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

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 tuberomammillary nucleus. The involvement of dopaminergic mechanisms was indicated by results showing that dopaminergic 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 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.     

Behavioral and neurochemical indices of barrel cortex-basal ganglia interaction.

Previous experiments from our laboratory have shown a wide variety of time-dependent lateralized changes in behavior and nigrostriatal function following unilateral manipulation of the mystacial vibrissae of rats. The present experiment investigated the effects of unilateral radiofrequency lesion of the cortical vibrissae representation (the barrel fields) in light of these results. We measured lateralized changes in behavior as well as tissue monoamines in neostriatum and substantia nigra, between 1 and 16 days post-lesion. Short-term asymmetries in exploratory behavior (thigmotactic scanning) and neostriatal serotonin metabolism that lasted up to day 6 were seen. In substantia nigra, time-related asymmetries in dopamine concentrations were found with higher ipsilateral values on day 3 and higher contralateral values on day 6. After day 6, the animals had recovered from these acute effects and thereafter, neostriatal dopamine metabolism became asymmetrical. Also during this time, they showed a directional bias in spontaneous and apomorphine-induced turning. Finally, neostriatal serotonin was bilaterally elevated on day 16. These results parallel some of the effects previously seen following unilateral removal of the vibrissae, indicating that the barrel cortex is a critical link in the functional interaction between the vibrissae and basal ganglia.     

Activation and lateralization of sensorimotor field for perioral biting reflex by intranigral GABA agonist and by systemic apomorphine in the rat

In Experiment 1 unilateral injection of the GABA agonist, muscimol (20 ng in 0.1 μl saline) into the substantia nigra (SN) of rats elicited contraversive turning and a correlated transient asymmetry in responsiveness to tactile stimulation of the mouth area. On the side of the face contralateral to the injected SN they responded stronger than on the ipsilateral side, and, furthermore, they responded to tactile stimulation with a withdrawal of the lip, followed by a vigorous biting of the probe. In Experiment 2, systemic injection of apomorphine also sensitized the perioral biting response to tactile stimulation. Unilateral injection into the SN of 8 μg 6-OHDA blocked this response to stimulation of the side of the face ipsilateral to the lesion. The experiments demonstrate: (1) pharmacological control of sensory-motor neglect, the asymmetry being determined by the direction of turning; and (2) a possible neuropharmacological basis of the perioral biting reflex, which may be related to certain types of aggressive behaviors.     

Neuronal plasticity in the nigrostriatal system of the rat after unilateral removal of vibrissae

The vibrissae of rats were shaved from one side of the face daily for 10 days. To see whether or not this treatment had an effect on crossed and uncrossed striatal afferent connections from the midbrain, the tract tracer horseradish peroxidase was applied to the caudate-putamen on day 11. When the tracer was deposited on the side opposite the vibrissae removal, more labeled cells were found in the contralateral substantia nigra than when it was applied on the same side as the vibrissae removal, or placed in animals with intact vibrissae. Unilateral removal of vibrissae did not affect uptake of the tracer by the cells which give rise to the homolateral nigrostriatal projections. These changes in HRP labeling in the crossed projection from the substantia nigra were seen after 10 days of unilateral removal of the vibrissae; i.e., at a time when the animals have had opportunity to learn to compensate for vibrissotomy-induced behavioral asymmetries.     

Release of dopamine evoked by electrical stimulation of the motor and visual areas of the cerebral cortex in both caudate nuclei and in the substantia nigra in the cat

