Elsevier

NeuroImage

Volume 147, 15 February 2017, Pages 66-78
NeuroImage

Anatomical evidence for functional diversity in the mesencephalic locomotor region of primates

https://doi.org/10.1016/j.neuroimage.2016.12.011Get rights and content

Highlights

  • Investigating MLR functional connectivity in primates.

  • Tract tracing experiments in monkeys.

  • Diffusion-weighted imaging based tractography in humans.

  • The PPN integrates sensorimotor, cognitive and emotional information.

  • The CuN integrates predominantly emotional information.

Abstract

The mesencephalic locomotor region (MLR) is a highly preserved brainstem structure in vertebrates. The MLR performs a crucial role in locomotion but also controls various other functions such as sleep, attention, and even emotion. The MLR comprises the pedunculopontine (PPN) and cuneiform nuclei (CuN) but their specific roles are still unknown in primates. Here, we sought to characterise the inputs and outputs of the PPN and CuN to and from the basal ganglia, thalamus, amygdala and cortex, with a specific interest in identifying functional anatomical territories. For this purpose, we used tract-tracing techniques in monkeys and diffusion weighted imaging-based tractography in humans to understand structural connectivity. We found that MLR connections are broadly similar between monkeys and humans. The PPN projects to the sensorimotor, associative and limbic territories of the basal ganglia nuclei, the centre median-parafascicular thalamic nuclei and the central nucleus of the amygdala. The PPN receives motor cortical inputs and less abundant connections from the associative and limbic cortices. In monkeys, we found a stronger connection between the anterior PPN and motor cortex suggesting a topographical organisation of this specific projection. The CuN projected to similar cerebral structures to the PPN in both species. However, these projections were much stronger towards the limbic territories of the basal ganglia and thalamus, to the basal forebrain (extended amygdala) and the central nucleus of the amygdala, suggesting that the CuN is not primarily a motor structure. Our findings highlight the fact that the PPN integrates sensorimotor, cognitive and emotional information whereas the CuN participates in a more restricted network integrating predominantly emotional information.

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.

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