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Department of Neurobiology and Anatomy, Wake Forest University School of Medicine, Winston-Salem, North Carolina
Submitted 6 June 2006; accepted in final form 5 September 2006
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ABSTRACT |
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INTRODUCTION |
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). Thus the same stimulus conditions that enhance or depress the responses of SC neurons (e.g., Bell et al. 2001; Binns and Salt 1996; Kadunce et al. 1997; King and Palmer 1985; Meredith and Stein 1983, 1985; Peck 1996; Perrault et al. 2003; Stanford et al. 2005; Wallace et al. 1996; Zangenehpour and Chaudhuri 2001) also enhance or depress SC-mediated orientation behaviors (Frens and van Opstal 1998; Jiang et al. 2002; Stein et al. 1988, 1989).
The ability of SC neurons to engage in normal multisensory integration is dependent on influences from two adjacent cortical regions in the cat: the anterior ectosylvian (AES) and the rostral lateral suprasylvian (rLS) sulci (for a review, see Stein 2005). These cortico-collicular influences are particularly evident in the enhanced responses of multisensory SC neurons: when they are eliminated by reversible cortical deactivation, multisensory stimuli evoke responses that are no greater than those produced by the most effective unisensory component stimulus (Jiang and Stein 2003; Jiang et al. 2001; Wallace and Stein 1994). The physiological consequences resulting from disrupting these cortico-collicular influences in adults are paralleled by disruptions in their SC-mediated orientation behavior (Jiang et al. 2002; Wilkinson et al. 1996).
Although critical for normal SC function, cortical influences develop only gradually during early life (Stein et al. 1973; Wallace and Stein 1997; 2000) when the brain is maximally plastic (Buonomano and Merzenich 1998; Rauschecker 1999; Wickelgren and Sterling 1969) and the cortex is first gathering experience with cross-modal cues (Perrault et al. 2004; Wallace and Stein 1997). The plasticity of cortico-collicular circuits in multisensory processing became evident when neonatal ablation of either AES or rLS was shown to produce no obvious alteration in the development of the multisensory enhancement capabilities of SC neurons (Jiang et al. 2006), a finding that was unexpected in light of the serious consequences of deactivating either of these areas in normal adults (Jiang et al. 2001, 2002). These data suggested that the developing brain compensates for the loss of either AES or rLS. In contrast, when neonatal lesions included both AES and rLS, little developmental compensation was noted: a permanent physiological disruption of SC multisensory enhancement capabilities was produced. Thus few SC neurons developed this capability and those that did appeared to do so because of islands of spared tissue at the lesion site (see Jiang et al. 2006). The present study was initiated to determine the effect of these early lesions on the animals’ ability to use cross-modal cues to control overt orientation behavior.
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METHODS |
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). Thus the ablation procedures are only briefly summarized here. Neonatal cortical ablation
Cortical ablations were performed at 3 wk postnatal. This is before visual stimuli can activate neurons in the multisensory (i.e., deep) layers of the structure and 1 wk before cortex first begins to mediate multisensory integration in SC neurons (Kao et al. 1994; Stein et al. 1973; Wallace and Stein 2000; Wallace et al. 1997). Each animal was anesthetized with ketamine hydrochloride (15–30 mg/kg, administered intramuscularly) and isoflurane (0.2–3%, inhalation). A unilateral craniectomy exposed the cortex over AES, rLS, or both areas. The area of interest was removed by aspiration. An attempt was made to remove all cortical gray matter and the ablations often included some of the underlying white matter. The surgical area was then covered with Gelfoam, the bone was replaced, and the skin was sutured closed. Animals were given postsurgical analgesics (butorphanol tartrate, 0.1–0.4 mg·kg–1·6 h–1) as needed and received antibiotic treatments for 7–10 days (ceftriaxone 20 mg·kg–1·b.i.d. or enrofloxacin 5 mg·kg–1·b.i.d.).
