Muscle tone suppression and stepping produced by stimulation of midbrain and rostral pontine reticular formation

Stimulation of the midbrain retrorubral (RRN), ventral paralemniscal tegmental field (vFTP), reticular tegmental (TRN), and pedunculopontine tegmental (PPN) nuclei was found to produce bilateral suppression of muscle tone in the unanesthetized, decerebrate animal. The RRN is the most rostral area shown to produce such suppression. This muscle tone suppression was frequency- and intensity-dependent. At low stimulus intensities, bilateral suppression was produced at these sites. At higher current and frequency levels, 2 types of muscle responses were found, excitation in PPN and RRN and initial suppression followed by excitation in TRN and vFTP. The mean latency to muscle tone suppression was not significantly different in TRN (36.8 msec) and RRN (36.5 msec). However, muscle tone suppression latency was significantly shorter in vFTP (31 msec) and PPN (27.1 msec). In addition to muscle tone suppression, stepping-like activity could be elicited at the same points by consecutive train stimulations in PPN and single train stimulation in TRN and vFTP. Thus, systems producing atonia are colocalized with those producing locomotion. We hypothesize that the midbrain atonia regions control more caudal regions producing muscle tone suppression in REM sleep, and that the locomotor and atonia eliciting regions are normally coactivated during REM sleep.     

Parallel suppression of extensor muscle tone and respiration by stimulation of pontine dorsal tegmentum in decerebrate cat

This paper describes the pontine brainstem area responsible for the suppression of postural muscle tone as well as of respiration in acute precollicular-postmammillary decerebrate (mesencephalic) cats. Stimulation of the dorsal part of the pontine tegmentum (DTF) along the midline (P4-P7, H-5 to H-6) decreased the bilateral tone of the hindlimb extensor muscles and the diaphragmatic activity. Tonic discharges of the extensor muscles were suppressed by DTF stimulation and the suppression of muscle activity continued for more than 5 min after termination of the stimulation. In contrast, the suppression of the diaphragmatic activity, which resulted in apnea in some of the animals tested, resumed in spite of the continuation of the stimulation. However, the rebound augmentation of the diaphragmatic activity appeared immediately after the termination of the stimulation. The existence of such a rebound phenomenon suggested that the suppressive effects on the diaphragmatic activity persisted during the entire period of the stimulation. The recovery of respiratory movements during the stimulation led us to suggest that the strong respiratory drives emerge to overcome the exerted DTF-elicited suppressive effects on respiration. In the paralyzed and vagotomized animal, the DTF-elicited suppressive effects on phrenic neural discharges were minimal when the end-tidal pCO2 was set at a higher level than during spontaneous breathing.     

Descending inhibitory pathway responsible for simultaneous suppression of postural tone and respiration in decerebrate cats

The present study was performed in order to elucidate whether the suppressive effects on postural tone and respiration evoked by stimulation of the dorsal tegmental field (DTF) of the pons are relayed through the neurons in the ponto-medullary reticular formation. First, the DTF was functionally identified, and then a microelectrode was inserted into the caudal pontine and medullary reticular formation to investigate the distribution of the neurons monosynaptically activated by stimulation of the DTF. The monosynaptically activated neurons were distributed within the nucleus reticularis gigantocellularis (NRGc) in the caudal pons and medulla. The spinal cord (L1) was stimulated to study whether such monosynaptically activated neurons project to the spinal cord. Almost all the neurons monosynaptically activated by DTF stimulation were antidromically activated by spinal stimulation. This result indicates that the neurons in the NRGc activated monosynaptically by DTF stimulation send axons to the spinal cord. Tonic micro-stimulation was then delivered to the site in the NRGc, from which the monosynaptically driven units were recorded by DTF stimulation. The stimulation resulted in the parallel suppression of postural tone and respiration, similar to the suppressive effects elicited by DTF stimulation. The present study suggests the possible existence of a descending inhibitory pathway through the reticulospinal neurons in the NRGc responsible for parallel suppression of postural tone and respiration.     

