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1Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298-0709; and 2Department of Psychology and Neuroscience, The University of Lethbridge, Lethbridge, Alberta T1K 3M4, Canada
Submitted 18 March 2004; accepted in final form 15 April 2004
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ABSTRACT |
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INTRODUCTION |
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). Decades of research have established monocular deprivation (MD) studies as a classic animal model of synaptic plasticity and human amblyopia. However, attempts to develop models in which cortical binocularity recovers following a period of MD have met with limited success (Mitchell et al. 1977; Movshon 1976; Olson and Freeman 1978; Van Sluyters 1978; Wiesel and Hubel 1965b). Inducing recovery of deprived eye responses by reverse suture has been the recovery protocol most commonly used, but this results in loss of responses from the newly deprived eye, precluding studies of binocular recovery. Systematic attempts to characterize recovery of deprived eye orientation selectivity are also lacking in the literature. For this reason, we have little information regarding the mechanisms that mediate recovery of binocularity or how recovery might be developmentally regulated, even though this information is highly relevant to understanding cortical plasticity and recovery from amblyopia.
Loss of binocularity following MD has traditionally been regarded as the result of a competitive process. The deprived eye loses cortical representation to its more active, nondeprived counterpart. In contrast, binocular competition cannot drive recovery following deprivation because the previously deprived eye is unable to activate action potential activity in cortical neurons. The disparate nature of afferent activity in these two situations suggests that each may rely on different signaling cascades. New evidence has pointed to a mechanistic dichotomy between loss and recovery of binocularity, with function of the cAMP/Ca2+ response element binding protein (CREB) being required for loss of binocularity (Mower et al. 2002) but not for recovery (Liao et al. 2002). Additionally, clinical studies indicate that recovery from amblyopia can occur after the end of the critical period for the effects of MD (Birnbaum et al. 1977), or paradoxically, may not occur when normal visual input is restored during the critical period (Birch and Stager 1988; Taylor et al. 2001; Williams et al. 2002). Collectively, these findings raise the possibility that different sensitive periods characterize loss and recovery of deprived eye responses. Furthermore, early deprivations, which seem to carry the worst prognosis for recovery, occur during development of crucial receptive field properties such as orientation selectivity. Thus the potential for recovery may be related to the timing of deprivation because different receptive field properties mature during different stages of development (Daw 1998). In this study, we examined whether there is potential for recovery of deprived eye responses beyond the critical period for ocular dominance plasticity and whether recovery is affected by the timing of deprivation.
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METHODS |
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). After 5–7 days of MD, ocular dominance was examined in some animals (n = 5), while other animals (n = 5) had ocular dominance and orientation selectivity examined following 3–7 days of binocular vision. In the second group of animals (late long-term deprivation, n = 9), animals were deprived starting at approximately P49, near the peak of ocular dominance plasticity and when orientation selectivity is mature. Animals in this group were examined at the end of the period of deprivation (n = 5), around P73, or following restoration of binocular vision starting at P73-P83 (n = 5), after the end of the critical period for ocular dominance plasticity (Issa et al. 1999). To examine the time course of recovery, response properties were examined 3–19 days after binocular vision had been restored. In the third group (early long-term deprivation, n = 9), recovery of cortical binocularity and orientation selectivity was examined in animals that had never received visual experience through one eye. In this group, the eyelid was sutured before eye opening (around P32 in ferrets), and MD lasted 3 wk, encompassing the period for development of orientation selectivity (Chapman and Stryker 1993). Some of these animals (n = 4) were examined at the end of the period of deprivation, while other animals (n = 5) were examined following a period of binocular vision starting within the critical period for ocular dominance plasticity (Issa et al. 1999). To examine the time course of recovery, animals were examined 5–24 days after restoration of normal vision. The Institutional Animal Care and Use Committee at Virginia Commonwealth University approved all procedures described here.