Behavioral training and tests
Animals were allowed to mature to 1–2 yr of age, at which time they were trained on an SC-mediated spatial localization task using previously established methods (e.g., see Jiang et al. 2002; Stein et al. 1988, 1989; Wilkinson et al. 1996). Training and testing took place within a 90-cm semicircular array of light-emitting diodes (LEDs) and speakers placed at 15° intervals to the left (–), right (+), and centered on a fixation point at 0° (see Fig. 1). Animals were trained to fixate on the fixation point and, within 3 s of the appearance of a briefly (40-ms) illuminated LED, to approach that LED. The animals were also trained to maintain fixation during trials in which no stimulus appeared ("catch" trials) and also in response to brief (40-ms) bursts of broadband noise (60 dB). In all cases correct performance was rewarded with a small food reward (175-mg pellet). During training, LEDs appeared at maximum intensity (3.0 x 10–3 fc), first at 0° then randomly at other eccentricities (±15, ±30, and ±45°). Training was complete when an animal’s responses were accurate on 95% of the trials. Visual intensities were then lowered to elicit between 30 and 50% response accuracy to the visual target stimulus at each location. The intensity of the auditory stimulus was unchanged. During testing, visual and auditory stimuli could appear alone (as in training), simultaneously at the same location, or not at all (catch trials).
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). Data acquisition and analysis
Unisensory and multisensory orientation behavior in contralesional and ipsilesional space was evaluated so that each animal served as its own control. These data were also compared with controls drawn from previous studies with normal animals performing the same tasks in this apparatus (Jiang et al. 2002; Stein et al. 1988, 1989; Wilkinson et al. 1996). Error patterns (erroneous localizations vs. No-Go responses) were also recorded to determine the possible influence of response bias. Approximately four to eight trials per stimulus type were conducted per day, allowing estimation of daily accuracy between 13 and 25%. The data were analyzed separately for each animal. For each stimulus location within the perimetry device for each animal, the following was calculated.
) and provides a measure of the percentage change in the localization of the visual stimulus caused by the addition of the auditory stimulus
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RESULTS |
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Four of six animals receiving neonatal lesions were later found suitable for behavioral training as adults: two had dual cortical ablations (i.e., both AES and rLS were removed) and two had single cortical ablations (i.e., either AES or rLS was removed). All data are organized so that contralesional space is always to the left (–) and ipsilesional space is always to the right (+). All cortical ablations were performed at 3 wk postnatal and all animals were allowed to reach maturity (i.e., 1–2 yrs of age) before beginning training and subsequent behavioral testing. The histological reconstructions of these lesions and their consequences for multisensory integration in single SC neurons of these animals were published previously (see Jiang et al. 2006). Schematics of lesion locations are reproduced as insets in Fig. 1. Briefly, the extensive nature of the lesions and the early maturational stage at which they were made produced developmental changes in the geometry of nearby sulci and gyri and distinguished the ipsilesional and contralesional cortices. These conformational changes in cortical morphology were likely enhanced by the inclusion of the underlying white matter in some of the lesions and would have been expected to produce functional changes that were greater than those associated with the dimensions of the lesions on the cortical surface. Thus it was surprising to find only minimal changes in the properties of multisensory SC neurons (for discussion, see Jiang et al. 2006) and the behaviors that depend on them (see following text) after early ablation of either AES or rLS.
Behavioral consequences of neonatal lesions
Although the behavioral consequences of combined neonatal AES and rLS ablation matched the severity of the effects observed with adult animals when these cortices were temporarily deactivated (Jiang et al. 2002), the effects of treating these regions individually were strikingly different in adults and neonates. In adults, the deactivation-induced loss of AES or rLS influences severely disrupted multisensory orientation behavior, whereas neonatal lesions of either area alone had no apparent effects on these behaviors. The performance data for animals with each of the neonatal ablation conditions (AES and rLS, AES alone, and rLS alone) are plotted in Fig. 1.
