- Email: [email protected]
Pedunculo-pontine control of visually guided saccades
Progress in Brain Research, Vol. 143 ISSN 0079-6123 Copyright ß 2004 Elsevier BV. All rights reserved
CHAPTER 41
Pedunculo-pontine control of visually guided saccades Yasushi Kobayashi*, Yuka Inoue and Tadashi Isa Department of Integrative Physiology, National Institute for Physiological Sciences, Okazaki 444-8585, Japan
Abstract: The cholinergic pedunculopontine tegmental nucleus (PPTN) is one of the major ascending arousal systems in the brainstem, and it is linked to motor, limbic and sensory centers. Despite an abundance of anatomical and physiological data, however, the functional role of PPTN neurons in behavioral control is still unresolved. In this chapter, we hypothesize that the PPTN is implicated in the integrative control of movement, particularly the reinforcement of tasks performed during conscious behavior. We present a new model of the PPTN’s involvement in the control of arousal, attention and reinforcement aspects of motor behavior, with a focus on the control of saccadic eye movements.
Introduction
(DRN; Koyama and Kayama, 1993). It has been proposed that this basal ganglia–PPTN–catecholaminergic complex is important for gating movement and controlling several attentive behaviors (GarciaRill, 1991; see also Takakusaki et al., Garcia-Rill, et al., Skinner et al., and Grantyn et al., Chapters 23, 27, 28 and 40 of this volume). Despite the abundant anatomical findings, however, the functional importance of the PPTN is far from understood. Several anatomical-connection and lesion studies across several species have suggested, however, that the PPTN is involved in the control of attention and motor control (Steckler et al., 1994a) and reinforcement learning (Brown et al., 1999). Saccades are rapid (ballistic) eye movements, which can be triggered by a variety of cues (auditory, visual, memory, etc.). Since their onsets are easy to identify, their preparation and execution processes can be phase-related to neuronal activity. In addition, saccades are altered by attentional (Kustov and Robinson, 1996) and motivational (Kawagoe et al., 1998) states, which are also modifiable by task sequences during experimental sessions. Thus, oculomotor tasks, especially those involving saccades and recording PPTN neuronal activity in awake monkeys, are an optimal cmeans of investigating the neural control of movement, attention and reinforcement
The brainstem’s pedunculopontine tegmental nucleus (PPTN) and laterodorsal tegmental nucleus (LDTN) are central components of the reticular-activating system, which complex provides background excitation for several sensory and motor systems, and is essential for perception (Lindsley, 1958) and cognitive processes (Steckler et al., 1994b). The PPTN contains both cholinergic and glutamatergic neurons (Hallanger and Wainer, 1988), and it is one of the major sources of cholinergic projections in the brainstem. The cholinergic system is a key modulatory neurotransmitter system in the brain, controlling, for example, neuronal activity involved in selective attention. There is also anatomical and physiological evidence that supports the idea of a ‘cholinergic component’ of conscious awareness (Perry et al., 1999). The PPTN has reciprocal connections with the basal ganglia, including the subthalamic nucleus, globus pallidus and substantia nigra (Edley and Graybiel, 1983; Lavoie and Parent, 1994), and catecholaminergic systems in the brainstem, including the locus coeruleus (LC) and dorsal raphe nucleus *Corresponding author: Tel.: þ 81-564-55-7857; Fax: þ 81-564-55-7790; E-mail: [email protected]
439 DOI: 10.1016/S0079-6123(03)43041-0
440
learning. In this chapter, our group presents a new model of the PPTN’s involvement in the control of arousal, attention and reinforcement aspects of motor behavior, with a focus on the control of saccadic eye movements (see also Isa and Kobayashi, and Grantyn et al., this volume).
Execution of saccadic eye movements There have been reports of the PPTN’s involvement in the control of arm movements (Matsumura et al., 1997) and posture and locomotion (Garcia-Rill, 1991). It has also been shown that lesions of the PPTN reduce the frequency of eye movements during rapid eye-movement sleep (Shouse and Siegel, 1992). The frontal eye field (FEF; Bruce and Goldberg, 1985) and substantia nigra pars reticulata (SNr; Hikosaka and Wurtz, 1983) participate in the control of saccadic eye movements and there is evidence that FEF neurons project to the PPTN (Matsumura et al., 2000), which structure receives GABAergic input from SNr (Gerfen et al., 1982; Granata and Kitai, 1991). These findings suggest that the PPTN may well contribute to the control of eye movements. Furthermore, the PPTN strongly innervates the intermediate layer of the superior colliculus (SC) in several mammalian species (Graybiel, 1978; Beninato and Spencer, 1986; Hall et al., 1989; Henderson and Sherriff, 1991; Ma et al., 1991; Schnurr et al., 1992; Jeon et al., 1993). The SC is a key structure for the generation of saccadic eye movements (Sparks and Hartwich-Young, 1989). Neuronal activity in its intermediate layer that precedes saccade execution is influenced by attentional shifts (Kustov and Robinson, 1996), movement selection (Glimcher and Sparks, 1992) and the extent of motor preparation (Dorris and Munoz, 1998). Thus, cognitive influences on saccades and their execution signals may well depend on activation of the PPTN. Accordingly, our group proposes that the PPTN coordinates the relay of visuosensory information to the cerebral cortex and SNr for the execution of saccades. To clarify the role of cholinergic input to the intermediate layer of the SC for the elaboration of saccades, our group has examined the effect of microinjection of nicotine into the SC on visually guided saccades in the monkey (Aizawa et al., 1999).
