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Experimental studies of pedunculopontine functions: Are they motor, sensory or integrative?
Parkinsonism and Related Disorders 14 (2008) S194eS198 www.elsevier.com/locate/parkreldis
Experimental studies of pedunculopontine functions: Are they motor, sensory or integrative?* Philip Winn School of Psychology, University of St. Andrews, St. Mary’s Quad, South Street, St. Andrews, Fife, Scotland KY16 9JP, UK
Abstract The pedunculopontine tegmental nucleus (PPTg) is involved in Parkinson’s disease and has become a therapeutic target. However, its normal functions are uncertain: are they motor, sensory or integrative? This position paper reviews PPTg structure and considers experiments designed to understand its behavioural functions. The PPTg is part of the corticostriatal architecture and, consistent with this, a core deficit following lesion is the inability to properly establish actioneoutcome associations. Understanding normal PPTg structure and function will provide insight into the role it has in Parkinson’s disease and related disorders, and will benefit the development of surgical treatments aimed here. Ó 2008 Elsevier Ltd. All rights reserved. Keywords: Associative learning; Basal ganglia; Comparative anatomy; Corticostriatal; Deep-brain stimulation; Locomotion
1. Introduction There are several recent thorough reviews of the structure and function of the pedunculopontine tegmental nucleus (PPTg), for example by Mena-Segovia and his colleagues [1], Pahapill and Lozano [2] and Winn [3] to which readers are referred. The present article is a position paper rather than a comprehensive review. In it, I outline why the PPTg is of interest in Parkinson’s disease (PD) and present the view that PPTg is best considered, structurally and functionally, in relation to the functions of corticostriatal systems. (Corticostriatal systems being the interconnected, looped systems incorporating cortical, striatal, pallidal and thalamic structures. The basal ganglia are part of this: what is present in addition are those ventral striatal circuits whose functions can be dissociated from basal ganglia proper.) Essentially, the argument here is that the PPTg has higher order functions than has previously been thought and should be approached as an important contributor to corticostriatal function. * This article is based on a presentation given at the LIMPE Seminars 2007 ‘‘Experimental Models in Parkinson’s Disease’’ held in September 2007 at the ‘‘Porto Conte Ricerche’’ Congress Center in Alghero, Sardinia, Italy. E-mail address: [email protected]
1353-8020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2008.04.030
2. Why is there interest in the pedunculopontine in Parkinson’s disease? The involvement of the PPTg in PD has been known for many years [2,3] but has been a matter of, at best, peripheral interest. Cholinergic neurons in the PPTg appear to show changes in activity early in the disease, though the effect of these changes is uncertain: do they help maintain function or do they contribute to the pathology? [See 3 for review.] However, cholinergic neurons are lost as the disease progresses, and Lewy neurites accumulate during Braak’s stages 3 and 4 [4]. In addition, pallidal input to the PPTg changes. Experimental studies [5] indicate increased metabolic activity in the PPTg, consistent with heightened synaptic activity that is probably GABA-mediated inhibition. Nevertheless, interest has grown significantly with the recent demonstrations that deep-brain stimulation (DBS) in the PPTg e despite some controversy [6,7] e has therapeutic benefit, with gait and postural instability improved [8e10]. Given these surgical interventions, it is a matter of concern that the normal functions of the PPTg are not well understood. This article highlights recent work with experimental animals and contextualizes how the structure and function of the PPTg might best be considered.
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3. The structure of the pedunculopontine The structure of the PPTg was given definition by Jacobsohn at the beginning of the 20th century and was being described in textbooks in the 1940s. ‘‘At the junction of the pons and mesencephalon, the cells of the reticular formation are displaced laterally by the decussation of the brachium conjunctivum producing at this level a rather dense accumulation of medium-sized cells, the pedunculopontile tegmental nucleus (pe p tg)’’ (p. 416e7) [11]. It also became clear (and this is important, given that the hypotheses presented here are derived from animal studies) that PPTg structure is consistent across species. This can be seen in the pioneering studies of Elizabeth Crosby and her colleagues (see volume 78 part 3 of the Journal of Comparative Neurology, which contains a series of papers describing the midbrain and isthmus of various species) and has been re-emphasized by contemporary comparative anatomists (see Ref. [3]). It is also worth noting that the basal ganglia e to which the PPTg is intimately connected e are remarkably conserved, unsurprisingly given their role in action selection. It has been argued that the basal ganglia provide a mechanism for deciding which of many competing possible actions will capture the machinery of motor control [12]. Given the fundamental importance of being able to do this, it is not surprising that the basal ganglia appear early in the course of evolution. Teleost fish for example, present 250 million years ago and the dominant marine life by 65 million years ago, have both basal ganglia and PPTg [13]. The most striking feature of the PPTg is the population of cholinergic neurons, easily identifiable by their morphology. They cluster in posterior PPTg, at the lateral tip of the superior cerebellar peduncle, but extend rostrally into anterior PPTg. Adjacent to, and interdigitated with them, are non-cholinergic neurons, some of which contain GABA and some of which contain glutamate. The ascending projections of cholinergic neurons are all aimed at the thalamus e all the cholinergic neurons project to the thalamus e with extensive collaterals to other sites including corticostriatal systems, and sites of non-specific projection to the cerebral cortex (such as the basal forebrain and lateral hypothalamus). The descending connections aim at sites in the pontine and medullary reticular formations, and spinal cord. Forebrain inputs come principally from the basal ganglia and extended amygdala. What the purpose of bringing together information from these, and whether they target the same PPTg neurons, is not clear. It recalls the notion of a ‘‘limbicemotor interface’’ [14], once thought to describe the nucleus accumbens, allowing novel information access to mechanisms of motor selection. (See Ref. [15] for discussion of this in relation to PPTg.) The PPTg also receives polymodal sensory input from sites including the superior and inferior colliculi, the lemniscal nuclei, parabrachial nucleus and the trigeminal complex. The auditory component of this is very fast in both cat [16] and rat [17] e auditory stimuli evoke firing with a mean latency of w8 ms. This sensory information appears to target the posterior parts of the PPTg, in contrast to the descending inputs from the forebrain, which target the anterior and medial parts.
