1. IMPLICATIONS FOR UPSTREAM SYSTEMS
Our results have shown that individual neurons within the rat vestibular nuclei, like those in other species, modulate their activity in response to eye movements in addition to head movements, during passive rotations and fixation. This confirms that the rat vestibular nuclei, like those in other species, are the site of multi-modal convergence and that individual neurons within the nuclei process signaIs from more than one source.
Vestibular-only neurons are the most accurate source ofhead velocity information in the rat vestibular nuclei, and given the similarity between the properties of the vestibular-only neurons in the rat and those in the primate, it is reasonable to hypothesize that these similarities will carry over in other behavioural conditions. This could potentially mean that during active, voluntary movements, like in the primate (Roy and Cullen, 2002), neurons in the rat vestibular nuclei may not accurately encode head velocity. The
question that subsequently arises, is that if this is indeed the case, where do head direction cells, known to be active during voluntary movements, receive their information
concerning the movement of the head? There are several alternate possibilities to be considered.
An often-mentioned potential source of head position infonnation is the nucleus prepositus hypoglossi. In an mammals in which it has been studied, this nucleus is prominently involved in the saccade generating circuitry, and in primates appears to be the neural integrator that transfonns an eye velocity signal into an eye position signal (Fuchs and Kimm, 1975). The nucleus prepositus' proximity and anatomical connections with the medial vestibular nucleus and the dorsal tegmental nucleus, have led to the hypothesis that this nucleus may also integrate head velocity inputs into head positions signaIs that can subsequently be transmitted to head direction cens (Taube et al. 1996).
There are several problems with this hypothesis, though. So far, there is no evidence that the nucleus prepositus hypoglossi processes any head related infonnation - although it is possible that this could be occurring in subpopulation of cens that have not yet been characterized (Brown et al, 2002). Secondly, since it is very possible that the vestibular nuclei in the rat, like those in the primate, do not accurately encode head velocity during voluntary movements, the mystery of the origin of the head velocity signal remains, even if this undiscovered class of cells does exist.
Another possible source of vestibular infonnation to the head direction cell network is the cerebellum. Afferents from the vestibular end organs, as mentioned, branch off and send projections to the vestibulo-cerebellum as weIl as the vestibular nuclei (Bannack, 2003). It is possible, that while neurons within the vestibular nuclei do not encode head velocity during active movements, those in the vestibulo-cerebellum do and could potentially send this infonnation to structures containing head direction and place cens. Anatomical evidence shows that the vestibulo-cerebellum does have connections with the thalamus, that contains head direction cens, as wen as the hippocampus and entorhinal cortex, both ofwhich contain place cens (Kaufman et al.
1996). As mentioned, head direction cells exhibit activity that requires a coordinate transformation of head position, from a body-referenced to an environment-based scheme. Interestingly, the cerebellum itselfhas been shown to encode information about head orientation in a variety ofreference frames (Shaikh et al. 2004), which is believed to be produced with inputs from neck proprioceptors (Manzoni et al. 1999). This cerebellum hypothesis can even be reconciled with evidence from lesion studies that shows that head direction cell activity is aboli shed when the vestibular system is lesioned (Stackman and Taube, 1997). Given the extensive reciprocal connections between the vestibular nuclei and the cerebellum (reviewed in Barmack, 2003), it is quite reasonable that a lesion to one area willlead to an alteration in the behaviour of other upstream areas. Rather than receiving information about he ad velocity from the vestibular nuclei and then integrating it into head position and then subsequently changing the frame of reference aIl by themselves, it is possible that head direction cells receive this information prepackaged from the cerebellum.
So far we have only considered possibilities of building up head direction and place cells from available sensory cues, from the bottom up, so to speak. It is quite possible that the properties of these cells are imparted to them from an interaction with the cortex. The associative parietal cortex has already been shown to interact with
hippocampal place cells, and seems to be required for normal place cell functioning (Save et al. 2005; Berthoz, 1997). It is possible that the necessary sensory integration and coordinate reference changes are performed by areas in the cortex that receive vestibular inputs, such as the parietal cortex, insular cortex or even the frontal lobes (Duque-Parra, 2004) which then interact with place cell and head direction cell populations.
II. FUTURE DIRECTIONS
Considerably more studies are required before the nature of the interaction between head direction cell activity and vestibular input can be satisfactorily described.
First and foremost, it must be established whether neurons in the rat vestibular nuclei accurately encode he ad velocity during voluntary movements. This will establish whether there is any accurate information about head velocity that could potentially be transmitted to upstream head direction cells from the vestibular nuclei during active movements, and whether it is worthwhile to continue investigating the source of vestibular information in the vestibular nuclei. This was beyond the scope of the present experiments because it requires that the electrode be stabilized on the head and that head movements be isolated from whole body movements. Additionally, it would also be useful to characterize the behaviour of neurons within the nucleus prepositus hypoglossi in response to eye and head movements, since the rat has not been a popular model for studies of this nucleus in the past. This would reveal whether neurons in the rat prepositus mainly encode eye position information, and potentially reveal whether any head related information is also present. A lesion study, inactivating the prepositus while recording from upstream head direction cells would also help to elucidate its potential role in spatial navigation, although this would be technically challenging given the small size of the nucleus and its proximity to the vestibular nuclei. Other hypotheses would also benefit from lesion studies. For example, lesion studies to vestibular-related cerebellar areas, such as the vermis, the nodulus and uvula, and rostral fastigial nucleus while recording from populations ofhead direction cells would help to establish whether the cerebellum plays a role in generating the head direction cell signal. The cerebellum could prove to be
the solution to many of the mysteries that still surround head direction and place cells.
However, despite the long-standing ancillary evidence alluding to its potential role, research into the cerebellum's involvement in spatial navigation is still in its infancy (see Rondi-Reig and Burguiere, 2005 for review). Future studies trying to define the nature of vestibular inputs will benefit most from confining themselves to the vestibular nuclei and cerebellum before branching out in the cortex, where isolating variables becomes a far greater challenge.
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Appendix
The proceeding page contains a copy of the Animal Use Protocol that was approved by the McGill University Animal Care Committee and Ethics Subcommittee.