The basal ganglia-orofacial system: Studies on neurobehavioral plasticity and sensory-motor tuning

Neuroscience & Biobehavioral Reviews. Vol. 14. pp. 433--446. © Perg~l~,~n ~

plc, 1990. Printed in the U.S.A.

0149-7634/90 $3.00 + .00

The Basal Ganglia-Orofacial System: Studies on Neurobehavioral Plasticity and Sensory-Motor Tuning J. P. H U S T O N , H. S T E I N E R , H . - T . W E I L E R , S. M O R G A N A N D R. K. W . S C H W A R T I N G

Institute o f Physiological Psychology I Heinrich-Heine University o f Diisseldorf Universitgitsstr. 1, D-4000 Diisseldorf, FRG

HUSTON, J. P., H. STEINER, H.-T. WEILER, S. MORGAN AND R. K. W. SCHWARTING. The basal ganglia-orofacial system: Studies on neurobehavioral plastici~., and senso~.-motor tuning. NEUROSCI BIOBEHAV REV 14(4) 433--446, 1990.--We have employed the unilateral removal of the vibrissae as a tool to examine ensuing behavioral changes in relation to concomitant changes in the central nervous system. In this paper we review a series of studies showing that unilateral removal of the vibrissae leads to behavioral asymmetries (e.g., in thigmotactic scanning) from which rats recover over time. Time-related to these behavioral changes we found neuronal alterations in striatal afferents, that is, in uncrossed and crossed projections from the substantia nigra and the ~beromammillary nucleus. The involvement of dopaminergic mechanisms w a s indicated by results showing that dopaminergi~ agonists can induce asymmetries in thigmotactic scanning and turning; the direction of these asymmetries was also dependent on time after vibrissae removal. Furthermore, it was shown that endogenous preferential use of one vibrissae side in thigmotactic scanning interacts with the expression of spontaneous and drug-induced behavioral asymmetries exhibited after unilateral vibrissae removal. Neurochemical studies indicated that both unilateral vibrissae removal and unilateral perioral stimulation can have lateralized effects on biogenic amines in the brain. Finally, using electrical stimulation of the substantia nigra, evidence was found for a lateralized and bidirectional interaction between basal ganglia and the orofacial systems, indicating an involvement in mechanisms of motivation and reinforcement, including the tuning of the nervous system to respond to particular stimulation. These results are important from several perspectives. One, they indicate functional links between the orofacial systems and the basal ganglia. Two, they raise the possibility that unilateral removal of the vibrissae can serve as a model (a) to investigate the dynamics of recovery of function after CNS insults, in general, and specifically, (b) to study neuronal plasticity in the nigrostriatal and tuberomammillary-striatal pathways, and (c) to investigate the neuropharmacology of catecholamine systems in the brain. Vibrissae Trigeminal system Substantia nigra Tuberomammillary nucleus Caudate-putamen Dopamine Horseradish peroxidase Hemivibrissotomy Electrical stimulation Turning behavior Thigmotactic scanning Rat

OUR investigation of the interaction between orofacial systems and the basal ganglia was guided by a bidirectional research approach. On the one hand, we manipulated the trigeminal system peripherally by removal of the vibrissae, or by stimulation of the perioral area, and analyzed concomitant neuronal changes in the basal ganglia. On the other hand, we manipulated basal ganglia function by chemical and electrical stimulation, or lesion, and studied changes in orofacial function as the dependent variable. One aim of this research was to learn more about the functional relationship between orofacial systems and the basal ganglia-systems which were treated as separate units until recently, possibly because of the dearth of knowledge regarding anatomical interconnections between them. Another reason for our interest in orofacial-basal ganglia interaction is that these systems offer the opportunity to study neuronal plasticity in relation to recovery of function. Much is known about neuronal plasticity in the basal ganglia in relation to recovery from behavioral deficits after brain lesions, as caused, for

example, by the neurotoxin 6-hydroxydopamine (6-OHDA). We found that manipulation of the trigeminal system simply by unilateral removal of vibrissae leads to transient behavioral asymmetries and concomitant neuronal changes, similar to changes that we have observed after making unilateral lesions in the nigrostriatal system. We became interested in the vibrissae tactile system when we found evidence for a functional relationship between this orofacial system and the basal ganglia. Manipulating the neuronal activity of the substantia nigra (SN) by lesion or by injection of neurotransmitter agonists resulted in a changed responsiveness to tactile stimulation in the vibrissae region of the face (37, 111, 112). Unilateral intranigral injection of the GABA agonist muscimol, substance P, or a metenkephalin analogue led to an increased sensitivity of the side of the face contralateral to the injection [reviewed in (113)]. This effect was manifested in the perioral biting reflex: touching the face or the vibrissae around the mouth with a probe on the side contralateral to the injection resulted in

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vigorous biting of the probe. A systemic injection of the dopamine (DA) receptor agonist apomorphine (APO) sensitized the biting reflex bilaterally. This response was also lateralized after a unilateral lesion of the SN by 6-OHDA: animals which circled contraversively under APO also displayed a much stronger biting reflex upon stimulation of the side of the face contralateral to the lesion (37). Our studies furthermore indicated that the influence of the basal ganglia on perioral reactivity involves DAergic receptors in the caudate-putamen (CPU), the SN, and its descending output to the deep layers of the superior colliculus (37, 111, 113, 114). Recently, we obtained additional evidence for a functional relationship between the vibrissae system and the basal ganglia (35). Removing the vibrissae on one side of the face led to plasticity in nigrostriatal projections: ten days after unilateral removal of vibrissae the CPU of the hemisphere contralateral to vibrissae removal (i.e., the sensory-deprived hemisphere) received an increased crossed input from the SN. These neuronal changes are similar to those observed after unilateral nigrostriatal lesions by 6-OHDA: such lesions resulted in an increase in strength of the crossed projection from the intact SN to the deafferented CPU (74). This analogy prompted us to examine whether hemivibrissotomy could be used as a model to assess neuronal plasticity in relation to behavior by way of this noninvasive manipulation of the brain. The following sections summarize the relevant experiments.

