Anatomical evidence for functional diversity in the mesencephalic locomotor region of primates
Introduction
The pedunculopontine nucleus (PPN) is located within the mesencephalic reticular formation of the upper brainstem. Together with the cuneiform nucleus (CuN), they have been named “the mesencephalic locomotor region” (MLR) because early studies showed that electrical stimulation of the MLR produces locomotion in various animal species (Garcia-Rill et al., 2014). Because of its anatomical location and the possibility to generate locomotor pattern, the MLR is considered to be a key generator of gait in the brain. However, the specific roles of the PPN and the CuN remain unclear, even if in decerebrate cat, stimulation of the CuN elicits locomotor patterns whereas stimulation of the PPN is able to change muscle tone (Takakusaki et al., 2003). Because the PPN and the CuN have no clear cut boundaries and are composed of clusters of various neuronal types (GABAergic, glutamatergic, cholinergic) (Mena-Segovia et al., 2009, Wang and Morales, 2009), their precise anatomical identification leads to divergence between authors and increases the confusion between these two nuclei. Recently, deep brain stimulation (DBS) of the PPN area has been attempted in patients with Parkinson disease to improve gait disorders (Ferraye et al., 2009, Mazzone et al., 2005, Moro et al., 2010). Even if expected alleviation of gait remains disappointing, clinical and electrophysiological results strongly suggest that the MLR controls locomotion also in humans (Lau et al., 2015, Piallat et al., 2009, Tattersall et al., 2014). However, the precise implantation target within the MLR remains undefined, some suggests that DBS of the CuN should give better results than PPN DBS (Moro et al., 2010).
Besides locomotion, the MLR is known to control many other functions in the brain. As a part of the ascending reticular activating system, the PPN regulates sleep and arousal in rat (Datta, 2002, Steriade et al., 1990). Lesioning the rat PPN also affects attentional resources (Ainge et al., 2006, Okada et al., 2009), learning, reward and reinforcement processes (Inglis et al., 2001, Kozak et al., 2004, Steiniger and Kretschmer, 2004). PPN manipulations in rat are able to alter self-administration of nicotine and cocaine (Corrigall et al., 2002). In the macaque, PPN neurons send positive reward-related signals to nigral neurons where dopaminergic neurons are known to encode motivational values (Hong and Hikosaka, 2014, Okada and Kobayashi, 2013). In PD patients, DBS of the PPN has been shown to modulate non-motor functions. Indeed, PPN DBS could significantly improve sleep (Arnulf et al., 2010), executive functions and working memory (Stefani et al., 2013). These results emphasise the complex and integrative role of the PPN (Lau et al., 2015). The role of the CuN is much less known but this nucleus seems implicated in locomotion if related to aversive reactions, and in the perception of nociception in rodents (Allen et al., 1996). This result highlights the fact that the CuN is not just devoted to generating locomotion – it also integrates contextual information.
Analysis of the detailed connectivity of the MLR should help us understand the specific role that the PPN and CuN could play in motor, cognitive and emotional functions. Tract tracing studies in monkey have revealed that the PPN receives afferents from the motor cortices (Matsumura et al., 2000), from the output structures of the basal ganglia (internal pallidum (GPi) and substantia nigra (SN)) and from the subthalamic nucleus (STN) (Lavoie and Parent, 1994a, Lavoie and Parent, 1994b, Shink et al., 1997). The PPN ascending pathway projects to non-specific nuclei of the thalamus, in particular to the centre-median-parafascicular nuclei (CM-PF) (Parent et al., 1988, Steriade et al., 1988). The PPN descending outputs project to the ponto-bulbar reticulospinal formation (Rolland et al., 2011). Even if the connections of the CuN are less known, it has been demonstrated in monkey that the CuN only receives projections from the SN (Rolland et al., 2011) and projects back to various thalamic nuclei (Lavoie and Parent, 1994a), to dopaminergic neurons of the mesencephalon (Hong and Hikosaka, 2014), and to the reticulospinal formation (Rolland et al., 2011). Anatomical connectivity has also been explored in vivo in primates using diffusion weighted imaging (DWI). This technique is the only non-invasive method allowing access to white matter structural connectivity (Le Bihan et al., 1986) through tractography algorithms (Mori and van Zijl, 2002). Results of DWI-based analyses provide evidence for strong connections between the PPN and the cortex, pallidum, STN, thalamus and spinal cord in macaque and human (Aravamuthan et al., 2007, Aravamuthan et al., 2009, Muthusamy et al., 2007).
