Divergent motor projections from the pedunculopontine nucleus are differentially regulated in Parkinsonism

Martinez-Gonzalez, Cristina; Andel, Judith van; Bolam, J. Paul; Mena‐Segovia, Juan

doi:10.1007/s00429-013-0579-6

Cited by 21 publications

(26 citation statements)

References 39 publications

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“…To define the boundaries between rostral PPN and caudal PPN, we adapted a method based on the subdivision of the PPN into equally spaced segments in the sagittal plane using concentric circles, as described previously (Mena-Segovia et al, 2009). Thus, using the center of the substantia nigra pars reticulata (SNr) as a reference point, two equally sized segments of 1400 m width were defined.…”

Section: Methodsmentioning

confidence: 99%

“…Axon collaterals of striatal-projecting neurons in the brainstem also innervate the dopaminergic midbrain and the thalamus Cholinergic neurons of the brainstem are known to innervate dopaminergic nigrostriatal/mesolimbic regions and the intralaminar thalamic nuclei (for review, see Martinez-Gonzalez et al, 2011), and as such have the potential to modulate two of the most significant inputs to the striatal complex. To determine whether it is the same brainstem neurons that innervate the striatal complex that, via collaterals, also innervate midbrain and thalamic targets, we injected a viral vector associated with the WGA-Cre fusion protein (AAV-EF1a-DIO-WGA-Cre-mCherry) in the NA core of wild-type rats (n ϭ 3).…”

Section: Ppn Rostral Striatummentioning

confidence: 99%

“…The PPN is associated with arousal/attentional functions mainly through its projections to the intralaminar thalamic nuclei (Steriade et al, 1988;Parent and Descarries, 2008) and with motor functions through projections to structures embedded in different motor circuits (e.g., SNc, subthalamic nucleus, gigantocellular nucleus; Bolam et al, 1991;Kita and Kita, 2011;Martinez-Gonzalez et al, 2013). In contrast, the LDT is associated with limbic functions underscored by its connections with limbic structures, including the VTA (Omelchenko and Sesack, 2005), midline thalamic nuclei, and infralimbic and cingulate cortex (Cornwall et al, 1990), and its involvement in motivational behavior (Lammel et al, 2012). Furthermore, we observed recently that PPN and LDT cholinergic neurons selectively target distinct subtypes of dopamine neurons in the VTA and induce different modes of discharge in their postsynaptic targets (our unpublished data).…”

Section: Functional Organization Of the Cholinergic Brainstemmentioning

confidence: 99%

“…Indeed, data from earlier tract-tracing studies suggest that this may be the case (Saper and Loewy, 1982;Smith and Parent, 1986;Hallanger and Wainer, 1988;Nakano et al, 1990). In view of the importance of cholinergic mechanisms in the regulation of dopamine release (Cachope et al, 2012;Threlfell et al, 2012) and network activity in the striatum (Carrillo-Reid et al, 2009;Goldberg et al, 2012), we aimed to determine whether cholinergic neurons in the brainstem directly innervate the striatum.…”

Section: Introductionmentioning

confidence: 99%

“…In the case of the PPN, its cholinergic and noncholinergic neurons innervate most basal ganglia structures (Mena-Segovia et al, 2004). The PPN and LDT have been proposed to influence activity within the striatum by two routes: (1) by innervation of midbrain dopamine neurons (Gould et al, 1989;Bolam et al, 1991;Oakman et al, 1995), in which acetylcholine modulates the activity of dopamine neurons (Lacey et al, 1990;Zhang et al, 2005) and leads to increased dopamine release in the striatal complex (Hernández-Ló pez et al, 1992; Blaha and Winn, 1993; Blaha et al, 1996); (2) cholinergic neurons of the brainstem innervate neurons of the intralaminar and midline thalamus (Smith et al, 1988;Kobayashi and Nakamura, 2003;Mena-Segovia et al, 2008;Parent and Descarries, 2008) that in turn project to the striatal complex (Erro et al, 1999). …”

Section: Introductionmentioning

confidence: 99%

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A Major External Source of Cholinergic Innervation of the Striatum and Nucleus Accumbens Originates in the Brainstem

et al. 2014

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Cholinergic transmission in the striatal complex is critical for the modulation of the activity of local microcircuits and dopamine release. Release of acetylcholine has been considered to originate exclusively from a subtype of striatal interneuron that provides widespread innervation of the striatum. Cholinergic neurons of the pedunculopontine (PPN) and laterodorsal tegmental (LDT) nuclei indirectly influence the activity of the dorsal striatum and nucleus accumbens through their innervation of dopamine and thalamic neurons, which in turn converge at the same striatal levels. Here we show that cholinergic neurons in the brainstem also provide a direct innervation of the striatal complex. By the expression of fluorescent proteins in choline acetyltransferase (ChAT)::Cre ϩ transgenic rats, we selectively labeled cholinergic neurons in the rostral PPN, caudal PPN, and LDT. We show that cholinergic neurons topographically innervate wide areas of the striatal complex: rostral PPN preferentially innervates the dorsolateral striatum, and LDT preferentially innervates the medial striatum and nucleus accumbens core in which they principally form asymmetric synapses. Retrograde labeling combined with immunohistochemistry in wild-type rats confirmed the topography and cholinergic nature of the projection. Furthermore, transynaptic gene activation and conventional double retrograde labeling suggest that LDT neurons that innervate the nucleus accumbens also send collaterals to the thalamus and the dopaminergic midbrain, thus providing both direct and indirect projections, to the striatal complex. The differential activity of cholinergic interneurons and cholinergic neurons of the brainstem during reward-related paradigms suggest that the two systems play different but complementary roles in the processing of information in the striatum.