The Vibrissae Probably all mammals, with the exception of humans, possess the long, tactile facial hairs referred to as "'vibrissae" or "whiskers." In rats, such tactile hairs are found on the upper lip (mystacial), lower lip, chin, brow, and cheek, (26,103) (Fig. 1). The 30-35 mystacial vibrissae on each side of the snout of the rat are arranged in five horizontal rows, each containing five to nine large vibrissae (103, 107, 123). Sensory information arising out of vibrissa displacement relative to its follicle is carded along the trigeminal system through the u'igeminal nuclear complex to the contralateral ventrobasal complex of the thalamus and from there to the somatosensory cortex; in layer IV of the cortex each vibrissa projects to a distinct group of cells called "barrel" (3, 16, 49, 72, 104, 107, 116, 123). The vibrissae system is important for a great variety of behaviors [for review, see (2,27)]. For example, in a novel environment rats whisk their vibrissae over surfaces and edges, presumably, in order to sample tactile stimuli (87, 102, I10, 123). There is evidence that such tactile information from the vibrissae is analyzed in a complex form so as to allow shape or pattern perception (87). The importance of the vibrissae for the rat is also reflected by the large neuronal representation, as about 20% of the somatosensory cortex has been found to respond to stimulation of the vibrissae region of the face (107). Input from the vibrissae is of importance for the development of the anatomical organization of the brain, especially of the trigeminal/somatosensory system. The development of the distinct architecture of this system is critically dependent on sensory input from the vibrissae. Removing this input in neonatal rat and mouse by destruction of vibrissae follicles results in gross distortions in the anatomical organization of the trigeminal/somatosensory system (5, 48, 50, 101L This phenomenon seems to be agedependent, since major anatomical alterations have only been found after follicle damage in the first postnatal week (39, 46, 48). In the adult animal, however, both destruction of the follicle (11, 109, 115) and removal of the sensory hair (14, 53, 115) have been shown to lead to a reduction in metabolic and neuronal activity in corresponding "barrels."

FIG. 1. Illustrations of the appearance of the vibrissae in the rat's face.

BEHAVIORAL ASYMMETRIES AFTER HEMIVIBRISSOTOMY

After the initial finding of an influence of hemivibrissotomy on the crossed nigrostriatal projection (35), it was of interest to know if this experimental intervention would also lead to behavioral asymmetries and recovery therefrom. Therefore, we examined the rat's behavior after unilateral removal of vibrissae in a series of studies. In these studies thigmotactic scanning and turning behavior were analyzed. The behavioral parameter of thigmotactic scanning is based on the natural tendencies of the rat (a) to prefer the proximity of lateral surfaces (thigmotaxis), and (b) to "'explore" a new environment. Thus, we measured the time the rat moved along the wall of an open field with the vibrissae-intact or the vibrissae-clipped side of the face oriented towards the wall. Clipping of vibrissae on one side led to an asymmetry in thigmotactic scanning. Such rats preferentially scanned the wall with the vibrissae-intact side (94). In contrast to scanning behavior, asymmetries in spontaneous turning behavior could not be observed after hemivibrissotomy (85). We then asked, whether or not rats can recover from the asymmetry in thigmotactic scanning induced by removal of the vibrissae. In order to examine the extent of this behavioral asymmetry over time, different groups of rats were tested once at various times after unilateral removal of the vibrissae (65). It was found that animals scanned the. wall longer with the vibrissae-

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FIG. 2. A: Duration (mean---SEM. in seconds) of thigmotactic scanning with the vibrissae-intact side (full line) and the vibrissae-clipped side (broken line) through a 5-min test session. Different groups of rats were tested once between 1 h and 24 days after unilateral clipping of vibrissae; regrown stubs were removed daily. Rats tested between 1 h and 3 days after hemivibrissotomy exhibited a strong asymmetry in scanning during the first minute of testing, as they scanned more with the vibrissae-intact side. Such a behavioral asymmetry was absent in rats tested 6 days, or later, after trimming the vibrissae. B: Pooled data of asymmetrical groups ( I h-3 days) and of recovered groups (6-24 days).

intact than the clipped side up to 3 days after removal of vibrissae (Fig. 2). This asymmetry was strongest during the first minute of testing, when the rats showed the most exploratory activity. Animals tested 6 days after hemivibrissotomy, or later, did not exhibit such a scanning asymmetry (Fig. 2). The rapid return to behavioral symmetry between the days 3 and 6 after removal of the vibrissae resulted from changes on both sides of the face, that is, a reduction in scanning with the vibrissae-intact side and an increase in scanning with the vibrissae-clipped side (65). Thus. despite the absence of vibrissae on one side of the snout (the regrown stubs were removed daily), rats recovered from the asymmetry in thigmotactic scanning within a few days after hemivibrissotomy. These results show that unilateral vibrissae removal can lead to behavioral asymmetries from which rats can recover. Interestingly, similar behavioral asymmetries can be induced by unilateral depletion of striatal DA. For example, a unilateral lesion of the SN by 6-OHDA leads to turning behavior towards the side of the lesion and a loss of responsiveness to sensory stimulation on the body surface contralateral to the lesion [e.g., (57, 61, 99)]. We found that such a 6-OHDA lesion induces an asymmetry in

thigmotactic scanning like that found after hemivibrissotomy. Rats with this lesion scanned less with the side contralateral to the lesion (93l. Over time, rats can also recover from the 6-OHDA lesion-induced behavioral asymmetries. For one, ipsiversive turning behavior decreases, and orientation to sensory stimulation on the side contralateral to the lesion increases with time (6, 57, 61, 69, 99). Secondly, rats also recovered from the lesion-induced asymmetry in thigmotactic scanning. The return to behavioral symmetry involved both a decrease in duration of scanning with the side ipsilateral to the lesion and an increase in duration of scanning with the side contralateral to the lesion (93). Recovery from behavioral asymmetries after 6-OHDA lesions has been related to pre- and postsynaptic changes in the affected nigrostriatal system, including an increase in turnover and release of the transmitter dopamine, changes in interhemispheric nigrostriatal activity or innervation, and DA receptor supersensitivity [reviewed in (36, 62, 83, 120)]. We asked whether a relationship also exists between recovery from behavioral asymmetries after hemivibrissotomy and such changes in the basal ganglia. NEURONAL CHANGES IN STRIATAL AFFERENTS

