Mesencephalic Locomotor Region

Cross references:   Early Behavior   Pre-Chordate Locomotion     Chordate Locomotion    
Spinal Locomotor Generator
  Reticular Activating Sytem    Cerebellum  
Nucleus Accumbens Septi     Salamander Brain Diagram     
Perinatal Behavior   Extrapyramidal System    Dictionary     Rhombencephalon  
Cuneiform Nucleus      Pedunculopontine Nucleus       Ventral Pallidum     


    I need a clearer understanding of the Mesencephalic Locomotor Region (MLR) How about the  Spinal Locomotor Generator (SLG)?   Just off hand, I would guess that the causal sequence is MLR > RAS > SLG, but I need to pin this down.  Also, which neurotransmitters and which neuromodulators are used?  Where does GABA fit in?  Does it function as a neurotransmitter or as a neuromodulator or both?   

The Mesencephalic Locomotor Region (MLR) is embedded in, and part of, the middle and upper portions of the Reticular Formation. It supplements the Spinal Locomotor Generator (SLG) by controlling the movement of the four limbs in the context of side-to-side body motion which is still controlled by the SLG.  
My comment
    This statement needs references.     


Midbrain (Wiki) 
    "The midbrain or mesencephalon (from the Greek mesos - middle, and enkephalos - brain[1]) is a portion of the central nervous system associated with vision, hearing, motor control, sleep/wake, arousal (alertness), and temperature regulation.[2] Anatomically, it comprises the tectum (or corpora quadrigemina), tegmentum, the ventricular mesocoelia (or "iter"), and the cerebral peduncles, as well as several nuclei and fasciculi. Caudally the mesencephalon adjoins the pons (metencephalon) and rostrally it adjoins the diencephalon (Thalamus, hypothalamus, etc.)."  
    "
The mesencephalon is considered part of the brainstem. Its substantia nigra is closely associated with motor system pathways of the basal ganglia. The human mesencephalon is archipallian in origin, meaning its general architecture is shared with the most ancient of vertebrates. Dopamine produced in the substantia nigra plays a role in motivation and habituation of species from humans to the most elementary animals such as insects.
"  


Undulatory locomotion (Wiki) 
    "Undulatory locomotion is the type of motion characterized by wave-like movement patterns that act to propel an animal forward. Examples of this type of gait include crawling in snakes, or swimming in the lamprey. Although this is typically the type of gait utilized by limbless animals, some creatures with limbs, such as the salamander, choose to forgo use of their legs in certain environments and exhibit undulatory locomotion."  
    "
Wavelike motor pattern typically arise from a series of coupled segmental oscillator. Each segmental oscillator is capable of producing a rhythmic motor output in the absence of sensory feedback. One such example is the half center oscillator which consist of two neurons that are mutually inhibitory and produce activity 180 degrees out of phase. The phase relationships between these oscillators are established by the emergent properties of the oscillators and the coupling between them.[15]  
    Forward swimming can by accomplished by a series of coupled oscillators in which the anterior oscillators have a shorter endogenous frequency than the posterior oscillators. In this case, all oscillators will be driven at the same period but the anterior oscillators will lead in phase.

    "
The lamprey moves using lateral undulation and consequently left and right motor hemisegments are active 180 degrees out of phase.  
    Also, it has been found that the endogenous frequency of the more anterior oscillators is higher than that of the more posterior ganglia.[15] 
    In addition, inhibitory interneurons in the lamprey project 14-20 segments caudally but have short rostral projections. Sensory feedback may be important for appropriately responding to perturbations, but seems to be less important for maintaince of appropriate phase relations.
"    



The references, below, are
from two different sources.  

1.  Searching Pub Med  for "mesencephalic locomotor" brought up 201 references.  I've included four below.


2. 
The first page of Google hits for "mesencephalic locomotor region" yielded nine more possible references.   


1973   

On the Descending Control of the Lumbosacral Spinal Cord from the Mesencephalic Locomotor Region
No PubMed Abstract:  
   
http://www.ncbi.nlm.nih.gov/pubmed/4348892   
but there is a Google Abstract: 
   
http://onlinelibrary.wiley.com/doi/10.1111/j.1748-1716.1973.tb05396.x/abstract          
    "
Continuous stimulation (60 c/s) of a region below the inferior coliculus can induce locomotion on the treadmill of precollicular, postmammilar cats.  This study aims at revealing what changes occur in the spinal cord, when the “locomotor region” is stimulated. This stimulation enables the cat to walk if the treadmill is moved.
  
    After controlling the threshold for evoking good locomotion, the cats were curarized. Stimulation at a strength that evoked walking prior to curarization induced a depression of inhibitory short-latency reflex effects to a-motoneurones from cutaneous, and high threshold muscular afferents without changing the direct excitability of a-motoneurones. The threshold for evoking longlasting reciprocally organized discharges was lowered.  
    The results suggest that the effects are induced by a slow fiber system, that releases the activity of the spinal stepping generating neurones.   The results would be explained if the noradrenergic reticulospinal system was activated from the mesencephalic locomotor region.
"  
My comment:  
    I need to learn more about the "noradrenergic reticulospinal system".       


1977
Role of pontine tegmentum for locomotor control in mesencephalic cat. (PubMed)   

Only abstract available online. 
    "
An attempt has been made to elucidate how direct stimulation of the mesencephalic locomotor region (MLR, with Horsley-Clarke coordinates P2, L4, and H0) is transmitted through the pons to the spinal cord where a stepping generator is presumed to exist.
    A longitudinal strip, termed the "pontine locomotor region" (PLR), was identified. It extends ventrocaudally throughout the lateral pontine tegmentum
"  
    "
Subthreshold MLR stimulation together with subthreshold PLR stimulation generated locomotion. Ipsilateral and contralateral MLR-PLR stimulations were of equal effectiveness for the generation of locomotion.
"  
My comment
    This is the first time I've encountered the "pontine locomotor region".  It has probably been given a different name by more recent authors.     
 