After such injection, the frequency of extremely short-latency saccades [express saccades; saccadic reaction time (SRT) <120 ms; Fischer and Weber, 1993; Pare and Munoz, 1996] increases dramatically. This result suggests that cholinergic PPTN inputs to the SC influence motor preparation signals and the timing of saccade initiation. Our laboratory also recently used slice preparations of the rat SC to show that activation of nicotinic acetylcholine receptors on neurons in the intermediate layer of the SC induces inward currents and depolarization, which may gate signal transmission in the direct visuomotor pathway (i.e., from the superficial to the intermediate layer of the SC; Isa et al., 1998a,b). These results suggest that the neural mechanisms we observed in the rat SC slice also apply to behaving monkeys (Aizawa et al., 1999), i.e., the PPTN’s cholinergic input to the SC may control SRT via activation of nicotinic acetylcholine receptors on neurons in the intermediate layer of the SC. Figure 1 shows our model of the PPTN’s involvement in the control of saccades. Neuronal burst activity related to saccade executions may be observed in the PPTN just as it is in the caudal part of the SC. Crossed descending projections from the SC terminate in the PPTN (cat— Huerta and Harting, 1982; rat—Redgrave et al., 1987;
Fig. 1. Model of the PPTN’s involvement in controlling saccadic eye movement. Abbreviations: SC, superior colliculus; SNr, substantia nigra pars reticulata; PPTN, pedunculopontine tegmental nucleus. See text for further explanation of this and the subsequent figures.
441
monkey—May and Porter, 1992), which structure receives ipsilateral projections from motor areas in cerebral cortex in the cat (Edley and Graybiel, 1983) and monkey (Matsumura et al., 2000). In the monkey, the PPTN also receives ipsilateral projections from the infralimbic and prelimbic areas (Chiba et al., 2001) and the FEF (Matsumura et al., 2000). The cause of the saccade burst in the SC may also be explained by disinhibition of GABAergic input from the SNr (Gerfen et al., 1982; Granata and Kitai, 1991). Moreover, a pause in PPTN neuron discharge during a saccade occurs in phase with one in fixation neurons in the rostral pole of the SC. The stimulus for this pause may involve inputs from the SC, basal ganglia and cerebral cortex. Fig. 1 shows that GABAergic inputs from the SNr, glutamatergic inputs from the cerebral cortex, and glutamatergic and cholinergic inputs from the PPTN may all regulate the SC, where multimodal signals converge and interact. In summary, the PPTN has the capacity to integrate several saccade-related signals, which it receives from the SC, basal ganglia and cerebral cortex. The PPTN-processed signals are then returned to their sites of origin. Clearly, the PPTN is ideally situated to work cooperatively with other brain structures for the initiation and execution of saccades.
but also in their response to sensory stimulation. Some of these LDTN neurons may also function to induce a global attentive state in response to a novel stimulus (Koyama et al., 1994). Figure 2 shows our model for the control of arousal and attention by the PPTN. Arousal-related neuronal activity can be generated by the LC–DRN– PPTN circuit, which is triggered by inputs from the cerebral cortex. Neuronal activity in brainstem cholinergic nuclei (LDTN) is related to tonic-activation processes in thalamo-cortical systems (Steriade et al., 1990). Cholinergic projections (McDonald et al., 1993) from the PPTN to the LGN are also a component of the reticular-activation system. Activation of the PPTN can also regulate visual responses of the LGN in the cat (Uhlrich et al., 1995). The thalamo-cortical projection and cortical projection to the PPTN (cat—Edley and Graybiel, 1983; monkey—Matsumura et al., 2000) form a recurrent PPTN–thalamus–cerebral cortex network. Reverberation of signals in this circuit may regulate sensorimotor processing and attentional modulation within the cerebral cortex. Scarnati and Florio (1997) found that movement performance in the rat was dramatically reduced by bilateral lesions of the PPTN, with the animal
Arousal and attention Many studies suggest that the PPTN and LDTN regulate vigilance levels like sleep and wakefulness. These structures are also involved in inducing an arousal and global attentive state in response to a novel stimulus (Steriade, 1996a,b). Regulation of arousal by the PPTN is coupled with the actions of catecholaminergic systems in the brainstem, the LC (noradrenergic) and DRN (serotonergic; Koyama and Kayama, 1993). A projection from the PPTN to the lateral geniculate nucleus (LGN) forms part of the reticular-activation system, and activation of the PPTN can lead to enhanced visual responses of the LGN in the cat (Uhlrich et al., 1995). Furthermore, in the head-restrained rat, LDTN neurons have heterogeneous properties not only with respect to their spontaneous activity during sleep and wakefulness
Fig. 2. Model of the PPTN’s involvement in controlling attention and arousal. Additional abbreviations: 5-HT, serotonin; ACh, acetylcholine; DRN, dorsal raphe nucleus; LC, locus coeruleus; NA, noradrenaline.
442
exhibiting significantly increased reaction time and slowed movement duration. In the conditioned cat, reversible inactivation of the PPTN by microinjection of lidocaine or muscimol dramatically slows intertrial intervals and the motor execution of lever release (Conde et al., 1998). These results suggest that the PPTN is involved in selecting the appropriate motor program and attentional state to perform the selected movement, including saccades. A number of studies have suggested that the PPTN induces a global attentive state in response to a novel stimulus (Steriade, 1996a,b). Recently, contextdependent activity in PPTN neurons was demonstrated in the operantly conditioned cat while performing a lever-release movement (Dormont et al., 1998). In this study, PPTN neurons exhibited excitation at a very short latency after the cue stimulus. Similar PPTN neuronal activity has been observed during a visually guided saccade task (Kobayashi et al., 2002). In this latter case, a fixation point (FP) appeared at an earlier stage of the task. The proposed PPTN neuronal activity (sustained tonic activity related to task performance or response to the FP) during saccade tasks may enhance responsiveness of the thalamus and thereby modulate sensorimotor processing at the cortical level. Such PPTN activity should improve processing for perception of the next target and the execution of subsequent saccades.