Nigrostriatal Projection As mentioned above, an initial experiment provided evidence for neuronal changes in the nigrostriatal projection after hemivibrissotomy. Evidence was found for an increase in strength of the crossed nigrostriatal projection to the CPU of the hemisphere contralateral to vibrissae removal (i.e., the hemisphere deprived of vibrissal input) [Fig. 3; (35)]. This apparent neuronal asymmet r y - s t r o n g e s t in the projection from the rostral part of the S N - - w a s found ten days after hemivibrissotomy, at a point in time when the rats had had sufficient time to recover from behavioral asymmetries (see above). If, as we speculated (36), a functional relationship exists between plasticity in crossed efferents of the SN and recovery from sensorimotor asymmetries, then the changes in the crossed nigrostriatal projection would be expected to follow a similar time course as that of behavioral recovery (65). Therefore, we decided to investigate the time course of the neuronal changes in the nigrostriatal projection. The tract tracer horseradish peroxidase (HRP) was applied iontophoretically into the CPU of rats, either 1-3 days after hemivibrissotomy (during the period of behavioral asymmetry), or 4-20 days thereafter (when rats had recovered). Half of the animals received the tracer into the CPU on the vibrissae-clipped side, the other half on the side opposite to vibrissae removal. The results were as follows: as found in the previous experiment 10 days after hemivibrissotomy (35), rats examined 4-20 days after

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vibrissae removal had more retrogradely labeled neurons in the crossed nigrostriatal projection from the rostral SN to the CPU opposite to vibrissae removal [Fig. 4; (95)]. They also had more labeled cells in the uncrossed nigrostriatal projection to the CPU on the vibrissae-intact side, an effect that was found throughout the SN, but was also most substantial in its rostral part. In contrast, rats examined 1-3 days after hemivibrissotomy exhibited an opposite asymmetry in the crossed nigrostriatal projection. More labeled cells were in the projection to the CPU on the clipped side.

Interaction with Striatal Compartmentalization Recent investigations have revealed that two subsets of dopaminergic nigrostriatal projections exist. Neurons located in a dorsal sheet in the SN pars compacta project to the striatal matrix (nigro-matrixal), and neurons of a ventral sheet in the SN pars compacta and neurons from the SN pars reticulata project to the striosomes (nigro-striosomal) (20, 43, 54). We, therefore, examined whether or not hemivibrissotomy had a differential influence on these two subsets of crossed nigrostriatal projections (96). Surprisingly, the neuronal asymmetry found 1-3 days after hemi-

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vibrissotomy, with more HRP labeling in the crossed projection from the rostral SN to the CPU on the side of vibrissae removal, was mostly due to an asymmetry in the nigro-matrixal subset, and the opposite asymmetry appearing 4-20 days after clipping the vibrissae, with more HRP labeling in the projection to the sensory-deprived hemisphere, was limited to the nigro-striosomal subset (Fig. 4; see Fig. 6, for a schematic summary of these findings). Thus, these results indicate a functional dissociation of nigromatrixal and nigro-striosomal projections. We can only speculate on the nature of this dissociation. There are several possibilities: (a) One is that activity in the nigro-matrixal projection is related to sensorimotor asymmetries (as apparent asymmetries in this projection were found during the initial time period after hemivibrissotomy when behavioral asymmetries occur), and that, in contrast, the nigro-striosomal projection plays a role in compensatory processes leading to recovery of function (since neuronal asymmetries in this projection were only detected during the time period when rats had recovered from the behavioral asymmetries). Such compensatory processes could subsume mechanisms simply of repair, as well as mechanisms of learning, or both. (b) Alternatively, if we assume that the active compensatory processes occur during the period of behavioral asymmetry, the nigro-matrixal projection could be considered to be involved in compensatory or repair processes, whereas the nigro-striosomal changes could then be a result or trace of such processes. (c) A third, most intriguing possibility is that two kinds of compensating processes take place during the periods of asymmetry and recovery therefrom, for example, initially "behavioral" compensation or adaptation, involving learning (learning to cope with the asymmetrical sensory input), later structural compensations, involving processes of neuronal repair and compensation (e.g., reactive synaptogenesis, regeneration). Correspondingly, in this case the nigro-matrixal projection would be involved in learning processes, the nigrostriosomal projection in postlesion neuronal compensatory pro-

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We also analyzed the size of the labeled somata of the crossed nigrostriatal projections after hemivibrissotomy and found evidence for time-dependent changes in the somatic size (crosssectional area) of neurons of both subsets, with larger cell sizes in the projections to the CPU of the sensory-deprived hemisphere (96). Taken together, neuronal changes in the nigrostriatal pathway appeared correlated in time with behavioral changes induced by unilateral removal of vibrissae, and could, therefore, be part of the neuronal correlate of behavioral asymmetry, on the one hand, and of recovery of function (repair and/or learning), on the other.

Tuberomammillalw-Striatal Projections Neuronal changes in striatal afferents after unilateral trimming of vibrissae were, however, not restricted to the nigrostriatal pathway. We also analyzed striatal afferents from the tuberomammillary nucleus in the basal hypothalamus [Fig. 5; (106)] and found the following. Rats examined 4-20 days after hemivibrissotomy showed apparent neuronal asymmetries in crossed and uncrossed striatal projections from both the caudal magnocellular and the postmammillary caudal magnocellular subnuclei, with more HRP labeling also in the projections to the CPU of the sensory-deprived hemisphere, as found in nigrostriatal projections. In contrast to the nigrostriatal system, however, no asymmetries in HRP labeling were seen 1-3 days after hemivibrissotomy (see also Fig. 6, for summary). These results indicate that after hemivibrissotomy neuronal changes occur in different afferent systems to the CPU in concert.