1981
Pallidal projections to the mesencephalic locomotor region (MLR) in the cat (Goog) -  
Only abstract available online. 
    "
The
Entopeduncular Nucleus  (EN) in the cat, the homologue of the primate internal Globus Pallidus and main output of the basal ganglia, is known to project to the mesencephalic tegmentum. We have been able to elicit antidromic responses in single EN neurons from a site in the posterior mesencephalon, then transect the brainstem (precollicular-postmamillary) and elicit locomotion and rhythmic movements of the limbs by stimulation of the same site in the same animal. These studies demonstrate the existence of a direct projection from the EN to the mesencephalic locomotor region (MLR). However, this is not a particularly large pathway since fewer than 5% of the EN cells appear to project to the MLR.
    In a parallel series of anatomical experiments, injections of fluorescent dyes into the area of the MLR induced retrograde labeling of cell bodies in the EN and motor cortex. Injections of tritiated amino acids into the motor cortex resulted in labeling in the area anterior to the MLR. We assume that these connections may be involved, in part, in the sequencing and ordering of series of voluntary movements in which locomotion is involved.
"  



1983   21<22  &  22<23     * *      Free full text   
Neural projections from nucleus accumbens to globus pallidus, substantia innominata, and lateral preoptic-lateral hypothalamic area 
http://www.ncbi.nlm.nih.gov/pubmed/6822855   
    "...
projections of the subpallidal region, which may include an output to the mesencephalic locomotor region
    See:  Nucleus Accumbens Septi   for full Abstract, Similar articles, Cirted by's and Full Free Text


1984
The mesencephalic locomotor region (MLR) in the rat (Goog)  
Only abstract available online. 
    "
These studies demonstrate the presence of the MLR in the rat brain.
    Controlled locomotion on a treadmill could be induced by low level stimulation (< 50 µA) of an area in the posterior midbrain following a precollicular-prenigral brainstem transection. This area included the lateral part of the
Cuneiform Nucleus  and anterior as well as posterior portions of the Pedunculopontine Nucleus
     In addition, the presence of a subthalamic locomotor region in the fields of Forel was determined in rats after prethalamic transections.
"  


1984   
Evidence for a projection from the lateral
Preoptic Area and Substantia Innominata to the mesencephalic locomotor region in the rat (Goog)  
Only abstract available online. 
    "
A series of anatomical and electrophysiological experiments have been carried out to examine the organization of a direct projection from the substantia innominata and the lateral preoptic area of the hypothalamus, referred to collectively as the subpallidal region, to the
Pedunculopontine Nucleus and adjacent parts of the dorsal midbrain in the adult rat." 
    "They also indicated that individual fibers from the subpallidal region innervate both the pedunculopontine nucleus and adjacent parts of the central gray, and that the pathway innervates areas along the length of the 
Medial Forebrain Bundle  on its way to the dorsal midbrain."  
    "In a third series of experiments the retrogradely transported fluorescent tracer True Blue was injected into upper thoracic levels of the spinal cord, and it was found that the region of the pedunculopontine nucleus that receives the densest input from the subpallidal region contained many retrogradely labeled neurons on both sides of the brain." 
    "These results clearly suggest that the subpallidal region projects directly to the pedunculopontine nucleus and adjacent regions including the central gray and the
Superior Colliculus .
    Since the subpallidal region appears to receive its major input from the
Nucleus Accumbens Septi , and since the pedunculopontine nucleus lies within the ‘mesencephalic locomotor region’, the possibility is discussed that this pathway may play a role in limbic region influences on behaviors that involve locomotor activity."  


1985
Excitatory and inhibitory postsynaptic potentials in alpha-motoneurons produced during fictive locomotion by stimulation of the mesencephalic locomotor region. (PubMed)   
Only abstract available online. 
    "
We tested the hypothesis that stimulation of the mesencephalic locomotor region (MLR) activates polysynaptic pathways that project to lumbar spinal motoneurons and are involved in the initiation of locomotion.
"  
    "
 We concluded that MLR stimulation that evokes fictive locomotion produces both excitation and inhibition of spinal motoneurons. Spinal interneuronal systems are implicated and may be those involved in the initiation and control of locomotion."  


1986
Projections of the mesencephalic locomotor region in the rat (Goog)   
Only abstract available online. 
Some interesting links, but the abstract itself was uninformative.  


198

Cholinergic vs. noncholinergic efferents from the mesopontine tegmentum to the extrapyramidal motor system nuclei.
http://www.ncbi.nlm.nih.gov/pubmed/2461392 

Abstract
    "Previous studies have suggested that the pedunculopontine tegmental nucleus (PPTn) is reciprocally connected with extrapyramidal motor system nuclei (EPMS) whereas other studies have implicated the PPTn in behavioral state control phenomena such as sleep-wakefulness cycles. Many of these studies define the nonprimate PPTn as an area of mesopontine tegmentum which is labeled from injections of anterograde tracers into the basal ganglia.  
    Recently, we have defined the rat PPTn as a large-celled, cholinergic nucleus. The rat PPTn is cytologically distinct from a group of smaller, noncholinergic neurons that are medially adjacent to the PPTn. This noncholinergic group is further distinguished from the PPTn by its afferent input from the globus pallidus, entopeduncular nucleus, and substantia nigra. We refer to the latter area as the midbrain extrapyramidal area (MEA).
    Using combined choline acetyltransferase immunohistochemistry of the PPTn and WGA-HRP retrograde tracing from the EPMS, we investigated the efferent connections of the MEA and PPTn to the EPMS in the rat.  
    The noncholinergic MEA, rather than the PPTn, is the major source of tegmental innervation to the globus pallidus, caudate-putamen, subthalamic nucleus, entopeduncular nucleus, substantia nigra, and motor cortex. In contrast, the cholinergic PPTn is the major source of tegmental innervation to the ventrolateral thalamic nucleus.    This finding is in contradistinction to thalamic projections from the surrounding reticular formation, which are identified only after WGA-HRP injections into "nonspecific" thalamic nuclei.  
    This body of evidence suggests that the noncholinergic MEA represents an additional component of the EPMS and may correspond to the "mesencephalic locomotor region." The cholinergic PPTn may play a role in more global thalamic functions such as the "reticular activating system" rather than a primary role in motor function. 
    6 Cited by's
http://www.ncbi.nlm.nih.gov/pubmed?linkname=pubmed_pubmed_citedin&from_uid=2461392   


1993   
408<518 
Decreases in rat locomotor activity as a result of changes in synaptic transmission to neurons within the mesencephalic locomotor region.
   