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PPTg cholinergic neurons (and those of the adjacent laterodorsal tegmental nucleus, with which there are interactions [18]) make monosynaptic contact with midbrain dopamine (DA) neurons, exciting them to release DA in the ipsilateral striatum with a triphasic pattern as follows: (i) rapid release (w60 s) dependent on nicotinic and ionotropic glutamate receptors in the midbrain; (ii) reduction in release to below baseline (dependent on M2 muscarinic receptors in the mesopontine tegmentum); and (iii) sustained increase (w30 min in the anaesthetized rat) that requires activation of M5 receptors in the midbrain [19]. With regard to PPTg connections with DA neurons, the anatomical division of the PPTg made by Olszewski and Baxter [20] is still significant. The posterior parts of the PPTg, equivalent to the pars compactus of Olszewski and Baxter, receive most of the sensory input and project to the ventral tegmental area (VTA), which in turn activates the ventral striatum. The anterior portion e pars dissipatus e receives more of the forebrain input and projects to the substantia nigra pars compacta (SNc) [21]. The hypothesis we can therefore advance (illustrated in Fig. 1) is that posterior PPTg receives more of the sensory input and activates the VTA (and ventral striatal structures), whereas anterior PPTg receives more of the forebrain output (from basal ganglia and extended amygdala) and activates SNc (and dorsal striatum/basal ganglia). That the inputs to midbrain DA neurons
Dorsal striatum
GP SNr STn
Ventral striatum
SNc
VTA
Anterior PPTg
VS output
Posterior PPTg
Fast sensory input Fig. 1. Schematic illustrating the corticostriatal connections of anterior (solid grey boxes) and posterior (white boxes) PPTg. Anterior PPTg has monosynaptic input (ACh and glutamate) to SNc, which projects to dorsal striatum, and reciprocal connections with principal basal ganglia output stations (GP, SNr, STn). Not shown (for simplicity) but important are extended amygdala inputs to anterior PPTg. Posterior PPTg receives fast, polymodal sensory input and connects via VTA (ACh and glutamate) to ventral striatum. Ach, acetylcholine; GP, globus pallidus; PPTg, pedunculopontine tegmental nucleus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STn, subthalamic nucleus; VS, ventral striatum; and VTA, ventral tegmental area.
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from the PPTg are organized in this way complements the hypothesis that the VTA/ventral striatum is involved with processing information related to goal-directed actions, whereas the SNc/dorsal striatum is concerned with stimuluseresponse habit learning [22]. 4. The functions of the pedunculopontine Older literature emphasizes locomotion and sleep as functions of the PPTg. Neurons in the PPTg change their activity across the sleepewake cycle and are important for regulating thalamic state: the switch between bursting and single spiking is dependent on cholinergic activity [23]. As such, the PPTg is important in the control of sleep, but two considerations qualify this: (i) many neurons in structures throughout the midbrain and brainstem (the locus coeruleus and raphe nuclei, for example) show differential activity across behavioural states; and (ii) bilateral excitotoxic lesions restricted to the PPTg do not affect normal sleep patterns in the rat (though REM rebound is affected after sleep deprivation) [24]. It is perhaps better to consider the PPTg as a component part of a distributed network of structures and neurons controlling sleep rather than as a unique regulator of behavioural state or ‘‘master switch’’ for REM sleep. The issue of locomotor control and the PPTg is bound up with the mesencephalic locomotor region (MLR). The MLR is a region of brain (defined functionally rather than morphologically or hodologically) from which locomotion can be elicited in pre-collicular post-mammillary transected animals. However, bilateral excitotoxic lesions of the whole PPTg have repeatedly been shown [25e29] not to affect locomotor activity. The only data that indicate a motor deficit after PPTg lesions come from studies of non-human primates [30,31], but these are compromised by use of the neurotoxin kainate (which always produces very large lesions after microinjection; it is orders of magnitude more potent than excitotoxins that work through NMDA receptors) and the time course. In both studies the behavioural testing occurred within 2 weeks of lesion induction, when non-specific effects of lesioning can still be apparent. To understand how the MLR works, and why excitotoxic lesions have no effect on locomotion, it is necessary to consider the PPTg in a larger context. A cogent argument in favour of considering brains as layered architectures has recently been presented [32]. The argument is that brains can be described as layered systems in which there is ‘‘.decomposition of . control system[s] into multiple levels of competences with lower levels dissociable from those above’’ (p. 103). That is, brains can be considered as systems in which, for particular functions, different levels operate: all levels have sensory input and motor output properties and can effect decision making, with simple and fast decisions taken at lower levels. Two-way interaction between layers ensures effective information flow, and that low-level (impulsive or premature) decision making can be suppressed. Moreover, these interactions mean that these architectures are not simple hierarchies but have heterarchical properties. Such an analysis fits the