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Section: Methodsmentioning

confidence: 99%

Section: Ppn Rostral Striatummentioning

confidence: 99%

Section: Functional Organization Of the Cholinergic Brainstemmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Major External Source of Cholinergic Innervation of the Striatum and Nucleus Accumbens Originates in the Brainstem

et al. 2014

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Are the basal ganglia actually controlling movement or quite the opposite?

Trigo‐Damas

Rey

2016

Mov Disord.

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PR, Lalive AL, Kreitzer AC. Pathway-specific remodeling of thalamostriatal synapses in parkinsonian mice. Neuron 2016;89:734-740. Roseberry TK, Lee AM, Lalive AL, Wilbrecht L, Bonci A, Kreitzer AC. Cell-type-specific control of brainstem locomotor circuits by basal ganglia. Cell 2016;164:526-537.In Parkinson's disease (PD) patients, levels of dopamine in basal ganglia (BG) are lowered, leading to the imbalance in neuronal activity between the direct and indirect pathways, which, in turn, hinder proper movement and walking. However, neither the pathophysiological mechanisms nor the role of the basal ganglia and connecting structures involved in gait and locomotion in PD are well understood. Two new studies from the group of Prof. Kreitzer provide some new insight into these eluding issues.The first study, published in Neuron by Parker and colleagues, 1 carefully examined the changes of the strength of synaptic inputs in a PD mouse model. They performed whole-cell recordings in both direct and indirect medium spiny neurons (MSNs) neurons while optically stimulating sensorimotor cortex or thalamus. They discovered that dopamine loss results in a miscommunication between the thalamus and the BG, producing reduced activation of the direct pathway and slowness and disruption of movements. This was restored by blocking the thalamostriatal terminals using chemo and optogenetic tools. These findings underscore the role of thalamus in PD motor features. However, it should be noted that their results might be difficult to reconcile with data from previous studies where they described cell loss in the thalamus of PD animals 2 or lack of motor benefit after chemical ablation of thalamic projections in parkinsonian monkeys. 3 The second study, published in Cell by Roseberry and colleagues, 4 combined techniques, such as optogenetics, single-cell recording, and virus-based mapping, in mice in order to examine the mechanisms underlying the control of the mesencephalic locomotor region (MLR) by the BG pathways. Interestingly, their results revealed that the direct pathway selectively activated one type of these MLR neurons, the glutamatergic ones, in the brainstem and that these are the ones triggering locomotion, and the indirect pathway inhibits them, stopping movement. Outstandingly, they found that the power of the brainstem neurons could trump BG signals given that they were able to optogenetically control the initiation of movement in the animal regardless of the signal coming from the direct or indirect pathways. Nonetheless, because of the technical complexity of the experiments and the multiple parallel pathways from BG nuclei to the MLR region, 5 cautious relevance should be given to these findings.Together, both articles may give rise to further studies on non-BG regions, perhaps leading to newer therapeutic developments for this major challenge and unmet need in clinical practice. References1. Parker PR, Lalive AL, Kreitzer AC. Pathway-specific remodeling of thalamostriatal synapses in parkinsonian mice. Neuron. 2016;...

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The connectome of the basal ganglia

et al. 2014

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The basal ganglia of the laboratory rat consist of a few core regions that are specifically interconnected by efferents and afferents of the central nervous system. In nearly 800 reports of tract-tracing investigations the connectivity of the basal ganglia is documented. The readout of connectivity data and the collation of all the connections of these reports in a database allows to generate a connectome. The collation, curation and analysis of such a huge amount of connectivity data is a great challenge and has not been performed before (Bohland et al. PloS One 4:e7200, 2009) in large connectomics projects based on meta-analysis of tract-tracing studies. Here, the basal ganglia connectome of the rat has been generated and analyzed using the consistent cross-platform and generic framework neuroVIISAS. Several advances of this connectome meta-study have been made: the collation of laterality data, the network-analysis of connectivity strengths and the assignment of regions to a hierarchically organized terminology. The basal ganglia connectome offers differences in contralateral connectivity of motoric regions in contrast to other regions. A modularity analysis of the weighted and directed connectome produced a specific grouping of regions. This result indicates a correlation of structural and functional subsystems. As a new finding, significant reciprocal connections of specific network motifs in this connectome were detected. All three principal basal ganglia pathways (direct, indirect, hyperdirect) could be determined in the connectome. By identifying these pathways it was found that there exist many further equivalent pathways possessing the same length and mean connectivity weight as the principal pathways. Based on the connectome data it is unknown why an excitation pattern may prefer principal rather than other equivalent pathways. In addition to these new findings the local graph-theoretical features of regions of the connectome have been determined. By performing graph theoretical analyses it turns out that beside the caudate putamen further regions like the mesencephalic reticular formation, amygdaloid complex and ventral tegmental area are important nodes in the basal ganglia connectome. The connectome data of this meta-study of tract-tracing reports of the basal ganglia are available for further network studies, the integration into neocortical connectomes and further extensive investigations of the basal ganglia dynamics in population simulations.

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Divergent motor projections from the pedunculopontine nucleus are differentially regulated in Parkinsonism

Cited by 21 publications

References 39 publications

A Major External Source of Cholinergic Innervation of the Striatum and Nucleus Accumbens Originates in the Brainstem

A Major External Source of Cholinergic Innervation of the Striatum and Nucleus Accumbens Originates in the Brainstem

Are the basal ganglia actually controlling movement or quite the opposite?

The connectome of the basal ganglia

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