Visuospatial Abilities

VISUOSPATIAL ABILITIES

Robert Lalonde Neurology Service, Unit of Behavioral Neurology, Neurobiology, and Neuropsychology, Hotel-Dieu Hospital Research Center, and Departments of Medicine and Psychology and Neuroscience Research Center, University of Montreal, Montreal, Quebec, Canada H2W 1TB

I. Introduction II. Evaluation of Spatial Learning A. Morris Maze B. Radial Maze C. Spatial Alternation D. Hole Board III. Conclusions References

The importance of the hippocampus and its anatomical connections, including the medial septum, thalamic nuclei, and neocortical regions in many spatial tasks including the Morris water maze, has been emphasized. Studies in mutant mice with cerebellar atrophy and in rats with electrolytic lesions of the cerebellum have indicated that the cerebellum has a role in visuospatial and visuomotor processes in the Morris maze. Directional deficits in the water have also been noted in rats whose cerebellum was exposed to X-rays during different developmental stages. Cerebellar interactions with the superior colliculus, the hippocampus, and the neocortex via thalamic nuclei are suggested to be the basis of the cerebellar modulation of directional sense in maze tests.

I. Intraduction

The purpose of this chapter is to present available data concerning the effects of cerebellar damage on maze tests in animals. The role of the hippocampus in visuospatial memory has been well characterized. More recently, it has been noted that some of the spatial deficits found in rats with hippocampal lesions can also be found in animals with cerebellar lesions. It is proposed that this result is due to cerebella-hippocampal interactions, together with cerebellar modulation of other subcortical and neocortical regions. An emphasis is placed on the Morris water maze beINTE.RNATIONAI. REVIEW OF NEUROBIOLOGY, VOL. 41

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ROBERT LALONDE

cause this paradigm offers the possibility of dissociating spatial defects from visuomotor defects.

II. Evaluation of Spatial Learning

The two maze tasks most frequently employed in the evaluation of the neurobiological bases of spatial learning in rodents are the Morris water maze (Morris et al., 1982) and the radial maze (Olton and Papas, 1979). During spatial learning in the Morris water maze, rat.s or mice are placed in a pool containing a platform hidden from view. Two frequently used measures are the distance swum and escape latencies before reaching the platform. During sensorimotor testing in the same maze, the platform is raised above water level and is thereby visible from all areas of the pool. In the radial maze, rats (or more rarely mice) are placed in the center of a maze containing eight or more arms spread out like spokes in a wheel. To be able to retrieve a food pellet, the rat must enter each arm once. A second entry into the same arm within a trial is not rewarded and is counted as an error. In one version of the task, food is placed at the end of four of the arms but not at the remaining four. Entries into food-baited arms previously visited are tabulated as errors of working memory, whereas entries into nonbaited arms are tabulated as errors of reference memory (Crusio et al., 1993). The hidden platform task of the Morris maze is considered to he a reference memory task because of the unchanging position of the platform.

A. MORRIS MAZE

1. MelhodotoJfim[ Considerations When deficits in spatial orientation occur, distance swum and escape latencies are increased. High escape latencies in the absence of longer path lengths are an indication of slower swim speed, as reported for a spinocerebellar mutant (Lalonde et al., 1993). During some manipulations, e.g., morphine administration, both values are high; subsequent testing revealed that this was due to a decrease in motivation rather than to a spatial defect (McNamara and Skelton, 1992). In many reports, the animals are first evaluated in the hidden platform condition and then in the visible platform condition. Naive animals learn that only one escape platform is available and learn to locate that platform on the basis of extramaze cues. At the beginning of training, the animals

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tend to explore mostly the perimeter of the basin. Once they abandon that strategy, normal animals acquire the task rapidly. During visible platform performance, their previous training may help them abandon the wallhugging strategy, guiding them more effectively toward the goal, located in a new area of the pool. The animals must learn to avoid perseverative responses toward the previously located hidden platform. When first evaluated in the visible platform task, the animals often explore the perimeter of the basin as well. When the location of the invisible platform is changed, they must learn not to perseverate in swimming toward the previously located visible platform. A methodological difference between studies that may be of some importance is the presence or absence of corrected trials when the cutoff time is exceeded. In some studies, the rat is placed on the platform (corrected trials), whereas in others the rat is removed from the pool (uncorrected trials). It has been argued that this methodological difference explains the presence or absence of a lesion effect (de Bruin et al., 1994). 2.