1996  
A mesencephalic relay for visual inputs to reticulospinal neurones in lampreys.
http://www.ncbi.nlm.nih.gov/pubmed/8773792    
    "
Visual stimuli elicit motor responses in lampreys. These responses rely, in part, on the activation of reticulospinal (RS) neurones which constitute the main descending pathway in these early vertebrates. This study sought to identify and characterize possible mesencephalic relays for visual inputs to RS neurones of the rhombencephalon. The anatomical substrate subserving this function was investigated by iontophoretically ejecting cobalt-lysine, a retrograde tracer, in the middle rhombencephalic reticular nucleus in the in vitro isolated brainstem preparation of young adult Petromyzon marinus. Several populations of cells were retrogradely labeled in the brainstem.  
    Of particular interest were the cell populations found on each side of rostral mesencephalon, located in the tectum and pretectum. There were, on average, 113 cells labeled contralateral to the injection site and 80 cells labeled ipsilateral to the injection site. The cells were morphologically similar on both sides, except that the contralateral group had larger cell bodies as compared to the group on the ipsilateral side.  
    To determine whether the axons of the cells contacted reticulospinal neurones, electrophysiological experiments were carried out in which the region containing these cells was microstimulated. Large post-synaptic potentials were recorded intracellularly in RS neurones. Furthermore, microstimulation of the optic nerve on the same side as the recorded cell (i ON) evoked responses with a pattern similar to those resulting from stimulation of the optic tectum contralateral to the cell recorded (co OT), except for the longer response latencies. Local ejection of xylocaine (1% lidocaine hydrochloride) or CNQX (1 mM) onto the co OT reversibly abolished the responses evoked from stimulation of the i ON. There were no significant effects observed when the drug was ejected onto optic tectum ipsilateral to the cell.  
    Taken together, the results from this study indicate that the crossed tectoreticular pathway is involved in relaying optic nerve inputs to RS neurones of the middle rhombencephalic reticular nucleus. Moreover, cells of origin of this pathway appear, in all respect, homologous to cells giving rise to the crossed tectobulbar pathway in other vertebrates."  
    and 2 Cited by's. 


1998    
Diencephalic and mesencephalic projections to rhombencephalic reticular nuclei in lampreys.
http://www.ncbi.nlm.nih.gov/pubmed/9748487
    "Behavioral studies in lampreys of the northern genera, Ichthyomyzon, reveal that sensory inputs initiate and modulate locomotion by activation of reticulospinal (RS) neurones, which constitute the primary descending system involved in motor activity.  
    The interneurones relaying afferent vestibular, trigeminal, lateral line, cutaneous and proprioceptive inputs are localized in the rhombencephalic region of the lamprey brainstem, unlike the visual inputs that are relayed in the mesencephalic region.  
    The knowledge of diencephalic-mesencephalic cell distributions that project to the RS neurones is limited. They were isolated by iontophoretically injecting cobalt-lysine in vitro into the middle (MRRN) and posterior (PRRN) rhombencephalic reticular nuclei of Petromyzon marinus and Ichthyomyzon unicuspis, Fourteen of 31 injections were successful (MRRN, 7; PRRN, 7).  
    Cell groups were labeled ipsilateral to the injection site in the thalamus (corpi geniculati; pars dorsalis thalami lateralis and medialis; nucleus (n.) subhabenularis lateralis), in the epithalamus (n. commissura posteriori) and in the pretectum.  
    Cell groups were labeled bilaterally within the dorsal region along the diencephalic-mesencephalic border (caudal pretectum and rostral tectum opticum), in tectum opticum, torus semicircularis, and tegmentum mesencephali.  
    There were more backfilled cells from MRRN injections (538-6466 cells) than from PRRN injections (53-553 cells) (MW Rank Sum, p < 0.001). The cell bodies were less than 40 microns long ipsilateral to the injection site, and longer contralaterally. Those greater than 50 microns were backfilled from PRRN injections.  
    The location and organization of the cell groups identified is comparable to that of other vertebrates."
    145 Related citations:
http://www.ncbi.nlm.nih.gov/pubmed?linkname=pubmed_pubmed&from_uid=9748487  


2000     
Stimulation of the mesencephalic locomotor region elicits controlled swimming in semi-intact lampreys.
    "Taken together, the present results indicate that, as higher vertebrates, lampreys possess a specific mesencephalic region that controls locomotion, and the effects onto the spinal cord are relayed by brainstem RS neurons."  
   See:  Initiation of Locomotion in Lampreys  for full Abstract, Related citations and Cited by's.            
   