The effects of unilateral focal electrical stimulation of the deep cerebellar nuclei on the activity of the nigrostriatal dopaminergic neurons on both sides of the brain were examined in halothane anaesthetized cats. For this purpose, push-pull cannulae were inserted into both caudate nuclei and both substantia nigrae, and the release of [3H] dopamine ([3H]DA) continuously formed from [3,5-3H]L-tyrosine was estimated in superfusates. The unilateral electrical stimulation of the right cerebellar dentate nucleus induced a long-lasting increase in the release of [3H]DA in the left caudate nucleus and a simultaneous decrease in the release of [3H]transmitter in the right caudate nucleus. These changes were associated with opposite fluctuations in the release of [3H]DA from the corresponding substantia nigrae. Thus, the electrical stimulation of the right dentate nucleus induced a pronounced decrease in the release of the [3H]-amine in the [3H]transmitter in the corresponding substantia nigra, whereas the activity of the contralateral substantia nigra, whereas the release in the ipsilateral substantia nigra was simultaneously increased. In contrast, the unilateral electrical stimulation of the right cerebellar fastigial nucleus resulted only in an increased release of [3H]DA in the ipsilateral (right) caudate nucleus, associated with a decreased release of the [3H]transmitter in the corresponding substantia nigra, whereas the activity of the contralateral (left) dopaminergic system was not significantly affected. These results support a direct functional interaction between the cerebellum and the basal ganglia. They also suggest that the release of DA from dopaminergic axonal terminals is inversely correlated to the extent of the transmitter release from dendrites.     

Unilateral 6-hydroxydopamine lesions of dopamine neurons produce bilateral self-stimulation deficits

Sixteen rats, which had electrode implants in each hemisphere which generated comparable self-stimulation rate-intensity functions, were used in this study. Eight of the rats received unilateral 6-hydroxydopamine injections into the substantia nigra pars compacta, which produced severe unilateral losses of dopamine and were effective in generating apomorphine-induced turning away from the injected hemisphere. Of the remaining 8 rats, 5 received unilateral 6-hydroxydopamine lesions aimed at the ventral tegmental area and 3 were give vehicle injections. The vehicle injections were without effect on self-stimulation and the ventral tegmental injections had an overall transient facilitative effect on self-stimulation. The 6-hydroxydopamine lesions of the pars compacta, however, had variable effects. In some rats there was a marked bilateral reduction in self-stimulation over 8 weeks; whereas, there was little, if any, effect in other rats. The rats which sustained the bilateral deficits also sustained the greatest unilateral loss of dopamine. The unilateral 6-hydroxydopamine lesions of the pars compacta consistently blocked the facilitative influence of 0.5 mg/kg of D-amphetamine on self-stimulation bilaterally, and this effect persisted over 8 weeks of postoperative testing. These results were considered supportive of a response rather than reinforcement role for dopamine in the mediation of self-stimulation behavior.     

Prefrontal cortex lesions attenuate substantia nigra self-stimulation: a reward summation analysis

A curve-shift paradigm was used to assess the effects of lesions of the prefrontal cortex on self-stimulation from electrode sites in the substantia nigra. Combined lesions of the medial and sulcal cortical regions severely attenuated substantia nigra self-stimulation. These results are discussed in the context of the frontal cortex and the substantia nigra as belonging to a reinforcement system that is largely independent of the medial forebrain bundle system.     

Effect of lesions of the ventromedial nucleus of the thalamus on cerebral metabolism: experimental study in the rat using the 14C-deoxyglucose method

Local cerebral glucose utilization (LCGU) was studied quantitatively in awake rats one week and one month following unilateral electrolytic lesion of the ventromedial thalamic nucleus (VM). Significant decrease in LCGU were observed in the ipsilateral cortex as well as in some contralateral cortical areas and bilateral subcortical structures. The modifications by the VM lesion, of the metabolic activations induced by electrical stimulation of substantia nigra pars reticulata (SNR, main afference of the VM) were investigated also. Results suggest that VM is an important relay nucleus on the pathways directed from one SNR towards ipsilateral corticostriatal system and contralateral thalamus and basal ganglia. Finally, one month following the VM lesion a recovery of metabolic activations induced by SNR stimulation was observed whereas basal glucose consumption remained decreased.     

Substantia nigra unit responses to trigeminal sensory stimulation.