PPTg: (i) it has sensory and motor connections; (ii) it can influence processing in higher layers (striatal, thalamic and cortical); (iii) it is subject to strong inhibitory control from the forebrain; and (iv) it can, independently of the forebrain, influence brainstem and spinal motor processes. The MLR is understandable if considered as demonstrating that, in the absence of descending control from the forebrain, stimulation of brainstem sites (including the PPTg and other structures such as the cuneiform nucleus) can produce coordinated activity, as one would expect of a layered architecture from which higher control is disconnected. While the locomotion stimulated from the PPTg in decerebrate animals e and indeed the MLR en masse e is understandable, it is critical to acknowledge that ‘‘MLR functions’’ do not demonstrate that the primary purpose of the PPTg is control of locomotion. Because of its anatomical connections, several laboratories have used tests of corticostriatal functions in rats bearing excitotoxic lesions of the PPTg. My laboratory, for example, has shown that bilateral ibotenate lesions of the whole PPTg e made using a series of injections along the length of the PPTg e produce profound deficits in some tasks and none in others. Rats bearing such lesions have no impairment in basic activities such as feeding, drinking or grooming, and are essentially unimpaired in tasks such as the elevated plus maze or open field (which measure emotionality) [33]. However, on the radial arm maze, in tasks designed explicitly to test corticostriatal functions [34], PPTg-lesioned rats are profoundly impaired [35]. They move around the maze normally, but their selection of arms to enter is at no better than chance levels. In operant tests, rats show impairments in tasks with an associative component. Alderson and her colleagues [36] showed that rats bearing bilateral ibotenate lesions of the whole PPTg were incapable of learning to lever press for intravenous drug administration (D-amphetamine) on a low fixed ratio schedule, but if they had learned the lever pressereward association prior to lesioning, their performance was identical to that of sham operated controls. Considering that the PPTg is so often thought of as a basic motor structure, it is especially notable that in the pre-trained condition, even with bilateral PPTg lesions, rats emitted normal instrumental actions to obtain a reward. The implication of these data is that the presence of an intact PPTg is essential for making actioneoutcome associations. This hypothesis can explain a significant amount of data. It deals with the operant data described here (and data involving natural reinforcers [37]) as well as the radial maze data: rats that cannot make actioneoutcome associations will inevitably find any task that changes trial-by-trial impossible. It also explains the absence of effect in other tests: the elevated plus maze, for example, does not have an intrinsic associative element [33]. Electrophysiological data that link PPTg neuron firing to reinforcement processes rather than movement [16,17] strengthen this hypothesis, which is nevertheless still only an hypothesis, but one testable using standard techniques of reinforcer devaluation and contingency degradation that have been applied in the study of striatal actione outcome functions [38].
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These examinations of the behavioural effects of bilateral lesions of the whole PPTg establish a framework for understanding the functions of the PPTg that go beyond ‘‘sleep and locomotion’’. Rather, the data show that the PPTg can be considered as part of the basal ganglia family. Two major questions remain: (i) can different functions for neurochemically identified populations of neurons be established? What do the cholinergic neurons do? The answer is uncertain but might be more easily established following development of a fusion toxin selective for mesopontine cholinergic neurons [39]. (ii) What functions can be ascribed to different parts of the PPTg, identified by connectivity? We have started to investigate this while examining the relationships between PPTg and responding for nicotine, and have shown that anterior and posterior PPTg do have different functions. Selfadministration of nicotine is changed by posterior but not anterior PPTg lesions [40] and our most recent work has shown that posterior lesions also change the sensitized locomotor response to repeated nicotine administration. In these experiments we have shown that, while anterior PPTg lesions have no effect on the locomotor response to repeated nicotine, they produce a small, lasting reduction in spontaneous locomotion [41]. This is the first demonstration in the rat of a motor deficit following PPTg damage, and it is noteworthy that the damage is restricted to the anterior PPTg, which projects into the substantia nigra (Fig. 1). Establishing the precise functions of the various elements of the PPTg will be a major goal of research in the coming years. 5. Parkinson’s disease, the pedunculopontine and deepbrain stimulation As noted before, interest in the PPTg has developed following recent demonstrations that DBS here has therapeutic benefit, notably for gait and postural instability [8e10]. This is consistent with experimental studies in MPTP-treated nonhuman primates, where PPTg stimulation provides relief from akinesia [42]. However, the data from rodents bearing excitotoxic lesions of PPTg suggest that changes in psychological functions might be produced by PPTg DBS. In this regard, it is intriguing to note that in further examination of patients undergoing treatment [10], PET analyses have revealed more cortical activation after PPTg DBS than has been seen in other studies after DBS of the subthalamic nucleus. This was accompanied by improvements in neuropsychological tests that examine both motor and executive functions such as the trail-making test (Paolo Stanzione e personal communication). That there might be changes in psychological functioning after PPTg DBS is compatible with other neuroimaging and clinical studies. Smolka and colleagues [43] have shown that, in smokers who were deprived of nicotine and experiencing craving, the PPTg was activated by the presentation of cues associated with smoking, an effect compatible with the associative hypothesis. It has also been suggested that there are cognitive impairments reminiscent of those seen following lesions of the PPTg in rats [35] after pontine ischaemic stroke in human patients [44].
