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NEUROSCIENCE |
1 Dipartimento di Scienze Biomediche e Terapie Avanzate, Sezione di Fisiologia umana and Centro di Neuroscienze, Università di Ferrara, 44100 Ferrara, Italy
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Abstract |
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(Received 7 March 2006;
accepted after revision 9 May 2006;
first published online 11 May 2006)
Corresponding author G. Franchi: Dipartimento di Scienze Biomediche e Terapie Avanzate, Sezione di Fisiologia umana, Università di Ferrara, 44100 Ferrara, Italy. Email: fhg{at}dns.unife.it
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Introduction |
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After facial nerve transection in rats, forelimb, neck, eye and ipsilateral vibrissae movements occupy specific and orderly sites of the cortical region where the movement of the disconnected vibrissae is normally represented (Sanes et al. 1988, 1990; Toldi et al. 1996; Huntley, 1997a; Franchi, 2000b). After facial nerve transection, the vibrissae are atonically retropositioned, abnormally reducing the sensory input to M1. It has been proposed that the abnormal vibrissae input transmitted, via the infraorbital nerve, to the motor cortex mediates the short-term cortical reorganization after facial nerve lesion (Donoghue et al. 1990; Farkas et al. 1999, 2000; Krakauer & Ghez, 2000). To test this hypothesis we cut the infraorbital nerve, and then cut the facial nerve, the aim being to evaluate cortical reorganization without any aberrant, facial-nerve-lesion-induced sensory feedback. Differences in the M1 short-term reorganization after motor disconnection, with and without vibrissae sensory input, would support this hypothesis. In contrast, a lack of differences would demonstrate that selective vibrissae sensory feedback is not a sufficient stimulus to trigger M1 short-term reorganization.
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Methods |
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Experiments were carried out on 20 Albino rats, weighing 250–300 g. The experimental plan was designed according to the Italian law for care and use of experimental animals (DL116/92) and approved by the Italian Ministry of Health. For all experimental procedures rats were anaesthetized initially with ketamine hydrochloride (100 mg kg–1 I.P.). For the duration of the experiment, anaesthesia was maintained by supplementary ketamine injections such that a long latency and sluggish hindlimb withdrawal was achieved only with severe pinching of the hindfoot. Under anaesthesia, the body temperature was maintained at 36–38°C with a heat lamp.
The experimental plan is illustrated in the Fig. 1. The general procedures were as follows. First, 10 animals underwent bilateral, irreversible vibrissae pad input disconnection by severing the infraorbital nerve (ION cut). We chose bilateral ION severing to ensure a complete vibrissae pad input disconnection, since a large percentage of neurons in the rat's sensory motor cortex receive bilateral sensory input (Armstrong-James & George, 1988). Previous studies have shown that 2 weeks of recovery provide ample time for modulatory influences on motor cortex reorganization (Sanes et al. 1988, 1990; Donoghue et al. 1990; Toldi et al. 1996; Franchi, 2001). Therefore, 2 weeks later, the same animals underwent unilateral vibrissae pad output disconnection. In a group of five animals the facial nerve (VII cut) of one side was severed (ION + VII group: ION hemispheres and ION + VII hemispheres), while the remaining five animals were given a botulinum toxin (BTX) injection into the vibrissal pad of one side (ION + BTX group: ION hemispheres and ION + BTX hemispheres). The reversible blockade of motor activity induced with BTX leads to short-term M1 reorganization comparable to that induced by facial nerve lesion (Franchi, 2002). The use of two different type of vibrissa output disconnection provides an internal control of input-deprived M1 short-term reorganization and ensures more confidence in the results. Second, another group of five animals underwent facial nerve severing of one side (VII group: intact hemispheres and VII hemispheres). For each animal, M1 mapping of both hemispheres was performed 48 h after facial nerve lesion and BTX injection. Finally, in five animals both hemispheres were mapped as reference for normal M1 mapping (control group: right and left control hemispheres). The control and experimental groups were matched for gender (three males for each group), age (13–15 weeks), weight (250–300 g at the time of mapping procedure) and side of the lesion.