l/i~oca~jnus

The existence of hippocampal place cells (Foster et al., 1989; Sharp et al., 1995) and the impairments found after bilateral lesions of the hippocampus on a 14-unit T-maze (Jucker et al., 1990) and on a single T-maze (Wan et al., 1994) have underlined the importance of this brain region in spatial orientation. In comparison to a group with cortical lesions overlying the hippocampus and a control group (sham or no surgery), bilateral aspiration lesions of the hippocampus in rats increased distance traveled and escape latencies during acquisition of the hidden platform task (Morris et al., 1982). The visible platform task was minimally affected. Although the impairment was statistically significant, this appeared to be mostly due to high escape latencies during the first trial block. In a probe test, during which the platform was removed from the pool, control and cortically lesioned rats had higher crossings in the region where the platform was previously located than rats with hippocampal lesions, an indication that the hippocampal group had a spatial memory defect and not a loss in motivation. Sutherland and Rudy (1988) examined the effects of bilateral colchicine-induced lesions of the hippocampus on the visible platform task interspersed with hidden platform trials. During either condition, the platform was located in the same region of the pool. The distance traveled was not measured. The lesioned rats had higher escape latencies in the visible platform task only at the beginning of training. Higher escape latencies in the hidden platform condition occurred for the final two trial blocks. Identical platform positioning in the two tasks does not eliminate the spatial defect caused by hippocampal lesions. McDonald and White (1994)

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obtained similar results in the same paradigm after lesions of the fornix. Impairment of the place-learning task was found after lesions of the hippocampus by electrolysis and by administration of colchicine, kainatc (Sutherland et al., 1982, 1983), and quisqualate (Marston et al., 1993). Kolb et al. (1984) evaluated the effects of unilateral hippocampal lesions on spatial learning in the Morris maze. Left- or right-sided lesions of the hippocampus augmented escape latencies and the heading angle toward the hidden platform. When the platform was removed, the time spent in the previously correct quadrant was higher in the control group than in either lesioned group. Deficits of spatial orientation were also observed in hemidecorticate rats. Severe impairments in place learning were displayed hy totally decorticate rats (Whishaw and Knlb, 1984). These rats were also impaired during cued learning, but not to the same extent, Because hippocampallesions cause deficits in place learning whereas visuomotor coordination is spared or minimally impaired, the question arises as to which brain regions afferent or efferent to the hippocampus are important for spatially mediated information. Important afferent regions include the entorhinal cortex, the medial septum, and the amygdala. 3. Hippocampal Afferents

Schenk and Morris (1985) evaluated two lesioned groups: one with damage to the entorhinal cortex, the subiculum, and the pre- and parasubiculum, and the other with damage to the entorhinal cortex with less extensive damage to the other areas. A corrected trial procedure was used. In comparison to a control group comprising sham and unoperated animals, the two experimental groups had longer path lengths and higher escape latencies during the acquisition of place learning. The terminal performance of cued learning was not impaired by the lesions (initial performance values were not presented). Using aspiration, Nagahara et al. (1995) lesioned the entorhinal cortex touching the perirhinal cortex border and evaluated place learning with the correction procedure. The escape latencies of lesioned rats were higher than those of sham controls during acquisition of the hidden platform task. During probe trials, the lesioned group spent less time in the correct quadrant of the pool. There was no group difference in swimming speed during the probe trials nor was there a difference in visible platform performance. The importance of the perforant path linking the entorhinal cortex to the hippocampus was underlined by Skelton and McNamara (1992), who reported spatial learning deficits in rats with knife cuts to this structure. Electrolytic lesions of the perirhinal cortex increased escape latencies and the heading angle toward the platform during acquisition of place learning but not during visuomotor performance (Wii~ and Bilkey, 1994). No difference was detected for swim dis-

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tance. The lesioned group had fewer platform crossings during probe trials, indicating a loss in memory. The noncorrected trial procedure was used. However, Kolb et al. (1994), also using the noncorrection procedure, found no deficit in place learning after lesions of the posterior temporal cortex that included much of the perirhinal cortex. A number of reports exist concerning the effects of medial septal lesions on acquisition of place learning. Electrolytic lesions of the septum and the diagonal band (Segal et al., 1989) or only the medial septum (Decker et al., 1992; Kelsey and Landry, 1988; Miyamoto et al., 1987; Sutherland and Rodroguez, 1989) impaired acquisition of the hidden platform condition in the Morris task. Visible platform performance (Sutherland and Rodriguez, 1989) and performance with suspended lamp cues (Kelsey and Landry, 1988) were not affected by medial septal lesions. Spatial deficits have been found with neurotoxin-induced lesions (sparing axons of passage) of the medial septum and diagonal band of Broca (Decker et al., 1992; Hagan et al., 1988; Marston et al., 1993; McAlonan et al., 1995), but not with colchicine-induced cell shrinking of the medial septum (Barone et al., 1991). Baxter et al. (1995) lesioned the medial septum and the diagonal band of Broca more selectively with the use of 192 IgG-saporin, an immunotoxin of cholinergic neurons. With the correction procedure, rats with damage to the medial septum and diagonal band of Broca were not impaired. These results show that the medial septum is involved in spatial learning, and hippocampal afferents are not exclusively cholinergic. In contrast to the impairments reported in rats with entorhinal or medial septal damage, electrolytic lesions of the amygdala did not slow down the acquisition of place learning (Sutherland and McDonald, 1990). In the same experiment, hippocampal lesions caused by an ibotenatecolchicine solution or combined lesions of the hippocampus and amygdala increased hidden platform escape latencies.