Postural performance in decerebrated rabbit

It is known that animals decerebrated at the premammillary level are capable of standing and walking without losing balance, in contrast to postmammillary ones which do not exhibit such behavior. The main goals of the present study were, first, to characterize the postural performance in premammillary rabbits, and, second, to activate the postural system in postmammillary ones by brainstem stimulation. For evaluation of postural capacity of decerebrated rabbits, motor and EMG responses to lateral tilts of the supporting platform and to lateral pushes were recorded before and after decerebration. In addition, the righting behavior (i.e., standing up from the lying position) was video recorded. We found that, in premammillary rabbits, responses to lateral tilts and pushes were similar to those observed in intact ones, but the magnitude of responses was reduced. During righting, premammillary rabbits assumed the normal position slower than intact ones. To activate the postural system in postmammillary rabbits, we stimulated electrically two brainstem structures, the mesencephalic locomotor region (MLR) and the ventral tegmental field (VTF). The MLR stimulation (prior to elicitation of locomotion) and the VTF stimulation caused an increase of the tone of hindlimb extensors, and enhanced their responses to lateral tilts and to pushes. These results indicate that the basic mechanisms for maintenance of body posture and equilibrium during standing are present in decerebrated animals. They are active in the premammillary rabbits but need to be activated in the postmammillary ones.     

Suppression of attack behavior in cats by stimulation of ventral tegmental area and nucleus accumbens

Low frequency (6 pps) stimulation of ventral tegmental area (VTA) and nucleus accumbens (NA) produced EEG synchronization and suppressed attack behavior elicited by hypothalamic stimulation. Both quiet biting and affective attack with rage were suppressed. Autonomic and non-directed somatic motor components of the attack reaction were unaffected.High frequency (60 pps) stimulation of VTA failed to suppress any components of the attack reaction; high frequency stimulation of NA, however, did produce suppression of attack.Low frequency (6 pps) sensory stimulation, delivered by photic or lateral geniculate stimulation, produced EEG synchronization but failed to cause suppression of attack. These results indicate that low frequency stimulation per se does not cause suppression of ongoing behavior.This study demonstrates that VTA and NA, components of the mesolimbic dopamine system, are involved in the inhibition of emotional-type behaviors.     

Corticotropin-releasing factor mediated muscle atonia in pons and medulla

The dorsolateral pontine inhibitory area (PIA) and medial medullary reticular formation (MMRF) have been found to mediate the muscle atonia of REM sleep. Our previous studies have shown that acetylcholine (ACh) microinjection in the PIA and in the nucleus paramedianus of the medial medulla produces muscle atonia. Glutamate microinjection in both PIA and nucleus magnocellularis (NMC) of the medial medulla also produces muscle atonia. Since immunohistochemical studies have identified corticotropin-releasing factor (CRF) as a potential dorsolateral pontine and NMC transmitter, the present study was undertaken to determine whether this transmitter could produce suppression of muscle tone. Experiments were performed on unanesthetized, decerebrated cats. CRF was microinjected into points in the PIA and NMC at which electrical stimulation produced bilateral inhibition of muscle tone. We found that CRF produced a dose-dependent muscle tone suppression. At 10 nM concentration, the latency and duration of muscle inhibition produced by CRF injection were comparable with those ofl-glutamate, at 18.8 s and 4.1 min, respectively. This CRF-induced muscle inhibition was blocked by the CRF antagonist, α-helical [Glu²⁷]corticotropin-releasing factor 9–41 (CRF 9–41). Microinjection of CRF and non-NMDA agonists, kainate and quisqualate, into the same sites in PIA and NMC produced muscle atonia. Pontine sites at which CRF injection induces atonia are identical to those at which acetylcholine microinjection produces atonia. These results indicate that CRF may interact with glutamate and acetylcholine in the generation of muscle atonia.     