Reinforcement learning In the monkey, the PPTN receives limbic inputs from the hypothalamus and ventral tegmental area (Semba and Fibiger, 1992) and the limbic cortex (Chiba et al., 2001). Recent studies have emphasized that SNc dopaminergic neurons process the reward-related information necessary for the reinforcement of behavior (Schultz, 1998). Most dopamine neurons exhibit phasic activity after primary liquid and food rewards and conditioned, reward-predicting visual and auditory stimuli (for review, see Schultz, 1998). A recent computational model predicts that the PPTN is a major source of the excitatory signal to the substantia nigra pars compacta (SNc) and an important neural control component for reinforcement learning (Brown et al., 1999). The model made use of the finding that the PPTN projects to SNc
dopaminergic neurons (Beninato and Spencer, 1986), which may encode an error signal sufficient for such learning (Schultz, 1998). Brown et al.’s (1999) model successfully simulated the learning process. Dopamine neurons were activated by rewards during early trials in the learning sessions, when errors were frequent and rewards unpredictable. Activation by rewards was progressively reduced as performance was consolidated and the rewards became more predictable. The suppression of a reward response after learning may be caused by GABAergic input from striosomes (Gerfen, 1992). Recently, reinforcement-related single-unit activity in the PPTN has also been demonstrated in the cat (Dormont et al., 1998). Glutamatergic and cholinergic inputs from the PPTN make synaptic connections with SNc dopamine neurons in the cat (Futami et al., 1995; Takakusaki et al., 1996), and electrical stimulation of the PPTN induces a time-locked burst in analogous neurons in the rat (Lokwan et al., 1999). Clearly, SNc dopamine neurons can code errors in the prediction of the occurrence of rewards (Hollerman and Schultz, 1998). Reward-related activity in the PPTN has been observed in the monkey during saccade tasks, even during fully conditioned situations (Kobayashi et al., 2002). Since the PPTN can code primary (direct) reward signals, which are modified by cortical inputs, Fig. 3 shows that our group now hypothesizes that the reward prediction error signal coded by the SNc may be composed of an excitatory reward signal (derived from the PPTN), and inhibitory primary reward prediction signals from the striatum.
Cognitive processes PPTN neurons have axon collaterals that project to both the LGN and SC (Billet et al., 1999). Accordingly, we hypothesize that the PPTN coordinates the relay of attentive information to the cortex via the thalamus, and the PPTN’s effects on the onset and execution of orienting movements, which are mediated via the SC. Neuronal activity related to behavioral performance can improve visual and motor processing via the thalamus, including SC preparation signals in advance of a saccade. Therefore, activity is prominent in those PPTN
443
Fig. 4. Model of the PPTN’s interactions with brainstem/basal ganglia circuits for the control of saccades. Additional abbreviations: FEF, frontal eye field; V1, primary visual cortex.
Fig. 3. Model of the PPTN’s involvement in controlling reinforcement learning. Additional abbreviation: SNc, substantia nigra pars compacta.
during the elaboration of saccades by the conscious monkey serves as a powerful tool for investigating neural mechanisms for motor control, arousal, attention and reinforcement learning, and their interactions.
Acknowledgments neurons, which respond to both saccade execution and task performance. PPTN neurons, which have abundant axon collaterals, receive a wide variety of inputs from many areas of the brain. Hence, it is not surprising that some of them are active during both saccades and reward signals. Such neurons may also coordinate the relay of reward information to the SNc when saccades are being executed. Figure 4 shows our model for the involvement of the PPTN in the control of attention, saccades and reinforcement. The signals related to all three may be impressed on each single PPTN neuron. With regard to movement control, the PPTN can integrate saccade-related signals derived from the SC, FEF and SNr. During movement, the PPTN works cooperatively with the SC by virtue of their reciprocal connectivity. Reward-related signals from the PPTN can affect reinforcement learning within the basal ganglia via the SNc, and signals related to behavioral performance can affect attention at the cerebral cortex via the thalamus. In final summary, our group’s work has shown that by recording neuronal activity in the PPTN
We thank Chika Sasaki, Yasuyuki Takeshima and Junko Yamamoto for their technical assistance. This study was supported by grants from the Ministry of Education, Science, Sports and Culture of Japan to Y.K. (11780599, 13780647 and 13035052).
Abbreviations 5-HT ACh DRN FP FEF LC LDTN LGN NA PPTN SRT SNc SNr SC V1
serotonin acetylcholine dorsal raphe nucleus fixation point frontal eye field locus coeruleus laterodorsal tegmental nucleus lateral geniculate nucleus noradrenaline pedunculopontine tegmental nucleus saccadic reaction time substantia nigra pars compacta substantia nigra pars reticulata superior colliculus primary visual cortex
444
References Aizawa, H., Kobayashi, Y., Yamamoto, M. and Isa, T. (1999). Injection of nicotine into superior colliculus facilitates occurrence of express saccades in monkeys. J. Neurophysiol., 82: 1642–1646. Beninato, M. and Spencer, R.F. (1986). A cholinergic projection to the rat superior colliculus demonstrated by retrograde transport of horseradish peroxidase and choline acetyltransferase immunohistochemistry. J. Comp. Neurol., 253: 525– 538. Billet, S., Cant, N.B. and Hall, W.C. (1999). Cholinergic projections to the visual thalamus and superior colliculus. Brain Res., 847: 121–123. Brown, J., Bullock, D. and Grossberg, S. (1999). How the basal ganglia use parallel excitatory and inhibitory learning pathways to selectively respond to unexpected rewarding cues. J. Neurosci., 19: 10502–10511. Bruce, C.J. and Goldberg, M.E. (1985). Primate frontal eye fields. I. Single neurons discharging before saccades. J. Neurophysiol., 53: 603–635. Chiba, T., Kayahara, T. and Nakano, K. (2001). Efferent projections of infralimbic and prelimbic areas of the medial prefrontal cortex in the Japanese monkey, Macaca fuscata. Brain Res., 888: 83–101. Conde, H., Dormont, J.F. and Farin, D. (1998). The role of the pedunculopontine tegmental nucleus in relation to conditioned motor performance in the cat. II. Effects of reversible inactivation by intracerebral microinjections. Exp. Brain Res., 121: 411–418. Dormont, J.F., Conde, H. and Farin, D. (1998). 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., 121: 401–410. Dorris, M.C. and Munoz, D.P. (1998). Saccadic probability influences motor preparation signals and time to saccadic initiation. J. Neurosci., 18: 7015–7026. Edley, S.M. and Graybiel, A.M. (1983). The afferent and efferent connections of the feline nucleus tegmenti pedunculopontinus, pars compacta. J. Comp. Neurol., 217: 187–215. Fischer, B. and Weber, H. (1993). Express saccade and visual attention. Behav. Brain Sci., 16: 553–610. Futami, T., Takakusaki, K. and Kitai, S.T. (1995). Glutamatergic and cholinergic inputs from the pedunculopontine tegmental nucleus to dopamine neurons in the substantia nigra pars compacta. Neurosci. Res., 21: 331–342. Garcia-Rill, E. (1991). The pedunculopontine nucleus. Prog. Neurobiol., 36: 363–389. Gerfen, C.R. (1992). The neostriatal mosaic: multiple levels of compartmental organization. Trends Neurosci., 15: 133–139. Gerfen, C.R., Staines, W.A., Arbuthnott, G.W. and Fibiger, H.C. (1982). Crossed connections of the substantia nigra in the rat. J. Comp. Neurol., 207: 283–303.