4. Hippocampal EJJerents The hippocampal efferent system includes the association cortex of the frontal lobe and the parietal lobe (Rosene and Van Hoesen, 1977), anterior thalamus, mammillary bodies (Aggleton et al., 1986), and brain stem precerebellar nuclei, namely the inferior olive and pontine nuclei (Saint-Cyr and Woodward, 1980). Kolb et al. (1982) evaluated rats with either medial frontal cortex or dorsomedial thalamic lesions during the acquisition of place learning. Whereas rats with thalamic lesions performed like controls, rats with medial frontal lesions had higher escape latencies and a higher heading angle toward the platform. The visible platform condition was not assessed. Sutherland et al. (1982) and Kolb et al. (1983, 1994) confirmed the deleterious effects of medial frontal lesions on place learning. An

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absence of a deficit on visible platform training after medial frontal lesions, whether fixed in one position or varied randomly from one trial to the next, was reported by Kolb et at. (1994). Sutherland et at. (1988) compared the effects of suction ablation of the anterior or posterior cingulate cortex and colchicine-induced degeneration of the hippocampus to shamoperated controls on acquisition of place learning. Higher escape latencies were observed in all three lesioned groups. Swimming speed was not affected. There was no assessmen t of visible platform performance. de Bruin et at. (1994) found an absence of a place-learning defect in rats with medial frontal lesions or smaller lesions encompassing either ventral or dorsal parts. A visible platform deficit in the early part of training was found in all three lesioned groups. This task comprised shifting of platform locations from an identical starting point and was interpreted as a perseveration rather than as a visuomotor problem. They list methological differences between their study and previous ones and conclude that the most importam factor explaining the lack of a spatial deficit was the presence of corrected trials. In the Kolb et at. (1982, 1983, 1994) and the Sutherland et at. (1982. 1988) studies. whenever a rat failed to find the hidden platform within the allowed time, the animal was retrieved from the water. The corrected trial procedure permits early recognition of the position of the platform. In the noncorrected procedure, an animal unable to reach the platform learns only where the platform is not and not where the platform is. In contrast, lesions of the parietal cortex impaired acquisition of the hidden platform condition with both the corrected and the noncorrected trial procedure. Kolb et at. (1983, 1994), using the noncorrected trial procedure, reported that aspiration lesions of the posterior parietal cortex (area 7) in rats increased escape latencies and the heading angle toward the submerged platform. The visible platform condition was not assessed. Using aspiration, DiMattia and Kesner (1988) lesioned a larger section of the parietal lobe, comprising areas 5, 7, 39, 40, and 43. Lesions of the parietal lobe and the hippocampus increased escape latencies and the heading angle toward the submerged platform. A corrected trial procedure was adopted. There was no assessment of the visible platform condition. Crowne et at. (1992), using the noncorrected trial procedure, measured the effects of unilateral aspiration of area 7. In comparison to sham-operated rats, these authors found that lesions of the right parietal lobe increased escape latencies and a target-nontarget quadrant ratio but not the heading angle toward the invisible platform. Left-sided lesions had no effect on any measure. There was no assessment of the visible platform condition. No study has yet undertaken the effects ofparietal lesions on visible platform training. The vulnerability of the right parietal lobe on spatial functions in humans had often been emphasized (Botez et al., 1985). The results of this study

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indicate that hemispheric lateralization of spatial functions in the parietal lobe is not limited to humans. Sutherland and Rodriguez (1989) evaluated the effects offornix lesions and its target structures: the anterior thalamus, mamillary bodies, and nucleus accumbens. The latter structure also receives projections from the amygdala. Lesions of the fornix, the anterior thalamus, the mammillary bodies, and the nucleus accumbens lengthened escape latencies in the hidden platform condition. None of these lesions impaired visible platform performance except for the first of four trial blocks among rats with mammillary body lesions. Segal et al. (1989) also reported deficits of spatial localization in rats with knife cuts of the fornix. Table I summarizes the results of lesioning hippocampal afferent and efferent regions. If studies using the noncorrection procedure are included, all hippocampal afferent and efferent regions disrupt place learning except the amygdala. A selective place-learning deficit with a minimal or no deficit in visuomotor coordination has been demonstrated for subcortical structures (the fornix, the septum, the anterior thalamus, the mamillary bodies, and the nucleus accumbens) but not as yet for neocortical structures (prefrontal and parietal cortices). If studies using the correction procedure are included, a place-learning deficit is found after lesions of two main afferent areas, the medial septum and the entorhinal cortex and one efferent area, the parietal cortex, but not the prefrontal cortex.

