Control of Movement Spinal Interneurons Proprioceptive afferents have a variety of termination patterns in the spinal cord. This can be seen by filling physiologically-identified fibers with HRP, so their morphology can be identified. Bill Yates Depts. Otolaryngology & Neuroscience Room, Eye & Ear Institute Phone: 647-9614 E-mail: byates@pitt.edu Note that the parent axon courses in the dorsal columns, and provides collaterals at regular intervals. There is a heavy termination in lamina IX (suggesting powerful monosynaptic inputs to motoneurons), as well as the intermediate parts of the spinal gray matter.
In contrast, group II afferents have only a small projection to the motor column, and mainly terminate in the spinal intermediate gray. Group Ib afferents have terminations exclusively in the intermediate parts of the spinal gray matter. Thus, it is presumed that Ib afferents do not provide monosynaptic inputs to motoneurons.
Monosynaptic Proprioceptive Inputs to -Motoneurons The main aspects of the myotatic reflex, which causes a stretched muscle to reflexively contract, are shown in the adjacent diagram. Group Ia afferents make connections with most of the motoneurons innervating the muscle that has been stretched, as well as the synergist motoneurons, as shown in the adjacent table. Ia inputs are also relayed to motoneurons via premotor interneurons. The inclusion of interneurons in reflex circuitry provides for flexibility in motor output. Descending pathways can act upon the interneurons to adjust the intensity of a reflex, or even to shut it off. However, since the myotatic reflex includes powerful monosynaptic connections, it is almost impossible to consciously abolish this reflex. Group II spindle afferents also make monosynaptic connections with -motoneurons, although the terminal boutons appear to be on the terminal dendrites. Thus, monosynaptic group II inputs make only a weak contribution to motoneuron excitability.
Turning Off a Contraction Renshaw Cells Renshaw Cells Motoneurons Before an -motoneuron axon leaves the spinal cord via the ventral root, it sends off collaterals to a group of interneurons located medial to the motoneuron pool. These interneurons, called Renshaw cells, make inhibitory synapses on the motoneurons whose axons excited them. Since the motoneurons are inhibiting their own activity, this inhibition is referred to as recurrent inhibition. Renshaw cells prevent motoneurons from expressing a long train of action potentials to a brief stimulus. However, sometimes we want prolonged contractions. In these cases, descending motor pathways inhibit the Renshaw cells. Further physiological properties of the Renshaw cell are shown in this diagram. A shows that Renshaw cells can receive both excitatory and inhibitory descending inputs, which can either facilitate or diminish their responses. B shows how facilitating or inhibiting a Renshaw cell by descending inputs can affect the relationship between synaptic inputs to a motoneuron and its outputs. C shows our current concept of Renshaw cell outputs. In addition to motoneurons, Renshaw cells also inhibit -motoneurons and a special type of interneuron, the IA inhibitory interneuron. Note that Ia, Ib and II afferents do not provide inputs to Renshaw cells.
Reciprocal Inhibition--IA Inhibitory Interneurons Ia inputs also produce the inhibition of motoneurons of antagonist muscles. This provides for a more powerful reflex: the possible resistance of the antagonistic muscles is eliminated. The inhibition of the antagonist muscles is mediated by an interneuron, and is disynaptic. The interneurons that mediate this inhibition are called Ia inhibitory interneurons. Excitatory Ia inhibitory interneurons also receive input from Renshaw cells. In fact, they are the only known interneurons that receive Renshaw inhibition, that tends to shut-off the inhibition of the antagonist muscle as the homonymous motoneurons begin to fire. The inhibition mediated by the Ia interneurons is called reciprocal inhibition, and is an effective means to have opposite actions at agonist and antagonist motoneurons without requiring dual innervation of both groups. It is not surprising that many pathways that provide inputs to motoneurons also send signals to Ia inhibitory interneurons to provide for inhibition of the antagonist. This is an example of conservation within central neural circuitry. These connections are summarized in the diagram below.