The influence of trigeminal sensory stimulation on substantia nigra units was investigated in cats anesthetized with chloralose. Low-intensity electrical stimulation was applied to primary sensory afferents (inferior dental nerve, trigeminal mesencephalic nucleus), and a high proportion of substantia nigra units showed evoked changes in activity. Responses were typically excitatory. Peripheral receptive fields were assessed by applying natural mechanosensory and also electrical stimulation to the face, perioral, and intraoral tissue. Substantia nigra units responded to light tactile stimuli; the majority of the receptive fields were bilateral, and all subsumed at least two branches of the trigeminal nerve. Latency considerations suggest that these sensory responses were not conveyed via striatonigral connections. The findings have implications in relation to the role of the basal ganglia, in general, in oropharyngeal sensorimotor processes.     

Evaluation of stressor effects on intracranial self-stimulation from the nucleus accumbens and the substantia nigra in a current intensity paradigm

The effect of uncontrollable footshock was evaluated in animals responding for intracranial self-stimulation from the nucleus accumbens and the substantia nigra (pars compacta) in a descending current intensity paradigm. Responding for brain stimulation from the nucleus accumbens was found to be affected by the stressor at the upper end of the rate-intensity curve. In contrast, responding for brain stimulation from the substantia nigra was unaffected by the stressor at any of the current intensities employed. The variations of responding for self-stimulation from the nucleus accumbens were unrelated to alterations of locomotor activity or rearing. It is suggested that stressor-provoked reductions of responding for intracranial self-stimulation are not a result of the brain stimulation taking on aversive properties, but rather reflect a reduction in the reinforcing or motivational value associated with the stimulation.     

Self-stimulation at the lateral hypothalamus and locus coeruleus after specific unilateral lesions of the dopamine system

A group of rats was trained to press levers for electrical stimulation from bipolar electrodes aimed at the lateral hypothalamus (LH), and another group was trained to self-stimulate from electrodes in the locus coeruleus (LC). All rats in both groups were subjected to unilateral injections of 6-hydroxydopamine into the substantia nigra and midbrain ventral tegmentum. The lesions produced profound depletions of dopamine from the ipsilateral frontal cortex, nucleus accumbens/olfactory tubercle, and corpus striatum. Pretreatment with desmethylimipramine prevented loss of noradrenaline in excess of that caused by electrode implantation. The destruction of the dopamine projections produced a persistent and pronounced deficit in intracranial self-stimulation from ipsilateral electrodes in both the LH and LC groups, but only transient effects on self-stimulation from contralateral electrodes at these sites. These results suggest that an intact dopamine system is required for the expression of self-stimulation behaviour.     

Lateralized wall-facing versus turning as measures of behavioral asymmetries and recovery of function after injection of 6-hydroxydopamine into the substantia nigra

The tendency of a rat to approach the wall of an open-field and to travel along the perimeter of the field (termed as "peritaxis" or "wall-facing") is affected by unilateral removal of the vibrissae. Peritaxis is lateralized by hemivibrissotomy. The finding that the dopamine agonist apomorphine reversed the direction of wall-facing asymmetry after 10 days of vibrissae removal suggested a link between this sensorimotor asymmetry and dopamine transmission. The present experiment examined the influence of a unilateral injection of 6-hydroxydopamine into the substantia nigra on peritaxis and compared this behavioral measure with turning behavior as an index of lesion-induced sensorimotor asymmetries and of recovery of function. The lesion of the substantia nigra reduced wall-facing with the side contralateral to the lesion to near-zero values. During the first week after the injection animals with incomplete dopamine depletion recovered from this asymmetry. The changes in wall-facing behavior were paralleled by turning asymmetries. Wall-facing was at least as sensitive to application of amphetamine and apomorphine as turning behavior. We concluded that lateralized wall-facing, or peritaxis, can serve as a useful index of dysfunction in the nigrostriatal dopamine system and the influence of catecholaminergic drugs. Wall-facing can also serve as a measure of recovery of function.     