TABLE I EFFECTS OF LESIONING HIPPOCAMPAL AFFERENT AND EFFERENT REGIONS ON PLACE LEARNING IN THE MORRIS WATER MAzE WITH OR WITHOUT THE CORRECTION PROCEDURE

Deficit Correction procedure Entorhinal cortex Medial septum Parietal cortex Noncorrection procedure Medial septum Perirhinal cortex Parietal cortex Medial frontal cortex Cingulate cortex Anterior thalamus Mammillary bodies

No deficit

Medial frontal cortex

Amygdala Posterior temporal cortex Dorsomedial thalamus

19R

ROBERT IALONDE

5. Prermrbellar Nuclei

In addition to hippocampal efferents at levels higher than the midbrain, it is worth exploring brain stem hippocampal efferents projecting to the cerebellum. Electrical stimulation of the fornix alters Purkinje cell activity via climbing fiber and mossy fiber pathways (Saint-Cyr and Woodward, 1980). To the author's knowledge, there is only one report concerning the effects of brain stem precerebellar nuclei lesions on the Morris maze task. Dahhaoui et at. (1992b) injected 3-acetylpyridine in rats, causing degeneration of inferior olive cells, the single source of climbing fibers, and then assessed place learning. The rats began a trial from the same pool region, and not from all four cardinal points. A learning criterion of five consecutive trials with escape latencies lower than 9 sec was adopted. Rats with inferior olive lesions took more trials before reaching criterion than saline-injected controls. Visible platform performance was not assessed. This study introduces the possibility of a role for a hippocampo-olivoponto-cerebellar system on spatial orientation or visuomotor performance. Moroever, it is known that hippocampal place cells are dependent on the preparedness of movement (Foster et al., 1989). In conditions of restraint, the spatially selective discharge of pyramidal cells was abolished. Their spatial firing patterns were influenced by visuomotor and vestibular information (Sharp el al., 1995). Visuomotor information may be received from the neocortex and from the cerebellum. The midline cerebellum may provide the hippocampus with the sensorimotor integration necessary to execute spatially mediated behavior (Lalonde and Botez, 1990). 6. Cerebellum Stein (1986) and Stein and Glickstein (1992) have hypothesized that the neocortico-ponto-cerehellar pathway is involved in the visual guidance of movements, Such considerations have been based on the control of limb and eye movements rather than on whole body movements of animals performing spatial tasks. Attempts have been made to answer the question ,IS to whether cerebellar damage causes deficits in the whole body guidance of movements in water mazes. Neuropsychological studies have indicated that cerebellar damage affects spatial abilities even in tasks not requiring movement (Botez et at., 1989; Botcz-Marquard and Botez, 1993, Botez-Marquard and Routhier, 1995; Fehrenbach et al., 1984; Kish et al., 1988). a. Mutant Mouse Models: Patholol!J. The effects of cerebellar damage on water maze learning have been evaluated in five types of mutant mice, with cerebellar degeneration arising during different developmental stages (Table II). These mutants were tested in the water maze at 1-2 months of

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VISUOSPATIAL ABILITIES TABLE II NP:UKOPATHOLOGY OF CEREBELLAR MUTANT MICE AT

I OR 2

MONTHS OF AGE

Mutant

Cerebellar atrophy

Extracerebellar atrophy

Lurcher

Granule, Purkinje

Inferior olive

Staggerer

Granule, Purkinje

Inferior olive

Weaver

Granule

Substantia nigra pars compacta

pcd

Purkinje

Inferior olive

Hot-foot

Purkinje cell

Unknown

dendritic spines

age. At 1 month of age, in lurcher (Caddy and Biscoe, 1979) and in staggerer (Herrup and Mullen, 1979a) mutant mice, there is a massive degeneration of cerebellar granule and Purkinje cells. Abnormalities in the internal and the external granular layers have been detected in lurcher mutants as early as postnatal day 3 (Heckroth, 1992). There is also maldevelopment of basket cell processes around Purkinje cells (Heckroth, 1992). The staggerer mutation has been linked to the chromosome 9 gene site of the neural cell adhesion molecule (D'Eustachio and Davisson, 1993). A decrease of inferior olive neurons has been described in adult lurcher mutants (Heckroth and Eisenman, 1991) and in staggerer mutants as early as 10 days of age (Shojaeian et al., 1985) and in the adult (Blatt and Eisenman, 1985b). It has been determined by studies in chimeric mice that the degeneration of inferior olive cells and of cerebellar granule cells in staggerer mutants is an indirect cause of the staggerer gene action on Purkinje cells (Herrup, 1983; Herrup and Mullen, 1979b; Zanjani et al., 1990). Similarly, the loss of cerebellar granule cells and of inferior olive cells in lurchers is considered to be a secondary consequence of Purkinje cell degeneration (Wetts and Herrup, 1982ab). Nevertheless, there is a loss of granule cell number on postnatal day 4, prior to the beginning of Purkinje cell deneneration on day 8 (Caddy and Biscoe, 1979). Heckroth (1992) reports that the external granular layer of lurcher mutants on days 8 and 9 is approximately half as thick as that of controls. He postulates that the early granule cell loss is the result of a lack of trophic influences provided by Purkinje cells on granule cell development. In lurcher mutants, a 20% drop in deep nuclei numbers occurs at 3 months of age, possibly by means of an anterograde transsynaptic mechanism (Heckroth, 1994), as shown to be the case in Purkinje cell degeneration (pcd) mutants (Triarhou et al., 1987).