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Animals were premedicated by subcutaneous injection of acepromazine (2 mg/kg) and methyl atropine bromide (0.2 mg/kg), anesthetized with intraperitoneal sodium pentobarbital (35 mg/kg, Abbott Laboratories, North Chicago, IL), and placed in a stereotaxic frame. No procedures were started until the animal was sufficiently anesthetized, which was ascertained by the loss of withdrawal and cornea-blink reflexes. Body temperature, respiratory rate, and anesthesia level were monitored continuously during surgery. Surgery consisted of a craniotomy (3–5 mm diam) over the region in primary visual cortex where recordings were conducted. A tracheal cannulation was performed, and the animal placed on a ventilator. Heart rate and expired CO2 and O2 were monitored continuously during the experiment and maintained at 
4.0% and >90%, respectively. Body temperature was maintained at 38°C using a homeostatic blanket. The eyelids were opened, nictitating membranes were retracted using phenylephrine hydrochloride (2.5%), the pupils were dilated with atropine sulfate (1%), and contact lenses placed on the corneas. Animals were paralyzed using pancuronium bromide (0.2 mg/kg, ip) at the start of the recording session. Supplemental doses of pentobarbital (12 mg/kg, ip) and pancuronium bromide (0.1 mg/kg, ip) were given every hour throughout the experiment or when heart rate or expired CO2 increased. Subcutaneous injections of 10% dextrose and 0.9% saline were given during the experiment as needed. Judicious supplementation of pentobarbital anesthesia preserves visual responses over time (Medina et al. 2003). To comply with National Institutes of Health guidelines for use of paralytic agents and certify that the animals were maintained at an appropriate level of anesthesia, use of muscle relaxants was omitted during the experiment, and withdrawal reflexes were monitored in some animals. Similar procedures have been previously described and shown to be appropriate for visual physiology studies conducted in ferrets (Medina et al. 2003).
Single unit recordings were conducted using a tungsten-in-glass tungsten microelectrode lowered into the primary visual cortex through the craniotomy. All recordings were made within the binocular region of the ferret visual cortex. After isolation of a single unit, its receptive field, ocular dominance, and preferred orientation, direction, and velocity were determined qualitatively using a moving bar of light (0.5° wide and 20° long). Ocular dominance and orientation selectivity were quantitatively determined under computer control. To assess orientation selectivity, the moving bar of light was presented to each eye separately at four orientations centered about the optimal. To assess ocular dominance, only the optimal stimulus orientation was used. One stimulus presentation consists of the bar of light moving across the receptive field in one direction and back across in the opposite direction. A computer collected spikes over 10 stimulus presentations at each orientation using Spike2 software (Cambridge Electronic Design, Cambridge, UK). Spontaneous activity was determined by recording in the absence of stimulation for 2 s following each presentation. Repeated qualitative evaluation of receptive field position as well as examination of computer generated times of spike firing were used to examine eye movements during recordings of responses from each neuron. On the conclusion of the experiment, the animal was killed with Euthasol (125 mg/kg, ip, Delmarva Laboratories, Midlothian, VA).
To provide a quantitative estimate of response properties, an ocular dominance index and orientation selectivity index were calculated for each cell. Differences between experimental groups were determined by submitting these indices to a Wilcoxon Mann-Whitney test.
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RESULTS |
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To examine the full potential for recovery of binocularity and orientation selectivity in ferrets, we first characterized recovery in animals subjected to short-term MD starting at P45, during the peak of ocular dominance plasticity (Issa et al. 1999). Animals were monocularly deprived 5–7 days and then had the eyelid opened to restore binocular vision. Quantitative in vivo electrophysiology was conducted to assess cortical binocularity and orientation selectivity of primary visual cortical neurons following 
7 days of binocular vision. To quantify ocular dominance, we calculated an ocular dominance index (ODI) using the equation EE/(EE+DE), where EE is the response to stimulation of the experienced eye (or left eye in normal ferrets) and DE is for the deprived eye (or right eye for normal ferrets and recovering eye for recovering ferrets). An ocular dominance index of 1.0 indicates a cell responsive to only the experienced (or left) eye; an index of 0.0, a cell responsive only to the deprived (or recovering, or right) eye. Figure 2 shows that 5–7 days of MD induces an almost complete, saturating shift in ocular dominance toward a predominance of the nondeprived eye (Fig. 2B). Despite this marked loss of responses to the deprived eye, binocular vision restored cortical binocularity so that the ocular dominance profile was similar to normal (cf. Fig. 2, A and C; P > 0.05, Wilcoxon Mann-Whitney test).
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Having established that cortical binocularity fully recovers in animals subjected to short-term MD, we examined whether binocularity can also recover after a prolonged period of deprivation. In the case of late long-term deprived animals specifically, we asked whether recovery of normal responses can occur after the end of the critical period for ocular dominance plasticity.
Ferrets were monocularly deprived for 
3 wk starting around P49, near the peak of ocular dominance plasticity (Issa et al. 1999) and when orientation selectivity is mature (Chapman and Stryker 1993). Following a prolonged period of deprivation, binocular visual experience was restored in animals ranging from P73 to P83 in age, after the end of the critical period for ocular dominance plasticity (Issa et al. 1999). Prolonged MD induced an almost complete shift in ocular dominance in favor of the nondeprived eye (Fig. 4A). Nevertheless, binocularity was rescued, and a majority of neurons (78% of 159 cells) recovered robust responses to the previously deprived eye (ODI < 0.8; Fig. 4B).