Non-Reciprocal Inhibition--IB Inhibitory Interneurons Ib afferent Ib inhibitory interneuron Group Ib fibers, which originate in tendon organs, have different actions. Stimulation of these afferents produces inhibition of motoneurons innervating the muscle associated with the tendon that has been stretched. Since antagonist muscles are not affected, the Ib inhibitory interneurons are sometimes referred to as non-reciprocal inhibitory interneurons. Motoneuron to muscle associated with the stretched tendon Inhibitory synapse Excitatory synapse It was originally believed that Ib afferents were activated only when muscle contractions were very strong, suggesting that non-reciprocal inhibition serves a protective role. More recently it was learned that Ib afferents are highly sensitive to muscle contraction. It is now thought that Ib inhibition serves to help smooth an ongoing contraction. Ib interneurons also receive inputs from a number of sources, including Ia afferents, lowthreshold cutaneous afferents, and descending pathways. Ib inhibition may serve to decrease the force of a muscle contraction if an unexpected event happens during the movement (i.e., the limb coming in contact with a surface).
Propriospinal Neurons Propriospinal neurons are cells whose axons project between segments of the spinal cord. One example of propriospinal neurons are cells whose axons project between parts of the spinal cord that innervate the arms and the legs. These connections allow for interlimb coordination. The best-studied propriospinal neurons are located in the C3-C4 spinal cord segments, and send their axons to the forelimb enlargement. These neurons are important in relaying integrated signals to forelimb motoneurons. Central Pattern Generators and their Role in Motor Control It is often convenient for the central nervous system to generate rhythmic motor patterns through central pattern generators. There are three possibilities to account for any rhythmic output: 1) A pacemaker system, in which membrane properties of cells account exclusively for the establishment of the rhythm. A pacemaker system regulates the contraction of the heart. 2) A network system, in which a group of neurons with conventional biophysical properties establish the rhythm through their synaptic interactions. 3) A hybrid system, in which the rhythm is generated by a network of neurons, some of which have unique membrane properties Perhaps the best described central pattern generator is the pattern generator for respiration, whose neurons are located in the brainstem. The respiratory central pattern generator is responsible for imparting the rhythmic activity onto diaphragm and other motoneurons that produces breathing.
Production of Locomotion: Interaction of Brainstem and Spinal Cord Pattern Generators In quadrupeds, locomotion is a complex process that involves the coordination of the movement of the four limbs. The patterns are illustrated in the following figure: The coordinated movement of the limbs during locomotion appears to be mainly mediated by central pattern generators in the spinal cord. A cat with its spinal cord transected can be induced to walk by stimulation of this pattern generator. This stimulation can be produced by activation of spinal afferents (e.g., by putting the cat on a treadmill), injecting L-DOPA intravenously to enhance norepinephrine release in the spinal cord, etc. The locomotion generator in the spinal cord is very complex. Low levels of stimulation produce an alternate movement of opposite limbs, whereas more rapid stimulation produces a simultaneous flexion or extension of opposite limbs, as normally happens during running in quadrupeds. Locomotion can also be induced in decerebrate animals by stimulation of locomotor regions in the brainstem. The first such locomotor region discovered is the mesencephalic locomotor region (MLR). A second, more rostral, locomotor region is called the subthalamic locomotor region. For the purposes of this course, we will mainly concentrate on the better known MLR.
The MLR is located in the midbrain, just ventral to the inferior colliculus. The mesencephalic locomotor region receives input from many regions, including the basal ganglia and the limbic system. Apparently, descending pathways from the mesencephalic locomotor region are important in triggering locomotion in intact animals. A lateral pathway also can induce locomotion when stimulated. This lateral pathway includes the medial mesencephalic locomotor region (mmlr) and the pontomedullary locomotor strip, which is a column in the dorsolateral brainstem that, when stimulated, can induce bouts of locomotion that are less profound than those induced by MLR stimulation. It is believed that the lateral pathway provides inputs to the spinal central pattern generator, whereas the medial pathway including the MLR proper plays the principal role in inducing locomotion. The importance of the MLR in eliciting locomotion is primarily due to its inputs, which come from the basal ganglia, limbic system, and lateral hypothalamus. The MLR appears to be under strong inhibitory influence from the subthalamic nucleus. The subthalamic nucleus signals to the MLR may be transmitted in part through the substantia nigra, pars reticulata. The globus pallidus (also referred to as the entopeduncular nucleus in the cat) also has influences on the MLR, which are both direct and indirect through the substantia nigra pars reticulata. The limbic system also modulates activity of the MLR. The nucleus accumbens, which is located rostral to the hypothalamus, provides signals to the MLR via a relay in the globus pallidus. The signals from the nucleus accumbens to the MLR can be modified by inputs from the hippocampus or amygdala. With this pattern of connections, the MLR can be switched on when the basal ganglia sense the need to initiate a voluntary movement or when the limbic system senses the need to trigger locomotion based on affective issues (e.g., danger in the environment; need to hunt prey).