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pcd mutant mice lose nearly all Purkinje cells at the end of the first postnatal month (Mullen et al., 1976). Cerebellar granule cell degeneration occurs later (Triarhou et al., 1985). Neuronal counts in the cerebellar deep nuclei are normal during the third postnatal week and reduced during the tenth month (Triarhou et al., 1987). There is a more ~radualloss of retinal photoreceptors than of Purkinje cells in pcd mutants, attaining approximately 25% by 2 months of age (Mullen and LaVail, 1975). Retinal degeneration was not observed in staggerer or weaver mutants, Inferior olive cell numbers are decreased during the third postnatal week (Ghetti et al., 1987) and later stabilize (Triarhou and Ghetti, 1991). The loss of thalamic cells (O'Gorman and Sidman, 1985) and the loss of mitral cells in the olfactory bulb (Greer and Shepherd, 19R2) do not occur until 2 months of age. At 1 and 2 months of age, hot-foot mutant mice have abnormal spines on Purkinje cell dendrites, together with slight granule cell necrosis (Guastavino etal., 1990). It remains to be determined whether cerebellar afferents are altered in this mutation. At the end of the first month, weaver mutant mice are characterized by the degeneration of cerebellar granule cells (Hirano and Dembitzer, 1973; Sotelo and Changeux, 1974). Mouse chimera studies indicate that a site of gene action is the cerebellar granule cell (Goldowitz and Mullen, 1982). There is also degeneration of substantia nigra cells during developmental stages in weaver mutants (Triarhou et al., 1988), leading to a reduction in dorsal striatal dopamine concentrations, a result not observed in staggerer and pcd mutants (Roffler-Tarlov and Graybiel, 1984, 1986, 1987). The protein content is reduced in the dorsal striatum, but not in the olfactory tuhercle and nucleus accumbens (Roffler-Tarlov and Grabiel, 1984, 1987). A reduced number of tyrosine-hydroxylase immunoreactive neurons in the substantia nigra occurs at. postnatal days 20 and 90 in weaver mutants. A reduction of cell numbers also occurs in retrorubral and ventral tegmental area", but only on day 90 (Triarhou et al., 1988). A reduction of striatal dopamine uptake and an increase of striatal serotonin uptake occur in weaver mutants (Stotz et al., 1994). In addition to the reduction of dopamine uptake sites in the weaver striatum, there is a reduction of Dl receptors (Panagopoulos et al., 1993). However, D2 sites are increased in the dorsolateral part (Kaseda et al., 1987). The number of cerebellar dopamine uptake sites is diminished in weaver mutants, together with Dl and D2 receptor sites (Panagopoulos et al., 1993). There is no degeneration of inferior olive neurons, probably due to the relative sparing of Purkinje cells (Blatt and Eisenman, 1985a). There is no evidence of neocortical or hippocampal maldevelopment in any of the mutants. The electrophysiological properties of CAl hippocampal pyramidal cells are normal in staggerer mutants (Fournier and

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Crepel, 1984) but have not been tested in other cerebellar mutants. All mutants have lower body weights in comparison to littermate controls, possibly because of a diminished ability to feed themselves during developmental stages. This may be the reason why the weight of some brain regions outside the cerebellum, such as the telencephalon, is lower in nervous, weaver, staggerer, and pcd mutants (Goodlett et al., 1992; Miret-Duvaux et al., 1990; Ohsugi et al., 1986). However, despite a lower body weight, adult staggerer mutants eat more than normal mice of the same C57BL/6J strain (Guastavino et al., 1991). This result is in contrast to cerebellectomized rats, whose food intake and body weight are lower than those of controls and then recover (jacquart et al., 1989; Mahler et al., 1993). Some behavioral deficits observed in cerebellar mutants may be caused by alterations in feeding patterns during developmental stages, but this possibility is difficult to assess. b. Mutant Mouse Models: Experimental Observations. Lurcher (Lcl +) mutant mice were compared to normal (+ I +) mice of the same background strain (C3H) in a rectangular water basin containing either a hidden or a visible platform (Lalonde et al., 1988). The number of quadrant entries and escape latencies was higher in lurcher mutants than in normal mice under both conditions. Because of the presence of the retinal degeneration gene on the C3H background, the mice were switched to the C57BL/6 background. Visible platform escape latencies of lurcher mutants were still higher. Jackson Laboratory subsequently switched the genetic background to B6CBACa-Aw-JI A. When the order of presentation was changed (visible platform followed by the invisible platform) and the task simplified by starting the mice from a single point, the number of quadrant entries and escape latencies was still higher in lurcher mutants under both conditions (Lalonde and Thifault, 1994). There was no correlation in either mutants or controls between hidden platform escape latencies and latencies before falling in a motor coordination test (a coat hanger comprising a suspended thin horizontal bar made of steel and flanked by two diagonal side bars). The absence of an intertestcorrelation in the mutants is an indication of the presence of distinct physiopathological processes underlying navigational as opposed to motor coordination abilities. In the same rectangular water basin, weaver mutant mice (wv/wv) were compared to normal mice (+ I?) of the same background strain (B6CBA) in the visible platform task, with the task being simplified by starting the mice from a single point (Lalonde and Botez, 1986). Weaver mutants had higher escape latencies than normal mice. In a water maze spatial alternation test, weaver mutants committed more errors than controls, an indication of the directional nature of their navigational deficit. Weaver mutants have cell losses in the substantia nigra (Triarhou et al., 1988) and