Glimcher, P.W. and Sparks, D.L. (1992). Movement selection in advance of action in the superior colliculus. Nature, 355: 542–545. Granata, A.R. and Kitai, S.T. (1991). Inhibitory substantia nigra inputs to the pedunculopontine neurons. Exp. Brain Res., 86: 459–466. Graybiel, A.M. (1978). A stereometric pattern of distribution of acetylthiocholinesterase in the deep layers of the superior colliculus. Nature, 272: 539–541. Hall, W.C., Fitzpatrick, D., Klatt, L.L. and Raczkowski, D. (1989). Cholinergic innervation of the superior colliculus in the cat. J. Comp. Neurol., 287: 495–514. Hallanger, A.E. and Wainer, B.H. (1988). Ascending projections from the pedunculopontine tegmental nucleus and the adjacent mesopontine tegmentum in the rat. J. Comp. Neurol., 274: 483–515. Henderson, Z. and Sherriff, F.E. (1991). Distribution of choline acetyltransferase immunoreactive axons and terminals in the rat and ferret brainstem. J. Comp. Neurol., 314: 147–163. Hikosaka, O. and Wurtz, R.H. (1983). Visual and oculomotor functions of monkey substantia nigra pars reticulata. I. Relation of visual and auditory responses to saccades. J. Neurophysiol., 49: 1230–1253. Hollerman, J.R. and Schultz, W. (1998). Dopamine neurons report an error in the temporal prediction of reward during learning. Nat. Neurosci., 1: 304–309. Huerta, M.F. and Harting, J.K. (1982). Tectal control of spinal cord activity: neuroanatomical demonstration of pathways connecting the superior colliculus with the cervical spinal cord grey. Prog. Brain Res., 57: 293–328. Isa, T., Endo, T. and Saito, Y. (1998a). Nicotinic facilitation of signal transmission in the local circuits of the rat superior colliculus. Soc. Neurosci. Abstr., 24: 60.13. Isa, T., Endo, T. and Saito, Y. (1998b). The visuo-motor pathway in the local circuit of the rat superior colliculus. J. Neurosci., 18: 8496–8504. Jeon, C.J., Spencer, R.F. and Mize, R.R. (1993). Organization and synaptic connections of cholinergic fibers in the cat superior colliculus. J. Comp. Neurol., 333: 360–374. Kawagoe, R., Takikawa, Y. and Hikosaka, O. (1998). Expectation of reward modulates cognitive signals in the basal ganglia. Nat. Neurosci., 1: 411–416. Kobayashi, Y., Inoue, Y., Yamamoto, M., Isa, T. and Aizawa, H. (2002). Contribution of pedunculopontine tegmental nucleus neurons to performance of visually guided saccade tasks in monkeys. J. Neurophysiol., 88: 715–731. Koyama, Y. and Kayama, Y. (1993). Mutual interactions among cholinergic, noradrenergic and serotonergic neurons studied by ionophoresis of these transmitters in rat brainstem nuclei. Neuroscience, 55: 1117–1126. Koyama, Y., Jodo, E. and Kayama, Y. (1994). Sensory responsiveness of ‘broad-spike’ neurons in the laterodorsal tegmental nucleus, locus coeruleus and dorsal raphe of awake
445 rats: implications for cholinergic and monoaminergic neuronspecific responses. Neuroscience, 63: 1021–1031. Kustov, A.A. and Robinson, D.L. (1996). Shared neural control of attentional shifts and eye movements. Nature, 384: 74–77. Lavoie, B. and Parent, A. (1994). Pedunculopontine nucleus in the squirrel monkey: projections to the basal ganglia as revealed by anterograde tract-tracing methods. J. Comp. Neurol., 344: 210–231. Lindsley, D.B. (1958). The reticular system and perceptual discrimination. In: Jasper H.H. (Ed.), The Reticular Formation of the Brain. Little Brown & Co, Boston, pp. 513–534. Lokwan, S.J., Overton, P.G., Berry, M.S. and Clark, D. (1999). Stimulation of the pedunculopontine tegmental nucleus in the rat produces burst firing in A9 dopaminergic neurons. Neuroscience, 92: 245–254. Ma, T.P., Graybiel, A.M. and Wurtz, R.H. (1991). Location of saccade-related neurons in the macaque superior colliculus. Exp. Brain Res., 85: 21–35. Matsumura, M., Watanabe, K. and Ohye, C. (1997). Singleunit activity in the primate nucleus tegmenti pedunculopontinus related to voluntary arm movement. Neurosci. Res., 28: 155–165. Matsumura, M., Nambu, A., Yamaji, Y., Watanabe, K., Imai, H., Inase, M., Tokuno, H. and Takada, M. (2000). Organization of somatic motor inputs from the frontal lobe to the pedunculopontine tegmental nucleus in the macaque monkey. Neuroscience, 98: 97–110. May, P.J. and Porter, J.D. (1992). The laminar distribution of macaque tectobulbar and tectospinal neurons. Vis. Neurosci., 8: 257–276. McDonald, C.T., McGuinness, E.R. and Allman, J.M. (1993). Laminar organization of acetylcholinesterase and cytochrome oxidase in the lateral geniculate nucleus of prosimians. Neuroscience, 54: 1091–1101. Pare, M. and Munoz, D.P. (1996). Saccadic reaction time in the monkey: advanced preparation of oculomotor programs is primarily responsible for express saccade occurrence. J. Neurophysiol., 76: 3666–3681. Perry, E., Walker, M., Grace, J. and Perry, R. (1999). Acetylcholine in mind: a neurotransmitter correlate of consciousness?. Trends Neurosci., 22: 273–280. Redgrave, P., Mitchell, I.J. and Dean, P. (1987). Descending projections from the superior colliculus in rat: a study using