Units in tegmental nuclei responding to stimulation of gastric vagal and greater splanchnic fibers in the cat

The response of neurons in the ventral and dorsal tegmental nuclei during electrical stimulation of the gastric vagal fibers which serve the proximal stomach and the left greater splanchnic fibers were evaluated in chloralose-anesthetized cats. The mean latency of 181 gastric vagally evoked unitary responses recorded in the tegmental nuclei was 352.2 ms, whereas the latency of the left greater splanchnic-evoked tegmental response was significantly less (63.2 ms). The unitary responses to the gastric vagal and greater splanchnic fibers stimulation were bilaterally distributed in the ventral and dorsal tegmental nuclei. Convergence of the gastric vagal input from the proximal stomach and the left greater splanchnic input was observed in 151 units (83 percent). Stimulation of the greater splanchnic nerve usually resulted in a short latency excitation followed by an inhibitory effect on gastric vagally evoked responses. The results suggested that some convergent splanchnic inhibition of gastric vagally evoked responses was mediated via an interneuron. Projections from the nucleus tractus solitarius and the parabrachial nucleus to the tegmental nuclei were also identified electrophysiologically by direct microstimulation of the two former areas. The significant number of gastric vagal and splanchnic evoked unitary responses recorded in the ventral and dorsal tegmental nuclei suggested that they may serve as an important pontine site for processing of visceral information between the nucleus tractus solitarius and forebrain sites.     

Circling from intracranial morphine applied to the ventral tegmental area in rats

Crystalline morphine applied unilaterally to the ventral tegmental area in rats caused circling away from the side of application. This circling was reversed by naloxone (3 mg/kg) and blocked by pretreatment with pimozide (0.5 mg/kg). When tested in an open field the animals followed the perimeter of the enlcosure; thus the radius of the circles described was determined by environmental rather than central factors. Morphine induced forward locomotion in all four limbs; there were no major signs of postural asymmetry noted in the longitudinal axis of the animal's body. This study suggests that morphine activates a population of A-10 dopamine cells known to be involved in locomotion.     

Hypocretinergic facilitation of synaptic activity of neurons in the nucleus pontis oralis of the cat

The present study was undertaken to explore the neuronal mechanisms of hypocretin actions on neurons in the nucleus pontis oralis (NPO), a nucleus which plays a key role in the generation of active (REM) sleep. Specifically, we sought to determine whether excitatory postsynaptic potentials (EPSPs) evoked by stimulation of the laterodorsal tegmental nucleus (LDT) and spontaneous EPSPs in NPO neurons are modulated by hypocretin. Accordingly, recordings were obtained from NPO neurons in the cat in conjunction with the juxtacellular microinjection of hypocretin-1 onto intracellularly recorded cells. The application of hypocretin-1 significantly increased the mean amplitude of LDT-evoked EPSPs of NPO neurons. In addition, the frequency and the amplitude of spontaneous EPSPs in NPO neurons increased following hypocretin-1 administration. These data suggest that hypocretinergic processes in the NPO are capable of modulating the activity of NPO neurons that receive excitatory cholinergic inputs from neurons in the LDT.     

Influence of caloric labyrinthine stimulation on oesophageal motor function

There is incomplete understanding of the factors regulating smooth muscle primary peristalsis and of the reflux-associated transient lower oesophageal sphincter relaxations which are under postural control and which occur independently of swallowing. We examined the effects of labyrinthine stimulation on basal lower oesophageal sphincter tone, the frequency of non-swallow associated lower oesophageal sphincter relaxation and on the amplitude of primary peristalsis in the distal oesophagus. In 13 healthy volunteers, labyrinthine stimulation was produced by infusion of water at 10°C into the external auditory canal for 5 minutes, or until nausea ensued. A manometric sleeve catheter assembly monitored lower oesophageal sphincter pressure while side holes recorded pharyngeal, mid and lower oesophageal, and gastric pressures. Recordings were made during labyrinthine stimulation and during matched control periods. Caloric stimulation caused a minor but significant fall in mean basal lower oesophageal sphincter pressure of 14% (P = 0.04) and had no detectable effect on oesophageal peristalsis. In association with vomiting induced by labyrinthine stimulation in 3 subjects, lower oesophageal sphincter pressure fell rapidly by 61% (P = 0.03) from control levels and this inhibition persisted for up to 20 minutes after vomiting. For 10 minutes post-emesis, primary peristaltic amplitude was reduced by 50% (P < 0.001). Swallowing triggered a completely propagated peristaltic wave significantly less often during the post-emetic period. The rate of occurrence of transient lower oesophageal sphincter relaxations was not influenced significantly by labyrinthine stimulation. These findings are consistent with a functionally important role for the brainstem in the control of motor function of the smooth muscle oesophagus but do not permit distinction of a direct effect from a secondary humoral effect as part of the vomiting reflex.     