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Is the PPTg a suitable target for DBS? The answer is yes e patients have been successfully treated e but questions remain. How does it work e what neural systems are changed by this treatment? Are there key intra-PPTg targets? Which aspects of parkinsonism will be most effectively treated, and for how long? It is to be hoped that authoritative scientific data, drawn from studies of humans and experimental animals, will answer these questions. 6. Conclusions What are the functions of the PPTg? The position taken here is that, although the PPTg has motor and sensory properties, its functions are not best considered in these terms. Rather, it has functions that integrate sensory and motor data, and it is specifically proposed that this is related to actioneoutcome association, a process that involves both motor abilities and sensory capacities. This function is related strongly to the functions of corticostriatal systems and establishes a higher order function for the PPTg than had previously been supposed. Conflict of interest None declared. Role of the funding source The work of my laboratory, described in this article, has been supported by the Wellcome Trust, the Biotechnology and Biological Sciences Research Council (UK) and the Leverhulme Trust. The author has retained full editorial control and responsibilities throughout the preparation of the manuscript. Acknowledgements I am grateful to colleagues at the meeting for their discussion and to my laboratory colleagues for their invaluable labour and insights over many years. References [1] Mena-Segovia J, Bolam JP, Magill PJ. Pedunculopontine nucleus and basal ganglia: distant relatives or part of the same family? Trends Neurosci 2004;27:565e88. [2] Pahapill PA, Lozano AM. The pedunculopontine nucleus and Parkinson’s disease. Brain 2000;123:1767e83. [3] Winn P. How best to consider the structure and function of the pedunculopontine tegmental nucleus: evidence from animal studies. J Neurol Sci 2006;248:234e50. [4] Braak H, Del Tredici K, Ru¨ba U, de Vos RAI, Jansen Steur ENH, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003;24:197e211. [5] Mitchell IJ, Clarke CE, Boyce S, Robertson RG, Peggs D, Sambrook MA, et al. Neural mechanisms underlying Parkinsonian symptoms based upon regional uptake of 2-deoxyglucose in monkeys exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neuroscience 1989;32: 213e26.
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[6] Mazzone P, Stanzione P, Lozano A, Scarnati E, Peppe A, Galati S, et al. The peripeduncular and pedunculopontine nuclei: a putative dispute not discouraging the effort to define a clinically relevant target. Brain 2007; 130:E74. [7] Zrinzo L, Zrinzo LV, Hariz M. The pedunculopontine and peripeduncular nuclei: a tale of two structures. Brain 2007;130:E73. [8] Mazzone P, Lozano A, Stanzione P, Galati S, Scarnati E, Peppe A, et al. Implantation of human pedunculopontine nucleus: a safe and clinically relevant target in Parkinson’s disease. NeuroReport 2005;16:1877e81. [9] Plaha P, Gill SS. Bilateral deep brain stimulation of the pedunculopontine nucleus for Parkinson’s disease. NeuroReport 2005;16:1883e7. [10] Stefani A, Lozano AM, Pepper A, Stanzione P, Galati S, Tropepi D, et al. Bilateral deep brain stimulation of the pedunculopontine and subthalamic nucleus in sever Parkinson’s disease. Brain 2007;130:1596e607. [11] Ranson SW. The anatomy of the nervous system. 6th ed. Philadelphia, London: WB Saunders Company; 1939. [12] Redgrave P, Prescott TJ, Gurney K. The basal ganglia: a vertebrate solution to the selection problem. Neuroscience 1999;89:1009e23. [13] Brantley RK, Bass AH. Cholinergic neurons in the brain of a teleost fish (Porichthys notatus) located with a monoclonal antibody to choline acetyltransferase. J Comp Neurol 1988;275:87e105. [14] Mogenson GJ, Jones DL, Yim CY. From motivation to action: functional interface between the limbic system and the motor system. Prog Neurobiol 1980;14:69e97. [15] Winn P, Brown VJ, Inglis WL. On the relationships between the striatum and the pedunculopontine tegmental nucleus. Crit Rev Neurobiol 1997; 11:241e61. [16] Dormont JF, Conde´ H, Farin D. The role of the pedunculopontine tegmental nucleus in relation to conditioned motor performance in the cat. I. Context-dependent and reinforcement-related single unit activity. Exp Brain Res 1998;121:401e10. [17] Pan W-X, Hyland BI. Pedunculopontine tegmental nucleus controls conditioned responses of midbrain dopamine neurons in behaving rats. J Neurosci 2005;25:4725e32. [18] Lodge DJ, Grace AA. The laterodorsal tegmentum is essential for burst firing of ventral tegmental area dopamine neurons. Proc Natl Acad Sci U S A 2006;103:5167e72. [19] Forster GL, Blaha CD. Pedunculopontine tegmental stimulation evokes