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a reduction in the concentrations of striatal dopamine (Roffler-Tarlov and Grayhiel, 1986). Because dopamine depletion in the striatum leads to a visuomotor deficit (Whishaw and Dunnett, 1985), this depletion, together with the cerebellar granule cell loss (Hirano and Dembitzer, 1973; Sotelo and Changeux, 1974), probably contributes to the impairment of navigational abilities displayed by weaver mutants, Staggerer (sg/sg) mutant mice were compared to normal (+ I?) mice of the same background strain (C57BL/~J) under hidden and visible platform conditions in the same water basin as tested in the other mutants (Lalonde, 1987). Quadrant entries and escape latencies were higher in staggerer mutants when the platform was submerged but not when it was visible. In a cerebellar mutant, this pattern reproduces a hippocampal-like deficit. However, Bensoula et al. (1995) compared staggerer mutants to normal mice in two other water maze tests. In the first test, mice were placed in a circular basin starting from a single point where they could reach a visible platform found at the opposite end positioned against the wall. The escape latencies were higher in staggerer mutants. In the secund test (water escape pole-climbing test), mice were placed in a small circular basin containing a pole in the center. The water escape latencies of staggerer mutants and of hut-foot mutants were higher than those of normal mice (Fig. 1). When staggerer mutants first perform the invisible platform task followed by the visible platform task, they show a hippocampal-type dissociation. However, when first exposed to a condit.ion where they could see a platform or a pole, they were impaired. In the water escape pole-climbing test, considerable wall-hugging perseveration was displayed by the staggerer mutants. This was not observed during visible platform testing when the animals had first performed the invisible platform task. These observations underline the importance of the order of presentation of the tests in some pathological conditions. Goodlett et at. (1992) compared pcd mutant mice to normal (+ I?) mice of the same background strain (C57BL/6J) at three age levels (30, 50, and 110 days old) first during visible platfurm training and then during hidden platform training in the circular Morris maze. During visible platform trials, the mice began a trial from different points and the platform location changed from one trial to the next. During hidden platform trials, the mice began a trial from different points but the platform location was fixed. At 30 days of age, there was no difference in path lengths among the bTfOUps during visible platform training. However, in the invisible platform condition, the path lengths of ped mutants were higher. At 50 days of age, the pcd mutants had longer path lengths in the visible platform task during the first four trial blocks but not during the fifth. Distance traveled in the hidden platform trials was higher in ped mutants. When the mice were

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retested in the visible platform condition, no group difference emerged. At 110 days of age, longer path lengths were displayed by pcd mutants on the third trial block but not on the first two or final three trial blocks. A deficit occurred during hidden platform trials but not during a visible platform trial block at the end of testing. At all age levels, pcd mutants were more impaired in the invisible platform condition than in the visible platform condition. These results are consistent with the hypothesis that the cerebellum is involved in spatial orientation. The presence of retinal degeneration in this mutant (Mullen and LaVail, 1975), although more slowly progressing than the cerebellar pathology, may reduce the perception of distal cues, thereby causing a deficit. As the authors point out, the number of photoreceptors is normal at 30 days of age and lower by 30% at 50 and 50% at 110 days of age. Therefore, I-month old mutants show a hippocampal-type deficit that cannot be explained by retinal degeneration. In summary (Table III), water maze testing in cerebellar mutant mice indicates the importance of the cerebellum in the visuomotor coordination necessary to navigate toward a visible platform. This was especially evident

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TABLE III WAI"J::R MAzE PERFORMANCF. IN 1- TO 2-MoNTH-OW CF.RF.I\F.I.lAR MUTANT MICE

