Locomotion and head scanning initiated by hypothalamic stimulation are inversely related.

Stimulation in the hypothalamus elicits locomotor stepping. Before stepping is initiated, head scanning movements occur. We determined the relationships between the latency of locomotor initiation and the number, extent and direction of the head scanning movements. Chronic stimulation electrodes were stereotaxically implanted in and around the hypothalamus of 29 rats. Under awake conditions, 38 locomotor sites were tested in a runway apparatus. Behaviors occurring between the onset of stimulation and the first step were recorded on videotape. Points on the rat were digitized at sampling rate of 6 Hz to produce measures of head angles in the vertical, horizontal, and sagittal planes. The priming paradigm was used with a current selected for each site that was minimally sufficient to produce reliable stepping. In trials at approximately 1-min intervals, a 5-s train of stimulation (the control) was followed by a second train (the test) delivered 5-20 s later. Initiation latency on control trains was strongly correlated with head movement measures. Vertical and lateral head movements were independent of one another. Together, their frequency and extent accounted for 85% of the variance in locomotor initiation latencies. In effective priming trials, when locomotor initiation latencies were reduced on the test train, the frequency and extent of vertical and lateral head movements were also reduced. In non-effective priming trials, when latencies were not reduced, head movements were not reduced. Head scanning and locomotor initiation reflect reciprocal processes.

GABA injected into the anterior dorsal tegmentum (ADT) of the midbrain blocks stepping initiated by stimulation of the hypothalamus.

Previous work showed that the activity rates of certain neurons in the anterior dorsal tegmentum (ADT) of the midbrain correlated with the onset of stepping elicited by hypothalamic stimulation. This study determined if reversible inactivation of the ADT would block locomotion elicited by hypothalamic stimulation of anesthetized rats (urethane, 800 mg/kg). GABA (concentrations 0.25-1.0 mg/microl in saline) were injected in 52 sites in 21 rats. GABA at volumes of 0.1 or 0.2 microl blocked hindlimb stepping in 18 cases. Locomotor blocks occurred within 5 min of the injection, and typically recovered within 10-20 min. The effective blocking sites were clustered around the interstitial nucleus of the medial longitudinal fasciculus. Sites more dorsal and more anterior were not as effective as sites in and ventral to this nucleus. The data are consistent with a role for the ADT of the midbrain in locomotor initiation.

Coordination of neck and hindlimb extension during the initiation of locomotion elicited by hypothalamic stimulation.

We tested the hypothesis that during the initiation of stepping elicited by hypothalamic stimulation, hindlimb extension was coordinated with head extension in the sagittal plane. Chronic stimulation electrodes (monopolar stainless-steel, 125 microm diameter) were implanted bilaterally into the perifornical hypothalamus of anaesthetized rats (N = 15) under stereotaxic control. Under freely moving and awake conditions, 18 sites which reliably elicited forward locomotion at a latency of approximately 3 s were tested in a videotaping session. The locomotor stimulation was a constant current train of 5 s duration composed of biphasic pulses at 40-50 Hz. The videotape records were digitized at a sampling rate of 6 Hz for seven points on the rat: Nose, pinnae, midpoint of inter-pinnae line, right forepaw, right hindpaw and base of tail. A characteristic pattern of coordinated movements preceded, by approximately 0.5 s, the execution of the first locomotor step. The pattern included a movement of the pelvis in the anterior or superior direction that was produced by hindlimb extension and an extension of the neck forward along the sagittal plane. There was considerable flexibility in this pattern, but it was invariant to the extent that it occurred at a variety of latencies and after several types of head movements. Associated with the coordinated extensions of the neck and hindlimbs was a lowering of the head angle which had a more variable time course. These data indicate that there is significant coupling between the systems that produce hindlimb extension and control head position when the rat prepares to step.

Priming of locomotor initiation by electrical stimulation in the hypothalamus and preoptic region in the anesthetized rat.

Electrical stimulation at a locomotor site can prime (i.e., shorten the latency to initiate) stepping elicited by subsequent stimulation of the same or a different site. We tested for the priming effect in representative sites along the medial forebrain bundle, and determined if its magnitude showed regional differences. Rats (n = 20) were anesthetized with Nembutal and held in a stereotaxic apparatus over a wheel. Stepping was detected by accelerometers attached to the hindlimbs. Priming and test trains of stimulation (0.5-ms cathodal pulses, 50 Hz, 25-75 microA, 7-9-s train duration) separated by 20 s were delivered every 90 s. When the priming and test stimulations were applied to the same site, the priming effects were similar along the entire extent of the medial forebrain bundle. When the priming and test sites were different, the priming effect depended on their relative positions. Anterior stimulation primed posterior sites at magnitude comparable to those produced by stimulating the same posterior site. Posterior stimulation primed anterior sites at a level half of that produced by stimulation of the same anterior site. This pattern was found for priming and test sites that were ipsilateral and contralateral. Priming is a general and robust phenomenon with properties that may be useful for studying locomotor initiation pathways.

Neural activity in the midbrain correlated with hindlimb extension initiated by locomotor stimulation of the hypothalamus of the anesthetized rat.

