How best to consider the structure and function of the pedunculopontine tegmental nucleus: Evidence from animal studies

doi:10.1016/j.jns.2006.05.036

Journal of the Neurological Sciences

Volume 248, Issues 1–2, 25 October 2006, Pages 234-250

https://doi.org/10.1016/j.jns.2006.05.036 Get rights and content

Abstract

This review presents the hypothesis that the best way to consider the pedunculopontine tegmental nucleus is by analogy with the substantia nigra. The substantia nigra contains two main compartments: the pars compacta and the pars reticulata. The former contains dopamine neurons that project widely within the basal ganglia while the latter is in receipt of corticostriatal output. Similarly, the PPTg contains the Ch5 acetylcholine containing neurons that project to the thalamus and corticostriatal systems (notably the pars compacta of substantia nigra and the subthalamic nucleus) while the non-cholinergic neurons of the pedunculopontine are in receipt of corticostriatal output. Assessment of the location, composition and connections of the pedunculopontine tegmental nucleus is made to support the hypothesis that it has structural similarities with substantia nigra. Assessment of the motor, sensory and cognitive functions of the pedunculopontine is also made, suggesting functional similarities exist also. Having a clear model of pedunculopontine structure and function is a matter of some importance. It is clearly involved in Parkinson's disease and could potentially be a target for therapeutic intervention. If this is to be realized it will be best to have as clear an understanding as possible of pedunculopontine structure and function in order to maximize positive benefits.

Introduction

This is a modest review of recent findings from studies of experimental animals concerning the structure and functions of the pedunculopontine tegmental nucleus (PPTg). Other authors have produced excellent reviews recently concerning the PPTg, particularly in regard to Parkinson's disease [1] and the present essay will not attempt to duplicate what has already been said. It will briefly consider the relationships that the PPTg has with Parkinson's disease, but its primary objective is to consider how best to conceive of the PPTg. The premise of this review is that in both anatomical and functional (behavioral and psychological) terms it is appropriate to consider the PPTg as being a two component structure analogous to the substantia nigra. In support of this, consideration will be given first to the location, composition and connectivity of the PPTg, and second to the behavioral and psychological functions with which the PPTg is involved. In both regards, the PPTg can be seen best if it is considered as containing two separate components analogous to the pars compacta and pars reticulata of substantia nigra. The principal advantage of engaging this comparison is that it enables a better contextualization of the connectivity and functions of the PPTg.

Section snippets

Location and composition of the PPTg

The pedunculopontine tegmental nucleus (PPTg) sits in the mesopontine tegmentum. In the rat (the lab animal most commonly used for PPTg research) it extends from the posterior pole of substantia nigra (where ectopic cholinergic neurons from the PPTg are occasionally found) back to the lateral tip of the superior cerebellar peduncle. With some slight variations, this is the position that it has been found to occupy in all species so far studied, from teleost fish, through amphibians, lizards and

Connections of the PPTg

There are many ascending and descending PPTg connections to most parts of the CNS. Before describing these it is worth noting two points: first, the connections do not all arise from separate pools of neurons—PPTg neurons emit branched axons that communicate with different structures [54], [55]. Second, the extent to which the ascending projections travel contralaterally as well as ipsilaterally remains uncertain. There is strong evidence of some contralateral projections to the ventrobasal

Functions of the PPTg: overview

What, under normal circumstances, does the PPTg do–what behavioral and psychological processes is it important for–and how might these be better understood by considering it in the way we consider substantia nigra? The functions of substantia nigra are best considered in so far as they relate to SNc and SNr separately. The DA containing neurons of SNc have been associated with many processes. Initial studies–naturally enough given the loss of these neurons in Parkinson's disease–focused on the

Functions of the PPTg: locomotion

In the rat, recent research using excitotoxins to make discrete, fiber-sparing bilateral lesions of the PPTg, has shown no impairment in spontaneous locomotion, measured over short periods (< 3 h) or 24 h [142], [143], [144], [145] or in exploratory tests in the open field [146]. There have been reports of changed activity on the elevated plus maze–some have argued that PPTg lesions have an anxiogenic effect [147], [148], though others have failed to replicate this [149], [150]–but this changed

Functions of the PPTg: reaction time performance and stereotypy

An overt impairment in locomotion cannot be described in rats bearing bilateral excitotoxic lesions of the PPTg. Moreover, rats bearing bilateral excitotoxic lesions of the PPTg show normal spontaneous behavior—eating, drinking, grooming are all unimpaired [168] and there is no impairment in lever pressing or the manipulation of 45 mg food pellet rewards in operant tasks (see below). Nevertheless disturbances in the execution of tasks do exist, but these take a higher-order form than an