Mutant

Hidden platform

Visible platform

Lurchcr

Deficit

Deficit

Weaver

Deficit

Deficit

Staggerer

Deficit

No deficit

ped

Deficit

No deficit

in lurcher mutant mice, characterized by the massive degeneration of cerebellar granule and Purkinje cells in the absence of known basal ganglia, limbic, or neocortical abnormalities. These results are consistent with the hypothesis (Stein, 1986; Stein and Glickstein, 1992) that the cerebellum is involved in the visual guidance of movements. The involvement of the cerebellum in higher-level spatial processing is indicated by the selective vulnerability of young pcd mutants in the invisible platform condition (Goodlett et al., 1992). A more selective deficit in pcd mutants than lurcher mutants may be due to the higher degree of cerebellar pathology in the latter. Staggerer mutants display a mixed form of navigational deficits depcnding on methodological factors, but are probably more similar to lurcher mutants than pcd mutants, reflecting their morphological similarities. c. Anatomic Correlates. It is possible that the cerebellum exerts an influence on both spatial orientation and visuornotor coordination. The nature of the deficit displayed by a brain-damaged animal may depend on the extent and regional distribution of the cerebellar pathology. For example, midline as opposed to lateral cerebellar lesions may cause a different profile in navigational abilities. This hypothesis was tested in rats with lesions of either the midline cerebellum. comprising the vermis and the fastigial nucleus. or the lateral cerebellum, comprising the hemispheres and dentate (Joyal et al., 1996). Quadrant entries and escape latencies were higher in rats with midline cerebellar lesions but. not in rats with lateral cerebellar lesions during visible platform performance. In contrast, the lateral cerebellar group had higher quadrant entries and escape latencies than a shamoperated group during the hidden platform task. These behavioral differences may be explained by the different anatomical connections of the midline as opposed to the lateral cerebellum. The midline cerebellum has reciprocal connections with the vestibular system (Walberg, 1972), the superior colliculus (Brodal and Bjaalie, 1992; Carpenter and Batton, 1982; Hirai et al., 1982; May et at., 1990; Saint-Cyr and Courville, 1982; Yamada and Noda, 1987), and the lateral geniculate

VISUOSPATIAL ABILITIES

205

nucleus of the thalamus (Graybiel, 1974). The fastigial efferent system includes the frontal eye field via thalamic relay nuclei (Kyuhou and Kawaguchi, 1987). Connections with the superior colliculus, frontal eye fields, and lateral geniculate are involved in eye movements in primates, but their functions in rodents remain to be determined. Vermal Purkinje cells receive hippocampal input via brain stern nuclei (Saint-Cyr and Woodward, 1980). In turn, fastigial stimulation alters hippocampal and septal neurons via a multisynaptic pathway (Heath et al., 1978; Newman and Reza, 1979). These anatomical connections indicate that the midline cerebellum may integrate visual and vestibular signals in such a way as to permit effective visuomotor coordination. Visual ambient guidance is crucially dependent on the superior colliculus. During water maze testing, lesions of the superior colliculus cause visuomotor deficits (Lines and Milner, 1985). Vestibular stimulation caused by a rotating platform impaired spatial orientation in the Morris maze, underlining the importance of vestibular cues during oriented swimming movements (Semenov and Bures, 1989). Mice with genetic lesions of the vestibular system sink beneath the water level (Douglas et al., 1979). This is not the case with midline cerebellar lesions. Other brain regions important in sensorimotor integration may be involved in different aspects of visual guidance. For example, lesions of the striatum or dopamine depletion in the same area impaired visible platform performance in the Morris maze (Whishaw and Dunnett, 1985; Whishaw et al., 1987). Lesioned animals perseverate in wall hugging, but with repeated training abandon this strategy (McDonald and White, 1994). It remains to be determined whether rats with midline cerebellar lesions can reach normal values with repeated training on the visible platform. Striatal damage causes the release of pcrseverative, inappropriate strategies (Whishaw et al., 1987). The dorsal striatum receives vestibular input and may process vestibular information during food-motivated maze tasks (Potegal, 1982) and during guided swimming movements. Midline cerebellar damage may decrease the animal's ability to use visual and vestibular stimuli during guided swimming movements. Hippocampal pyramidal cells may use the sensorimotor integration provided by the midline cerebellum for navigational place learning. Lesions of the fastigial nucleus impaired acquisition of the hidden platform task but not visible platform performance (Joyal et al., 1996). Thus, visible platform performance is affected by midline cerebellar lesions but not by fastigiallesions. These results imply that some degree of sensorimotor integration for swimming toward a visible goal occurs at the level of the vermis and the flocculonodular lobe. The lateral cerebellum receives neocortical input from association parts of the frontal and parietal lobes via rostral pontine nuclei (Brodal, 1978; Schmahmann and Pandya, 1989,