Midbrain neuronal activity that correlated with the initiation of locomotion produced by hypothalamic stimulation was studied. Locomotion was elicited by electrical stimulation in the perifornical hypothalamus of 59 rats anesthetized with Nembutal. The first hindlimb extension indexed stepping onset. Single and multiple neurons were recorded ipsilateral to the stimulation site at 2230 sites in the anterior and posterior midbrain. To classify responses, activity patterns averaged around stimulation onset and around the extension onset were examined. Responses with specific correlations to extension onset were Type I; responses not specifically related to the extension onset were Type II. In the anterior midbrain, 6% of sites were Type I and 8% were Type II. The larger Type I responses were frequent in the anterior tegmentum near the central gray. The relative frequency of Type I patterns in the posterior ventrolateral tegmentum was similar. Other regions showed relatively more Type II responses; they included the ventral tegmental area, and the regions near the superior cerebellar peduncle and the posterior central gray. Regional population profiles showed that during the initiation of locomotion, neurons in the posterior peribrachial region responded early and neurons in the anterior dorsal and the posterior ventrolateral tegmentum responded later. The initiation-related activity of Type I neurons in the anterior and posterior midbrain tegmentum suggest that they warrant further study for a role in locomotor initiation.

Preoptic and hypothalamic neurons and the initiation of locomotion in the anesthetized rat.

Despite its insensate condition and apparent motoric depression, the anesthetized rat can provide useful information about the systems involved in locomotor initiation. The preparation appears to be particularly appropriate for the study of the appetitive locomotor systems and may be more limited for the study of the circuits involved in exploratory and defensive locomotion. In the anesthetized rat, pharmacological evidence indicates that the preoptic basal forebrain contains neurons which initiate locomotor stepping. Mapping with low levels of electrical stimulation indicates, but does not prove, that a region centered in the lateral preoptic area might be the location of these neurons. Several lines of evidence indicate that locomotor stepping elicited by electrical stimulation of the hypothalamus is mediated by neurons in the perifornical and lateral hypothalamus. Locomotor effects of hypothalamic stimulation persist in the absence of descending fibers of passage from the ipsilateral preoptic locomotor regions but are severely impaired by kainic acid lesions in the area of stimulation. Injections of glutamate into the perifornical and lateral hypothalamus elicit locomotor stepping at short latencies. Anatomical evidence suggests that the two regions are components of a network for appetitive locomotion. The recognition that multiple systems initiate locomotion both clarifies and complicates the study of locomotion. It provides a framework that incorporates disparate findings but it also underscores the need for increased attention to behavioral issues in studies of locomotor circuitry.

Locomotor sites mapped with low current stimulation in intact and kainic acid damaged hypothalamus of anesthetized rats.

To determine whether local neurons mediated the locomotor effects of electrical stimulation of the lateral hypothalamus, kainic acid injections (0.5-1.25 micrograms), intended to destroy neural somata as opposed to fibers of passage, were made unilaterally in the tuberal-posterior hypothalamus of 22 rats. The area of lesion and its contralateral homolog were mapped for locomotor stepping sites in Nembutal-anesthetized rats mounted in a stereotaxic apparatus such that locomotor stepping rotated a wheel. Stimulation (25 and 50 microA, 50 Hz, 0.5-ms cathodal pulses, 10-s trains) was delivered through 50-80 microns glass pipettes filled with 2 M saline. Contralateral to the lesion, locomotor stepping sites were common in the perifornical lateral and medial hypothalamus and less dense in the zona incerta. On the side of the kainic-acid lesion, locomotor sites were generally absent in the central part of the damaged area. If they did appear within the area of lesion, they tended to be near the border with intact tissue. In a few cases, locomotor stepping sites were found centrally located in the lesion amidst widespread loss of somata. In four rats, additional maps of anterior locomotor regions in the preoptic area ipsilateral to the lesion suggested that their descending fibers were largely spared by the kainic lesions. Local neurons appear to be major contributors to the locomotion elicited by electrical stimulation of the lateral hypothalamus, but fibers of passage may also participate.

Locomotor stepping initiated by glutamate injections into the hypothalamus of the anesthetized rat.

Glutamate (50 mM, 50 nl) injected into the tuberal and posterior hypothalamus was tested for capacity to elicit locomotor stepping. Rats (n = 23) were anesthetized with Nembutal and suspended by a sling in a stereotaxic apparatus such that locomotor stepping rotated a wheel. In 61 of 275 sites tested, stepping was initiated by glutamate injections within 60 s. Positive sites were widespread and contained in the lateral hypothalamus, the perifornical area, the dorsomedial nucleus, and the zona incerta. The perifornical and lateral hypothalamic sites were most likely to have locomotor responses and the shortest latencies. These findings indicate that selective activation of hypothalamic neurons as opposed to fibers of passage can initiate locomotion.

Latency to initiate locomotion elicited by stimulation of the diencephalon positively correlates in awake and anesthetized rats.