orthograde transport of wheatgerm-agglutinin conjugated horseradish peroxidase. Exp. Brain Res., 68: 147–167. Scarnati, E. and Florio, T. (1997). The pedunculopontine nucleus and related structures. Functional organization. Adv. Neurol., 74: 97–110. Schnurr, B., Spatz, W.B. and Illing, R.B. (1992). Similarities and differences between cholinergic systems in the superior colliculus of guinea pig and rat. Exp. Brain Res., 90: 291–296. Schultz, W. (1998). Predictive reward signal of dopamine neurons. J. Neurophysiol., 80: 1–27. Semba, K. and Fibiger, H.C. (1992). Afferent connections of the laterodorsal and the pedunculopontine tegmental nuclei in the rat: a retro- and antero-grade transport and immunohistochemical study. J. Comp. Neurol., 323: 387– 410. Shouse, M.N. and Siegel, J.M. (1992). Pontine regulation of REM sleep components in cats: integrity of the pedunculopontine tegmentum (PPT) is important for phasic events but unnecessary for atonia during REM sleep. Brain Res., 571: 50–63. Sparks, D.L. and Hartwich-Young, R. (1989). The deep layers of the superior colliculus. Rev. Oculomot. Res., 3: 213–255. Steckler, T., Keith, A.B. and Sahgal, A. (1994a). Lesions of the pedunculopontine tegmental nucleus do not alter delayed non-matching to position accuracy. Behav. Brain Res., 61: 107–112. Steckler, T., Inglis, W., Winn, P. and Sahgal, A. (1994b). The pedunculopontine tegmental nucleus: a role in cognitive processes?. Brain Res. Brain Res. Rev., 19: 298–318. Steriade, M. (1996a). Awakening the brain. Nature, 383: 24–25. Steriade, M. (1996b). Arousal: revisiting the reticular activating system. Science, 272: 225–226. Steriade, M., Datta, S., Pare, D., Oakson, G. and Curro Dossi, R.C. (1990). Neuronal activities in brain-stem cholinergic nuclei related to tonic activation processes in thalamocortical systems. J. Neurosci., 10: 2541–2559. Takakusaki, K., Shiroyama, T., Yamamoto, T. and Kitai, S.T. (1996). Cholinergic and noncholinergic tegmental pedunculopontine projection neurons in rats revealed by intracellular labeling. J. Comp. Neurol., 371: 345–361. Uhlrich, D.J., Tamamaki, N., Murphy, P.C. and Sherman, S.M. (1995). Effects of brain stem parabrachial activation on receptive field properties of cells in the cat’s lateral geniculate nucleus. J. Neurophysiol., 73: 2428–2447.
CHAPTER 41
Pedunculo-pontine control of visually guided saccades Yasushi Kobayashi*, Yuka Inoue and Tadashi Isa Department of Integrative Physiology, National Institute for Physiological Sciences, Okazaki 444-8585, Japan
Abstract: The cholinergic pedunculopontine tegmental nucleus (PPTN) is one of the major ascending arousal systems in the brainstem, and it is linked to motor, limbic and sensory centers. Despite an abundance of anatomical and physiological data, however, the functional role of PPTN neurons in behavioral control is still unresolved. In this chapter, we hypothesize that the PPTN is implicated in the integrative control of movement, particularly the reinforcement of tasks performed during conscious behavior. We present a new model of the PPTN’s involvement in the control of arousal, attention and reinforcement aspects of motor behavior, with a focus on the control of saccadic eye movements.
Introduction
(DRN; Koyama and Kayama, 1993). It has been proposed that this basal ganglia–PPTN–catecholaminergic complex is important for gating movement and controlling several attentive behaviors (GarciaRill, 1991; see also Takakusaki et al., Garcia-Rill, et al., Skinner et al., and Grantyn et al., Chapters 23, 27, 28 and 40 of this volume). Despite the abundant anatomical findings, however, the functional importance of the PPTN is far from understood. Several anatomical-connection and lesion studies across several species have suggested, however, that the PPTN is involved in the control of attention and motor control (Steckler et al., 1994a) and reinforcement learning (Brown et al., 1999). Saccades are rapid (ballistic) eye movements, which can be triggered by a variety of cues (auditory, visual, memory, etc.). Since their onsets are easy to identify, their preparation and execution processes can be phase-related to neuronal activity. In addition, saccades are altered by attentional (Kustov and Robinson, 1996) and motivational (Kawagoe et al., 1998) states, which are also modifiable by task sequences during experimental sessions. Thus, oculomotor tasks, especially those involving saccades and recording PPTN neuronal activity in awake monkeys, are an optimal cmeans of investigating the neural control of movement, attention and reinforcement
The brainstem’s pedunculopontine tegmental nucleus (PPTN) and laterodorsal tegmental nucleus (LDTN) are central components of the reticular-activating system, which complex provides background excitation for several sensory and motor systems, and is essential for perception (Lindsley, 1958) and cognitive processes (Steckler et al., 1994b). The PPTN contains both cholinergic and glutamatergic neurons (Hallanger and Wainer, 1988), and it is one of the major sources of cholinergic projections in the brainstem. The cholinergic system is a key modulatory neurotransmitter system in the brain, controlling, for example, neuronal activity involved in selective attention. There is also anatomical and physiological evidence that supports the idea of a ‘cholinergic component’ of conscious awareness (Perry et al., 1999). The PPTN has reciprocal connections with the basal ganglia, including the subthalamic nucleus, globus pallidus and substantia nigra (Edley and Graybiel, 1983; Lavoie and Parent, 1994), and catecholaminergic systems in the brainstem, including the locus coeruleus (LC) and dorsal raphe nucleus *Corresponding author: Tel.: þ 81-564-55-7857; Fax: þ 81-564-55-7790; E-mail: [email protected]
439 DOI: 10.1016/S0079-6123(03)43041-0
440
learning. In this chapter, our group presents a new model of the PPTN’s involvement in the control of arousal, attention and reinforcement aspects of motor behavior, with a focus on the control of saccadic eye movements (see also Isa and Kobayashi, and Grantyn et al., this volume).