The figure illustrates that all animals exhibited the typical enhancement in the localization of an ipsilesional visual target when it was accompanied by a simultaneous and spatially coincident auditory stimulus (15° increments in eccentricity from 0 to 45° were tested). Multisensory response enhancement as measured by the Multisensory Index (MSI) ranged from 68 to 160% and all differences between multisensory and unisensory performance were statistically significant (P < 0.05). This response enhancement occurred despite the fact that the auditory stimulus was "neutral" and was not, itself, a target for a response. Furthermore, the MSI was comparable to that obtained previously with normal adult cats (see Jiang et al. 2002; Stein et al. 1988, 1989; Wilkinson et al. 1996). Therefore the response scores at each location for each individual animal were used as a control to predict that animal’s overall performance accuracy as well as to predict the MSI in the matching contralesional locations.
Animals that had neonatal ablation of both AES and rLS exhibited profound deficits in contralesional multisensory performance. The multisensory response accuracy was on average 38% less than that predicted based on ipsilesional performance, a difference that was statistically significant at each perimetric location examined for each animal (P < 0.05). Similarly, the MSI was 76% less than that expected. In contrast, animals that lost only one of these areas (either AES or rLS) were unimpaired. Their average multisensory response accuracy was equivalent to that in ipsilesional space (the average <9% difference observed was not statistically significant) and the same was true of their average MSI (<14% decrement was not statistically significant). In short, no significant deficits in contralesional multisensory orientation performance were noted in the single cortical lesion animals.
Despite the magnitude of the multisensory dysfunction in animals with combined AES and rLS ablation, close inspection of the data revealed that averaged multisensory response accuracy was slightly, albeit statistically significantly, enhanced at two contralesional locations (–15 and –45°) in one animal. The underlying cause of these small putative multisensory response "enhancements" was evaluated by considering the possible influence of response bias. In Fig. 2, the percentage of incorrect orientation responses in both ipsilesional and contralesional space was plotted in that animal (Cat 9907).
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; Wilkinson et al. 1996). In contrast, response bias proved to be a major factor in the marginally enhanced performance in response to contralesional stimuli. Wherever this animal showed what appeared to be a statistically significant contralesional multisensory enhancement, there was no corresponding significant decrease in the percentage of orientation errors. Apparently, the auditory stimulus increased the number of accurate responses by increasing the overall number of orientations, without actually improving the overall degree of response accuracy.
The results of the various lesions on multisensory performance are summarized in Fig. 3. Here the index of enhanced multisensory performance, MSI, is plotted against unisensory response accuracy for each location in contralesional and ipsilesional space for each animal. The data in each hemifield were collapsed across perimetric locations and then fit by linear regression. Animals with ablation of AES and rLS showed significant ipsilesional–contralesional differences (F-test, P < 0.05) that were not seen in animals that lost only one of these cortical regions. The "principle of inverse effectiveness" (see Stein and Meredith 1993) was also evident in the performance of all animals on both sides of space; that is, the MSI was greatest when the unisensory response accuracy was lowest. The figure also shows a great deal of consistency in ipsilesional performance across animals, which is consistent with previous observations (see Jiang et al. 2002; Stein et al. 1988, 1989; Wilkinson et al. 1996).
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DISCUSSION |
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, 1989). As a consequence, the coupling of the neutral auditory cue with the visual target in contralesional space failed to enhance orientation performance, a result that closely parallels that obtained during reversible deactivation of AES and rLS (see Jiang et al. 2002; Wilkinson et al. 1996). This developmental failure did not appear to be attributable to a lesion-induced hearing loss. The animals showed no obvious impairments in responses to sound, an auditory stimulus could induce shifts in their response bias, and the incidence of auditory-responsive neurons in the ipsilesional SC was similar to that of normal animals (see Jiang et al. 2006). In addition, previous studies showed that deactivation of AES and rLS compromises neither SC auditory responses nor orientation to an auditory target in these perimetric tests (Jiang et al. 2001, 2002; but also see Malhotra et al. 2004). Rather, the contralesional anomaly was likely a result of the failure to develop normal ipsilesional multisensory processes as indicated by the misregister in the visual and auditory receptive fields of multisensory neurons here and the inability of these neurons to integrate cross-modal stimuli (see Jiang et al. 2006). Yet, the unisensory responses of these neurons were like those of normal animals, thereby paralleling their overt orientation responses to modality-specific stimuli.