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All surgical procedures were performed under ketamine anaesthesia (100 mg kg–1 I.P., and then supplemental doses I.M. as needed). In 10 animals, under the operating microscope, the infraorbital nerve of both sides was exposed, separated from its adjacent tissues and legated; then it was cut distally to eliminate all remaining fine branches. The proximal stump was dried and covered with acrylic tissue adhesive (Histoacryl) to prevent the proximal axons from sprouting. The skin was closed with 6-0 sutures and cleansed with an antibiotic solution. In the postoperative period none of the rats displayed complications such as self-mutilation, infection, or overt signs of discomfort. Clinical observation during natural whisking clearly showed that the deafferented vibrissa displayed bilateral rhythmical movements but did not suddenly retract when it hit against targets, as would normally be the case. After deafferentation the vibrissal pad proved unreactive to light pain-inducing sensory stimuli (i.e. light touching, squeezing or piercing). The loss of vibrissal pad sensitivity following deafferentation was clearly evidenced in all animals for the entire survival period (for more details see Franchi, 2001).
In five animals that underwent bilateral infraorbital nerve severing, and in five intact animals using surgical procedures similar to the above, the facial nerve of one side was exposed at the point where it exits the stilomastoid foramen, and transected just beyond the point of origin of the digastric nerve. Following facial nerve severing, the animals lacked vibrissae movement and blinking on the operated side (for more details see Franchi, 2000a,b).
In the remaining five animals that underwent bilateral infraorbital nerve severing, a single injection of BTX (8 u dissolved in 0.08 ml of saline; Botox; Allergan Sweepstakes Center, Ballsbridge, Dublin, Ireland) was delivered at a single site in the middle of the vibrissae pad of one side (for more details see Franchi, 2002). After BTX injection, the affected vibrissa lacked rhythmical movements during sniffing behaviour; they were also atonic and positioned backward.
Intracortical stimulation mapping
Intracortical microstimulation (ICMS) mapping was aimed at defining the extent of the vibrissa representation and the current threshold required to elicit vibrissa movements. The mapping procedure was similar to that described by Donoghue & Wise (1982) and Sanes et al. (1990), and detailed elsewhere (Franchi, 2000a). Briefly, the animals were placed in a Kopf stereotaxic apparatus and the frontal cortex was exposed by a large craniotomy. The dura remained intact, and was kept moist with a 0.9% saline solution. The electrode penetrations were regularly spaced out over a 500 µm grid. Alteration in the coordinate grid, up to 50 µm, was sometimes necessary to prevent the electrode from penetrating the surface blood vessels. These adjustments in the coordinate grid were not reported in the reconstruction maps. When adjustment exceeded 50 µm, penetration was not performed at this site. Glass insulated tungsten electrodes (0.6–1 M
impedance at 1 kHz) were used for stimulation. The electrode was lowered vertically to 1.5 mm below the cortical surface and adjusted ±200 µm so as to evoke movement at the lowest threshold. In a previous experiment this depth was found to correspond to layer V of the frontal agranular cortex (Franchi, 2000a). Cathodal monophasic pulses (30 ms train duration at 300 Hz, 200 µs pulse duration) of a maximum of 60 µA were passed through the electrode with a minimum interval of 2.5 s. Starting with a current of 60 µA, intensity was decreased in 5 µA steps until the movement was no longer evoked; then intensity was increased to a level at which nearly 50% of the stimulations elicited movement. This level defined the current threshold. If no movements or twitches were evoked with 60 µA, the site was recorded as negative (ineffective site). When movement was observed in two different body parts or bilateral vibrissa, current thresholds were determined for each component. In general, at threshold current levels, only one movement was elicited from any given point. Body parts activated by microstimulation were identified by visual inspection and/or muscle palpation. The terms ‘forelimb movement’ and ‘hindlimb movement’ refer collectively to distal and proximal joint movements. Forelimbs and hindlimbs were approximately half-way between flexion and extension and were alternately flexed and extended, particularly when defining representational borders.