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However, unlike in the nigrostriatal pathway, apparent neuronal asymmetries in the tuberomammillary-striatal projections were only found during the time period when rats had recovered from the behavioral asymmetry. Neurons of the tuberomammillary system release a variety of neuroactive compounds, such as histamine, GABA, galanin, substance P and other neuropeptides, and several of them seem to be colocalized within these neurons [e.g., (51, 68, 91)]. About 50% of the tuberomammillary-striatal projections have been found to be histaminergic (92); and interestingly, histamine seems to interact with the striatal DA transmission (9, 45, 97). Given the coincidence of changes in striatal afferents from the substantia nigra and from the tuberomammillary nucleus (Fig. 6), both being correlated in time with recovery from behavioral asymmetries after hemivibrissotomy, it is conceivable that an interaction between histamine and the dopamine transmission plays a role in compensatory processes and recovery of function.

Role of the Nigro-Striosomal and Tuberomammillary-Striatal Projections in Recovery of Function After Brain Lesions? What happens in nigrostriatal and tuberomammillary-striatal projections after neurotoxic lesion of the SN? After 6-OHDA lesions neuronal changes have been described in the nigrostriatal system on several levels. For example, changes in the crossed

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FIG. 6. Schematic summary of neuronal changes in striatal afferents from the substantia nigra and the tuberomammillary nucleus found after unilateral removal of vibrissae.

nigrostriatal projection have been observed subsequent to a unilateral lesion in the SN. That is, an increase in HRP labeling in the projection from the intact SN to the denervated CPU was found, and these changes were also correlated in time with recovery from lesion-induced behavioral asymmetries (74). So far, it is unknown whether or not this apparent increase in strength of the crossed nigrostriatal projection after the 6-OHDA lesion also reflects changes in the nigro-striosomal subset. Based on the various p a r a l l e l s in the e f f e c t s of 6 - O H D A lesions and hemivibrissotomy, as summarized in this paper [see also (38)], it can be expected that recovery of function after 6-OHDA lesions in the SN is also accompanied by differential changes in nigrostriatal subsets and striatal compartments. Also, nothing is known so far about plasticity in tuberomammillary-striatal projections in relation to recovery of function after lesions. It is tempting to speculate that, in analogy to our findings after hemivibrissotomy, neuroplasticity in these projections could also be involved in behavioral recovery after lesions.

Possible Anatomical Routes From the Trigemh~al System to the Basal Ganglia The findings summarized here indicate a functional interaction between the trigeminal system and the basal ganglia. The question arises then as to the anatomical route by which trigeminal sensory input may reach the basal ganglia. Possible bridges from the trigeminal system to SN and CPU are: (a) Direct projections from the somatosensory ("barrel") cortex to the CPU (60,108), as well as corticonigral projections [e.g., (7,79)] have been demonstrated. (b) An input route for trigeminal sensory information to the basal ganglia via striatal afferents from intralaminar nuclei of the thalamus has been suggested (52). (c) Evidence also exists for a trigemino-striatal

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projection (117), a trigemino-pontine-nigral pathway (81), a route from the trigeminal nuclear complex via raph~ nuclei (58) to SN and CPU, or connections via cerebellum (105) to the SN (89). Therefore. several anatomical routes seem to exist to link the trigeminal system to the basal ganglia. So tar, we do not know the relative contribution of these different connections to trigeminalbasal ganglia function.

In our experiments, the striatal afferents were examined with the horseradish peroxidase tract-tracing technique, and apparent neuronal changes were indicated by differences in number of retrogradely labeled neurons. What kind of neuronal changes could be reflected by these differences in cell counts? Variation in retrograde HRP marking has been related to several factors, For one, the number and size of axon terminals present at the HRP injection site have been considered to be main deternainants of the cell's capacity to accumulate HRP (44). Therefore, an increase in HRP labeling could be indicative of morphological changes, such as sprouting of axon ternfinals or collaterals. In tact, there is evidence that such a phenomenon can lead to enhanced retrograde HRP labeling [e.g., (25)]. However, the appearance of differences in our cell counts already 1-3 days after hemivibrissotomy may rule out mechanisms such as terminal sprouting, at least at this early time point. [In the corticohippocampal projection, for example, both sprouting and the increase in number of HRP-labeled neurons could only be demonstrated 6-8 days (or later) after entorhinal lesions (25).] Moreover, even after lesions in the nigrostriatal pathway, it is unclear whether or not sprouting occurs in remaining DAergic terminals in the denervated CPU [(30,75), but see (73)]. On the other hand, it has been demonstrated that in nigrostriatal neurons the synaptic activity may change, for example, in response to denervation. DAergic neurons in this projection that survive a 6-OHDA lesion can show an increased transmitter metabolism and release (1, 28, 77, 90, 119, 121) and, possibly, firing rate (31,32). Data obtained with a variety of neuronal tissue, and under various experimental conditions, indicate that the synaptic activity is another main determinant of uptake and retrograde axonal transport of HRP [(8, 13, 15, 29, 33, 56, 71,80, 88). but see (12)]. Therefore, an increase in HRP labeling could also reflect an increase in neuronal activity. For now, we have to leave open the question of which of the possible mechanisms--changes in number and/or size of terminals and/or changes in neuronal activity--could account for the changes in number of HRP-labeled neurons that were found after unilateral removal of vibrissae or after unilateral 6-OHDA lesions. We favor the interpretation that the observed differences in cell counts reflect differences in neuronal activity. However, since the underlying mechanisms still await elucidation, we used the neutral term "changes in strength" to refer to the neuronal changes observed. BEHAVIORAL ASYMMETRIESAFTER DOPAMINERGICDRUGS Above we have shown how hemivibrissotomy can lead to asymmetries in spontaneous behavior and to recovery therefrom. Related in time to these behavioral changes, we found changes in striatal afferents. Both behavioral and anatomical changes are similar to those found after unilateral 6-OHDA lesions of the nigrostriatal DA system, suggesting that this system may also play a role in behavioral changes that follow hemivibrissotomy. Thus. it coutd be expected that challenging hemivibrissotomized rats with DAergic agonists would have behavioral effects similar to