Altogether, these anatomical results provide insights into the complex connectivity of the MLR and its close relationship with basal ganglia. However, the delineation of the PPN remains controversial, the CuN connectivity remains poorly studied, and the connectivity of these two specific nuclei has not been determined in relation to the anatomo-functional subdivisions of different brain structures. This partial anatomical knowledge of the MLR limits our understanding of the specific role of the PPN and the CuN. The aim of our study was to examine the PPN and the CuN inputs and outputs focusing on how projection patterns relate to the cortical, basal-ganglia, amygdala and thalamic anatomo-functional territories that process sensorimotor, cognitive and emotional information. For this purpose, we used tract-tracing experiments in monkeys and DWI-based tractography in humans.
Section snippets
Monkeys and volunteers
All experiments were carried out in strict accordance with the European Community Council Directive of 2010 (2010/63/UE) for care and use of laboratory animals. The authorisation for conducting our experiments was approved by the local Committee on the Ethics of Animal Experiments. The animals were kept under standard conditions (12-h light/dark cycle [light on at 20 h], 23 °C and 50% humidity). We used five adult monkeys weighing between 2 and 5 kg (four Macaca fascicularis, MI53, MI58, MI82,
Injections sites
In monkey, we performed two BDA injections into the PPN, one restricted to the anterior part (CA8) and one to the posterior part of the nucleus (MIW7). Similarly, we performed two BDA injections into the CuN, one restricted to the anterior part (MI58), and one to the posterior part of the nucleus (MI53, left side). A fifth larger injection including both PPN and CuN was also performed (MI53, right side) (Fig. 2A).
Cortical projections to the PPN and CuN
In monkey, numerous retrogradely labelled cell bodies were found in the premotor
Discussion
Our study supports the view that both the PPN and the CuN project to the sensorimotor, associative and limbic anatomo-functional territories of the basal ganglia and the thalamus in monkeys and humans. The analysis of these projections highlights the fact that the PPN could act as an integrator of sensorimotor, cognitive and emotional information, with the anterior part of the PPN more devoted to motor control in the monkey. In contrast, the CuN appears to participate in a more restricted
Conclusion
Overall, our results suggest that MLR connectivity could form the anatomical basis for the integration of numerous and varied sources of information in order to generate and adapt locomotor behaviour to the environmental context. The PPN appears to be a structure where motor, cognitive and emotional information converge whereas the CuN serves to preferentially process emotional information.
Funding sources for study
Research wad funded by "Investissements d’avenir" (investing in the future) program ANR-10-IAIHU-06, and the ATIP-Avenir program and Sanofi-Aventis R&D to BL. SS has been supported by the Bettencourt Schueller Foundation and by the National Agency for Research under the program "Investissements d’avenir" ANR-10-EQPX-15. Human data were provided by the Human Connectome Project, WU-Minn Consortium (Principal Investigators: David Van Essen and Kamil Ugurbil;1U54MH091657) funded by the 16 NIH
Financial disclosures
The authors declare that there are no financial considerations that represent potential conflicts of interest.
Conflict of interest
The authors declare no conflicts of interest.
Acknowledgements
The authors would like to thank Max Westby for language editing.
References (81)
- et al.
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 Res. Bull.
(1996) - et al.