Excitability level-setting mechanisms in the pons: their behavioral support in decerebrate, reflex standing and freely moving, intact cats

In the acute precollicular-postmammillary decerebrate cat, stimulation of the mesencephalic locomotor region (MLR) induces "controlled locomotion" on a moving treadmill. Stimulation of the dorsal area and of the ventral area of the pons at its midline elicited a long-lasting decrease and an increase in the tone of the hindlimb extensor muscles, respectively. By selecting the stimulus strength according to the stimulus site, it was possible to set the extensor muscle tone level, that is the "background excitability" of the brain stem and the spinal cord. Locomotor effects induced by MLR stimulation were greatly modified by the set level of background excitability. When the background excitability was high, MLR stimulation evoked "spastic" locomotor movement, while "atonic" locomotor movement was evoked when it was low. Furthermore, stimulation of the ventral area alone also evoked "spastic" locomotor movement. During locomotion in intact cats, stimulation of the dorsal area evoked a series of postural changes. Within a few seconds from the beginning of stimulation, the cat ceased to walk, but maintained a standing posture with or without a locomotor figure. With continuation of this stimulation, it squatted and then lay down on the floor in a sequential manner. Stimulation of the ventral area of the pons evoked an almost opposite series of postural changes. Within a few seconds from the beginning of stimulation, the cat changed from a lying to a squatting posture, and then stood, started to walk and continued to walk during the period of stimulation. All these results demonstrate that an increase in extensor muscle tone and activation of the spinal stepping generator are not separate phenomena, and suggest that integration of neuronal mechanisms involved in the setting of the background excitability and in locomotor movement is a prerequisite for successful expression of locomotor behavior both in decerebrate and intact cats.     

Subpallidal outputs to the nucleus accumbens and the ventral tegmental area: anatomical and electrophysiological studies

The goal of this study was to investigate the functional organization of the subpallidal → accumbens direct and indirect feedback loops by both anatomical and electrophysiological methods. The results of the dextran-conjugated rhodamine injections into the subpallidal area has shown three distinct projections: (1) a substantial pathway from the subpallidal area to the ventral tegmental area, (2) a more diffuse rostral projection from the subpallidal area to the core area of the nucleus accumbens, and (3) a sparse pathway projecting rostrodorsally from the subpallidal area toward the thalamic regions. Electrical or chemical stimulation of the subpallidal region, which was studied by the axonal tracer, evoked inhibitory responses in the majority (60 and 80%, respectively) of the accumbens and ventral tegmental area neurons in a standard extracellular recording study. Less than13 of the accumbens or ventral tegmental area cells showed an increase in the mean firing rate. The majority (77.5%) of all responded neurons had a latency of less than 10 ms. Furthermore, injection of glutamate into the subpallidal area not only altered the firing pattern of the accumbens neurons, but also attenuated their excitatory responses elicited by the electrical stimulation of the ventral subiculum. Our results indicate that the subpallidal area plays a predominantly inhibitory role in the ventral tegmental area-accumbens-subpallidal circuitry, presumably by its GABAeroic projections, and may also modulate subicular input into the nucleus accumbens.     

Stimulation of ventral tegmental area and nucleus accumbens reduce receptive fields for hypothalamic biting reflex in cats

Stimulation of the ventral tegmental area (VTA) and nucleus accumbens (NA) suppressed attack behavior elicited by hypothalamic stimulation. Because the nondirected somatic motor and autonomic components of attack were not affected by VTA or NA stimulation, and previous work had demonstrated the importance of sensory guidance in attack, the mechanism for suppression was postulated to be on the sensory component of the attack reaction. We investigated the effects of VTA and NA stimulation on the biting reflex, one of the sensory-controlled components of hypothalamically elicited attack behavior. The receptive field for biting was measured during hypothalamic stimulation with and without concurrent VTA and NA stimulation. At stimulation parameters that inhibited attack, the extent of the receptive field was reduced. Thus, VTA and NA may produce inhibition of attack by acting on the sensory component of the response mechanism. We suggest that reduction of receptive fields is a mechanism by which behavioral inhibition is mediated in the central nervous system.     