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To examine recovery of orientation selectivity following a prolonged period of MD, we compared OSIs to stimulation of the dominant eye in normal animals and the recovering eye in animals that had been monocularly deprived. Figure 5 shows that OSI distributions for the recovering (filled symbols, n = 41 neurons) and normal (open symbols, n = 86) eyes overlap (P > 0.05). This finding indicates that responses to the deprived eye fully recovered selectivity to stimulus orientation. Together, these results show a remarkable potential for recovery of deprived eye responses after the end of the critical period for ocular dominance plasticity.
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We examined whether recovery of binocularity and orientation selectivity can occur following early long-term MD. Ferrets were monocularly deprived beginning 1 day before eye opening, and binocular visual experience restored at P51, within the critical period for ocular dominance plasticity (Issa et al. 1999). This is approximately the same age at which we restored binocular vision to animals in the short-term MD group (Table 1). Animals were allowed binocular vision for periods of 5–24 days and examined for binocularity and orientation selectivity of cortical neurons. Figure 6 shows that MD during this period induced a saturating shift in ocular dominance so that most neurons were dominated by the nondeprived eye (Fig. 6A; n = 119 cells in 4 animals). Relatively little recovery of cortical binocularity was detected following restoration of binocular vision (Fig. 6B; n = 169 cells in 5 animals). Most cells responded preferentially to the experienced eye, indicating that recovery was substantially less pronounced following early long-term deprivation than short-term and late long-term deprivation. Moreover, recovery did not increase further following longer periods of binocular vision lasting 24 days (Fig. 6C).
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DISCUSSION |
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). Despite the profound anatomical and functional effects of MD, cortical binocularity and orientation selectivity in recovering animals were indistinguishable from normal. Especially remarkable is the finding of substantial recovery of deprived eye responses beyond the critical period for ocular dominance plasticity, which in ferrets ends around P65–P70 (Issa et al. 1999). Both orientation selectivity and binocularity recovered within a few days of binocular vision starting as late as P83, the oldest age examined. These findings show that recovery of deprived eye responses is not constrained by the closure of the critical period for ocular dominance plasticity and are consistent with the idea that different mechanisms underlie loss and recovery of cortical binocularity (Liao et al. 2002). This is the first time that substantial recovery of binocularity and orientation selectivity has been shown to occur after the end of the critical period. However, we have also found that recovery is affected by the timing of deprivation. Recovery of connections to highly selective cells, which presumably are an integral part of normal visual function, was not seen in animals that had never received normal visual stimulation through the deprived eye but was seen in animals subjected to late MD.
Previous studies had shown recovery of influence from the deprived eye when reverse suture was conducted in kittens during the critical period (Blakemore and Van Sluyters 1974; Blakemore et al. 1981) but did not examine recovery of cortical binocularity and orientation selectivity. Furthermore, extreme manipulations such as enucleation of the nondeprived eye (Kratz and Spear 1976) and blockade of intracortical inhibition (Burchfiel and Duffy 1981) after the critical period were found to restore deprived eye responses in a minority of cortical neurons, but the receptive field properties of cells responding to the deprived eye were abnormal. Collectively, the present results are the first to indicate that the potential for recovery of cortical binocularity and orientation selectivity is not directly linked to the critical period.
Different mechanisms for loss and recovery of cortical binocularity
We know considerably more about mechanisms regulating loss than recovery of deprived eye responses. Although a very large number of genes may be involved in loss of deprived eye responses (Prasad et al. 2002) and the mechanisms involved are likely to be complex, information has been obtained on some key factors that may be required for this type of plasticity. These include N-methyl-D-aspartate (NMDA) receptors (Bear et al. 1990; Roberts et al. 1998), GABA receptors (Hensch et al. 1998), and may also include neurotrophins (Galuske et al. 2000; Gillespie et al. 2000). Increased calcium influx through the NMDA receptor–associated channel and other membrane calcium channels activates protein kinases, including 
calcium-calmodulin kinase type II (Taha et al. 2002), protein kinase A (Beaver et al. 2001), and extracellular signal-regulated kinase (Di Cristo et al. 2001). A common mechanism through which these kinases might act in ocular dominance plasticity is phosphorylation of the CREB protein (Mower et al. 2002; Pham et al. 1999), which binds to a consensus sequence known as cAMP response element (CRE) (Montminy et al. 1990) to regulate the transcription of plasticity-related genes (Deisseroth et al. 1996; Finkbeiner et al. 1997).
The NMDA receptor and the CREB system of gene activation are also potentially interesting in the context of recovery from the effects of MD. Contrary to expectations, however, a recent study has indicated that CREB activity is not necessary for recovery of cortical binocularity (Liao et al. 2002). Our finding that full recovery from the effects of MD can occur after the end of the critical period for loss of deprived eye responses, when CREB is thought to be no longer activated by MD (Pham et al. 1999), is consistent with the hypothesis that different mechanisms underlie loss and recovery of cortical binocularity. However, it should be noted that definition of the end of the critical period varies with the length of deprivation and that some weak residual ocular dominance plasticity can be observed after P70 in ferrets deprived for >2 wk (Issa et al. 1999). Furthermore, other forms of adult cortical plasticity different from classic ocular dominance plasticity have been observed in several species (Gilbert 1998; Issa et al. 1999; Sawtell et al. 2003).