2003       
Differential contribution of reticulospinal cells to the control of locomotion induced by the mesencephalic locomotor region. (PubMed)   
    Full length HTML available online for free. 
from the abstract   
    "In lampreys as in other vertebrates, the reticulospinal (RS) system
(Reticular Formation) relays inputs from the mesencephalic locomotor region (MLR) to the spinal locomotor networks  (Spinal Locomotor Generator) .    
    Semi-intact preparations of larval sea lamprey were used to determine the relative contribution of the middle (MRRN) and the posterior (PRRN) rhombencephalic reticular nuclei to swimming controlled by the MLR. Intracellular recordings were performed to examine the inputs from the MLR to RS neurons. Stimulation of the MLR elicited monosynaptic excitatory responses of a higher magnitude in the MRRN than in the PRRN. This differential effect was not attributed to intrinsic properties of RS neurons. Paired recordings showed that at threshold intensity for swimming, spiking activity was primarily elicited in RS cells of the MRRN. Interestingly, cells of the PRRN began to discharge at higher stimulation intensities only when MRRN cells had reached their maximal discharge rate.  
    Glutamate antagonists were ejected in either nucleus to reduce their activity. Ejections over the MRRN increased the stimulation threshold for evoking locomotion and resulted in a marked decrease in the swimming frequency and the strength of the muscle contractions. Ejections over the PRRN decreased the frequency of swimming.  
    This study provides support for the concept that RS cells show a specific recruitment pattern during MLR-induced locomotion. RS cells in the MRRN are primarily involved in initiation and maintenance of low-intensity swimming. At higher frequency locomotor rhythm, RS cells in both the MRRN and the PRRN are recruited." 
My comments:       
1.  "
In lampreys as in other vertebrates, the reticulospinal (RS) system (
Reticular Formation) relays inputs from the mesencephalic locomotor region (MLR) to the spinal locomotor networks (Spinal Locomotor Generator)."  This is a very important statement.  What references does the paper give?
2.  "
Ejections over the MRRN increased the stimulation threshold ..."   They're still conflating Neuromodulators  with Neurotransmitters .  Please see:   Neuromodulators vs Neurotransmitters  .
from the HTML          
    "
Locomotion is a rhythmic motor activity generated by spinal neural networks, referred to as a central pattern generator (CPG) (Grillner and Wallén 1999; Rossignol and Dubuc 1994). "  
    "
Most of the connectivity to and from the MLR has been studied in mammals, and the major findings have been reviewed (Grillner et al. 1997; Jordan 1998). There are several lines of evidence showing that stimulation of the MLR activates the CPG through a monosynaptic activation of reticulospinal (RS) neurons located in both the pons and the medulla."  
    "
The MLR has been described in lampreys, a lower vertebrate model with a comparatively simpler nervous system (Sirota et al. 2000). This locomotor region provides mixed monosynaptic inputs, mostly glutamatergic and cholinergic, onto RS cells (Le Ray et al. 2003). The RS system of lampreys constitutes the main descending pathway and provides excitatory inputs to the spinal locomotor networks (Buchanan et al. 1987; Ohta and Grillner 1989). "   
    "
The MRRN and PRRN are the primary sources of inputs to the spinal cord, representing ~90% of the descending neurons (Bussières 1994)."  
    "
The connectivity between the MLR and RS cells was first investigated by applying single stimulation shocks in the MLR. Intracellular recordings were made from 70 RS cells in 15 preparations. Of these, 42 cells were located in the MRRN and 28 in the PRRN. The evoked postsynaptic potentials (PSPs) were examined and compared with respect to their peak amplitude, duration, and slope."  
    "
The MLR elicited monosynaptic EPSPs of a greater magnitude in RS cells of the MRRN than of the PRRN. As the MLR stimulation intensity was increased, RS cells of the MRRN were first recruited until they reached a plateau in their firing rate. Only then, RS neurons of the PRRN were recruited."  
    "
By testing the synaptic connections, we showed that the largest part (if not all) of the MLR inputs onto RS cells is monosynaptic. Reticulospinal cells of the PRRN showed synaptic responses with a longer latency than those of the MRRN (ca. 3.8 ms). Although we cannot exclude the presence of an additional relay neurons between the MLR and PRRN cells, this difference is likely to result from the longer distance between the MLR and the PRRN compared with the MRRN."  
    "
A salient finding of the present study is that the monosynaptic MLR-evoked responses had a significantly greater magnitude in RS cells of the MRRN as compared with those of the PRRN. "  
    "
A considerable body of evidence suggests an involvement of the RS system in initiating and modulating locomotor activity in all vertebrates (Drew 1991; Jordan 1998; Ohta and Grillner 1989; Orlovsky 1972). As was first proposed in cats by Orlovsky (1970), RS cells play a key role in relaying the MLR command to the spinal CPGs. This was demonstrated in a number of vertebrate species afterwards (see for review Grillner et al. 1997)."  
    "
In mammals, neurophysiological investigations have demonstrated that the medial medullary reticular formation plays an important role in goal-directed behavior by relaying MLR inputs to the spinal locomotor networks via the ventrolateral funiculus (Atsuta et al. 1990; Garcia-Rill and Skinner 1987a,b; Iwakiri et al. 1995; Marlinsky and Voitenko 1991; Noga et al. 1991; Orlovsky 1970). These findings are supported by neuroanatomical evidence showing dense projections to the medullary reticular formation from MLR, specifically to the n. gigantocellularis and n. magnocellularis (Lai et al. 1999; Skinner et al. 1990; Steeves and Jordan 1984).  
    We show here, in lampreys, that MLR inputs are larger in RS cells of the MRRN than those of the PRRN. The phylogenetic homology between the reticular formation of mammals and that of the lamprey is not established, but according to its anatomical position, the MRRN would correspond to the pontine reticular formation of mammals, whereas the PRRN would be part of the medullary reticular formation. Large RS cells in the MRRN (Müller cells) send their axons medially in the spinal cord (Rovainen et al. 1973)."  
My additional comments:   
3.   Much, but not all, of the this paper discusses  EPSPs.  These have the advantage of not being subject to the Neuromodulators vs Neurotransmitters  confusion.