Cortical and subcortical connections within the pedunculopontine nucleus of the primate Macaca mulatta determined using probabilistic diffusion tractography
J. Clin. Neurosci.
(2009) - et al.
Topography of cortical and subcortical connections of the human pedunculopontine and subthalamic nuclei
Neuroimage
(2007) - et al.
White matter fiber tracts of the human brain: three-dimensional mapping at microscopic resolution, topography and intersubject variability
Neuroimage
(2006) - et al.
Efferent projections of infralimbic and prelimbic areas of the medial prefrontal cortex in the Japanese monkey, Macaca fuscata
Brain Res.
(2001) - et al.
Automatic parcellation of human cortical gyri and sulci using standard anatomical nomenclature
Neuroimage
(2010) - et al.
The primate thalamostriatal systems: anatomical organization, functional roles and possible involvement in Parkinson's disease
Basal Ganglia
(2011) - et al.
The minimal preprocessing pipelines for the Human Connectome Project
Neuroimage
(2013) - et al.
Rivastigmine for gait stability in patients with Parkinson's disease (ReSPonD): a randomised, double-blind, placebo-controlled, phase 2 trial
Lancet Neurol.
(2016) - et al.
Pedunculopontine tegmental nucleus neurons provide reward, sensorimotor, and alerting signals to midbrain dopamine neurons
Neuroscience
(2014)
Selective deficits in attentional performance on the 5-choice serial reaction time task following pedunculopontine tegmental nucleus lesions
Behav. Brain Res.
Confirmation of functional zones within the human subthalamic nucleus: patterns of connectivity and sub-parcellation using diffusion weighted imaging
Neuroimage
Fronto-striatal connections in the human brain: a probabilistic diffusion tractography study
Neurosci. Lett.
Quantification of cholinergic and select non-cholinergic mesopontine neuronal populations in the human brain
Neuroscience
Organization of somatic motor inputs from the frontal lobe to the pedunculopontine tegmental nucleus in the macaque monkey
Neuroscience
Topographical projections from the thalamus, subthalamic nucleus and pedunculopontine tegmental nucleus to the striatum in the Japanese monkey, Macaca fuscata
Brain Res.
Gait is associated with an increase in tonic firing of the sub-cuneiform nucleus neurons
Neuroscience
Further evidence for segregated output channels from superior colliculus in rat: ipsilateral tecto-pontine and tecto-cuneiform projections have different cells of origin
Brain Res.
Differential connections of caudate nucleus and putamen in the squirrel monkey (Saimiri sciureus)
Neuroscience
Advances in diffusion MRI acquisition and processing in the Human Connectome Project
Neuroimage
Effects of ibotenate pedunculopontine tegmental nucleus lesions on exploratory behaviour in the open field
Behav. Brain Res.
Projections of cholinergic and non-cholinergic neurons of the brainstem core to relay and associational thalamic nuclei in the cat and macaque monkey
Neuroscience
Basal ganglia efferents to the brainstem centers controlling postural muscle tone and locomotion: a new concept for understanding motor disorders in basal ganglia dysfunction
Neuroscience
Robust determination of the fibre orientation distribution in diffusion MRI: non-negativity constrained super-resolved spherical deconvolution
Neuroimage
The WU-Minn Human Connectome Project: an overview
Neuroimage
An assessment of the contributions of the pedunculopontine tegmental and cuneiform nuclei to anxiety and neophobia
Neuroscience
Experimental studies of pedunculopontine functions: are they motor, sensory or integrative?
Park. Relat. Disord.
A three-dimensional, histological and deformable atlas of the human basal ganglia. I. Atlas construction based on immunohistochemical and MRI data
Neuroimage
The pedunculopontine tegmental nucleus and responding for sucrose reward
Behav. Neurosci.
A functional dissociation of the anterior and posterior pedunculopontine tegmental nucleus: excitotoxic lesions have differential effects on locomotion and the response to nicotine
Brain Struct. Funct.