Locomotor stepping can be elicited by brain stimulation at various diencephalic sites under moderate levels of Nembutal. This study determined if locomotor initiation measured under anesthesia provides a valid measure of the intersite factors which determine initiation in the awake condition. We compared the latencies to initiate locomotor stepping elicited by electrical stimulation (50 microA, 0.5-msec pulses, 10 to 160 Hz) by rats tested while awake and unrestrained in a rotary runway or anesthetized and held in a stereotaxic apparatus. In the latter tests, initial anesthesia was provided by Nembutal (25 mg/kg) and 2% halothane and maintenance anesthesia was provided by 7 mg/kg as needed and local injections of lidocaine. For 30 sites in 16 rats, average locomotor initiation latency in the awake condition and the shortest latencies in the anesthetized condition were positively correlated (r = .78). Locomotion at sites with long latencies in the awake condition was frequently blocked in the anesthetized condition, but sites with short latencies were rarely blocked. The results indicate that the shortest locomotor latencies in the anesthetized condition approximate the latencies measured in the awake condition. It is concluded that the anesthetized condition can provide valid initiation measures, but sites with long latencies in the awake condition are prone to depression under anesthesia.

Locomotor stepping elicited by electrical stimulation of the hypothalamus persists after lesion of descending fibers of passage.

Locomotion initiated by electrical stimulation of the lateral hypothalamus could be due to activation of local neurons or of fibers of passage descending from locomotor regions in the basal forebrain. This study mapped hypothalamic sites for electrically elicited locomotion in six rats with electrolytic lesions of the ipsilateral basal forebrain sources of descending fibers of passage. For mapping, anesthetized rats were held in a stereotaxic apparatus supported by a sling so that stepping movements rotated a wheel. Anesthesia was maintained by periodic injections of Nembutal (7 mg/kg) supplemented by lidocaine injections. Stimulation (25 and 50 microA, 50 Hz, 0.5 msec cathodal pulses, 10 sec trains) was applied through 50-80 microns diameter pipettes filled with 2 M saline. In all cases, locomotor stepping could be elicited by stimulation in sites ipsilateral to the lesion at currents of 50 microA or less. In the one case in which 25-microA sites were not found in the lateral hypothalamus, the lesion extended caudally to within 1 mm of the stimulation sites. These findings do not exclude a locomotor role for fibers of passage but they suggest that activation of lateral hypothalamic neurons is sufficient to initiate locomotion.

Midbrain areas required for locomotion initiated by electrical stimulation of the lateral hypothalamus in the anesthetized rat.

Locomotor stepping in the Nembutal-anesthetized rat was elicited by electrical stimulation of either of two sites in the right or left posterolateral hypothalamus. Essential midbrain loci were identified by reversibly blocking the elicited locomotion through local injections of the anesthetic procaine (15%, 0.5 microliter). Two types of critical midbrain sites were found. At ipsilateral block sites (n = 21), procaine blocked only that locomotion elicited by ipsilateral stimulation. These sites could be along the course of a direct descending ipsilateral pathway although a possible bidirectional pathway is not to be excluded. At bilateral block sites (n = 21), procaine blocked locomotion elicited by both ipsilateral and contralateral stimulation. These sites could be involved in functions prerequisite for the initiation of locomotion or in the generation of the stepping pattern. Procaine injections in 35 sites had no effect on locomotion. Ipsilateral and bilateral block sites were intermixed and generally located in regions ventral to the midbrain central gray: chiefly the anterior ventromedial midbrain, the pontis oralis nucleus and the pedunculopontine nucleus. Negative sites were located in both the dorsal and ventral midbrain. Ipsilateral block sites were relatively prevalent in the anterior midbrain, indicating that the locomotor initiation signals are lateralized at this level. Bilateral block sites were more prevalent in the posterior levels, suggesting that the initiation signals are proximal to, or interact with, circuits that have a bilateral influence on locomotion.

Midbrain stimulation in the anesthetized rat: direct locomotor effects and modulation of locomotion produced by hypothalamic stimulation.

The midbrain contains circuits that modulate locomotion. To delineate some of the involved regions, low-level stimulation (25 microA, 10 s train of 0.5 ms pulses at 50 Hz) was applied to the midbrain during locomotor stepping. Stepping was elicited in the anesthetized (pentobarbital, 40 mg/kg) rat by stimulating the hypothalamus with 0.5 ms pulses at 40 Hz at various currents. The rat was held in a stereotaxic apparatus such that locomotor stepping movements turned a wheel. Facilitation of locomotion was produced by stimulation in the anterior ventromedial midbrain and in the posterodorsal midbrain. When presented alone, such stimulation produced locomotion. Inhibition of locomotion was produced by stimulation of the superior colliculus (ventral layers) and the ventromedial midbrain. Additional inhibitory sites were found in the central gray and the lateral tegmentum. Inhibitory collicular stimulation, when presented alone, was characterized by the absence of any hindlimb response. Inhibitory ventromedial stimulation, when presented alone, frequently produced poststimulation locomotion and when presented with hypothalamic stimulation was characterized by postinhibitory increases in locomotion. These results indicate that: (1) the locomotor effects of stimulation in midbrain and hypothalamic sites can summate: (2) multiple locomotor suppressive systems are present in the midbrain and among them are a collicular system and a ventromedial system.