striatal dopamine efflux by activation of acetylcholine and glutamate receptors in the midbrain and pons of the rat. Eur J Neurosci 2003;17: 651e62. [20] Olszewski J, Baxter D. Cytoarchitecture of the human brain stem. 2nd ed. Basel, New York: S. Karger; 1982. [21] Winn P, Rostron PR, Latimer MP, Zahm DS. Afferents of the rat pedunculopontine tegmental nucleus: investigation with Fluoro-Gold. Program No. 301.8. Society for Neuroscience Abstract Viewer/Itinerary Planner, Society for Neuroscience. Washington, DC; 2005. [22] Everitt BJ, Robbins TW. Neural systems of reinforcement for drug addition: from actions to habits to compulsion. Nat Neurosci 2005;8:1481e9. [23] Steriade M. Grouping of brain rhythms in corticothalamic systems. Neuroscience 2006;137:1087e106. [24] Deurveilher S, Hennevin E. Lesions of the pedunculopontine tegmental nucleus reduce paradoxical sleep (PS) propensity: evidence from a shortterm PS deprivation study in rats. Eur J Neurosci 2001;13:1963e76. [25] Inglis WL, Allen LF, Whitelaw RB, Latimer M, Brace HM, Winn P. An investigation into the role of the pedunculopontine tegmental nucleus in the mediation of caudateeputamen and nucleus accumbens output. Neuroscience 1994;58:817e33. [26] Inglis WL, Dunbar JS, Winn P. Outflow from the nucleus accumbens to the pedunculopontine tegmental nucleus: a dissociation between
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locomotor activity and the acquisition of responding for conditioned reinforcement stimulated by amphetamine. Neuroscience 1994;62:51e64. Olmstead MC, Franklin KBJ. Lesions of the pedunculopontine tegmental nucleus block drug-induced reinforcement but not amphetamine-induced locomotion. Brain Res 1994;638:29e35. Steiniger B, Kretschmer BD. Effects of ibotenate pedunculopontine tegmental nucleus lesions on exploratory behavior in the open field. Behav Brain Res 2004;151:17e23. Swerdlow NR, Koob GF. Lesions of the dorsomedial nucleus of the thalamus, medial prefrontal cortex and pedunculopontine nucleus: effects on locomotor activity mediated by nucleus accumbens-ventral pallidal circuitry. Brain Res 1987;412:233e43. Kojima J, Yamaji Y, Matsumura M, Nambu A, Inase M, Tokuno H, et al. Excitotoxic lesions of the pedunculopontine tegmental nucleus produce contralateral hemiparkinsonism in the monkey. Neurosci Lett 1997; 226:111e4. Munro-Davies LE, Winter J, Aziz TZ, Stein JF. The role of the pedunculopontine region in basal ganglia mechanisms of akinesia. Exp Brain Res 1999;129:511e7. Prescott TJ, Redgrave P, Gurney K. Layered control architectures in robots and vertebrates. J Adapt Behav 1999;7:99e127. Walker SC, Winn P. An assessment of the contributions of the pedunculopontine tegmental and cuneiform nuclei to anxiety and neophobia. Neuroscience 2007;150(2):273e90. Floresco SB, Braaksma DN, Phillips AG. Thalamic-cortical-striatal circuitry subserves working memory during delayed responding on a radial arm maze. J Neurosci 1999;19:11061e71. Keating GL, Winn P. Examination of the role of the pedunculopontine tegmental nucleus in radial maze tasks with or without a delay. Neuroscience 2002;112:687e96. Alderson HL, Latimer MP, Blaha CD, Phillips AG, Winn P. An examination of d-amphetamine self-administration in pedunculopontine tegmental nucleus lesioned rats. Neuroscience 2004;125:349e58. Alderson HL, Brown VJ, Latimer MP, Brasted PJ, Robertson AH, Winn P. The effect of excitotoxic lesions of the pedunculopontine tegmental nucleus on performance of a progressive ratio schedule of reinforcement. Neuroscience 2002;112:417e25. Yin H, Ostlund SB, Knowlton BJ, Balleine BW. The role of the dorsomedial striatum in instrumental conditioning. Eur J Neurosci 2005;22:513e23. Clark SD, Nothacker H-P, Alderson HL, Latimer MP, Winn P, Civelli O. Fusion of diphtheria toxin and urotensin II produces a neurotoxin selective for cholinergic neurons in the rat mesopontine tegmentum. J Neurochem 2007;102:112e20. Alderson HL, Latimer MP, Winn P. The incentive properties of nicotine are altered by lesions of the posterior, but not the anterior, pedunculopontine tegmental nucleus. Eur J Neurosci 2006;23:2169e75. Alderson HL, Latimer MP, Winn P. 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 2008, in press. doi:10.1007/s00429-008-0174-4. Jenkinson N, Nandi D, Miall RC, Stein JF, Aziz T. Pedunculopontine nucleus stimulation improves akinesia in a Parkinsonian monkey. NeuroReport 2004;14:2621e4. Smolka M, Bu¨hler M, Klein S, Zimmerman U, Mann K, Heinz A, et al. Severity of nicotine dependence modulates cue-induced brain activity in regions involved in motor preparation and imagery. Psychopharmacology 2006;184:577e88. Vataja R, Pohjasvaara T, Ma¨ntyla¨ R, Ylikoski R, Leppa¨vuori A, Leskela M, et al. MRI correlates of executive dysfunction in patients with ischaemic stroke. Eur J Neurol 2003;10:625e31.