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those induced in animals with a unilateral 6-OHDA lesion of the SN. It could also be expected that such behavioral effects after hemivibrissotomy would be time-dependent, like those in the 6-OHDA model. These questions were investigated in a series of experiments, which will be summarized here [(64, 85, 94), Steiner et al.. in preparation]. In these studies, thigmotactic scanning and turning were measured in animals either acutely (4 hours) or 9 - I 1 days after hemivibrissotomy. Ten minutes prior to behavioral testing rats received systemic injections of the indirect DA agonist amphetamine (AMPH) or the DA receptor agonist apomorphine (APO).

Thigmotactic Scanning In hemivibrissotomized rats application of the receptor agonist APO led to asymmetries in scanning behavior, the direction of which was dependent on time after vibrissae removal (Fig. 7). Rats tested 4 hours after unilateral trimming of vibrissae spent significantly more time scanning the wall of the testing environment with the sensory intact side. In contrast, rats with vibrissae removed for 10 days showed a reversed asymmetry. They spent more time scanning the wall with the vibrissae-clipped side of the face [(94), Steiner et al., in preparation]. A similar reversal was observed under AMPH (Fig. 7): four hours after vibrissae removal there was more scanning with the intact side, whereas in the chronic state rats scanned more with the clipped side (64). Furthermore, it was found that the occurrence of the APO-induced reversal 9 days after hemivibrissotomy is related to the asymmetry in spontaneous scanning (64). Comparing degree and direction of asymmetry in spontaneous behavior with that in the drugged state revealed a negative correlation between the two asymmetries in the chronic state (Fig. 8). That is, those animals which showed more asymmetry towards the intact side during spontaneous testing (nonrecovered rats), displayed more asymmetry towards the clipped side under APO, indicating that the likelihood of an APO-induced

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ANIMAL

FIG. 8. Asymmetry indices for thigmotactic scanning in spontaneous behavior (open bars) and under apomorphine (APO, 0.75-1.5 mg/kg, SC) (full bars) of individual animals tested either 4-6 hours (ACUTE state) or 9 days after hemivibrissotomy (CHRONIC state). Each rat was tested twice; first, the spontaneous behavior was analyzed (spontaneous asymmetry index is based on behavior of first minute of test), and two hours later, the drug-induced behavior was measured (asymmetry index based on 5-rain testing period). Behavioral asymmetry is expressed as relative duration (%) of scanning with clipped side. Therefore, 50% equals symmetry; values between 50% and 100% indicate more scanning with clipped side, and values between 0% and 50% indicate more scanning with vibrissae-intact side. Animals are ranked from left to right according to the degree of asymmetry in spontaneous behavior. In the chronic state, the asymmetry indices from spontaneous and drug-induced behavior were negatively correlated (p = 0.042, Spearman rank correlation test); this was not the case in the acute state (p= 0.119).

reversal can be predicted on the basis of the spontaneous behavior. This negative correlation in the chronic state was also observed when reexamining data from two other studies [(94), Steiner et al.. in preparation].

Turning Behavior Neither injections of saline nor of amphetamine led to asymmetries in turning behavior in rats tested 4 hours or 10 days after hemivibrissotomy (Fig. 9). In contrast, asymmetries were found in APO-injected animals. When tested 4 hours after vibrissae removal, such rats showed more quarter turns ('head-to-tail': see Fig. 9, for behavioral example) to the vibrissae-intact side than to the clipped side (85). Similar turning behavior under APO was observed by Szechtman (98): bandaging one side of the rat's face (including nostrils, snout, vibrissae, chin, eye and ear), thus,

20.,

s

i - ] 10 DAYS

FIG. 9. A: Mean (+SEM) number of quarter turns (with a diameter of less than 30 cm) towards the vibrissae-intact and the clipped side through a 5-min testing period. Rats were tested either 4 hours (stippled bars) or 10 days (open bars) after hemivibrissotomy. Prior to testing they received an injection (SC) of either vehicle (SALINE), 1.0 mg/kg amphetamine (AMPH), or 0.5 mg/kg apomorphine (APO). B: Schematic illustration of an open field with a rat turning head-to-tail towards the vibrissae-intact side, as seen 4 hours after hemivibrissotomy under the influence of APO.

influencing multiple sensory systems, led to turning towards the sensory intact side. Our data show that an imbalance in vibrissae input alone is sufficient to induce turning behavior under APO. The effect of APO on turning behavior was also dependent on time after vibrissae removal. APO-injected animals, tested 10 days after hemivibrissotomy, showed a different behavioral pattern than those tested in the acute state. Turning to the clipped and vibrissae-intact side was balanced (Fig. 9). However, compared to the acute group they showed a higher rate of turning to the side of vibrissae removal, and a lower rate to the intact side. Therefore, again a reversal in the direction of APO-induced behavioral asymmetry was observed 10 days after vibrissae removal (85).

Dopamine Receptor Supersensitivit 3' After Hemivibrissotomy? The reversing effects of APO in the hemivibrissotomy model are reminiscent of similar effects of APO in the 6-OHDA model. After degeneration of the nigrostriatal DA system, animals develop a behavioral supersensitivity to DA agonists (100). This phenomenon is explained in terms of a denervation-induced increase in sensitivity (proliferation) of postsynaptic DA receptors in the deafferented striatum [e.g., (10, 17. 66. 69, 100)]. After unilateral lesions, this supersensitivity is reflected by a reversing effect of DA receptor agonists on the direction of sensorimotor asymmetries, leading to a contralateral increase in tactile reactivity (37) and thigmotactic scanning (93), and to contraversive turning (100) (Fig. 10). Thus, in analogy to the lesion model, it can be postulated that the APO-induced reversal after hemivibrissotomy is related to development of receptor supersensitivity contralateral to the side of vibrissae removal (deafferentation-induced supersensitivity). Unlike the case in the 6-OHDA lesion model (93), however, a reversal in direction of thigmotactic scanning was also observed after the indirect DA agonist AMPH. After the lesion, the DAergic action of AMPH, which requires an intact DA neuron, is mediated predominantly through the CPU of the intact hemisphere (99), thus, leading to behavioral asymmetries ipsiversive to the lesion. In the case of unilateral vibrissae removal, there is no evidence for

440

HUSTON E T AL.