20(j

ROBERT LALONDE

1995) and sends information back to these areas via thalamic nuclei (Kakei and Shinoda, 1990; Middleton and Strick, 1994; Sasaki, 1979; Sasaki et al. 1979; Schmahmann and Pandya, 1990; Wannier et al., 1992; Yamamoto and Oka, 1993), In addition to VA-VL thalamic nuclei, the cerebellum projects to the dorsornedial and in tralaminar nuclei (Rouiller et al., 1994), the former innervating frontal association cortex and the latter widespread areas of the neocortex. The VA-VI, thalamic nuclei are involved in cerebellar input to the parietal cortex (Kakei and Shinoda, 1990; Sasaki, 1979; Sasaki et al., 1979; Schrnahmann and Pandya, 1990; Wannier etal., 1992; Yamamoto and aka, 1993). In addition to the parieto-ponto-cerebellar pathway, a parleto-rubro-olivo-cerehellar pathway exists (aka et al., 1979). The lateral cerebellum also sends input to the tectum (Hirai et al., 1982; May et al., 1990). The parietal cortex is important in navigational abilities (Crowne et al., 1992; Kolb et al., 1983; DiMattia and Kesner, 1988). The role of the medial frontal cortex is also important (Kolb et al., 1983, 1984; Sutherland et al., 1982), but is dependent on methodological factors (de Bruin et al., 1994). It has been proposed that the neocortico-ponto-cerebellar pathway controls the visual guidance of limb and eye movements (Stein, 1986; Stein and Glickstein, 1992). This theory may be extended to navigational abilities. Lesions of the lateral cerebellum in rat'! impaired the hidden platform task hut not the visible platform task, an indication of a deficit in spatial orientation and not in sensorimotor guidance (Joyal et al., 1996). On the basis of this study, it IIlay be hypothesized that the cerebellum is implicated in the cognitive processes required to conlrol whole body movemenls in space. Fastigial and dentate efferents to dopamine cells in the substantia nigra (Snider et al., 1976) may also influence the sensorimotor coordination necessary for visual guidance, as the depletion of striatal dopamine by means of 6-hydroxydopamine caused a visuomotor coordination deficit in the Morris maze (Whishaw and Dunnett, 1985). Ihotenate-induced lesions of the striatum also caused this defici t (Whishaw et al., 1987).

B.

RAu~ MAZF.

In the Morris maze, the effect.'! of brain lesions are often measured during acquisition of the task. In the radial maze, performance of the already acquired task is measured. Animals must first be trained to retrieve the food at the end of the maze arms before lesioning. As with the Morris maze (McDonald and White, 1994), fornix lesions impair radial maze performance (Packard et ul., 1989). The performance of spatial working- and

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207

reference memory correlates positively with the size of intra- and infrapyramidal fibers in the hippocampus (Crusio et al., 1993). There is only one report concerning the effects of cerebellar damage on radial maze performance. Goldowitz and Koch (1982) trained staggerer mutants and normal littermates to retrieve food pellets at the end of an eight-arm radial maze. Staggerer mutants had a higher number of working memory errors. These results are consistent with the hypothesis of a role for the cerebellum in spatial learning.

C. SPATIAL ALTERNATION

The left-right spatial alternation test is a simpler version of the radial maze test, with two instead of eight choices. Impairments of this task have been observed after hippocampal lesions in rats (Wan et al., 1994). Because cerebellar lesions cause Morris maze deficits, there is interest in determining to what extent these lesions affect other spatial tasks. Pellegrino and Altman (1979) X-irradiated the cerebellum during different developmental stages in the rat and assessed the acquisition of single and double water maze alternation tasks. An increase in errors was found in both single and double alternation tasks among irradiated rats. There was no group difference in swimming speed. Dissociations were found between different behavioral tests depending on the length and timing of the irradiations. Late irradiated rats were impaired in the water maze but not in motor coordination tests. When the lower molecular layer developed abnormally, motor coordination deficits were prominent. When the upper molecular layer developed abnormally, water maze deficits were prominent. The authors hypothesized that the early forming parallel fiber system is involved in motor coordination whereas the late forming parallel fiber system is involved in the programming of action. The role of the cerebellum in water maze alternation has been investigated in cerebellar mutant mice. When positioned at one point of a rectangular basin, the escape platform could be found on one side and when positioned at the opposite end, the same platform was found on the other side. More than one error could be commited per trial whenever a mouse strayed from the platform without turning toward the correct side. Both staggerer (Lalonde, 1987) and weaver (Lalonde and Botez, 1986) mutants committed more errors than their respective controls. A second task comprised route finding in a Z-maze configuration requiring successive leftright turns (Filali et al., 1996; Lalonde et al., 1996). All three cerebellar mutants tested (staggerer, hot-foot, lurcher) committed more errors and had higher escape latencies than their respective controls. The higher

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number or errors is a further indication of the directional nature of the navigational impairments in mice with hereditary cerebellar atrophy.

D.

HOLE BOARl.>

There is one report concerning the role of the cerebellum during spatial learning in a hole board (Dahhaoui et al., 1992a). Rats were cerebellectornized either before or after training in a hole board, requiring the retrieval of a single pellet in a Hi-hole matrix. Cerebellectomized rats committed more errors during acquisition and performance of this task. A similar food-searching task was sensitive to hippocampal lesions (Oades and Isaacson, 1978).

III. Condusions

Cerebellar damage in animals leads to visuomotor deficits, Depending on the degree or regional specificity of the lesion, cerebellar injury results in disorders of spatial orientation. These results concur with clinical studies showing- impairments in visuospatial organization in patients with cerebellar atrophy. Further models of cerebellar atrophy have yet be tested in the Morris maze, tugether with the elaboration of additional tests able to disting-uish spatial orientation from visuomotor coordination.

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