The anatomy and localization of the pedunculopontine nucleus determined using probabilistic diffusion tractography [corrected]
Br. J. Neurosurg.
Sleep induced by stimulation in the human pedunculopontine nucleus area
Ann. Neurol.
A three-dimensional histological atlas of the human basal ganglia. II. Atlas deformation strategy and evaluation in deep brain stimulation for Parkinson disease
J. Neurosurg.
Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging
Nat. Neurosci.
History of falls in Parkinson disease is associated with reduced cholinergic activity
Neurology
Clinical trial of blood-brain barrier disruption by pulsed ultrasound
Sci. Transl. Med.
Pharmacological manipulations of the pedunculopontine tegmental nucleus in the rat reduce self-administration of both nicotine and cocaine
Psychopharmacol. (Berl.).
Evidence that REM sleep is controlled by the activation of brain stem pedunculopontine tegmental kainate receptor
J. Neurophysiol.
A major external source of cholinergic innervation of the striatum and nucleus accumbens originates in the brainstem
J. Neurosci.
Measures of the amount of ecologic association between species
Ecology
Cited by (20)
Pedunculopontine tegmental Nucleus-evoked prepulse inhibition of the blink reflex in Parkinson's disease
2021, Clinical NeurophysiologyCitation Excerpt :The pedunculopontine tegmental nucleus (PPTg), a structure located at the level of the pontomesencephalic junction, is part of the locomotor pontomesencephalic region and is involved in a variety of motor and non-motor functions including sleep, arousal and cognition through its complex input–output relationships with several brain regions (Edley and Graybiel, 1983; Lavoie and Parent, 1994; Aravamuthan et al., 2007, 2008; Muthusamy et al., 2007; Androulidakis et al., 2008; Garcia-Rill, 2015; Sebille et al., 2017; Vitale et al., 2019).
The micropig model of neurosurgery and spinal cord injury in experiments of motor control
2020, The Neural Control of Movement: Model Systems and Tools to Study Locomotor FunctionStructure and function of the mesencephalic locomotor region in normal and parkinsonian primates
2019, Current Opinion in PhysiologyCitation Excerpt :The connectivity of the CuN differs markedly from the PPN. Cortical inputs originate preferentially from limbic cortices (e.g. subgenual cingulate and insular cortex), with no (macaque) or much weaker (human) connectivity between the CuN and motor cortices [24] (Figure 2). Connectivity with the basal ganglia and thalamus are also different, with stronger connectivity between the CuN and the limbic parts of the basal ganglia and thalamus than the PPN.
Deep brain stimulation of the pedunculopontine tegmental nucleus and arousal in Parkinson’s disease
2019, Arousal in Neurological and Psychiatric DiseasesSpecific subcortical structures are activated during seizure-induced death in a model of sudden unexpected death in epilepsy (SUDEP): A manganese-enhanced magnetic resonance imaging study
2017, Epilepsy ResearchCitation Excerpt :In these seizure models it has been shown that the acoustic stimulus activates the subcortical auditory structures, which interact with specific sensorimotor-limbic (SML) regions that results in behavioral seizures (Faingold et al., 1986a,b; Faingold et al., 1988; Garcia-Cairasco, 2002), and these structures were considered as potential regions of interest in the current study. Respiratory deficits that occur post-ictally in the DBA/1 mouse and lead to S-IRA may also potentially affect subcortical structures that are known to be involved in the respiratory network (Forster et al., 2012; Garcia-Rill et al., 2013; Lemaire et al., 2014; Sebille et al., 2016; Sowers et al., 2013; Welsh et al., 2002; Zeng et al., 2015). Therefore, the present MEMRI study also examined if changes in neural activity occur at respiratory structures.
The regulation of the pedunculopontine tegmental nucleus in sleep–wake states
2024, Sleep and Biological Rhythms
- 1
Authors contributed equally to this work.