UNDRUGGED

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FIG. 10. Sensorimotor asymmetries after a unilateral 6-OHDA lesion in the substantia nigra (SN) (9-11 days postlesion) during spontaneous behavior (UNDRUGGED), or under the influence of the dopamine receptor agonist apomorphine (APO). APO reverses the direction of asymmetries in turning behavior, thigmotactic scanning and tactile reactivity, as a result of its action on supersensitive DA receptors in the CPU ipsilateral to the lesion (see text).

a lateralized DAergic lesion [(85), Steiner et al.. in preparation]. Therefore, AMPH can increase DA availability at receptor sites of both hemispheres. However, the effect of DA might be stronger in the hemisphere contralateral to the side of vibrissae removal, as the hypothesis of supersensitive DA receptors would predict, thus, leading to behavioral asymmetries towards the side of vibrissae removal. Finally, the negative correlation observed between spontaneous and APO-induced thigmotactic scanning indicates that the possible development of receptor supersensitivity does not serve as a compensatory mechanism for recovery from spontaneous asymmetries after unilateral vibrissae removal. Thus, other mechanisms have to be considered. The similar time course of behavioral recovery and of plasticity in striatal afferents subsequent to vibrissae removal (see above) indicates that the occurrence of such neuronal changes could be positively correlated with behavioral recovery. INFLUENCES OF ENDOGENOUS ASYMMETRIES

It is known that the effects of unilateral behavioral and neuronal manipulations are influenced by endogenous asymmetries. Especially in the case of studies dealing with DAergic mechanisms and the basal ganglia it has been shown that the qualitative or quantitative effects of unilateral manipulations can be dependent on whether they are performed ipsilateral or contralateral with respect to a side preference. For example, it has been shown that (a) the effects of unilateral nigrostriatal lesions on turning behavior, (b) thresholds of rewarding brain stimulation in the lateral hypothalamus, and (c) the degree of operantly conditioned turning behavior are influenced by interhemispheric asym-

metries, which are reflected by preoperative turning asymmetries during nocturnal behavior (22), or after DAergic agonists (21, 22, 24, 40, 76). Endogenous neuronal mechanisms, which have been related to such behavioral asymmetries or preferences, are asymmetries in the nigrostriatal DA system, such as in striatal DA content or activity (41, 42, 78, 122), in DAergic receptors (23), and in crossed nigrostriatal projections (67). As the effects of hemivibrissotomy are also closely related to DAergic mechanisms in the nigrostriatal system (see above), it can be expected that these effects are also influenced by endogenous asymmetries. To test this hypothesis we analyzed untreated rats for spontaneous asymmetries in thigmotactic scanning (86). Subsequent to this baseline test (PRE; Fig. I 1), rats were assigned to one of two groups. In one group, the vibrissae were unilaterally removed on the side which had preferentially been used during scanning (i.e., the dominant side), whereas in the other group, the vibrissae from the opposite side were removed. Four hours after hemivibrissotomy the rats were again tested for spontaneous scanning behavior (POST), followed 1.5 hours later by an analysis of the effects of a systemic injection of APO (0.5 mg/kg). Figure I 1 shows the results of thigmotactic scanning for each of the 3 test sessions. Both groups were clearly asymmetrical during the PRE-test when the vibrissae had not yet been removed. However, when tested after vibrissae removal (POST), only the group, in which the vibrissae from the nondominant side had been removed, was still asymmetrical, as it showed more scanning with the vibrissae-intact side. In the other group, there was no difference between the clipped and the intact sides. The subsequent injection of APO yielded similar results: more scanning with the intact side in animals in which the nonpreferred side had been clipped, and no asymmetry in the other group. The simultaneous analysis of turning behavior yielded a different behavioral pattern (Fig. 12). During PRE- and POST-test there was no asymmetry in turning (diameter less than 30 cm) with respect to the side of vibrissae removal in either group. After the injection of APO both groups showed an asymmetry towards the vibrissae-intact side. However, this effect was more pronounced in the group in which the vibrissae from the dominant side had been removed. These results show that spontaneous side preferences in thigmotactic scanning can influence the behavioral effects of unilateral vibrissae removal. The higher level of spontaneous and APOinduced scanning with the sensory intact side (64, 65, 94) was not observed in animals in which the dominant side of vibrissae had been removed. Thus, as in the lesion model (22,76), endogenous asymmetries or preferences can account for variance in behavioral results after hemivibrissotomy. Furthermore, these results show that, in contrast to scanning, turning towards the sensory intact side under APO (85) was more pronounced in animals in which the preferred side had been clipped. These differential behavioral influences of spontaneous asymmetries suggest that different neuronal mechanisms are involved in turning and scanning. As indicated above, behavioral asymmetries or preferences have been related to endogenous asymmetries in DAergic content, activity, receptors, and crossed projections in the nigrostriatal systems. It remains to be determined whether such neuronal asymmetries in DAergic mechanisms on the level of the basal ganglia also underlie spontaneous asymmetries in scanning behavior. NEUROCHEMICAL CHANGES AFTER UNILATERAL MANIPULATIONS OF THE VIBRISSAE

Our anatomical and pharmacological experiments showed that unilateral removal of vibrissae leads to neuronal changes which involve striatal afferents and DAergic mechanisms. These results