Functions of the PPTg: reinforcement and learning

A relationship between the PPTg and reinforcement has been established through use of a variety of techniques. Early studies showed changed responding for intracranial self-stimulation with electric current [176], [177] (but no changes in perceived reward value [178]), while more recent studies have concentrated on conditioned place preference and operant responding for natural reinforcers and for drugs. The earliest general theory of PPTg involvement in reward was formulated by van der Kooy

Functions of the PPTg: sensation and attention

The hypothesis that the PPTg is involved in learning about the relationship between reinforcers and behavior, and that the PPTg provides an important source of information to midbrain DA neurons, has implicit within it the suggestion that the PPTg must be processing sensory data. The PPTg is known to be responsive to both auditory and visual stimuli [194], [195], [196], [197] but the exact source of the sensory data is not known. The superior colliculus is thought to project to PPTg [89] but

The PPTg and Parkinson's disease

Loss of neurons in the PPTg has been shown in several pathological conditions including Alzheimer type dementia [205], [206], multiple system atrophy [207] and progressive supranuclear palsy [205], [206], [208] (in which there is clear evidence of cognitive dysfunction with frontal features [209]). In addition, there were suggestions that there was an increase in PPTg neuron number in schizophrenia [210]. The increase was shown specifically in NO synthase positive neurons, over 90% of which, in

Summary and conclusions

In this essay I have attempted to review studies of experimental animals in order to understand better the structure and functions of the PPTg. I have advanced the hypothesis that the best way to consider the structure and functions of the PPTg is by analogy with the substantia nigra. The substantia nigra has three key features: (i) it is very clearly part of corticostriatal architecture; (ii) one compartment (SNc) contains neurons that provide what are essentially sensory data–prediction error

Acknowledgements

I wish to thank Dr. Helen Alderson for her critical reading of this manuscript and Dr. Marc-Andre Bedard for rekindling my interest in the PPTg and Parkinson's disease. Research in my laboratory is currently supported by the Wellcome Trust and the UK BBSRC.

References (231)

T. Honda et al.
An ultrastructural study of cholinergic and non-cholinergic neurons in the laterodorsal and pedunculopontine tegmental nuclei in the rat
Neuroscience
(1995)
K.F. Manaye et al.
Quantification of cholinergic and non-cholinergic mesopontine neuronal populations in the human brain
Neuroscience
(1999)
M.M. Mesulam et al.
Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1–Ch6)
Neuroscience
(1983)
S.R. Vincent et al.
Histochemical mapping of nitric oxide synthase in the rat brain
Neuroscience
(1992)
S.R. Vincent et al.
Neuropeptides and NADPH-diaphorase activity in the ascending cholinergic reticular system of the rat
Neuroscience
(1986)
P. Torterolo et al.
GABAergic neurons of the laterodorsal and pedunculopontine tegmental nuclei of the cat express c-fos during carbachol-induced active sleep
Brain Res
(2001)
K. Takakusaki et al.
Two types of cholinergic neurons in the rat tegmental pedunculopontine nucleus: electrophysiological and morphological characterization
Neuroscience
(1997)
L. Azam et al.
Co-expression of α7 and β2 nicotinic acetylcholine receptor subunit mRNAs within rat brain cholinergic neurons
Neuroscience
(2003)
Y.P. Hou et al.
Immunostaining of cholinergic pontomesencephalic neurons for α1 versus α2 adrenergic receptors suggests different sleep–wake state activities and roles
Neuroscience
(2002)
R. Fay et al.
5-HT2A receptor-like protein is present in small neurons located in rat mesopontine cholinergic nuclei, but absent from cholinergic neurons
Neurosci Lett
(2001)

D.A. Morilak et al.

5-HT(2) receptor immunoreactivity on cholinergic neurons of the pontomesencephalic tegmentum shown by double immunofluorescence

Brain Res

(1993)

S.D. Clark et al.

The urotensin II receptor is expressed in the cholinergic mesopontine tegmentum of the rat

Brain Res

(2001)

E. Rugg et al.

Excitotoxic lesions of the pedunculopontine tegmental nucleus: I. Comparison of the effects of various excitotoxins, with particular reference to the loss of immunohistochemically identified cholinergic neurons

Brain Res

(1992)

W.P. Gai et al.

Galanin containing fibers innervate substance P containing neurons in the pedunculopontine tegmental nucleus in humans

Brain Res

(1993)

W.L. Inglis et al.

The pedunculopontine tegmental nucleus: where the striatum meets the reticular formation

Prog Neurobiol

(1995)

B.J. Losier et al.