Experimental studies of pedunculopontine functions: Are they motor, sensory or integrative?* Philip Winn School of Psychology, University of St. Andrews, St. Mary’s Quad, South Street, St. Andrews, Fife, Scotland KY16 9JP, UK
Abstract The pedunculopontine tegmental nucleus (PPTg) is involved in Parkinson’s disease and has become a therapeutic target. However, its normal functions are uncertain: are they motor, sensory or integrative? This position paper reviews PPTg structure and considers experiments designed to understand its behavioural functions. The PPTg is part of the corticostriatal architecture and, consistent with this, a core deficit following lesion is the inability to properly establish actioneoutcome associations. Understanding normal PPTg structure and function will provide insight into the role it has in Parkinson’s disease and related disorders, and will benefit the development of surgical treatments aimed here. Ó 2008 Elsevier Ltd. All rights reserved. Keywords: Associative learning; Basal ganglia; Comparative anatomy; Corticostriatal; Deep-brain stimulation; Locomotion
1. Introduction There are several recent thorough reviews of the structure and function of the pedunculopontine tegmental nucleus (PPTg), for example by Mena-Segovia and his colleagues [1], Pahapill and Lozano [2] and Winn [3] to which readers are referred. The present article is a position paper rather than a comprehensive review. In it, I outline why the PPTg is of interest in Parkinson’s disease (PD) and present the view that PPTg is best considered, structurally and functionally, in relation to the functions of corticostriatal systems. (Corticostriatal systems being the interconnected, looped systems incorporating cortical, striatal, pallidal and thalamic structures. The basal ganglia are part of this: what is present in addition are those ventral striatal circuits whose functions can be dissociated from basal ganglia proper.) Essentially, the argument here is that the PPTg has higher order functions than has previously been thought and should be approached as an important contributor to corticostriatal function. * This article is based on a presentation given at the LIMPE Seminars 2007 ‘‘Experimental Models in Parkinson’s Disease’’ held in September 2007 at the ‘‘Porto Conte Ricerche’’ Congress Center in Alghero, Sardinia, Italy. E-mail address: [email protected]
1353-8020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2008.04.030
2. Why is there interest in the pedunculopontine in Parkinson’s disease? The involvement of the PPTg in PD has been known for many years [2,3] but has been a matter of, at best, peripheral interest. Cholinergic neurons in the PPTg appear to show changes in activity early in the disease, though the effect of these changes is uncertain: do they help maintain function or do they contribute to the pathology? [See 3 for review.] However, cholinergic neurons are lost as the disease progresses, and Lewy neurites accumulate during Braak’s stages 3 and 4 [4]. In addition, pallidal input to the PPTg changes. Experimental studies [5] indicate increased metabolic activity in the PPTg, consistent with heightened synaptic activity that is probably GABA-mediated inhibition. Nevertheless, interest has grown significantly with the recent demonstrations that deep-brain stimulation (DBS) in the PPTg e despite some controversy [6,7] e has therapeutic benefit, with gait and postural instability improved [8e10]. Given these surgical interventions, it is a matter of concern that the normal functions of the PPTg are not well understood. This article highlights recent work with experimental animals and contextualizes how the structure and function of the PPTg might best be considered.
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3. The structure of the pedunculopontine The structure of the PPTg was given definition by Jacobsohn at the beginning of the 20th century and was being described in textbooks in the 1940s. ‘‘At the junction of the pons and mesencephalon, the cells of the reticular formation are displaced laterally by the decussation of the brachium conjunctivum producing at this level a rather dense accumulation of medium-sized cells, the pedunculopontile tegmental nucleus (pe p tg)’’ (p. 416e7) [11]. It also became clear (and this is important, given that the hypotheses presented here are derived from animal studies) that PPTg structure is consistent across species. This can be seen in the pioneering studies of Elizabeth Crosby and her colleagues (see volume 78 part 3 of the Journal of Comparative Neurology, which contains a series of papers describing the midbrain and isthmus of various species) and has been re-emphasized by contemporary comparative anatomists (see Ref. [3]). It is also worth noting that the basal ganglia e to which the PPTg is intimately connected e are remarkably conserved, unsurprisingly given their role in action selection. It has been argued that the basal ganglia provide a mechanism for deciding which of many competing possible actions will capture the machinery of motor control [12]. Given the fundamental importance of being able to do this, it is not surprising that the basal ganglia appear early in the course of evolution. Teleost fish for example, present 250 million years ago and the dominant marine life by 65 million years ago, have both basal ganglia and PPTg [13]. The most striking feature of the PPTg is the population of cholinergic neurons, easily identifiable by their morphology. They cluster in posterior PPTg, at the lateral tip of the superior cerebellar peduncle, but extend rostrally into anterior PPTg. Adjacent to, and interdigitated with them, are non-cholinergic neurons, some of which contain GABA and some of which contain glutamate. The ascending projections of cholinergic neurons are all aimed at the thalamus e all the cholinergic neurons project to the thalamus e with extensive collaterals to other sites including corticostriatal systems, and sites of non-specific projection to the cerebral cortex (such as the basal forebrain and lateral hypothalamus). The descending connections aim at sites in the pontine and medullary reticular formations, and spinal cord. Forebrain inputs come principally from the basal ganglia and extended amygdala. What the purpose of bringing together information from these, and whether they target the same PPTg neurons, is not clear. It recalls the notion of a ‘‘limbicemotor interface’’ [14], once thought to describe the nucleus accumbens, allowing novel information access to mechanisms of motor selection. (See Ref. [15] for discussion of this in relation to PPTg.) The PPTg also receives polymodal sensory input from sites including the superior and inferior colliculi, the lemniscal nuclei, parabrachial nucleus and the trigeminal complex. The auditory component of this is very fast in both cat [16] and rat [17] e auditory stimuli evoke firing with a mean latency of w8 ms. This sensory information appears to target the posterior parts of the PPTg, in contrast to the descending inputs from the forebrain, which target the anterior and medial parts.