N. Accumbens Hippocampus & Amygdala Subthalamic N. Globus Pallidus (Internal) The MLR does not project directly to the spinal cord. Instead, it provides inputs to the medial reticular formation which relays the signals to the spinal cord. Of course, inputs from the MLR to the medial reticular formation are integrated with the host of other inputs to this region (vestibular, cerebellar, cortical, somatosensory, etc.). Ventral Globus Pallidus Substantia Nigra p. R. MLR The spinal interneurons that respond to MLR stimulation have been localized using recordings of field potentials and the c-fos technique (an anatomical technique that revealscells expressing a protein involved in transcription). These studies have shown that lamina VI- X (i.e., the ventral horn) contains neurons that respond to MLR stimulation. This finding is not surprising, as the ventral horn contains premotor neurons (and is also the site of termination of the reticulospinal tracts). Of course, there is a need to precisely control posture as locomotion takes place. Portions of the medial reticular formation, when activated, can produce either postural suppression or standing (enhancement of postural responses). Thus, the locomotor pattern that is produced is dependent on what parts of the reticular formation are activated by the MLR. Thus, despite its reputation as being a simple relay, the medial reticular formation plays an important role in integrating signals related to locomotion. Role of Afferent Inputs in Generating Locomotion Transection of the dorsal roots does not eliminate L-DOPA-induced locomotion in spinal cats or locomotion induced by MLR stimulation in decerebrate cats. Thus, peripheral inputs are not required for activation of the locomotion pattern generator. However, there is considerable evidence that peripheral inputs participate in shaping locomotion. Afferent feedback is particularly important in reinforcing the ongoing step cycle. Afferent feedback from extensor muscles is important in maintenance of posture during locomotion, and assuring that posture is adjusted to carry the load placed on a limb. Part of the extensor drive during stance comes from monosynaptic extensor IA inputs to motoneurons. In addition, new reflex pathways become active during locomotion, presumably due to an increase in background excitation on interneurons or removal of tonic inhibitory signals to these cells. The locomotor reflex pathway acts on extensor motoneurons, and is only active during the stance phase.
Recordings from spindle afferents in walking cats have shown that early during the stance phase, there is considerable activity in limb extensor group Ia, II and Ib spindle afferents. The simultaneous activation of all types of afferents is due to the load placed on the limb during stance. During normal conditions, Ib inhibitory interneurons would act to depress the activity of extensor motoneurons during stance. It appears as though Ib inhibitory interneurons are shut down during locomotion to prevent this from happening. Instead, the locomotor reflex pathway receives convergent IA and IB inputs and excites the extensor motoneurons. Enhanced inputs from proprioceptive afferents during stance will extend the period of the stance phase. Thus, for example, if the opposite limb stumbles during locomotion and the load continues for a prolonged period on a limb, the stance phase will persist. Due to the rhythmic nature of the central pattern generator, the extensor muscle force dissipates over time and flexor muscle activity begins. There is evidence that inputs from the flexor proprioceptive afferents will inhibit the extensor motoneurons (via IA inhibitory interneurons), thus facilitating the transition to the swing phase. The swing phase of locomotion is less modulated by afferent input than is the stance phase, although afferent input can affect this cycle of locomotion. Cutaneous afferents also can affect the locomotor rhythm, although the effects are complex. One example of cutaneous modulation of walking is the stumble response. If the dorsum of the foot is stimulated during the swing phase, a prolonged swing cycle is elicited, presumably to clear the foot from the obstacle. Summary of locomotion: 1) A rhythmic contraction of flexors and extensors is coordinated by the spinal cord network known as the central pattern generator. The central pattern generator is activated by descending signals from the MLR. 2) Ib inhibitory interneurons are shut down, and new interneurons are activated by the descending MLR commands. 3) During the stance phase of the limb, the extensor muscle activity is facilitated by Ia and Ib inputs from the limb. If environmental circumstances produce a large Ia/Ib input, then the extension phase occurs for a longer period of time. 4) If there are no perturbations, the central pattern generator produces a shift from extension to flexion of a limb. The flexion part of the locomotor cycle is under less afferent control than the extensor phase. 5) Cutaneous inputs can also modify the locomotor cycle. For example, if the foot contacts an obstacle during swing (i.e., stumbling occurs), the swing phase in that limb persists for an expanded period of time. 6) As with other movements, IA inhibitory interneurons play an important role in producing locomotion. They insure that limb flexors and extensors are never simultaneously active.
