesion, indicative of involvement in rebalancing central vestibular tone during the vestibular compensation process. Cluster analysis revealed distinct spatial (regional and ipsi-contra) and temporal patterns. The asymmetric genes were part of well-defined neuron-related networks and included multiple members of the glutamate and GABA neurotransmitter systems. Transcripts for D3 dopamine, glycine, and some GABA receptor signals increased quickly in the ipsilesional vestibular complex and then increased gradually in the contralateral region, restoring the expression symmetry. Alternatively, the NMDA binding subunit decreased gradually over the acute compensation period in the contralateral vestibular complex. There was evidence for numerous associations between signaling systems with PKC as one possible mediator between early changes in GABA and progressive changes in NMDA signaling. These data begin to define the compensatory response at the level of molecular cascades.

Fos responses to short-term adaptation of the horizontal vestibuloocular reflex before and after vestibular compensation in the Mongolian gerbil.

Fos expression in vestibular brainstem and cerebellar regions was evaluated during vestibular adaptation in the Mongolian gerbil. In addition, vestibular adaptation was evaluated in both normal and compensated animals, as vestibular compensation reorganizes the vestibular pathway constraining adaptive processes. Behaviorally, discordant optokinetic and vestibular input induced appropriate high and low gain in horizontal angular vestibuloocular reflex responses. In normal animals, low gain adaptation was more complete than high gain. However, in compensated animals, only low gain adaptation produced adaptive responses both toward and away from the lesion with appropriate gain shifts. High gain adaptation in compensated animals failed to result in gain adaptation for head movements toward the side of the lesion. Fos expression during acute vestibular adaptation in normal animals was found in the flocculus/paraflocculus, the dorsal cap of the inferior olive (IOK), and the prepositus hypoglossi (PrH). Floccular Fos labeling was increased under both high and low gain conditions. IOK and PrH labeling was increased and correlated during low gain conditions, but was reduced and uncorrelated during high gain conditions. The pattern of Fos labeling in compensated animals was asymmetric-favoring the ipsilesional flocculus and contralesional vestibular brainstem. Both compensated high and low gain adaptation groups displayed increased floccular and IOK Fos labeling, but only compensated high gain adaptation produced increased Fos labeling in the medial vestibular nucleus. The behavioral and Fos labeling results are consistent with visual-vestibular adaptation requiring direct vestibular input.

VOR and Fos response during acute vestibular compensation in the Mongolian gerbil in darkness and in light.

We measured binocular horizontal eye movements in the gerbil following unilateral labyrinthectomy during the acute phase (1-24 h) of vestibular compensation. Regardless of whether the animals compensated in the light or the dark, VOR gain progressively reduced following the lesion, and normal oculomotor symmetry was disrupted. Initially, the VOR was comparable at 1 h post-lesion for both visual conditions. However, by 3 h post-lesion the VOR response for head turns away from the lesion continued to drop in animals compensating in the dark. By 24 h, both groups displayed reduced VOR gains, but animals compensating in the light had improved frequency response characteristics. Optokinetic responses became unstable but were generally elevated compared to pre-lesion levels. Animals with vision had reduced optokinetic gains by 24 h, while the OKR response for animals in the dark remained elevated. Brainstem Fos labeling generally increased from 1 to 3 h, then decreased by 24 h. However, at 1 h, Fos labeling in the inferior olivary dorsal cap and prepositus contralateral to the lesion was significantly increased in animals compensating in the light. In both visual conditions, flocculus and paraflocculus Purkinje cell labeling was also observed, and some of the Fos-labeled cells in the medial vestibular nucleus were commissural. Fos in the dorsal cap and prepositus could be attributed to the presence of visual input. While the visually related prepositus Fos labeling preceded improved VOR performance, the dorsal cap appeared to be involved in resolving visual and motor deficits from spontaneous nystagmus.