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PPTg cholinergic neurons (and those of the adjacent laterodorsal tegmental nucleus, with which there are interactions [18]) make monosynaptic contact with midbrain dopamine (DA) neurons, exciting them to release DA in the ipsilateral striatum with a triphasic pattern as follows: (i) rapid release (w60 s) dependent on nicotinic and ionotropic glutamate receptors in the midbrain; (ii) reduction in release to below baseline (dependent on M2 muscarinic receptors in the mesopontine tegmentum); and (iii) sustained increase (w30 min in the anaesthetized rat) that requires activation of M5 receptors in the midbrain [19]. With regard to PPTg connections with DA neurons, the anatomical division of the PPTg made by Olszewski and Baxter [20] is still significant. The posterior parts of the PPTg, equivalent to the pars compactus of Olszewski and Baxter, receive most of the sensory input and project to the ventral tegmental area (VTA), which in turn activates the ventral striatum. The anterior portion e pars dissipatus e receives more of the forebrain input and projects to the substantia nigra pars compacta (SNc) [21]. The hypothesis we can therefore advance (illustrated in Fig. 1) is that posterior PPTg receives more of the sensory input and activates the VTA (and ventral striatal structures), whereas anterior PPTg receives more of the forebrain output (from basal ganglia and extended amygdala) and activates SNc (and dorsal striatum/basal ganglia). That the inputs to midbrain DA neurons
Dorsal striatum
GP SNr STn
Ventral striatum
SNc
VTA
Anterior PPTg
VS output
Posterior PPTg
Fast sensory input Fig. 1. Schematic illustrating the corticostriatal connections of anterior (solid grey boxes) and posterior (white boxes) PPTg. Anterior PPTg has monosynaptic input (ACh and glutamate) to SNc, which projects to dorsal striatum, and reciprocal connections with principal basal ganglia output stations (GP, SNr, STn). Not shown (for simplicity) but important are extended amygdala inputs to anterior PPTg. Posterior PPTg receives fast, polymodal sensory input and connects via VTA (ACh and glutamate) to ventral striatum. Ach, acetylcholine; GP, globus pallidus; PPTg, pedunculopontine tegmental nucleus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STn, subthalamic nucleus; VS, ventral striatum; and VTA, ventral tegmental area.
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from the PPTg are organized in this way complements the hypothesis that the VTA/ventral striatum is involved with processing information related to goal-directed actions, whereas the SNc/dorsal striatum is concerned with stimuluseresponse habit learning [22]. 4. The functions of the pedunculopontine Older literature emphasizes locomotion and sleep as functions of the PPTg. Neurons in the PPTg change their activity across the sleepewake cycle and are important for regulating thalamic state: the switch between bursting and single spiking is dependent on cholinergic activity [23]. As such, the PPTg is important in the control of sleep, but two considerations qualify this: (i) many neurons in structures throughout the midbrain and brainstem (the locus coeruleus and raphe nuclei, for example) show differential activity across behavioural states; and (ii) bilateral excitotoxic lesions restricted to the PPTg do not affect normal sleep patterns in the rat (though REM rebound is affected after sleep deprivation) [24]. It is perhaps better to consider the PPTg as a component part of a distributed network of structures and neurons controlling sleep rather than as a unique regulator of behavioural state or ‘‘master switch’’ for REM sleep. The issue of locomotor control and the PPTg is bound up with the mesencephalic locomotor region (MLR). The MLR is a region of brain (defined functionally rather than morphologically or hodologically) from which locomotion can be elicited in pre-collicular post-mammillary transected animals. However, bilateral excitotoxic lesions of the whole PPTg have repeatedly been shown [25e29] not to affect locomotor activity. The only data that indicate a motor deficit after PPTg lesions come from studies of non-human primates [30,31], but these are compromised by use of the neurotoxin kainate (which always produces very large lesions after microinjection; it is orders of magnitude more potent than excitotoxins that work through NMDA receptors) and the time course. In both studies the behavioural testing occurred within 2 weeks of lesion induction, when non-specific effects of lesioning can still be apparent. To understand how the MLR works, and why excitotoxic lesions have no effect on locomotion, it is necessary to consider the PPTg in a larger context. A cogent argument in favour of considering brains as layered architectures has recently been presented [32]. The argument is that brains can be described as layered systems in which there is ‘‘.decomposition of . control system[s] into multiple levels of competences with lower levels dissociable from those above’’ (p. 103). That is, brains can be considered as systems in which, for particular functions, different levels operate: all levels have sensory input and motor output properties and can effect decision making, with simple and fast decisions taken at lower levels. Two-way interaction between layers ensures effective information flow, and that low-level (impulsive or premature) decision making can be suppressed. Moreover, these interactions mean that these architectures are not simple hierarchies but have heterarchical properties. Such an analysis fits the
PPTg: (i) it has sensory and motor connections; (ii) it can influence processing in higher layers (striatal, thalamic and cortical); (iii) it is subject to strong inhibitory control from the forebrain; and (iv) it can, independently of the forebrain, influence brainstem and spinal motor processes. The MLR is understandable if considered as demonstrating that, in the absence of descending control from the forebrain, stimulation of brainstem sites (including the PPTg and other structures such as the cuneiform nucleus) can produce coordinated activity, as one would expect of a layered architecture from which higher control is disconnected. While the locomotion stimulated from the PPTg in decerebrate animals e and indeed the MLR en masse e is understandable, it is critical to acknowledge that ‘‘MLR functions’’ do not demonstrate that the primary purpose of the PPTg is control of locomotion. Because of its anatomical connections, several laboratories have used tests of corticostriatal functions in rats bearing excitotoxic lesions of the PPTg. My laboratory, for example, has shown that bilateral ibotenate lesions of the whole PPTg e made using a series of injections along the length of the PPTg e produce profound deficits in some tasks and none in others. Rats bearing such lesions have no impairment in basic activities such as feeding, drinking or grooming, and are essentially unimpaired in tasks such as the elevated plus maze or open field (which measure emotionality) [33]. However, on the radial arm maze, in tasks designed explicitly to test corticostriatal functions [34], PPTg-lesioned rats are profoundly impaired [35]. They move around the maze normally, but their selection of arms to enter is at no better than chance levels. In operant tests, rats show impairments in tasks with an associative component. Alderson and her colleagues [36] showed that rats bearing bilateral ibotenate lesions of the whole PPTg were incapable of learning to lever press for intravenous drug administration (D-amphetamine) on a low fixed ratio schedule, but if they had learned the lever pressereward association prior to lesioning, their performance was identical to that of sham operated controls. Considering that the PPTg is so often thought of as a basic motor structure, it is especially notable that in the pre-trained condition, even with bilateral PPTg lesions, rats emitted normal instrumental actions to obtain a reward. The implication of these data is that the presence of an intact PPTg is essential for making actioneoutcome associations. This hypothesis can explain a significant amount of data. It deals with the operant data described here (and data involving natural reinforcers [37]) as well as the radial maze data: rats that cannot make actioneoutcome associations will inevitably find any task that changes trial-by-trial impossible. It also explains the absence of effect in other tests: the elevated plus maze, for example, does not have an intrinsic associative element [33]. Electrophysiological data that link PPTg neuron firing to reinforcement processes rather than movement [16,17] strengthen this hypothesis, which is nevertheless still only an hypothesis, but one testable using standard techniques of reinforcer devaluation and contingency degradation that have been applied in the study of striatal actione outcome functions [38].