Major Descending Motor Pathways from the Brainstem that Regulate Movement Vestibulospinal Tracts Lateral Vestibulospinal Tract (LVST) The mammalian LVST arises mainly from the lateral vestibular nucleus, but there is some contribution from the inferior vestibular nucleus. The tract descends the entire spinal cord ipsilaterally. In the upper cervical cord, the tract is located in the ventrolateral funiculus, but it shifts medially at more caudal levels. The LVST terminates mainly in Rexed s lamina VIII and the medial portion of lamina VII, particularly at spinal levels below the upper cervical cord. It thus seems likely that most of the LVST inputs to motoneurons will be indirect, being relayed through interneurons. However there may be some direct LVST inputs to neck motoneurons. Some LVST axons branch tremendously, and innervate several segments of the spinal cord. Others only appear to provide inputs to one segment. MSNBIO/NROSCI 2012 & 2103 Page
LVST Terminals in the Spinal Gray Matter: The Medial Vestibulospinal Tract (MVST) The MVST originates in several vestibular nuclei (medial, lateral and descending), and enters the medial longitudinal fasciculus (MLF) to descend to the spinal cord. The MVST descends bilaterally, but only a very few fibers project more caudally than the cervical spinal cord. Thus, the main role of the MVST appears to be influencing neck and upper back musculature. The tract terminates mainly in laminae VII-VIII, although there is physiological evidence of direct MVST inputs to neck motoneurons. MSNBIO/NROSCI 2012 & 2103 Page
Vestibulospinal Influences on Limb Motoneurons As indicated above, limb motoneurons are influenced by the LVST, but not by the MVST. Physiological experiments have shown that the LVST mainly serves to excite extensor motoneurons and to inhibit flexor motoneurons. Although the LVST descends on the ipsilateral side, the INFLUENCES of the tract are bilateral. The actions of the tract on the contralateral side are accomplished through interneurons whose axons cross the midline; any spinal interneuron which influences cells on the opposite side of the cord is called a commissural neuron. The pattern of connections of the LVST is very practical. If an animal is at risk of falling over, extension of all 4 limbs will achieve postural stability. The LVST influences both and motoneurons acting on the limbs. Thus, the tract presumably both directly produces limb muscle contraction and enhances spindle inputs from the limb muscles. Reflexes evoked by proprioceptive afferents work in synchrony with the vestibulospinal reflex to maintain postural stability. Vestibulospinal Influences on Axial Motoneurons All axial muscles appear to be influenced by the LVST and/or the MVST, and many vestibulospinal inputs to axial motoneurons appear to be monosynaptic. Vestibular inputs to neck motoneurons serve to produce head stability. It appears that neck motoneurons are influenced less strongly by the vestibular system than limb motoneurons. The difference in vestibulospinal drive on neck and motoneurons may reflect the complexity in control of neck muscles.
Vestibular Inputs to LVST neurons Electrophysiological studies have shown that the anterior and posterior semicircular canals as well as otolith organs influence LVST neurons. Many LVST cells receive convergent otolith and canal signals as well as convergent signals from the anterior and posterior canals on the same side. The otolith inputs to LVST neurons mainly come from utricular receptors that are activated by side down tilt. As a result, the LVST is activated during ear down rotations. This response pattern seems practical for a quadruped, which is much more likely to fall to the side than forwards or backwards (because the forelimbs and hindlimbs are spaced far apart). Vestibular Inputs to Neck Motoneurons Neck motoneurons receive more heterogeneous vestibular signals than do limb motoneurons. The diagram to the left shows that as a group, neck motoneurons receive bilateral inputs from all 3 semicircular canals. In addition, neck motoneurons receive otolith signals. The vestibular signals to a particular neck motoneuron are dependent on the function of the associated motor unit in maintaining head stability. For example a dorsal neck muscle is likely to be activated by stimulation of both anterior canals, so that if the head falls forward a reflex will occur to return the head to the upright position.