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FIG. 11. Duration (mean+SEM, in seconds) of thigmotactic scanning with the vibrissae-dominant side (full bars) and the nondominant side (stippled bars) during a 5-min test session, before (PRE) and 4 hours after hemivibrissotomy (POST). and after an injection of APO (0.5 mg/kg, SC; It/., h after POST). In normal rats the side with which the animal performed more thigmotactic scanning (i.e., the vibrissae-dominant side) was first determined in a baseline test (PRE). Thereafter, half of the rats had the vibrissae on the dominant side clipped CA), the other half those on the nondominant side (B). *p=0.001-0.045.

indicate that hemivibrissotomy might affect the metabolism of DA in the brain, and that such an effect might be dependent on the interval between vibrissae removal and the time of testing. It could be expected that vibrissae removal would have different neurochemical effects before and after behavioral recovery from hemivibrissotomy. To test this hypothesis, brain samples ipsi- and contralateral to the side of hemivibrissotomy were analyzed either 4 hours or 10 days after vibrissae removal (85). About 20 min prior to sacrifice these animals had been injected with either APO (0.5 mg/kg), AMPH (1.0 mg/kg) or vehicle. The brain samples (CPU, septum, ventral mesencephalon--including SN and VTA) were examined for tissue levels of biogenic amines (including DA, DOPAC, HVA, 3-MT, 5-HT, 5-HIAA and NE) using high-performance liquid chromatography with electrochemical detection. Evidence for neurochemical changes was found in all 3 brain areas, and

FIG. 12. Mean (+SEM) number of quarter turns (with a diameter of less than 30 cm) towards the vibrissae-dominant side (as defined for thigmotactic scanning) (full bars) and towards the nondominant side (stippled bars) during a 5-min test session, before (PRE) and 4 hours after hemivibrissotomy (POST), and under APO (0.5 mg/kg, SC; IV,. h after POST). In normal rats the side with which the animal performed more thigmotactic scanning (i.e., the vibrissae-dominant side) was first determined (PRE-test). Thereafter, half of the rats had the vibrissae on the dominant side clipped CA), the other half those on the nondominant side (B). *p = 0.035. these changes were dependent on prior pharmacological treatment: 4 hours after vibrissae removal, the level of the DA metabolite 3-MT was higher in the CPU ipsilateral to the side of vibrissae removal after AMPH. After APO, 5-HT was contralaterally higher in the CPU, and ipsilaterally higher in the septum. Furthermore, after APO, bilateral differences between rats tested after 4 hours versus 10 days were found in the ventral mesencephalon, with lower levels of DOPAC, HVA and NE 4 hours after vibrissae removal. Thus, unilateral removal of vibrissae can have lateralized and bilateral effects not only on the metabolism of DA, but also of 5-HT and NE. In another study (Steiner et al., in preparation), further evidence for neurochemical asymmetries was found under APO: 4 hours after hemivibrissotomy, the levels of DA, DOPAC, and HVA were higher in the CPU ipsilateral to the side of vibrissae removal than in the opposite hemisphere. Thus, although the neurochemical results from the two experiments were not identical, both studies indicated that neurochemical asymmetries occur shortly (four hours) after hemivibrissotomy, at a time when rats display asymmetries in thigmotactic scanning towards the sensory intact side. Ten days after vibrissae removal, the levels of biogenic amines were symmetrical, that is, at a time Ca) when striatal input

442

HUSTON E T AL.

TABLE 1 THRESHOLDS FOR PERIORAL BITING REFLEX AND SELF-STIMULATION WITH ELECTRICAL STIMULATION IN THE SUBSTANTIA NIGRA

A

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Day 2

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had changed, (bl the asymmetry in spontaneous scanning had recovered, and (c) the behavioral response to DAergic agonists was reversed. Recently, employing the microdialysis technique in freely moving rats, we obtained evidence that peripheral stimulation of the trigeminal system can induce neurochemical asymmetries in the DAergic system (Adams et al.. in preparation). Unilateral vibro-tactile stimulation of the perioral area lincluding vibrissael led to increased extracellular levels of DA, DOPAC and HVA in the CPU ipsilateral to the side of stimulation. These lateralized increases, which probably reflect enhanced DA release, were found in the ventro-lateral part of the CPU, an area which has been related to mechanisms of oral behavior (471. Interestingly. these neurochemical asymmetries were observed during periods after the stimulation when rats showed asymmetries in thigmotactic scanning, with more scanning with the side contralateral to stimulation, thus, also contralateral to the increased levels of DA and metabolites. These findings in the freely moving rat confirm and extend findings in the anesthetized cat showing that unilateral sensory stimulation of paw or eye can have an asymmetrical effect on striatal DA release, including an increase ipsilateral to the side of stimulation (55,701. Taken together, lateralized effects on biogenic amines were found after unilateral sensory deprivation and after unilateral sensory stimulation. It remains to be determined whether such neurochemical effects are a consequence of the imbalance in sensory input per se, or whether they are related to behavioral asymmetries induced by the unilateral sensory manipulation.

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FIG. 13. Electrical self-stimulation in the substantia nigra (SN) after hemivibrissotomy, in the undrugged state (A), or under apomorphine (APO, 0.3 mg/kg, SCJ (B). The data are expressed as percentage (mean-'-SEM) of baseline testing (i.e.. prior to hemivibrissotomyl. Animals were tested for 30 min either 4 hours, 10 days, or 20 days after unilateral trimming of vibrissae, either in the SN on the same side as vibrissae removal (ipsi, stippled bars), or in the SN on the side opposite to vibrissae removal (contra, full bars): rats with intact vibrissae served as controls. *p = 0.023--0.025: Ap = 0.029 [versus values in undrugged state (A)].