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These examinations of the behavioural effects of bilateral lesions of the whole PPTg establish a framework for understanding the functions of the PPTg that go beyond ‘‘sleep and locomotion’’. Rather, the data show that the PPTg can be considered as part of the basal ganglia family. Two major questions remain: (i) can different functions for neurochemically identified populations of neurons be established? What do the cholinergic neurons do? The answer is uncertain but might be more easily established following development of a fusion toxin selective for mesopontine cholinergic neurons [39]. (ii) What functions can be ascribed to different parts of the PPTg, identified by connectivity? We have started to investigate this while examining the relationships between PPTg and responding for nicotine, and have shown that anterior and posterior PPTg do have different functions. Selfadministration of nicotine is changed by posterior but not anterior PPTg lesions [40] and our most recent work has shown that posterior lesions also change the sensitized locomotor response to repeated nicotine administration. In these experiments we have shown that, while anterior PPTg lesions have no effect on the locomotor response to repeated nicotine, they produce a small, lasting reduction in spontaneous locomotion [41]. This is the first demonstration in the rat of a motor deficit following PPTg damage, and it is noteworthy that the damage is restricted to the anterior PPTg, which projects into the substantia nigra (Fig. 1). Establishing the precise functions of the various elements of the PPTg will be a major goal of research in the coming years. 5. Parkinson’s disease, the pedunculopontine and deepbrain stimulation As noted before, interest in the PPTg has developed following recent demonstrations that DBS here has therapeutic benefit, notably for gait and postural instability [8e10]. This is consistent with experimental studies in MPTP-treated nonhuman primates, where PPTg stimulation provides relief from akinesia [42]. However, the data from rodents bearing excitotoxic lesions of PPTg suggest that changes in psychological functions might be produced by PPTg DBS. In this regard, it is intriguing to note that in further examination of patients undergoing treatment [10], PET analyses have revealed more cortical activation after PPTg DBS than has been seen in other studies after DBS of the subthalamic nucleus. This was accompanied by improvements in neuropsychological tests that examine both motor and executive functions such as the trail-making test (Paolo Stanzione e personal communication). That there might be changes in psychological functioning after PPTg DBS is compatible with other neuroimaging and clinical studies. Smolka and colleagues [43] have shown that, in smokers who were deprived of nicotine and experiencing craving, the PPTg was activated by the presentation of cues associated with smoking, an effect compatible with the associative hypothesis. It has also been suggested that there are cognitive impairments reminiscent of those seen following lesions of the PPTg in rats [35] after pontine ischaemic stroke in human patients [44].
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Is the PPTg a suitable target for DBS? The answer is yes e patients have been successfully treated e but questions remain. How does it work e what neural systems are changed by this treatment? Are there key intra-PPTg targets? Which aspects of parkinsonism will be most effectively treated, and for how long? It is to be hoped that authoritative scientific data, drawn from studies of humans and experimental animals, will answer these questions. 6. Conclusions What are the functions of the PPTg? The position taken here is that, although the PPTg has motor and sensory properties, its functions are not best considered in these terms. Rather, it has functions that integrate sensory and motor data, and it is specifically proposed that this is related to actioneoutcome association, a process that involves both motor abilities and sensory capacities. This function is related strongly to the functions of corticostriatal systems and establishes a higher order function for the PPTg than had previously been supposed. Conflict of interest None declared. Role of the funding source The work of my laboratory, described in this article, has been supported by the Wellcome Trust, the Biotechnology and Biological Sciences Research Council (UK) and the Leverhulme Trust. The author has retained full editorial control and responsibilities throughout the preparation of the manuscript. Acknowledgements I am grateful to colleagues at the meeting for their discussion and to my laboratory colleagues for their invaluable labour and insights over many years. References [1] Mena-Segovia J, Bolam JP, Magill PJ. Pedunculopontine nucleus and basal ganglia: distant relatives or part of the same family? Trends Neurosci 2004;27:565e88. [2] Pahapill PA, Lozano AM. The pedunculopontine nucleus and Parkinson’s disease. Brain 2000;123:1767e83. [3] Winn P. How best to consider the structure and function of the pedunculopontine tegmental nucleus: evidence from animal studies. J Neurol Sci 2006;248:234e50. [4] Braak H, Del Tredici K, Ru¨ba U, de Vos RAI, Jansen Steur ENH, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003;24:197e211. [5] Mitchell IJ, Clarke CE, Boyce S, Robertson RG, Peggs D, Sambrook MA, et al. Neural mechanisms underlying Parkinsonian symptoms based upon regional uptake of 2-deoxyglucose in monkeys exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neuroscience 1989;32: 213e26.
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