Histology
At the end of the experimental procedure, the animals were perfused transcardially. The brains were sectioned and stained with thionine to verify microelectrode positions and depths.
In each animal, gross postperfusion examination of the injured nerves evidenced no nerve continuity at the acrylic stopper level. Under the operating microscope, care was taken to ensure that all ION fascicles had been tied and axotomized. In some animals a few axons had sprouted at the periphery of the acrylic stopper without clear reinnervation of distal vibrissal pad.
In all the animals studied, the exposed ION was cut proximal to the site of nerve injury and prepared for histological examination. After postfixation in osmium tetroxide, toluidine blue was used to stain sections that were 1 µm thick. Morphological examination of sections (Axioskop Zeiss and DMC Polaroid camera for image acquisition) showed extensive degenerative processes involving all axons proximal to the lesion (Fig. 2).
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Using a dedicated plotting program (written with the Laboratory View Development System, see Acknowledgements), an on-line grid map was constructed by labelling electrode penetrations according to the distance (in millimetres) from the bregma. At a current intensity of 60 µA or less, threshold values were recorded on a sheet scrolling below the map grid. This procedure considers the cortical surface subdivided into a square grid where each movement threshold point was the centre of a square that was 500 µm wide. In each hemisphere, vibrissa and forelimb movements were mapped in order to determine the extent and location of these representations. Penetrations were not performed in correspondence of large vessels and these sites were not taken into account in the computations. This procedure presents several potential sources of variability that could affect the accuracy of the configuration and size of movement representations. To reduce the effect of experimental sources of variability, similar mapping density was maintained across all animals. This procedure cannot prevent electrode track distortions arising from curvature in the lateral portion of the frontal cortex. This mainly affects the forelimb sites situated in the more lateral position in rat M1. Because the goal of this study was to document reorganization in that part of M1 where the electrode was lowered perpendicularly into the cortex, no attempt was made to correct for any potential distortion in the more lateral sites (Figs 3–6). The cortex medial to the vibrissa representation was not systematically explored less than 1 mm lateral from midline. In normal animals, the cortex medial to the vibrissa representation was occupied by a small representation of eye, eye–eyelid movements (Hall & Lindholm, 1974; Donoghue & Wise, 1982; Toldi et al. 1996; Guandalini, 1998) and by a thin strip of cortex where ICMS evoked miosis (Gioanni & Lamarche, 1985; Guandalini, 2001, 2003). In any case eye, eye–eyelid, pupilar movements and ineffective sites formed the basis for delineating the medial border of the vibrissa representation. The sample of eye, eye–eyelid and miosis sites in each hemisphere was too small and these sites have been collectively referred to as ‘eye sites’ (Figs 3–6).
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2 tests. The 2 test was presented using a two- or five-way contingency table (2 x 2 or 5 x 2). In the table, the rows refer to the animal group, and the columns to the frequency of movement sites medial and lateral to 2.5 mm of the medial-lateral coordinate. This point corresponded to the overlap point of the vibrissa and forelimb sites medial-lateral frequency distribution in the control group (see Fig. 1B). A probability value of less than 0.05 was considered statistically significant. |
Results |
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The general features – size, shape and location – of vibrissal representation in the control hemispheres conform to previous descriptions of the rat M1 (Fig. 3A and B) (Donoghue & Wise, 1982). In general, the vibrissa representation is an anteroposteriorly elongated strip extending from the bregma 4 mm anteriorly and 1–2.5 or 1–3 mm laterally. In the hemispheres of the control group of animals, the electrical stimulation of vibrissa representation at the threshold current evoked contralateral vibrissa movement in the vast majority of sites; ipsilateral vibrissae movement were only occasionally observed at the threshold current (Fig. 7; 1.59% of total sites in the histograms). The forelimb representation is situated laterally to the vibrissa region at the same anteroposterior coordinates. Hindlimb representation delimited the posterior boundary of the vibrissa and forelimb representation. In the frontal cortex strip situated medially to the vibrissa representation, miosis or, less commonly, eye movement was induced under the chosen stimulation conditions (Hall & Lindholm, 1974; Donoghue & Wise, 1982; Gioanni & Lamarche, 1985; Guandalini, 2001, 2003). Ineffective sites formed the basis for delineating the rostral MI border.