It is interesting to note that physiological evaluation of these animals showed that some (15%) SC neurons did develop the capability to integrate cross-modal cues, a result attributed to the sparing of isolated areas of AES and/or rLS (see Jiang et al. 2006). The present observations indicate, however, that the proportion of these neurons was far too low to support the typical enhancement in multisensory orientation behavior that is seen in intact animals. Indeed, more than a majority of the normal complement of such neurons appears to be required to support this capability. Previously it was shown that although the deactivation of rLS in normal adult cats affected fewer ipsilateral multisensory SC neurons than did deactivation of AES, it still eliminated this capability in roughly 44% of these neurons. Behavioral tests demonstrated that the remaining 56% of the multisensory integrating population was insufficient to support enhanced multisensory orientation behaviors. The animals showed no better orientation responses to the cross-modal stimulus combination than to its unisensory component stimuli (Jiang et al. 2002). These observations indicate that cortico-collicular influences from both AES and rLS are normally necessary to support multisensory enhancement in orientation behavior and that even when they are both lost during early life, the brain does not craft alternate circuits to substitute for them in this role.
However, these observations do not indicate that AES and rLS are insensitive to early lesion-induced compensatory changes. In contrast to the dysfunctions in the animals with combined AES and rLS removal discussed above, those in which only one (either AES or rLS) area was removed appeared to be quite normal; the different receptive fields of multisensory SC neurons overlapped one another and these neurons showed the typical benefit from the combination of cross-modal cues in both hemifields. Apparently, the loss of potential cortical influences essential for SC multisensory integration (see Wallace and Stein 2000) and SC-mediated multisensory behavior during neonatal life is less disruptive than when their actual influences are removed in adulthood.
The contrast between the effects of dual and single cortical lesions during early life suggests that the compensatory processes initiated by single cortical lesions involved changes in the cortico-collicular projections from the remaining area. It is not yet known whether these cortico-collicular changes involved the retention of normally exuberant projections and/or the sprouting and growth of new projections from the intact cortical area and/or the involvement of other developmental changes. Furthermore, it is not yet known whether the capacity to initiate such compensatory changes is restricted to early development. Although this seems likely given the high degree of plasticity in the neonatal as compared with the adult brain, the possibility that similar lesion-induced compensatory mechanisms, even if less robust, could be initiated in adult animals cannot yet be excluded. This is because the comparison observations currently available in adult animals involve acute deactivation of AES and/or rLS—a method that not only retains the anatomical integrity of the pathways involved in SC multisensory integration, but one that also does not allow assessing possible long-term functional changes in that circuitry.
Irrespective of whether these compensatory changes are restricted to early life, however, their presence is surprising: comparable changes in the unisensory properties of ispilesional SC neurons are not seen after early ablation of the cortico-collicular regions on which they normally depend (see Stein and Gallagher 1981; Stein and Magalhães-Castro 1975). This distinction may reflect differences in the inherent plasticity of these cortical areas, but it seems highly likely that the critical factors include the unique and shared relationship between AES and rLS and the SC neurons involved in multisensory integration. SC multisensory integration depends on nearly equivalent influences from AES and rLS (Jiang et al. 2001), cortices that are not only highly interconnected (see Meredith 2004; Scannel et al. 1995), but also have overlapping terminal territories in the SC (Segal and Beckstead 1984; Stein et al. 1983). Indeed, they sometimes target the same multisensory SC neurons; a "redundant" input (see Jiang et al. 2001) that in this context would be expected to support the normal development of these "shared" SC target neurons as well as those with which they are uniquely coupled. Given the similarities in their tectopetal roles and territories, they are also well suited to substitute for one another by expanding or retaining their exuberant projections to SC neurons that normally are coupled uniquely with their cortical counterpart. In doing so they provide an alternate source of the higher-order influences that these SC neurons need to synthesize their cross-modal inputs, a role that other cortical regions appear unable to duplicate.
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GRANTS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: B. E. Stein, Dept. of Neurobiology and Anatomy, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1010 (E-mail: bestein{at}wfubmc.edu)
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ABSTRACT
INTRODUCTION