The soleus late response elicited by transcranial magnetic stimulation reflects agonist-antagonist postural adjustment in the lower limbs.

OBJECTIVES: We studied the origin and underlying mechanism of the soleus late response (SLR) at a mean latency of 90 ms following transcranial magnetic stimulation. METHODS: The soleus primary response (SPR) and SLR were recorded from the soleus (SOL) muscle in 27 normal subjects under various conditions using a double-cone coil. We also tested 28 patients demonstrating neurological disorders with postural disturbance. RESULTS: The amplitude of the SPR gradually increased and its latency gradually decreased against the voluntary contraction (0-80%) of the tibialis anterior (TA) muscle. In contrast, the SLR amplitude was the greatest at a 20% TA contraction while the SLR latency was the shortest at a 40% TA contraction. The preactivation of SOL enhanced the SPR response but did not evoke the SLR. The SPR amplitude was significantly augmented while standing, however, the SLR amplitude tended to decrease. The SLR was never obtained following the stimulation of the brainstem, lumbar roots and peroneal nerve. The SLR was abnormal in patients with cerebellar ataxia and Parkinson's disease while the SPR was normal. CONCLUSIONS: A lack of any correlation between the SPR and SLR suggests that the SLR does not originate in the corticospinal tract. The SLR may thus be a polysynaptic response related to the postural control of the agonist and antagonist organization between the TA and SOL.     

Raphespinal and reticulospinal axon collaterals to the hypoglossal nucleus in the rat.

Neurons in the medial tegmental field project directly to spinal somatic motoneurons and to cranial motoneuron pools such as the hypoglossal nucleus. The axons of these neurons may be highly collateralized, projecting to multiple levels of the spinal cord and to many diverse regions at different levels of the neuraxis. We employed a double fluorescent retrograde tracer technique to examine whether medial tegmental neurons that project to the spinal cord also project to the hypoglossal nucleus. Injections of Diamidino Yellow into the hypoglossal nucleus and Fast Blue into the spinal cord produced large numbers of double labeled neurons in the medial tegmental field, particularly in the caudal raphe nuclei and adjacent ventromedial reticular formation. In these structures the number of neurons projecting to both the hypoglossal nucleus and the spinal cord was equivalent to the number of neurons projecting to multiple levels of the spinal cord observed in control animals. Fewer neurons projecting to both the hypoglossal nucleus and the spinal cord were observed in several other nuclei and subregions of the medial tegmental field, while almost no such neurons were observed in the lateral tegmental field or other pontomedullary structures. These results demonstrate that neurons of the caudal raphe nuclei and adjacent ventromedial reticular formation project to both the spinal cord and the hypoglossal nucleus, and support the concept that the diffuse projections to motoneuron pools from the medial tegmental field globally modulate both spinal and cranial somatic motoneuron excitability.     

Evidence for GABAergic projections from the tegmental nuclei of Gudden to the mammillary body in the rat

Immunochemical studies have demonstrated the presence of large numbers of cells immunoreactive for glutamic acid decarboxylase (GAD) within the dorsal and ventral tegmental nuclei of gudden. Following injections of Fluoro-Gold into the medial mammillary nucleus, a substantial proportion of the retrogradely labeled neurons within the ventral tegmental nucleus displayed GAD-like immunoreactivity. Conversely, electrolytic or excitotoxic lesions of the ventral tegmental nucleus produced a large decrease in the number of fibers and terminals immunoreactive for GAD within the medial mammillary nucleus. In contrast, electrolytic lesions of the dorsal tegmental nucleus were found to produced a large decrease in GAD-like immunoreactivity which was restricted to the lateral mammillary nucleus. Control lesions placed caudal to the dorsal tegmental nucleus were without effect. These findings suggest that the dorsal and ventral nuclei send a substantial, topographically organized, GABAergic input to the mammillary body.     