  
 
2005    
Midbrain Ataxia: An Introduction to the Mesencephalic Locomotor Region and the Pedunculopontine Nucleus  (Goog)    
Full length HTML online for free. 
     "A careful study in the cat revealed that the predominant output of the mesencephalic locomotor region is through the reticulospinal system, including portions of the ventral and anterior parts of the nucleus gigantocellularis and posterior and ventral portions of the nucleus reticularis ventralis and nucleus reticularis magnocellularis
[3]. These efferents to the medioventral medulla in turn modulate spinal locomotor pathways  [10]." 
    "The output of the mesencephalic locomotor region seems to be bilaterally distributed to the reticulospinal cells in the ventromedial medulla, with an ipsilateral predominance [3]." 
    "Most reticulospinal cells in the ventromedial medulla receiving mesencephalic locomotor region input project to the spinal cord through the ventrolateral funiculus ipsilateral to the mesencephalic locomotor region—that is, through the medullary reticulospinal tract." 
    "A main component of the mesencephalic locomotor region is the PPN, which is thought on the basis of animal studies to be involved in the initiation and modulation of gait, among other functions [5]. The PPN is a heterogeneous population of neurons, lying in the dorsal midbrain as part of the mesencephalic reticular formation."  
    "Two main subdivisions of the PPN have been recognized: a pars compacta of the PPN (PPNc), located in the caudal part of the nucleus, and a second part known as the pars dissipatus (PPNd). These have been described in humans and monkeys [14]. Most of the PPNc neurons are cholinergic. The PPNd has a higher proportion of glutaminergic neurons [14]. Much work in humans remains to be done on the precise connectivity of the PPN. However, primate data suggest that the main inputs to the PPN are from the internal segment of the globus pallidus and the pars reticularis of the substantia nigra [15].   
    Other proposed inputs are from the subthalamic nucleus and the cerebral cortex [4]. Proposed outputs of the PPN in primates are to the globus pallidus, pars compacta of the substantia nigra, subthalamic nucleus, striatum, cerebral cortex, and descending efferents to the spinal cord from the PPNd [4].   
    Electrophysiologic studies suggest that the glutaminergic PPNd neurons are related to the initiation of programmed movements, whereas the cholinergic PPNc neurons are related to the maintenance of steady-state locomotion [16]. Furthermore, neuropathologic studies in humans show a significant loss of cholinergic neurons in the PPNc of patients with progressive supranuclear palsy, idiopathic Parkinson's disease, and combined Parkinson's and Alzheimer's disease [16, 17].   
    In addition to helping modulate locomotion, the PPN may also have a role in regulating postural muscle tone, based on efferents to areas of the pons known as the dorsal tegmental field and the ventral tegmental field [18, 19]."  


1. Afifi AK, Bergman RA. Functional neuroanatomy: text and analysis. New York, NY: McGraw-Hill, 1997:230
2. Steeves JD, Jordan LM. Autoradiographic demonstration of the projections from the mesencephalic locomotor region. Brain Res 1984; 307:263-276
    http://www.ncbi.nlm.nih.gov/pubmed/?term=6466996         
3. Garcia-Rill E, Skinner R. The mesencephalic locomotor region. 2. Projections to reticulospinal neurons. Brain Res 1987; 411:13-20   
    http://www.ncbi.nlm.nih.gov/pubmed/?term=3607422
        
4. Pahapill P, Lozano A. The pedunculopontine nucleus and Parkinson's disease. Brain 2000; 123:1767-1783   
    http://www.ncbi.nlm.nih.gov/pubmed/?term=10960043 

5. Garcia-Rill E, Houser CR, Skinner RD, Smith W, Woodward DJ. Locomotion-inducing sites in the vicinity of the pedunculopontine nucleus. Brain Res Bull 1987; 18:731-738
   
http://www.ncbi.nlm.nih.gov/pubmed/?term=3304544   
6. Bhidayasiri R, Hathout G, Cohen SN, Tourtellotte WW. Midbrain ataxia: possible role of the pedunculopontine nucleus in human locomotion. Cerebrovasc Dis 2003; 16:95-96      
   
http://www.ncbi.nlm.nih.gov/pubmed/?term=12766370  
7. Masdeu JC, Alampur U, Cavaliere R, Tavoulareas G. Ataxia and gait failure with damage of the pontomesencephalic locomotor region. Ann Neurol 1994; 35:619-621
   
http://www.ncbi.nlm.nih.gov/pubmed/?term=8179307  

8. Shik ML, Yagodnitzyn AS. Control of walking and running by means of electrical stimulation of the midbrain. Biofizika 1966; 11:755-765   
   
http://www.ncbi.nlm.nih.gov/pubmed/?term=4181500   
9. Lee PH, Lee JS, Lee MH, Lee JD, Huh K. Subtraction brain SPECT imaging in a patient with gait ignition failure. Mov Disord 2003; 18:1542-1545   
   
http://www.ncbi.nlm.nih.gov/pubmed/?term=14673896 
10. Orlovsky GN. Connections between reticulospinal neurons and locomotor regions of the brainstem. Biofizika 1978; 15:58-64  Not found in PubMed.  Google finds:   
    http://link.springer.com/article/10.1007/BF01126317#page-1   

11. Castiglioni AJ, Galloway MC, Coulter JD. Spinal projections from the midbrain in monkey. J Comp Neurol 1978; 178:329-346  No abstract but Related Citations and Cited By's:       
    
http://www.ncbi.nlm.nih.gov/pubmed/?term=415074      
12. Nutt JG, Mardsen CD, Thompson PD. Human walking and higher-lateral gait disorders particularly in the elderly. Neurology 1993; 43:268-279  
   
No abstract but Related Citations and Cited By's: 
   
http://www.ncbi.nlm.nih.gov/pubmed/?term=8437689   
13. Eidelberg E, Walden JG, Nguyen LH. Locomotor control in macaque monkeys. Brain 1981; 104:647-663
   
http://www.ncbi.nlm.nih.gov/pubmed/?term=7326562   
14. Mesulam MM, Geula C, Bothwell MA, Hersh LB. Human reticular formation: cholinergic neurons of the pedunculopontine and laterodorsal tegmental nuclei and some cytochemical comparisons to forebrain cholinergic neurons. J Comp Neurol 1989; 283:611-63
   
http://www.ncbi.nlm.nih.gov/pubmed/?term=2545747   
15. Shink E, Sidibe M, Smith Y. Efferent connections of the internal globus pallidus in the squirrel monkey. 2. Topography and synaptic organization of pallidal efferents to the pedunculopontine nucleus. J Comp Neurol 1997; 382:348-363  
   
http://www.ncbi.nlm.nih.gov/pubmed/?term=9183698     

16. Zweig RM, Jankel WR, Hedreen JC, Mayeux R, Price DL. The pedunculopontine nucleus in Parkinson's disease. Ann Neurol 1989; 26:41-46   
   
http://www.ncbi.nlm.nih.gov/pubmed/?term=2549845   
17. Jellinger K. The pedunculopontine nucleus in Parkinson's disease, progressive supranuclear palsy and Alzheimer's disease. J Neurol Neurosurg Psychiatry 1988; 51:540-543        http://www.ncbi.nlm.nih.gov/pubmed/?term=3379428   
   