Response properties of the perioral reflex in parkinson''s disease

Analyses of the response magnitudes of the short-latency perioral reflex were made in a group of Parkinson disease patients and control subjects. As a group, the parkinsonian subjects manifested reflex magnitudes which were increased relative to normal. For low-acceleration, mechanical displacements of perioral tissue (less than 500 cm/s2), the perioral reflex was not elicited in normal controls. However, such low-acceleration stimuli did elicit the perioral reflex in more than half of the parkinsonian subjects studied. These findings are consistent with earlier findings of increased sensitivity of facial and perioral reflexes associated with disturbances of the basal ganglia. These results contribute to the understanding of specific stimulus-response characteristics of the facial reflex and the role of the basal ganglia in orofacial motor control. The finding of increased sensitivity to mechanical stimuli in Parkinson's disease supports the hypothesis of basal ganglia gating or regulation of afferent information.     

Decreased resting membrane conductance as the proximate cause of burst modulation by an identified interneuron inHelix

Morphological, electrophysiological and behavioral studies were carried out in cats after unilateral kainic acid injection in the substantia nigra. A forced contralateral head turning and compulsive circling was observed after surgery. Fifteen days after, when asymmetry disappeared, apomorphine induced an ipsilateral head and body turning, that was blocked by haloperidol. The percentage of turning, after electrical stimulation in the superior colliculus or pulvinar-lateralis posterior complex, was affected by substantia nigra lesion. This work demonstrates that the nigro-pulvinar-lateral posterior and the nigrotectal projection modulate the capability of electrical stimulation of the target structures to elicit turning, and after unilateral substantia nigra lesion, two opposite directions of asymmetry appear, which are time-dependent and modulated by different neurotransmitters.     

Region-specific reductions of intracranial self-stimulation after uncontrollable stress: Possible effects on reward processes

Rates of responding for intracranial self-stimulation from the medial forebrain bundle, nucleus accumbens and substantia nigra were evaluated in mice that had been exposed to either escapable shock, yoked inescapable shock or no shock treatment. Whereas performance was unaffected by escapable shock, marked reductions of responding from the medial forebrain bundle and nucleus accumbens were evident following the uncontrollable shock treatment. Responding from the substantia nigra was unaffected by the stress treatment. Uncontrollable shock is thought to reduce the rewarding value of responding for electrical brain stimulation from those brain regions in which stressors are known to influence dopamine activity.     

Differential effects of morphine and D-amphetamine on self-stimulation from closely adjacent regions in rat midbrain

The effects of morphine were investigated on self-stimulation from numerous electrode placements in the area of the substantia nigra or in the ventral half of mesencephalic central gray matter. Before pharmacological testing, current intensity was reduced to yield stable, submaximal rates of self-stimulation. Rats were then injected daily with morphine for 10 days, and were tested three hours after injection. Between days 5 and 10 of treatment, many rats self-stimulated at more than 150% of baseline, but some others reduced self-stimulation to as little as 3% of baseline. Histological evaluation revealed that morphine facilitated self-stimulation when the electrode tip was located more than 0.3 mm from substantia nigra or more than 0.2 mm from the midline of central gray. In rats with electrode tips closer to substantia nigra or to the midline of central gray, morphine often reduced or failed to alter self-stimulation rates. The effects of a low dose of D-amphetamine (0.1 mg/kg) were investigated on electrode placements in the substantia nigra area. Placements close to the dorsal border of substantia nigra yielded less facilitation of self-stimulation by D-amphetamine than did placements located more dorsally or medially. Possible catecholaminergic substrates of these differential effects are discussed.     

Apomorphine reverses direction of asymmetry in facial scanning after 10 days of unilateral vibrissae removal in rat: vibrissotomy-induced denervation supersensitivity?