Statistical comparison between the right and left hemispheres of the control group of animals showed no significant difference in the mean size of the vibrissa movement representation (right hemisphere: mean size 4.35 ± 0.52 mm, range 3.5–5.5 mm; left hemisphere: mean size 3.9 ± 0.33 mm, range 3.25–4.5 mm; P
= 0.3, paired t test). Statistical comparison also showed no significant difference in the percentage of movement sites (eye, P
= 0.24; vibrissae, P
= 0.44; forelimb, P
= 0.9; paired t test) and in the mediolateral frequency distributions of the contralateral vibrissa and forelimb sites (Fig. 3B; vibrissae, 20.05;1
= 0.04; and forelimb, 20.05;1
= 0.002; 2 x 2, 2.5 mm as dividing point; P > 0.05 2 test). Similarly, no significant differences in evoked movement thresholds were found between the right and left hemispheres of the control group of animals (eye, P
= 0.96; vibrissae, P
= 0.26; forelimb, P
= 0.44; hindlimb, P
= 0.95; paired t test). The fact that there were no statistical differences between the right and left hemisphere of the control group of animals ensured that, in absence of peripheral manipulation, sources of variability were minor and not consistent between the right and left hemispheres of a small number of animals.
Hypothesis 1: the loss of an ION signal induces motor cortex plasticity
If the ION signals have an influence on M1 neurons, then it is possible that the persistent withdrawal of an ION input to M1 neurons could induce M1 plasticity. This hypothesis predicts that ION versus control hemispheres should be significantly different. Comparison of the ION (n
= 10) and control (n
= 10) hemispheres showed no significant difference in percentage of movement sites evoked in the two groups of hemispheres (Fig. 7 and Table 1; P > 0.05 Scheffé test) and in the mediolateral frequency distributions of the contralateral vibrissa (20.05;1
= 2.1; 2 x 2, 2.5 mm as dividing point; P > 0.05 2 test) and the forelimb sites (Fig. 8A, ION versus control, 20.05;1
= 0.4; 2 x 2, 2.5 mm as dividing point; P > 0.05 2 test). In comparison with the control hemispheres, the threshold currents required to evoke contralateral vibrissa movement in the ION hemispheres were slightly, but not significantly, higher (ION, 22.3 ± 0.6; control, 21.2 ± 1.8; Table 2, hypothesis 1; P > 0.05 Scheffé test). No significant differences in evoked movement thresholds were found in other types of movement (see Table 2; P > 0.05 Scheffé test). Thus, the present experiments showed no evidence that, after a period of more than 2 weeks, the vibrissa pad deafferentation produced significant plastic changes within the vibrissa motor representation. In sum, these data do not support the hypothesis 1.
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If the persistent withdrawal of an ION input to M1 neurons not produced significant plastic changes within the vibrissa motor representation, it is possible that the abnormal ION signal to M1 neurons after vibrissa muscle paralysis could trigger M1 reorganization. This hypothesis predicts that VII versus ION + VII and ION + BTX hemispheres should be significantly different.