Effects of gastric electrical field stimulation with long pulses on gastric emptying in dogs

The aim was to investigate the effects of electrical field stimulation (EFS) with long and short pulses on gastric emptying, gastric contractility and vagal activity in dogs. Sixteen dogs were equipped with a duodenal cannula, electrodes and strain gauges (10 dogs) in the stomach. Each dog was fed with Ensure and gastric effluent was collected from the cannula. Electrical stimulation was applied via two electrodes (about 12 cm apart, one in the corpus and the other in the antrum) with long pulses (a frequency of 6 cycles min-1, pulse amplitude of 6 mA and width of 100 ms) in 10 dogs and with short pulses (frequency of 30 Hz and pulse width of 300 micros) in six dogs. The electrocardiogram was also recorded and heart rate variability was derived to assess the vagal activity. It was found that: (i). EFS with long pulses did not alter gastric emptying during stimulation but increased gastric emptying during the 45 min immediately after stimulation; (ii). EFS with long pulses increased gastric contractility in both proximal and distal antrum during and after the stimulation; (iii). EFS with long pulses resulted in an increase in vagal tone during the 45 min immediately after stimulation. However, there is no difference during the 45 min period of stimulation; (iv). EFS with short pulses had no effect on gastric emptying. We concluded that long pulse gastric electrical field stimulation with one electrode in the corpus and the other electrode in the antrum has postponed effects on gastric emptying of liquid, gastric contractility and vagal activity.     

Discharges of neurons in the midpontine dorsal tegmentum of mesencephalic cat during locomotion

Discharges of neurons in the midpontine dorsal tegmental field (DTF neurons) were recorded and analyzed during locomotion and were compared with those of reticulospinal neurons (RS neurons) located lateral to the DTF area. The conduction velocity of the descending axon of the DTF neurons was significantly smaller than that of the RS neurons. During locomotion, the DTF neurons showed a tonic increase in the discharge rate. In contrast, the discharge rate of the RS neurons showed cyclic modulation in step with locomotion.     

The soleus late response elicited by transcranial magnetic stimulation reflects agonist–antagonist postural adjustment in the lower limbs

Objectives: We studied the origin and underlying mechanism of the soleus late response (SLR) at a mean latency of 90 ms following transcranial magnetic stimulation.Methods: The soleus primary response (SPR) and SLR were recorded from the soleus (SOL) muscle in 27 normal subjects under various conditions using a double-cone coil. We also tested 28 patients demonstrating neurological disorders with postural disturbance.Results: The amplitude of the SPR gradually increased and its latency gradually decreased against the voluntary contraction (0–80%) of the tibialis anterior (TA) muscle. In contrast, the SLR amplitude was the greatest at a 20% TA contraction while the SLR latency was the shortest at a 40% TA contraction. The preactivation of SOL enhanced the SPR response but did not evoke the SLR. The SPR amplitude was significantly augmented while standing, however, the SLR amplitude tended to decrease. The SLR was never obtained following the stimulation of the brainstem, lumbar roots and peroneal nerve. The SLR was abnormal in patients with cerebellar ataxia and Parkinson's disease while the SPR was normal.Conclusions: A lack of any correlation between the SPR and SLR suggests that the SLR does not originate in the corticospinal tract. The SLR may thus be a polysynaptic response related to the postural control of the agonist and antagonist organization between the TA and SOL.     

Opioid receptor subtypes associated with ventral tegmental facilitation of lateral hypothalamic brain stimulation reward

Rats were trained to lever-press for lateral hypothalamic electrical stimulation, and tested following ventral tegmental microinjections of morphine, delta ([D-Pen2,D-Pen5]enkephalin: DPDPE), or kappa (U-50, 488H) receptor agonists or saline. Across the range of effective stimulation frequencies, morphine (8 nmol) and DPDPE (8 nmol) reduced the current necessary to sustain responding, while U-50,488H (8 nmol) had no effect. Naloxone (1 mg/kg) blocked the effects of morphine and DPDPE. Since each of these opioids facilitates eating induced by stimulation of the lateral hypothalamus, but only the mu and delta agonists facilitate brain stimulation reward, it would appear that ventral tegmental kappa receptors are linked to circuit elements which play a role in eating but not lateral hypothalamic brain stimulation reward. Ventral tegmental mu and delta receptors, on the other hand, appear to be linked to circuit elements involved in both behaviors.