Dual projections of single cholinergic and aminergic brainstem neurons to the thalamus and basal forebrain in the rat

Brain Res

(1993)

K. Semba et al.

Single cholinergic mesopontine tegmental neurons project to both the pontine reticular formation and the thalamus in the rat

Neuroscience

(1990)

A. Mitani et al.

Cholinergic projections from the laterodorsal and pedunculopontine tegmental nuclei to the pontine gigantocellular tegmental field in the cat

Brain Res

(1988)

Y. Nakamura et al.

Monosynaptic nigral inputs to the pedunculopontine tegmental nucleus neurons which send their axons to the medial reticular formation in the medulla oblongata. An electron microscopic study in the cat

Neurosci Lett

(1989)

Y. Yasui et al.

Evidence for a cholinergic projection from the pedunculopontine tegmental nucleus to the rostral ventrolateral medulla in the rat

Brain Res

(1990)

R.A. Fay et al.

Identification of rat brainstem multisynaptic connections to the oral motor nuclei using pseudorabies virus. I. Masticatory muscle motor systems

Brain Res Rev

(1997)

R.A. Fay et al.

Identification of rat brainstem multisynaptic connections to the oral motor nuclei using pseudorabies virus. II. Facial muscle motor systems

Brain Res Rev

(1997)

R.A. Fay et al.

Identification of rat brainstem multisynaptic connections to the oral motor nuclei using pseudorabies virus. III. Lingual muscle motor systems

Brain Res Rev

(1997)

T. Honda et al.

Serotonergic synaptic input to cholinergic neurons in the rat mesopontine tegmentum

Brain Res

(1994)

C.S. Leonard et al.

Serotonergic and cholinergic inhibition of mesopontine cholinergic neurons controlling REM sleep: an in vitro electrophysiological study

Neuroscience

(1994)

T.A. Jenkins et al.

Determination of acetylcholine and dopamine content in thalamus and striatum after excitotoxic lesions of the pedunculopontine tegmental nucleus in rats

Neurosci Lett

(2002)

S. Kobayashi et al.

Synaptic organization of the rat parafascicular nucleus, with special reference to its afferents from the superior colliculus and the pedunculopontine tegmental nucleus

Brain Res

(2003)

D.D. Rasmusson et al.

Modification of neocortical acetylcholine release and electroencephalogram desynchronization due to brainstem stimulation by drugs applied to the basal forebrain

Neuroscience

(1994)

A. Parent et al.

Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop

Brain Res Rev

(1995)

P. Redgrave et al.

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

(1987)

M. Beninato et al.

A cholinergic projection to the rat substantia nigra from the pedunculopontine tegmental nucleus

Brain Res

(1987)

T. Futami et al.

Glutamatergic and cholinergic inputs from the pedunculopontine tegmental nucleus to dopamine neurons in the substantia nigra pars compacta

Neurosci Res

(1995)

A. Jackson et al.

Nucleus tegmenti pedunculopontinus: efferent connections with special reference to the basal ganglia, studied in the rat by anterograde and retrograde transport of horseradish peroxidase

Neuroscience

(1983)

P.A. Pahapill et al.

The pedunculopontine nucleus and Parkinson's disease

Brain

(2000)

R.K. Brantley et al.

Cholinergic neurons in the brain of a teleost fish (Porichthys notatus) located with a monoclonal antibody to choline acetyltransferase

J Comp Neurol

(1988)

G.C. Huber et al.

The mammalian midbrain and isthmus. Part I. The nuclear pattern

J Comp Neurol

(1943)

O. Marin et al.

Distribution of choline acetyltransferase immunoreactivity in the brain of anuran (Rana perezi, Xenopus laevis) and urodele (Pleurodeles waltl) amphibians

J Comp Neurol

(1997)

L. Medina et al.

Distribution of choline acetyltransferase immunoreactivity in the brain of the lizard Gallotia galloti

J Comp Neurol

(1993)

L. Medina et al.

Distribution of choline acetyltransferase immunoreactivity in the pigeon brain

J Comp Neurol

(1994)

C.R. Noback

Brain of a gorilla. II Brain stem nuclei

J Comp Neurol

(1959)

M.M. Mesulam et al.

Human reticular formation: cholinergic neurons of the pedunculopontine and laterodorsal tegmental nuclei and some cytochemical comparisons to forebrain cholinergic neurons

J Comp Neurol

(1989)

D.B. Rye et al.

Pedunculopontine tegmental nucleus in the rat: cytoarchitecture, cytochemistry, and some extrapyramidal connections of the mesopontine tegmentum

J Comp Neurol

(1987)

T.L. Steininger et al.