Free PMC Article      
18. Mori S, Matsui T, Kuze B, Asanome M, Nakajima K, Matsuyama K. Stimulation of a restricted region in the midline cerebellar white matter evokes coordinated quadrupedal locomotion in the decerebrate cat. J Neurophysiol 1999; 82:290-300 
     
http://www.ncbi.nlm.nih.gov/pubmed/?term=10400958   
Free full text   
   
http://jn.physiology.org/content/82/1/290.long  
19. Mori S, Kawahara K, Sakamoto T, Aoki M, Tomiyama T. Setting and resetting of level of postural muscle tone in decerebrate cat by stimulation of brainstem. J Neurophysiol 1982; 48:737-748    
   
http://www.ncbi.nlm.nih.gov/pubmed/?term=7131051   
    No abstract, but Related citations & Cited by's. 
20. Reese N, Garcia-Rill E, Skinner R. The pedunculopontine nucleus: auditory input, arousal and pathophysiology. Prog Neurobiol 1995; 42:105-133  
   
http://www.ncbi.nlm.nih.gov/pubmed/8711130  

   
2008    
Mesencephalic Locomotor Region - PAEI - Structures of Concern (Goog)    
Short full length HTML available online for free. 
    "
Locomotive behavioral routines are the product of central pattern generators controlled by descending brainstem reticulospinal pathways.
    The reticulospinal area receives inputs from the exploratory, appetitive and defensive locomotor systems through the MLR. Activity in the cerebellar fastigial nucleus may also induce locomotion through a relay in the reticulospinal area.  
    Appetitive and defensive input to the MLR comes from the lateral hypothalamus and medial hypothalamus/PAG, respectively. These two hypothalamic sources also send collateral inputs directly to the reticulospinal locomotor area.  
    The exploratory system is driven by inhibitory pallidal output from the basal ganglia that is thought to disinhibit the MLR.
"  
My comments
    In addition to the MLR, "two hypothalamic sources also send collateral inputs directly to the reticulospinal locomotor area".  So not all motor commands pass through the MLR.  Some go around it directly to the Spinal Locomotor Generator.

    Bibliography
1. Sinnamon, H. M. (1993). “Preoptic And Hypothalamic Neurons And The Initiation Of Locomotion In The Anesthetized Rat.”
    Progress in Neurobiology
, 41(323-344).
2. Allen, L. F., Inglis, W. L., & Winn, R. (1996). “Is The Cuneiform Nucleus A Critical Component Of The Mesencephalic Locomotor Region? An Examination Of The Effects Of Excitotoxic Lesions Of The Cuneiform Nucleus On Spontaneous and nucleus accumbens induced locomotion.”
    Brain Research Bulletin
41, (4), 201-210.
3. Jordan, L. M. (1998). “Initiation Of Locomotion In Mammals.”
    Annals Of The New York Academy of Sciences
, 860, 83-93.
4. Porges, S. W. (2001). “The polyvagal theory: phylogenetic substrates of a social nervous system.”
    International Journal of Psychophysiology, 42, 123-146.
5. Porges, S. W. (2003). “The Polyvagal Theory: phylogenetic contributions to social behavior.”
    Physiology & Behavior
, 79, 503-513.   


2008
Afferent and efferent connections of the mesencephalic reticular formation in goldfish.
http://www.ncbi.nlm.nih.gov/pubmed/18331918  
    "
The physiology of the mesencephalic reticular formation (MRF) in goldfish suggests its contribution to eye and body movements, but the afferent and efferent connections underlying such movements have not been determined. Therefore, we injected the bidirectional tracer biotinylated dextran amine into functionally identified MRF sites. We found retrogradely labelled neurons and anterogradely labelled boutons within nuclei of the following brain regions:  
    (1) the telencephalon: a weak and reciprocal connectivity was confined to the central zone of area dorsalis and ventral nucleus of area ventralis;  
    (2) the diencephalon: reciprocal connections were abundant in the ventral and dorsal thalamic nuclei; the central pretectal nucleus was also reciprocally wired with the MRF, but only boutons were present in the superficial pretectal nucleus; the preoptic and suprachiasmatic nuclei showed abundant neurons and boutons; the MRF was reciprocally connected with the preglomerular complex and the anterior tuberal nucleus;  
    (3) the mesencephalon: neurons and boutons were abundant within deep tectal layers; reciprocal connections were also present within the torus semicircularis and the contralateral MRF; neurons were abundant within the nucleus isthmi; and  
    (4) the rhombencephalon: the superior and middle parts of the reticular formation received strong projections from the MRF, while the projection to the inferior area was weaker; sparse neurons were present throughout the reticular formation; a reciprocal connectivity was observed with the sensory trigeminal nucleus; the medial and magnocellular nuclei of the octaval column projected to the MRF. These results support the participation of the MRF in the orienting response. The MRF could also be i
nvolved in other motor tasks triggered by visual, auditory, vestibular, or somatosensory signals."    
My comments
1.  Although we humans are not directly descended from  Teleosts  , I'm going to assume that the physiology presented here was already present in our common ancestor.    
2.  My interpretation of this reference assumes that MRF = MLR. 