Sensorimotor asymmetries of hemivibrissotomized rats were investigated in an open field. To examine possible behavioral plasticity after unilateral removal of the vibrissae, we compared two groups of rats which had experienced the sensory imbalance for different durations. One group was shaved on one side of the face daily for 10 days before behavioral testing (group 10-Days). The other group was first shaved 4 h prior to the behavioral testing and was sham-shaved for the preceding 10 days (group 4-H). On day 11, the undrugged behavior was examined, and then, one hour later, the behavior induced by apomorphine (0.75 mg/kg, s.c.) was analyzed. In the undrugged state both groups tended to scan the walls of the enclosure with the vibrissae side of the face. After injection of apomorphine, the 4-H group also scanned the walls preferentially with the vibrissae side. In contrast, the 10-Days group reversed the scanning asymmetry under the influence of this drug. That is, animals in this latter group now preferred to scan the walls with the shaved side of the face. These findings are suggestive of a plasticity in dopamine transmission subsequent to unilateral removal of vibrissae. The reversal in direction of asymmetry under apomorphine of the 10-Days group is reminiscent of the apomorphine-induced reversal in sensorimotor asymmetries found after unilateral 6-hydroxydopamine lesion of the substantia nigra, which has been attributed to dopamine receptor supersensitivity.     

经颅重复性低频磁刺激后大鼠苍白球及黑质HMW MAP-2表达的变化

观察经颅重复性低频磁刺激 (rTMS)对大鼠基底节输出结构高分子量微管相关蛋白 (HMWMAP 2 )阳性标记变化的影响。采用磁刺激器给予大鼠头部 1Hz,10 0mT的重复性刺激 ,然后用免疫组织化学ABC法检测苍白球外侧部 (GPe)、腹侧苍白球 (VGP)及黑质 (SN)等部位HMWMAP 2的免疫阳性产物。较之对照组动物 ,rTMS后苍白球外侧部和腹侧苍白球HMWMAP 2免疫反应物未见减少 ,且染色明显增强 ,阳性标记的纤维增粗 ;黑质特别是黑质网状部 (SNR)亦可见到染色明显增强的HMWMAP 2免疫标记出现。rTMS能够使基底节输出结构中HMWMAP 2的表达发生变化 ,推测可能通过树突重塑而致突触传递的变化等而发挥其临床治疗作用。     

Raclopride or high‐frequency stimulation of the subthalamic nucleus stops cocaine‐induced motor stereotypy and restores related alterations in prefrontal basal ganglia circuits

Motor stereotypy is a key symptom of various neurological or neuropsychiatric disorders. Neuroleptics or the promising treatment using deep brain stimulation stops stereotypies but the mechanisms underlying their actions are unclear. In rat, motor stereotypies are linked to an imbalance between prefrontal and sensorimotor cortico‐basal ganglia circuits. Indeed, cortico‐nigral transmission was reduced in the prefrontal but not sensorimotor basal ganglia circuits and dopamine and acetylcholine release was altered in the prefrontal but not sensorimotor territory of the dorsal striatum. Furthermore, cholinergic transmission in the prefrontal territory of the dorsal striatum plays a crucial role in the arrest of motor stereotypy. Here we found that, as previously observed for raclopride, high‐frequency stimulation of the subthalamic nucleus (HFS STN) rapidly stopped cocaine‐induced motor stereotypies in rat. Importantly, raclopride and HFS STN exerted a strong effect on cocaine‐induced alterations in prefrontal basal ganglia circuits. Raclopride restored the cholinergic transmission in the prefrontal territory of the dorsal striatum and the cortico‐nigral information transmissions in the prefrontal basal ganglia circuits. HFS STN also restored the N‐methyl‐d ‐aspartic‐acid‐evoked release of acetylcholine and dopamine in the prefrontal territory of the dorsal striatum. However, in contrast to raclopride, HFS STN did not restore the cortico‐substantia nigra pars reticulata transmissions but exerted strong inhibitory and excitatory effects on neuronal activity in the prefrontal subdivision of the substantia nigra pars reticulata. Thus, both raclopride and HFS STN stop cocaine‐induced motor stereotypy, but exert different effects on the related alterations in the prefrontal basal ganglia circuits.     

Intracranial self-stimulation: mapping against the lateral boundaries of the dopaminergic cells of the substantia nigra

The lateral boundaries of the substantia nigra, zona compacta, were mapped for intracranial self-stimulation in rats. The boundaries of the positive region for self-stimulation were found to correspond to the boundaries of the dopaminergic cell layer. These data strengthen the view that rewarding stimulation in this system activates the tegmental dopaminergic celss or, more likely, their immediate afferents.