Examination of the motor maps in Figs 4–6 revealed that the reorganization of vibrissae movement representation clearly emerges only in hemispheres where the contralateral vibrissae pad underwent motor-output disconnection. As shown in the plots in Figs 7–10, the reorganization of vibrissae motor representation 48 h after facial nerve transection is characterized by the following. (1) An increase in the percentage of ineffective sites inside the former vibrissa representation (Fig. 7 and Table 1, VII versus control hemispheres; P < 0.05 Scheffé test). (2) An increase in the percentage of ipsilateral vibrissa and neck sites (Fig 7C and D, and Table 1, VII versus control hemispheres; P < 0.05 Scheffé test). Ipsilateral vibrissa and neck sites consisted of contiguous or separated foci. In these sites, higher-than-threshold electrical stimulation often elicited both ipsilateral and neck movements. Thresholds for ipsilateral vibrissa and neck movements were higher than thresholds required to evoke contralateral vibrissa movement in the corresponding area in the control hemispheres. (3) An increase in the percentage of forelimb sites (Fig. 7E and Table 1, VII versus control hemispheres; P < 0.05 Scheffé test). In the VII hemispheres, forelimb sites distribution shifted medially when compared with the distribution in the control hemispheres (Fig. 8B, VII versus control hemispheres: 20.05;1
= 4.5; 2 x 2, 2.5 mm as dividing point; P < 0.05, 2 test). This means that the forelimb sites expand in the cortical region nearly corresponding to the lateral part of the normal vibrissa motor representation. Thresholds for forelimb movement in the VII hemispheres were slightly, but not significantly, higher than thresholds for forelimb movement in the control hemispheres (VII versus control hemispheres, 23.6 ± 2.9 versus 19.1 ± 3.4; Table 2; P > 0.05 Scheffé test). Figure 9 shows that the increase in the forelimb thresholds in the VII hemispheres involves selectively the forelimb sites localized up to 3 mm lateral to the midline (left bar, S20.05;5,24
= 22.8, P < 0.05; right bar, S20.05;5,24
= 0.006, P > 0.05, Scheffé test). That is, 48 h after severing facial nerve, the forelimb sites emerging in the cortical region that nearly corresponds to the lateral part of the normal vibrissa motor representation showed thresholds significantly higher than those found in sites normally devoted to forelimb movement.
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20.05;2
= 0.3; 3 x 2, 2.5 mm as dividing point; P > 0.05 2 test). (3) There was no significant differences in evoked movement thresholds (Table 2, P > 0.05 Scheffé test) and in the mediolateral distribution of forelimb thresholds were found between VII and ION + VII and ION + BTX hemispheres (Fig 10B; P > 0.05 ANOVA). All these data show that the vibrissae receptor input does not affect the type and threshold of movements emerging within the disconnected vibrissa motor region over time.
Quantitative comparisons between ION + VII and ION + BTX hemispheres showed no significant differences in the percentage of movement sites (Fig. 7 and Table 1; P > 0.05 Scheffé test) and in the mediolateral frequency distribution of the forelimb sites (Fig. 8B, ION + VII versus ION + BTX: 20.05;1
= 0.31; 2 x 2, 2.5 mm as dividing point; P > 0.05 2 test). Similarly, no significant differences in evoked movement thresholds were found (Table 2; P > 0.05 Scheffé test). This comparison showed that different types of motor disconnection in deafferented animals do not induce differences in the time course for the reorganization of vibrissae motor representation.
Thus, there was no evidence that persistent vibrissae pad deafferentation actually changes the short-term pattern of reorganization of the vibrissae motor representation after vibrissae pad motor-output disconnection. In the light of this, these data not support hypothesis 2.
Hypothesis 3: ION signal is irrelevant for motor cortex reorganization following vibrissa muscle paralysis
If the persistent withdrawal of the ION signal does not induce M1 plasticity, and the presence of an abnormal ION signal to M1 neurons does not trigger M1 plasticity, it is possible that the ION signal does not influence the large M1 reorganization following the vibrissae muscle paralysis. This hypothesis predicts that (1) ION and control hemispheres should be the same; (2) ION and VII hemispheres should be different; (3) beyond the predictions of hypothesis 2, hypothesis 3 predicts that ION, ION + VII and ION + BTX hemispheres should be different; (4) VII, ION + VII and ION + BTX hemispheres should be the same. All of these comparisons are clearly supported by the present results (see Figs 6–10, and Tables 1 and 2), which clearly support hypothesis 3. Thus, we can conclude that the reorganization of vibrissae movement representation clearly emerges only in hemispheres where the contralateral vibrissae pad underwent motor-output disconnection, and that the infraorbital signal is irrelevant for this form of motor plasticity.