FUNCTIONAL INTERACTIONS BETWEEN OROFACIAL SYSTEMS AND BASAL GANGLIA IN RELATION TO MECHANISMS OF/vlOTIVATION AND REWARD

As already mentioned in the introduction, previous studies from our lab have shown that unilateral chemical stimulation of the SN with a GABA agonist, or substance P. or a Met-enkephalin analogue led to an increased sensitivity of the perioral area (including the vibrissae) contralateral to the side of injection. This effect was manifested in the perioral biting reflex: touching the contralateral perioral area or vibrissae by a probe resulted in lateralized lip withdrawl, turning of the head towards the stimulus source and vigorous biting of the probe. A similar increase in sensory-motor reactivity of the contralateral perioral area was observed by Flynn and co-workers (18, 19, 59J during unilateral electrical stimulation of the lateral hypothalamus. They could show that this increased reactivity was an important aspect of aggressive behavior, namely the quiet biting attack. Unilateral electrical stimulation of the SN in the rat also sensitizes the contralateral perioral area tbr the biting reflex (84). Furthermore, the same sites in the SN can produce electrical self-stimulation. The thresholds to produce self-stimulation were found to be higher than those to elicit the biting reflex (Table 1I: however, the two thresholds were positively correlated, as found

previously for feeding and reinforcement derived from stimulation of the lateral hypothalamus (34). These results suggest an interaction between the SN and the orofacial systems in the control of mechanisms related to motivation and reinforcement. This hypothesis was substantiated by another experiment, which showed that manipulation of the vibrissae can affect self-stimulation in the SN (Fig. 13). Unilateral removal of the vibrissae led to a decrease in the rate of self-stimulation in the contralateral SN (84). Thus, self-stimulation was affected on the side of the brain, which had been deprived of vibrissae input. Moreover, this decrease could be reversed by an injection of the DA receptor agonist APO, since self-stimulation under this drug was increased in the contralateral SN (Fig. 13). However, these effects were only observed in animals tested 10 days, but not 4 hours, after vibrissae removal. Therefore, the effects on self-stimulation were observed at a time after vibrissae removal which, in the previous experiments, was shown to be related to behavioral recovery, lateralized changes in striatal afferents, and reversed behavioral responses to DAergic agonists, suggesting that the lateralized influences on nigral self-stimulation also reflect lateralized neuronal changes in response to unilateral removal of vibrissae.

THE BASAL GANGLIA-OROFACIAL SYSTEM

443

Taken together, these results provide evidence for a functional interaction between the orofacial systems (vibrissae, perioral area) and the basal ganglia. This interaction is lateralized and bidirectional, since stimulation (electrical, chemical) at the central level can increase tactile reactivity of the contralateral perioral area, whereas unilateral vibrissae removal can decrease self-stimulation in the contralateral SN. The increased reactivity, expressed as the perioral biting reflex (113), seems to be an important aspect of aggressive behavior (18, 19, 59). Our results and those of others (4) indicate that the basal ganglia are involved in the control and elicitation of behavior relevant to attack behavior. These results are in agreement with the hypothesis, that the basal ganglia are involved in the control of sensory-motor gating or tuning (37,82). Therefore, this system may control sensorimotor reactivity to environmental stimuli, such as to stimulation of the perioral area. Electrical stimulation in the SN was also effective in producing self-stimulation behavior, indicating an overlap of neuronal mechanisms involved in motivation (gating) and reinforcement. Interestingly, trigeminal lesions can impair food and water intake (118), and bilateral lesions of the nigrostriatal DA system are known to result in severe adipsia and aphagia (63). Thus, a functional relationship between the trigeminal system and the basal ganglia can be hypothesized. This interaction hlvolves the control of behaviors as the), are governed, on the one hand, by their consequences (reinforcement of operant behavior) and on the other hand, by state-stimulus-response interactions; here, the basal ganglia may control the tuning to and~or sensitication to (gating 039 relevant environmental stimulation and, thus, the appropriate responses in the context of state variables ('hungers '), the total#), of which comprises so-called "motivated" behaviors. CONCLUSIONS The results summarized here indicate a functional interaction between the basal ganglia and orofacial sensory/motor systems. The importance of the links between these systems is demonstrated by our findings, on one hand, of profound influences of trigeminal manipulations (vibrissae removal, perioral stimulationJ on basal ganglia systems at the neuroanatomical and neurochem-

ical levels, and, on the other hand, that basal ganglia manipulations (stimulation, lesion) have effects on orofacial function. We have proposed that an important function of the basal ganglia system is that it serves to tune the nervous system to respond selectively to stimulation. That is, the nervous system is sensitized (tuned) to attend to, and thus, respond adaptively to particular properties of sensory input, depending on state ( " n e e d " ) variables. Then, from another point of view, we have shown also that unilateral removal of vibrissae leads to behavioral asymmetries and recovery therefrom with concomitant neuronal changes in the basal ganglia. Therefore, these findings provide strong support for the conclusion that hemivibrissotomy can be used as a model for the analysis of recovery from behavioral asymmetries and correlated neuronal changes. Interestingly, parallels in the effects of hemivibrissotomy and basal ganglia lesions (6-OHDA) were found on several levels, indicating that this trigeminal manipulation might mimic damage to the nigrostriatal dopamine system to a certain degree, and that it might even serve as an adjunct model for basal ganglia insult. Therefore, hemivibrissotomy provides a useful new model for the study of neuronal and behavioral aspects of recovery of function. The advantages over lesion-type models are obvious: I) The peripheral manipulation of cutting the vibrissae is easy to perform. 2) The manipulation is a noninvasive technique, which does not destroy brain tissue. It is painless and can even be applied in the unanesthetized animal. 3) The manipulation is reversible and, thus, allowing not only analysis of compensation for the deficit, but also of mechanisms of readjustment during regrowth of the vibrissae. 4) Both brain hemispheres are available for intraindividual analysis. Whereas it is well known that destroying even one single vibrissae follicle has profound effects on the whole trigeminalto-"barrel" system, it becomes clear that the usefulness of the trigeminal manipulation as a model system extends beyond the barrels. ACKNOWLEDGEMENTS This work was supported by grant Hu 306/6-2 from the Deutsche Forschungsgemeinschaft.

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