Does recovery of binocularity require maturation of orientation selectivity?
Early lid suture is known to prevent the development of orientation maps (White et al. 2001) and maturation of orientation selectivity (Chapman and Stryker 1993) for the deprived eye. At the time when binocular vision was restored following the prolonged deprivations used in this study, orientation unselective inputs dominated by the deprived eye were given the opportunity to re-establish functional connections with a relatively mature visual cortex in which 75% of cells are orientation selective (Chapman and Stryker 1993). Assuming that orientation selectivity is at least partly dependent on the spatial organization of geniculocortical afferents (Chapman et al. 1991; Ferster 1986; Reid and Alonso 1995), inputs from the deprived eye that were not allowed sufficient visual experience to develop fully were likely to be morphologically quite different from those of the experienced eye. For the majority of cortical neurons that were highly orientation selective, signals from the deprived eye that are outside of a relatively narrow orientation range would not be detected as coincident with signals from the experienced eye and no recovery would occur. Therefore prolonged deprivation during the development of receptive field properties may destroy the ability of inputs from the deprived eye to reattach to the normal orientation scaffold that developed for the experienced eye.
These results raise the intriguing possibility that Hebbian mechanisms may actually prevent binocular recovery when responses elicited by the deprived eye are inappropriate for normal visual processing. This proposal is consistent with recent results showing that correlated binocular input is essential for recovery from MD following restoration of binocular vision (Kind et al. 2002). Manipulations such as reverse suture following prolonged deprivation silence normal functional maps for the experienced eye and may therefore allow recovering neurons to make inappropriate connections with deprived eye inputs. These binocular connections may generate abnormal receptive field properties that interfere with normal visual function, resulting in binocular amblyopia (Murphy and Mitchell 1986). While this study introduced the ferret as a novel model of binocular recovery, it also called attention to the need for recovery of response properties for full functional recovery from MD.
Potential clinical implications
These results suggest a potential role for binocular vision in recovery from amblyopia. Although clinical experience indicates that patching the better eye of a child is required to improve spatial resolution in the amblyopic eye, binocular vision may also have an important role in recovery. This conclusion is supported by our findings and a recent study showing that initial recovery of form vision after MD is faster when both eyes are open than in reverse-deprived animals (Mitchell et al. 2001). Strong support for a role of binocular recovery in treatment of amblyopia was also obtained in a clinical study showing that most improvements in visual performance of the amblyopic eye occur following prescription of appropriate spectacles but prior to unilateral occlusion (Moseley et al. 1997).
Our findings that recovery of deprived eye responses is not tightly linked to the terminus of the critical period may also be relevant to understanding clinical reports dealing with the outcome of amblyopia therapy according to age. Although a large proportion of patients remain amblyopic following treatment (Flynn et al. 1999), a more favorable outcome has been shown in children treated before 3 yr of age than in older children (Williams et al. 2002). Especially striking is the case of children born with congenital cataracts, who require surgery during the first 2 postnatal mo to obtain improved deprived eye function (Birch and Stager 1988; Taylor et al. 2001). Our finding that cortical binocularity as well as orientation selectivity failed to recover when normal vision was restored to the deprived eye halfway through the critical period may help explain why appropriate recovery of deprived eye responses requires very early intervention. The success of early treatment may be related to the existence of relatively early and narrow windows of opportunity for activity-dependent maturation of receptive field properties, especially orientation selectivity, in animals deprived from the time of eye opening.
In contrast to the finding that improvement of the amblyopic eye requires early intervention, other reports have shown clear improvement in some older children and even adults (Birnbaum et al. 1977; Mintz-Hittner and Fernandez 2000). Our finding that sufficient plasticity remains after the end of the critical period to allow recovery from MD is consistent with the reports of successful treatment in adults. Our results suggest that recovery from amblyopia may occur in older patients that developed amblyopia relatively late, after orientation selectivity had already reached a mature state. There is an urgent need to elucidate the mechanisms regulating recovery of deprived eye responses and the ferret model described here presents a unique opportunity to achieve this goal.
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GRANTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. S. Ramoa, Dept. of Anatomy and Neurobiology, Virginia Commonwealth Univ. School of Medicine, 1101 E. Marshall St., Sanger Hall Rm. 12-042, Richmond VA 23298-0709 (E-mail: asramoa{at}vcu.edu).
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ABSTRACT
INTRODUCTION