2011

Internal pallidum and substantia nigra control different parts of the mesopontine reticular formation in primate.
  
http://www.ncbi.nlm.nih.gov/pubmed/21469212  
    "The locomotor area has recently emerged as a target for deep brain stimulation to lessen gait disturbances in advanced parkinsonian patients. An important step in choosing this target is to define anatomical limits of its 2 components, the pedunculopontine nucleus and the cuneiform nucleus, their connections with the basal ganglia, and their output descending pathway.  
    Based on the hypothesis that pedunculopontine nucleus controls locomotion whereas cuneiform nucleus controls axial posture, we analyzed whether both nuclei receive inputs from the internal pallidum and substantia nigra using anterograde and retrograde tract tracing in monkeys. We also examined whether these nuclei convey descending projections to the reticulospinal pathway.  
    Pallidal terminals were densely distributed and restricted to the pedunculopontine nucleus, whereas nigral terminals were diffusely observed in the whole extent of both the pedunculopontine nucleus and the cuneiform nucleus. Moreover, nigral terminals formed symmetric synapses with pedunculopontine nucleus and cuneiform nucleus dendrites. 
    Retrograde tracing experiments confirmed these results because labeled cell bodies were observed in both the internal pallidum and substantia nigra after pedunculopontine nucleus injection, but only in the substantia nigra after cuneiform nucleus injection. 
    Furthermore, anterograde tracing experiments revealed that the pedunculopontine nucleus and cuneiform nucleus project to large portions of the pontomedullary reticular formation.  
    This is the first anatomical evidence that the internal pallidum and the substantia nigra control different parts of the brain stem and can modulate the descending reticulospinal pathway in primates. These findings support the functional hypothesis that the nigro-cuneiform nucleus pathway could control axial posture whereas the pallido-pedunculopontine nucleus pathway could modulate locomotion."  
My comment:   
    Interesting discussion of the pedunculopontine nucleus and the cuneiform nucleus, but nothing about neurotransmitters.     
    115 Related citations:   
See the PubMed abstract page.     


2011     
Chapter 4--supraspinal control of locomotion: the Mesencephalic Locomotor Region (Goog)   
Only abstract available online. 
    "
Locomotion is a basic motor function generated and controlled by genetically defined neuronal networks. The pattern of muscle synergies is generated in the spinal cord, whereas neural centers located above the spinal cord in the brainstem and the forebrain are essential for initiating and controlling locomotor movements.
"  
    "
The lamprey MLR is a well-circumscribed region located at the junction between the midbrain and hindbrain. Stimulation of the MLR induces locomotion with an intensity that increases with the stimulation strength. Glutamatergic and cholinergic monosynaptic inputs from the MLR are responsible for excitation of reticulospinal (RS) cells that in turn activate the spinal locomotor networks.
"  
   
The inputs are larger in the rostral than in the caudal hindbrain RS cells. MLR stimulation on one side elicits symmetrical excitatory inputs in RS cells on both sides, and this is linked to bilateral projections of the MLR to RS cells. 
   
In addition to its inputs to RS cells, the MLR activates a well-defined group of muscarinoceptive cells in the brainstem that feeds back strong excitation to RS cells in order to amplify the locomotor output. Finally, the MLR gates sensory inputs to the brainstem through a muscarinic mechanism. It appears therefore that the MLR not only controls locomotor activity but also filters sensory influx during locomotion.

    My comments
"
Glutamatergic and cholinergic monosynaptic inputs from the MLR are responsible for excitation of reticulospinal (RS) cells that in turn activate the spinal locomotor networks."  Where does GABA fit into this?           124 Related citations
http://www.ncbi.nlm.nih.gov/pubmed?linkname=pubmed_pubmed&from_uid=21333802    

2013
The multifunctional mesencephalic locomotor region. 
    "In 1966, Shik, Severin and Orlovskii discovered that electrical stimulation of a region at the junction between the midbrain and hindbrain elicited controlled walking and running in the cat. The region was named Mesencephalic Locomotor Region (MLR).  
    Since then, this locomotor center was shown to control locomotion in various vertebrate species, including the lamprey, salamander, stingray, rat, guinea-pig, rabbit or monkey.  
    In human subjects asked to imagine they are walking, there is an increased activity in brainstem nuclei corresponding to the MLR (i.e. pedunculopontine, cuneiform and subcuneiform nuclei). Clinicians are now stimulating (deep brain stimulation) structures considered to be part of the MLR to alleviate locomotor symptoms of patients with Parkinson's disease. However, the anatomical constituents of the MLR still remain a matter of debate, especially relative to the pedunculopontine, cuneiform and subcuneiform nuclei. Furthermore, recent studies in lampreys have revealed that the MLR is more complex than a simple relay in a serial descending pathway activating the spinal locomotor circuits. It has multiple functions. Our goal is to review the current knowledge relative to the anatomical constituents of the MLR, and its physiological role, from lamprey to man. We will discuss these results in the context of the recent clinical studies involving stimulation of the MLR in patients with Parkinson's disease."  
   



2014
Identification of a brainstem circuit regulating visual cortical state in parallel with locomotion.
http://www.ncbi.nlm.nih.gov/pubmed/25033185  

Abstract
    "Sensory processing is dependent upon behavioral state. In mice, locomotion is accompanied by changes in cortical state and enhanced visual responses. Although recent studies have begun to elucidate intrinsic cortical mechanisms underlying this effect, the neural circuits that initially couple locomotion to cortical processing are unknown. The mesencephalic locomotor region (MLR) has been shown to be capable of initiating running and is associated with the ascending reticular activating system. Here, we find that optogenetic stimulation of the MLR in awake, head-fixed mice can induce both locomotion and increases in the gain of cortical responses. MLR stimulation below the threshold for overt movement similarly changed cortical processing, revealing that MLR's effects on cortex are dissociable from locomotion. Likewise, stimulation of MLR projections to the basal forebrain also enhanced cortical responses, suggesting a pathway linking the MLR to cortex. These studies demonstrate that the MLR regulates cortical state in parallel with locomotion." 
    2 Cited by's
See article.  No link summary.     