Execution of saccadic eye movements There have been reports of the PPTN’s involvement in the control of arm movements (Matsumura et al., 1997) and posture and locomotion (Garcia-Rill, 1991). It has also been shown that lesions of the PPTN reduce the frequency of eye movements during rapid eye-movement sleep (Shouse and Siegel, 1992). The frontal eye field (FEF; Bruce and Goldberg, 1985) and substantia nigra pars reticulata (SNr; Hikosaka and Wurtz, 1983) participate in the control of saccadic eye movements and there is evidence that FEF neurons project to the PPTN (Matsumura et al., 2000), which structure receives GABAergic input from SNr (Gerfen et al., 1982; Granata and Kitai, 1991). These findings suggest that the PPTN may well contribute to the control of eye movements. Furthermore, the PPTN strongly innervates the intermediate layer of the superior colliculus (SC) in several mammalian species (Graybiel, 1978; Beninato and Spencer, 1986; Hall et al., 1989; Henderson and Sherriff, 1991; Ma et al., 1991; Schnurr et al., 1992; Jeon et al., 1993). The SC is a key structure for the generation of saccadic eye movements (Sparks and Hartwich-Young, 1989). Neuronal activity in its intermediate layer that precedes saccade execution is influenced by attentional shifts (Kustov and Robinson, 1996), movement selection (Glimcher and Sparks, 1992) and the extent of motor preparation (Dorris and Munoz, 1998). Thus, cognitive influences on saccades and their execution signals may well depend on activation of the PPTN. Accordingly, our group proposes that the PPTN coordinates the relay of visuosensory information to the cerebral cortex and SNr for the execution of saccades. To clarify the role of cholinergic input to the intermediate layer of the SC for the elaboration of saccades, our group has examined the effect of microinjection of nicotine into the SC on visually guided saccades in the monkey (Aizawa et al., 1999).
After such injection, the frequency of extremely short-latency saccades [express saccades; saccadic reaction time (SRT) <120 ms; Fischer and Weber, 1993; Pare and Munoz, 1996] increases dramatically. This result suggests that cholinergic PPTN inputs to the SC influence motor preparation signals and the timing of saccade initiation. Our laboratory also recently used slice preparations of the rat SC to show that activation of nicotinic acetylcholine receptors on neurons in the intermediate layer of the SC induces inward currents and depolarization, which may gate signal transmission in the direct visuomotor pathway (i.e., from the superficial to the intermediate layer of the SC; Isa et al., 1998a,b). These results suggest that the neural mechanisms we observed in the rat SC slice also apply to behaving monkeys (Aizawa et al., 1999), i.e., the PPTN’s cholinergic input to the SC may control SRT via activation of nicotinic acetylcholine receptors on neurons in the intermediate layer of the SC. Figure 1 shows our model of the PPTN’s involvement in the control of saccades. Neuronal burst activity related to saccade executions may be observed in the PPTN just as it is in the caudal part of the SC. Crossed descending projections from the SC terminate in the PPTN (cat— Huerta and Harting, 1982; rat—Redgrave et al., 1987;
Fig. 1. Model of the PPTN’s involvement in controlling saccadic eye movement. Abbreviations: SC, superior colliculus; SNr, substantia nigra pars reticulata; PPTN, pedunculopontine tegmental nucleus. See text for further explanation of this and the subsequent figures.
441
monkey—May and Porter, 1992), which structure receives ipsilateral projections from motor areas in cerebral cortex in the cat (Edley and Graybiel, 1983) and monkey (Matsumura et al., 2000). In the monkey, the PPTN also receives ipsilateral projections from the infralimbic and prelimbic areas (Chiba et al., 2001) and the FEF (Matsumura et al., 2000). The cause of the saccade burst in the SC may also be explained by disinhibition of GABAergic input from the SNr (Gerfen et al., 1982; Granata and Kitai, 1991). Moreover, a pause in PPTN neuron discharge during a saccade occurs in phase with one in fixation neurons in the rostral pole of the SC. The stimulus for this pause may involve inputs from the SC, basal ganglia and cerebral cortex. Fig. 1 shows that GABAergic inputs from the SNr, glutamatergic inputs from the cerebral cortex, and glutamatergic and cholinergic inputs from the PPTN may all regulate the SC, where multimodal signals converge and interact. In summary, the PPTN has the capacity to integrate several saccade-related signals, which it receives from the SC, basal ganglia and cerebral cortex. The PPTN-processed signals are then returned to their sites of origin. Clearly, the PPTN is ideally situated to work cooperatively with other brain structures for the initiation and execution of saccades.