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Discussion |
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Peripheral signals and M1 reorganization
We do not know what type of signal induces M1 reorganization minutes and hours after peripheral motor disconnection (Sanes et al. 1990; Toldi et al. 1996; Huntley, 1997a). However, the present results might be helpful in identifying such signals. The hypothesis that, in the adult rat, continuous vibrissae sensory feedback is not necessary to maintain M1 vibrissae representation has long been supported by data demonstrating normal shape and size of vibrissae motor representation after vibrissae trimming (Huntley, 1997b) or persistent ION injury (Franchi, 2001). The present study adds additional support for this conclusion, and shows that abnormal ION-mediated sensory feedback to M1 is not a cue for M1 reorganization after vibrissae motor-output disconnection.
Signals induced by nociceptors and conveyed through non-ION branches by C-fibres could trigger M1 reorganization in all VII-operated rats. The finding that, in ION-deafferented rats, the injection of BTX into pad muscles leads to a reorganization similar to that seen following severing of the facial nerve does not support this hypothesis.
The present experiment does not rule out the possibility that some other set of nondominant inputs from the face, neck and forelimb may be relayed to the vibrissa motor region (Schroeder et al. 1995; Moore & Nelson, 1998). Thus, abnormal nondominant input from face, neck and forelimb to the vibrissae motor region could trigger and drive the M1 reorganization after vibrissae motor output disconnection. According to this hypothesis, the nondominant forelimb input to the vibrissa motor region could drive the emergence (within hours, Sanes et al. 1988; Donoghue et al. 1990; Huntley, 1997a; present data) and the subsequent consolidation (after days, Sanes et al. 1990; Franchi, 2000b, 2002) of the forelimb movement inside the lateral part of the former vibrissa representation. However, this hypothesis does not explain the initial reaction that takes place within a few minutes and which disinhibits transcallosal connections between homotopic vibrissa regions in both hemispheres (Toldi et al. 1996, 1999; Farkas et al. 2000; Horvath et al. 2005). Hours later, when this initial reaction disappears, the subthreshold input might play a role in facilitation of the intra-areal connections between the vibrissa region and neighbouring representations.
The finding that M1 reorganization clearly emerges only when the motor nerve is severed or neuromuscular transmission is blocked, with or without ION signals, also suggests that the cortical reorganization may be triggered by signals starting from peripheral motor structures. Peripheral axotomy induces changes in the discharge properties of both motor and internuclear neurons in the central nervous system (De la Cruz et al. 2000). The early phase of the ‘axotomy reaction’ could be initiated by electrical disturbances that antidromically convey information regarding motor axon damage from the periphery to the motor neuron body (Mader et al. 2004), and this might have adverse effects on the firing of facial motor neurons. Moreover, the initial response of BTX-treated motor neurons resembles some of the functional changes found in these neurons following an axotomy (Delgado-Garcia et al. 1988; Pastor et al. 1997). Thus, the present results suggest that cortical reorganization could be secondary to changes in the firing of facial nucleus motor neurons and interneurons (Li et al. 2004; Ikeda & Kato, 2005; Vassias et al. 2005) triggered by both axotomy and inactivation of neuromuscular synapsis (see the scheme in the Fig. 11).