   

2015
The physiology of the pedunculopontine nucleus: implications for deep brain stimulation. http://www.ncbi.nlm.nih.gov/pubmed/24880787  
 
Abstract
    "This brief review resolves a number of persistent conflicts regarding the location and characteristics of the mesencephalic locomotor region, which has in the past been described as not locomotion-specific and is more likely the pedunculopontine nucleus (PPN).  
    The parameters of stimulation used to elicit changes in posture and locomotion we now know are ideally suited to match the intrinsic membrane properties of PPN neurons. The physiology of these cells is important not only because it is a major element of the reticular activating system, but also because it is a novel target for the treatment of gait and postural deficits in Parkinson's disease (PD). The discussion explains many of the effects reported following deep brain stimulation (DBS) of the PPN by different groups and provides guidelines for the determination of long-term assessment and effects of PPN DBS. A greater understanding of the physiology of the target nuclei within the brainstem and basal ganglia, amassed over the past decades, has enabled increasingly better patient outcomes from DBS for movement disorders. Despite these improvements, there remains a great opportunity for further understanding of the mechanisms through which DBS has its effects and for further development of appropriate technology to effect these treatments.  
We review the scientific basis for one of the newest targets, the PPN, in the treatment of PD and other movement disorders, and address the needs for further investigation."   
    1 Cited by
No link.  See article.         


04-02-16 

Subpallidal Area/Region references mentioning the MLR   .  

1983   21<22  &  22<23     * *      Free full text   
Neural projections from nucleus accumbens to globus pallidus, substantia innominata, and lateral preoptic-lateral hypothalamic area 
http://www.ncbi.nlm.nih.gov/pubmed/6822855   
    See:  Nucleus Accumbens Septi   for full Abstract, Similar articles, Cirted by's and Full Free Text   

1984  19<22 ,  20< 23  , 6<6 ,  7<7   
Evidence for a projection from the lateral preoptic area and substantia innominata to the 'mesencephalic locomotor region' in the rat   

http://www.ncbi.nlm.nih.gov/pubmed/6201228  
    "
These results clearly suggest that the subpallidal region projects directly to the pedunculopontine nucleus and adjacent regions including the central gray and the superior colliculus."  


1985  17<22 ,  15<23 ,  3<6 ,  5<7    * 
An electrophysiological study of the neural projections from the hippocampus to the ventral pallidum and the subpallidal areas by way of the nucleus accumbens.   
http://www.ncbi.nlm.nih.gov/pubmed/4047397   
    "
The presence of a projection from ventral pallidal and subpallidal regions to the brainstem mesencephalic locomotor region further supports the hypothesis that limbic (e.g. hippocampus) can influence somatomotor activities by way of the nucleus accumbens and its efferent projection to ventral pallidal and subpallidal regions."  
    Note:  "nucleus accumbens and its efferent projection to ventral pallidal and subpallidal regions"   
Is the nucleus accumbens the only input to the ventral pallidal and subpallidal regions?  If not, what else is there? 
I should come back to this.   


1985    16<23 , 4<6   * 
Evidence that projections from substantia innominata to zona incerta and mesencephalic locomotor region contribute to locomotor activity. 
http://www.ncbi.nlm.nih.gov/pubmed/3995314   
    "
Taken together these observations suggest the tentative working hypothesis that projections from the substantia innominata to the zona incerta as well as the pedunculopontine nucleus may contribute to the locomotor component of adaptive behaviors resulting from limbic forebrain integrative activities"  



1986    16<20   &  14<23 
Subpallidal projections to the mesencephalic locomotor region investigated with a combination of behavioral and electrophysiological recording tech...   
http://www.ncbi.nlm.nih.gov/pubmed/3011220   
    "
These observations provide additional evidence that subpallidal-MLR neurons are associated with locomotion."  


1988  13<22 
Hypothalamic substrates for brain stimulation-induced patterns of locomotion and escape jumps in the rat. 
http://www.ncbi.nlm.nih.gov/pubmed/3395850   
    "
Exploratory locomotion is mainly induced from the lateral hypothalamus, while flight-directed locomotion and escape jumps are evoked from the medial hypothalamus. The response area for exploratory locomotion reflects the lateral hypothalamic distribution of the subpallidal projection to the mesencephalic locomotor region."  




1988   10<23  *
Differential effects on locomotor activity of injections of procaine into mediodorsal thalamus and pedunculopontine nucleus. 
http://www.ncbi.nlm.nih.gov/pubmed/3370506   
    "
Since the pedunculopontine nucleus is part of the mesencephalic locomotor region (MLR) it appears that subpallido-pedunculopontine projections contribute to the locomotor component of adaptive behaviors associated with limbic integrative activities."  



1991  7<22 ,  1<6 ,  2<7 
The contribution of basal forebrain to limbic-motor integration and the mediation of motivation to action.  
http://www.ncbi.nlm.nih.gov/pubmed/1776572       
    "
Furthermore, both hippocampal output signals and dopaminergic input to the accumbens descend via ventral and subpallidal areas serially to the pedunculopontine nucleus, the region of the mesencephalic locomotor region. 



1993    4<23
Decreases in rat locomotor activity as a result of changes in synaptic transmission to neurons within the mesencephalic locomotor region. 
http://www.ncbi.nlm.nih.gov/pubmed/8402406     
    "
The mesencephalic locomotor region is defined as a functional region sending signals to the spinal cord generators of rhythmical limb movements for locomotion. It has been shown that the mesencephalic locomotor region plays a critical role in locomotion initiated from the nucleus accumbens or from the subpallidal region."  



1996  1<23    * * 
C-Fos immunohistochemical localization of neurons in the mesencephalic locomotor region in the rat brain. 
http://www.ncbi.nlm.nih.gov/pubmed/8951873   
    "
This strip of immunostained cells represents neurons which are involved in the initiation and maintenance of locomotor activity due to subpallidal activation (predominantly pedunculopontine and cuneiform nuclei)





SubC   
MLR:  150308 - 1104 (original)      






 


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