but also in their response to sensory stimulation. Some of these LDTN neurons may also function to induce a global attentive state in response to a novel stimulus (Koyama et al., 1994). Figure 2 shows our model for the control of arousal and attention by the PPTN. Arousal-related neuronal activity can be generated by the LC–DRN– PPTN circuit, which is triggered by inputs from the cerebral cortex. Neuronal activity in brainstem cholinergic nuclei (LDTN) is related to tonic-activation processes in thalamo-cortical systems (Steriade et al., 1990). Cholinergic projections (McDonald et al., 1993) from the PPTN to the LGN are also a component of the reticular-activation system. Activation of the PPTN can also regulate visual responses of the LGN in the cat (Uhlrich et al., 1995). The thalamo-cortical projection and cortical projection to the PPTN (cat—Edley and Graybiel, 1983; monkey—Matsumura et al., 2000) form a recurrent PPTN–thalamus–cerebral cortex network. Reverberation of signals in this circuit may regulate sensorimotor processing and attentional modulation within the cerebral cortex. Scarnati and Florio (1997) found that movement performance in the rat was dramatically reduced by bilateral lesions of the PPTN, with the animal
Arousal and attention Many studies suggest that the PPTN and LDTN regulate vigilance levels like sleep and wakefulness. These structures are also involved in inducing an arousal and global attentive state in response to a novel stimulus (Steriade, 1996a,b). Regulation of arousal by the PPTN is coupled with the actions of catecholaminergic systems in the brainstem, the LC (noradrenergic) and DRN (serotonergic; Koyama and Kayama, 1993). A projection from the PPTN to the lateral geniculate nucleus (LGN) forms part of the reticular-activation system, and activation of the PPTN can lead to enhanced visual responses of the LGN in the cat (Uhlrich et al., 1995). Furthermore, in the head-restrained rat, LDTN neurons have heterogeneous properties not only with respect to their spontaneous activity during sleep and wakefulness
Fig. 2. Model of the PPTN’s involvement in controlling attention and arousal. Additional abbreviations: 5-HT, serotonin; ACh, acetylcholine; DRN, dorsal raphe nucleus; LC, locus coeruleus; NA, noradrenaline.
442
exhibiting significantly increased reaction time and slowed movement duration. In the conditioned cat, reversible inactivation of the PPTN by microinjection of lidocaine or muscimol dramatically slows intertrial intervals and the motor execution of lever release (Conde et al., 1998). These results suggest that the PPTN is involved in selecting the appropriate motor program and attentional state to perform the selected movement, including saccades. A number of studies have suggested that the PPTN induces a global attentive state in response to a novel stimulus (Steriade, 1996a,b). Recently, contextdependent activity in PPTN neurons was demonstrated in the operantly conditioned cat while performing a lever-release movement (Dormont et al., 1998). In this study, PPTN neurons exhibited excitation at a very short latency after the cue stimulus. Similar PPTN neuronal activity has been observed during a visually guided saccade task (Kobayashi et al., 2002). In this latter case, a fixation point (FP) appeared at an earlier stage of the task. The proposed PPTN neuronal activity (sustained tonic activity related to task performance or response to the FP) during saccade tasks may enhance responsiveness of the thalamus and thereby modulate sensorimotor processing at the cortical level. Such PPTN activity should improve processing for perception of the next target and the execution of subsequent saccades.
Reinforcement learning In the monkey, the PPTN receives limbic inputs from the hypothalamus and ventral tegmental area (Semba and Fibiger, 1992) and the limbic cortex (Chiba et al., 2001). Recent studies have emphasized that SNc dopaminergic neurons process the reward-related information necessary for the reinforcement of behavior (Schultz, 1998). Most dopamine neurons exhibit phasic activity after primary liquid and food rewards and conditioned, reward-predicting visual and auditory stimuli (for review, see Schultz, 1998). A recent computational model predicts that the PPTN is a major source of the excitatory signal to the substantia nigra pars compacta (SNc) and an important neural control component for reinforcement learning (Brown et al., 1999). The model made use of the finding that the PPTN projects to SNc
dopaminergic neurons (Beninato and Spencer, 1986), which may encode an error signal sufficient for such learning (Schultz, 1998). Brown et al.’s (1999) model successfully simulated the learning process. Dopamine neurons were activated by rewards during early trials in the learning sessions, when errors were frequent and rewards unpredictable. Activation by rewards was progressively reduced as performance was consolidated and the rewards became more predictable. The suppression of a reward response after learning may be caused by GABAergic input from striosomes (Gerfen, 1992). Recently, reinforcement-related single-unit activity in the PPTN has also been demonstrated in the cat (Dormont et al., 1998). Glutamatergic and cholinergic inputs from the PPTN make synaptic connections with SNc dopamine neurons in the cat (Futami et al., 1995; Takakusaki et al., 1996), and electrical stimulation of the PPTN induces a time-locked burst in analogous neurons in the rat (Lokwan et al., 1999). Clearly, SNc dopamine neurons can code errors in the prediction of the occurrence of rewards (Hollerman and Schultz, 1998). Reward-related activity in the PPTN has been observed in the monkey during saccade tasks, even during fully conditioned situations (Kobayashi et al., 2002). Since the PPTN can code primary (direct) reward signals, which are modified by cortical inputs, Fig. 3 shows that our group now hypothesizes that the reward prediction error signal coded by the SNc may be composed of an excitatory reward signal (derived from the PPTN), and inhibitory primary reward prediction signals from the striatum.
Cognitive processes PPTN neurons have axon collaterals that project to both the LGN and SC (Billet et al., 1999). Accordingly, we hypothesize that the PPTN coordinates the relay of attentive information to the cortex via the thalamus, and the PPTN’s effects on the onset and execution of orienting movements, which are mediated via the SC. Neuronal activity related to behavioral performance can improve visual and motor processing via the thalamus, including SC preparation signals in advance of a saccade. Therefore, activity is prominent in those PPTN
443
Fig. 4. Model of the PPTN’s interactions with brainstem/basal ganglia circuits for the control of saccades. Additional abbreviations: FEF, frontal eye field; V1, primary visual cortex.
Fig. 3. Model of the PPTN’s involvement in controlling reinforcement learning. Additional abbreviation: SNc, substantia nigra pars compacta.
during the elaboration of saccades by the conscious monkey serves as a powerful tool for investigating neural mechanisms for motor control, arousal, attention and reinforcement learning, and their interactions.