Sub-cortical and cortical mechanisms of M1 reorganization
There is experimental evidence that, in the rat, rhythmic whisking is maintained by the whisking central pattern generator (CPG) at the level of medulla (Gao et al. 2001, 2003; Hattox et al. 2003), whereas voluntary initiation and modulation of the whisking pattern are mediated by cortical mechanisms (Carvel et al. 1996; Friedman et al. 2006). There is also evidence to support the hypothesis that the source of rhythmic activity in the vibrissa cortex, phase-locked with exploratory rhythmic whisking, can be the efference copy originating in the brainstem CPG and ascending to the M1 cortex (Ahrens & Kleinfeld, 2004; Friedman et al. 2006). However, there is as yet no direct evidence that such ascending pathway(s) exist.
The finding that M1 reorganization clearly emerges only when the motor nerve is severed or neuromuscular transmission is blocked, with or without ION signals, supports the suggestion that an altered efference copy could trigger and preserve vibrissa motor cortex reorganization. If the shaping and size of the vibrissa motor representation is based on efference copy, then it is possible to understand the lack of effect of ION nerve transection. When the motor output is blocked, the nature of the efference copy ascending to the motor cortex could change; in this way, an abnormal efference copy could trigger M1 reorganization and could explain how, in the absence of ION feedback, the motor cortex knows that its link to the vibrissae muscles is not normal. These explanations assume that the changes also occur in subcortical circuits closer to the periphery involving facial motor neurons and circuits that receive efference copy of motor commands which could act as a conduit for signals from the brainstem to thalamus and finally to the M1 cortex. Possible candidate pathways that could trigger M1 output reorganization might include all thalamic inputs to M1. Thus, after vibrissae output disconnection, the restriction of the vibrissae movement could first induce changes in motor-related structures outside the primary motor cortex. The observed changes in the M1 motor map might be triggered by input from either the basal ganglia (Sharp & Evans, 1982; Hauber et al. 1998), or the cerebellum (Kotchabhakdi & Walberg, 1977; Angaut & Cicirata, 1994), or both, and enabled by cholinergic inputs from the basal forebrain (Juliano et al. 1991; Höhmann et al. 1991; Webster et al. 1991). The scheme in the Fig. 11 shows the proposed mechanisms for short-term reorganization of input-deprived motor vibrissae representation following motor disconnection.
Animal work has demonstrated the role of the horizontal connections within M1 as a neural substrate for cortical plasticity (Donoghue, 1995; Hess et al. 1996; Hess & Donoghue, 1996; Huntley, 1997a; Sanes & Donoghue, 2000). It has been suggested that these horizontal corticocortical connections are long-range collaterals of pyramidal neurons normally suppressed by local inhibitory interneurons (Jones, 1993; Kew et al. 1997). In models of cortical map plasticity, the first step in cortical map reorganization is the loss of local interneuron inhibition (Calford & Tweedale, 1991; Jones, 1993; Donoghue, 1995; D'Amelio et al. 1996; Toldi et al. 1996; Calford, 2002). Motor cortex map plasticity in the adult rat can be evoked by intracortical injection of the GABAA receptor antagonist bicuculline. Bicuculline injection in M1 induces a blockade of local inhibitory interneurons and permits functional linking of separate motor cortical points, unmasking pre-existing horizontal connections within M1 (Jacobs & Donoghue, 1991; Schneider et al. 2002). The present results indicate that persistent vibrissae sensory deprivation does not mimic the effects of the intracortical injection of bicuculline in M1. In contrast, effects comparable to the intracortical injection of bicuculline (i.e. switching normal cortical output) are strictly triggered by the restriction of vibrissae movement in animals with or without vibrissae sensory input. Thus we conclude that persistent ION-deafferentation does not drive the persistent downregulation of local inhibitory interneurons in M1. The possibility of rapid deefferentation-induced changes in cortical inhibition has been evidenced in rat M1 (Farkas et al. 2000). Indeed, facial nerve injury resulted in rapid disinhibition of the disconnected cortex when the animals were tested by paired intracortical microstimulation. This observation and the present results lead to the hypothesis that the persistent downregulation of local inhibitory interneurons – with the unmasking of pre-existing horizontal connections between the vibrissa and forelimb representation – is triggered by the persistent abnormal motor output following the vibrissae output disconnection.
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