Ultrastructural study of cholinergic and noncholinergic neurons in the pars compacta of the rat pedunculopontine tegmental nucleus

J Comp Neurol

(1997)

K. Takakusaki et al.

Cholinergic vs. noncholinergic tegmental pedunculopontine projection neurons in rats revealed by intracellular labeling

J Comp Neurol

(1996)

M.D. Bevan et al.

Cholinergic, GABAergic and glutamate-enriched inputs from the mesopontine tegmentum to the subthalamic nucleus in the rat

J Neurosci

(1995)

B. Lavoie et al.

Pedunculopontine nucleus in the squirrel monkey: distribution of cholinergic and monoaminergic neurons in the mesopontine tegmentum with evidence for the presence of glutamate in cholinergic neurons

J Comp Neurol

(1994)

A. Charara et al.

Glutamatergic inputs from the pedunculopontine nucleus to midbrain dopaminergic neurons in primates: phaseolus vulgaris-leucoagglutinin anterograde labeling combined with postembedding glutamate and GABA immunohistochemistry

J Comp Neurol

(1996)

M.M. Moga et al.

Neuropeptide immunoreactive neurons projecting to the paraventricular hypothalamic nucleus of the rat

J Comp Neurol

(1994)

M.C. Ryan et al.

Anatomical localization by preproatrial natriuretic peptide messenger RNA in the rat brain by in situ hybridization histochemistry—novel identification in olfactory regions

J Comp Neurol

(1995)

C.D. Blaha et al.

Modulation of dopamine efflux in the striatum following cholinergic stimulation of the substantia nigra in intact and pedunculopontine tegmental nucleus-lesioned rats

J Neurosci

(1993)

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The PPTg is vastly interconnected with many brain regions including the basal ganglia, cerebellum, thalamus, as well as dopaminergic centers of the brain. It is involved in locomotion, arousal, Rapid Eye Movement (REM) sleep, and other cognitive functions like associative reward learning, reward prediction error processing, and decision making (Alderson et al., 2008; Cyr et al., 2015; Gut and Winn, 2016; Mori et al., 2016; Steidl et al., 2017b; Thompson and Felsen, 2013; Winn, 2006, 2008; Xiao et al., 2016). Recently, the PPTg has also become a target for human deep brain stimulation (DBS) in Parkinson’s disease patients (French and Muthusamy, 2018; Garcia-Rill et al., 2015; Wang et al., 2019).
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The pedunculopontine tegmental nucleus (PPTg) has been shown to have important functions relevant to the regulation of behavioral states and various motor control systems, including breathing control. The PPTg is considered an important nucleus in the mesopontine region with considerably cholinergic input to the ventral respiratory column. In addition, recent studies indicate that cholinergic innervation of the ventral respiratory column may play an important role in modulation of breathing. Here, we investigated the cholinergic stimulation of the PPTg and the changes in breathing output in conscious rats. Male Wistar rats (280–350 g, N = 5–12/group) with unilateral stainless steel cannula implanted into the PPTg were used. Respiratory parameters (tidal volume (V_T), respiratory frequency (f_R) and ventilation (V_E)) were analyzed by whole body plethysmography. In unrestrained awake rats, unilateral injection of the cholinergic muscarinic agonist carbachol (10 mM–100 nL) in the PPTg decreased f_R, and increase V_T, without changing V_E. The changes in f_R and V_T elicited by carbachol into the PPTg are abolished by previous blockade of the M4 muscarinic cholinergic receptors tropicamide into the PPTg. No significant changes in f_R and V_T elicited by carbachol were observed after blockade of the M1 and/or M3 muscarinic cholinergic receptors pirenzepine or 4-DAMP into the PPTg. Our data suggest that the changes in f_R and V_T produced by muscarinic cholinergic stimulation of PPTg is presumably mediated through a Gi-coupled M4 muscarinic receptors.
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Cholinergic neurons of the pedunculopontine nucleus (PPN) are interconnected with all the basal ganglia structures, as well as with motor centers in the brainstem and medulla. Recent theories put into question whether PPN cholinergic neurons form part of a locomotor region that directly regulates the motor output, and rather suggest a modulatory role in adaptive behavior involving both motor and cognitive functions. In support of this, experimental studies in animals suggest that cholinergic neurons reinforce actions by signaling reward prediction and shape adaptations in behavior during changes of environmental contingencies. This is further supported by clinical studies proposing that decreased cholinergic transmission originated in the PPN is associated with impaired sensorimotor integration and perseverant behavior, giving rise to some of the symptoms observed in Parkinson’s disease and progressive supranuclear palsy. Altogether, the evidence suggests that cholinergic neurons of the PPN, mainly through their interactions with the basal ganglia, have a leading role in action control.
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