Reticulospinal Systems The reticular formation is comprised of portions of the brainstem that are not clearly organized into tracts or nuclei. Thus, the reticular formation is the core of diffusely-organized cells in the brainstem. The diagram to the left shows the cytoarchitecture of the reticular formation. Large neurons are located in the medial reticular formation, particularly in the medulla. Thus, the medial medullary reticular formation is sometimes called the gigantocellular reticular formation. In contrast, the lateral reticular formation is composed of small cells. Many neurons in the medial formation project to the spinal cord, and have both direct and indirect effects on spinal motoneurons (as will be discussed below). Some neurons in the lateral reticular formation also project to the spinal cord, but the targets of the lateral neurons are either respiratory motoneurons or sympathetic/parasympathetic preganglionic neurons. In addition, the lateral reticular formation contains many neurons involved in integrating autonomic signals. Other neurons in the reticular formation have ascending projections to thalamus, projections to the cerebellum, and projections to many other locations in the brainstem. These reticular formation cells will be discussed at relevant points in this course. Reticulospinal neurons are located in the medial medullary and pontine reticular formation. The diagram above is a mapping of reticular formation neurons projecting to different levels of the spinal cord. Medullary reticulospinal neurons have axonal projections in the lateral spinal white matter. In contrast, pontine reticulospinal axons course in the ventromedial funiculus. Most of the projections are ipsilateral, although a few are on the opposite side as the cell body. The diagram to the left indicates the projections of reticulospinal neurons on the left side.
Reticulospinal neurons provide direct inputs to and motoneurons, as well as indirect inputs through interneuronal relays. Both flexor and extensor muscles are excited by reticulospinal pathways. Thus, the reticulospinal system has different actions than the vestibulospinal system, which excites extensors and inhibits flexors. The inputs to reticulospinal neurons come from three main sources: the vestibular system, the somatosensory system, and the cerebellum. Additional inputs come from other sources, including the cerebral cortex. Thus, reticulospinal neurons integrate a number of signals regarding body position in space. The rubrospinal system The red nucleus, which is located in the mesencephalon, also gives rise to projections to the spinal cord. The rubrospinal tract arises from large magnocellular neurons in the red nucleus, crosses in the brainstem, and descends the spinal cord entirely crossed in the dorsolateral funiculus. The red nucleus gets most of its inputs from the cerebral cortex (motor and premotor cortices) and the cerebellum (interpositus and dentate deep cerebellar nuclei). This pattern of inputs suggests that the rubrospinal tract participates in voluntary motor control. The red nucleus has only two major targets: the spinal cord and the cerebellum. Projections to the cerebellum are both direct and indirect, via the lateral reticular nucleus, external cuneate nucleus, and inferior olive. The importance of the rubrospinal tract in motor control varies from species to species. In rodents, the rubrospinal system is probably the major tract involved in voluntary motor control. In primates, the influences appear to be minimal. The rubrospinal tract extends the entire length of the spinal cord in rodents, but ends at the lower cervical level in primates. The rubrospinal tract has been explored most extensively in the cat. In this species, stimulation of the red nucleus produces EPSPs in contralateral flexor - motoneurons, and IPSPs in contralateral extensor -motoneurons. These observations suggest that the rubrospinal tract transmits impulses that facilitate flexor muscle tone. Furthermore, both static and dynamic -motoneurons receive rubrospinal inputs.
In humans, lesions of the red nucleus produce a number of contralateral motor disturbances of an involuntary nature (tremor, ataxia, choreiform movements). However, these deficits are due to interruption of red nucleus inputs to the cerebellum, and not the spinal cord. This observation points to the importance of the rubro-cerebellum connections in motor control. Other descending pathways from the brainstem The superior colliculus gives rise to the tectospinal tract, which provides inputs only to neck motoneurons. In primates, this projection is primarily involved in producing coordinated eye-head movements. Brainstem monoaminergic neurons located in locus coruleus (which produce norepinephrine) and the raphe nuclei (which produce serotonin) also make connections with motoneurons. These monoaminergic inputs play an important role in setting the background excitability of motoneurons. The corticospinal system In primates, the corticospinal tract plays a paramount role in controlling movement. This pathway will be discussed at length during.