Acknowledgments neurons, which respond to both saccade execution and task performance. PPTN neurons, which have abundant axon collaterals, receive a wide variety of inputs from many areas of the brain. Hence, it is not surprising that some of them are active during both saccades and reward signals. Such neurons may also coordinate the relay of reward information to the SNc when saccades are being executed. Figure 4 shows our model for the involvement of the PPTN in the control of attention, saccades and reinforcement. The signals related to all three may be impressed on each single PPTN neuron. With regard to movement control, the PPTN can integrate saccade-related signals derived from the SC, FEF and SNr. During movement, the PPTN works cooperatively with the SC by virtue of their reciprocal connectivity. Reward-related signals from the PPTN can affect reinforcement learning within the basal ganglia via the SNc, and signals related to behavioral performance can affect attention at the cerebral cortex via the thalamus. In final summary, our group’s work has shown that by recording neuronal activity in the PPTN
We thank Chika Sasaki, Yasuyuki Takeshima and Junko Yamamoto for their technical assistance. This study was supported by grants from the Ministry of Education, Science, Sports and Culture of Japan to Y.K. (11780599, 13780647 and 13035052).
Abbreviations 5-HT ACh DRN FP FEF LC LDTN LGN NA PPTN SRT SNc SNr SC V1
serotonin acetylcholine dorsal raphe nucleus fixation point frontal eye field locus coeruleus laterodorsal tegmental nucleus lateral geniculate nucleus noradrenaline pedunculopontine tegmental nucleus saccadic reaction time substantia nigra pars compacta substantia nigra pars reticulata superior colliculus primary visual cortex
444
References Aizawa, H., Kobayashi, Y., Yamamoto, M. and Isa, T. (1999). Injection of nicotine into superior colliculus facilitates occurrence of express saccades in monkeys. J. Neurophysiol., 82: 1642–1646. Beninato, M. and Spencer, R.F. (1986). A cholinergic projection to the rat superior colliculus demonstrated by retrograde transport of horseradish peroxidase and choline acetyltransferase immunohistochemistry. J. Comp. Neurol., 253: 525– 538. Billet, S., Cant, N.B. and Hall, W.C. (1999). Cholinergic projections to the visual thalamus and superior colliculus. Brain Res., 847: 121–123. Brown, J., Bullock, D. and Grossberg, S. (1999). How the basal ganglia use parallel excitatory and inhibitory learning pathways to selectively respond to unexpected rewarding cues. J. Neurosci., 19: 10502–10511. Bruce, C.J. and Goldberg, M.E. (1985). Primate frontal eye fields. I. Single neurons discharging before saccades. J. Neurophysiol., 53: 603–635. Chiba, T., Kayahara, T. and Nakano, K. (2001). Efferent projections of infralimbic and prelimbic areas of the medial prefrontal cortex in the Japanese monkey, Macaca fuscata. Brain Res., 888: 83–101. Conde, H., Dormont, J.F. and Farin, D. (1998). The role of the pedunculopontine tegmental nucleus in relation to conditioned motor performance in the cat. II. Effects of reversible inactivation by intracerebral microinjections. Exp. Brain Res., 121: 411–418. Dormont, J.F., Conde, H. and Farin, D. (1998). 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., 121: 401–410. Dorris, M.C. and Munoz, D.P. (1998). Saccadic probability influences motor preparation signals and time to saccadic initiation. J. Neurosci., 18: 7015–7026. Edley, S.M. and Graybiel, A.M. (1983). The afferent and efferent connections of the feline nucleus tegmenti pedunculopontinus, pars compacta. J. Comp. Neurol., 217: 187–215. Fischer, B. and Weber, H. (1993). Express saccade and visual attention. Behav. Brain Sci., 16: 553–610. Futami, T., Takakusaki, K. and Kitai, S.T. (1995). Glutamatergic and cholinergic inputs from the pedunculopontine tegmental nucleus to dopamine neurons in the substantia nigra pars compacta. Neurosci. Res., 21: 331–342. Garcia-Rill, E. (1991). The pedunculopontine nucleus. Prog. Neurobiol., 36: 363–389. Gerfen, C.R. (1992). The neostriatal mosaic: multiple levels of compartmental organization. Trends Neurosci., 15: 133–139. Gerfen, C.R., Staines, W.A., Arbuthnott, G.W. and Fibiger, H.C. (1982). Crossed connections of the substantia nigra in the rat. J. Comp. Neurol., 207: 283–303.
Glimcher, P.W. and Sparks, D.L. (1992). Movement selection in advance of action in the superior colliculus. Nature, 355: 542–545. Granata, A.R. and Kitai, S.T. (1991). Inhibitory substantia nigra inputs to the pedunculopontine neurons. Exp. Brain Res., 86: 459–466. Graybiel, A.M. (1978). A stereometric pattern of distribution of acetylthiocholinesterase in the deep layers of the superior colliculus. Nature, 272: 539–541. Hall, W.C., Fitzpatrick, D., Klatt, L.L. and Raczkowski, D. (1989). Cholinergic innervation of the superior colliculus in the cat. J. Comp. Neurol., 287: 495–514. Hallanger, A.E. and Wainer, B.H. (1988). Ascending projections from the pedunculopontine tegmental nucleus and the adjacent mesopontine tegmentum in the rat. J. Comp. Neurol., 274: 483–515. Henderson, Z. and Sherriff, F.E. (1991). Distribution of choline acetyltransferase immunoreactive axons and terminals in the rat and ferret brainstem. J. Comp. Neurol., 314: 147–163. Hikosaka, O. and Wurtz, R.H. (1983). Visual and oculomotor functions of monkey substantia nigra pars reticulata. I. Relation of visual and auditory responses to saccades. J. Neurophysiol., 49: 1230–1253. Hollerman, J.R. and Schultz, W. (1998). Dopamine neurons report an error in the temporal prediction of reward during learning. Nat. Neurosci., 1: 304–309. Huerta, M.F. and Harting, J.K. (1982). Tectal control of spinal cord activity: neuroanatomical demonstration of pathways connecting the superior colliculus with the cervical spinal cord grey. Prog. Brain Res., 57: 293–328. Isa, T., Endo, T. and Saito, Y. (1998a). Nicotinic facilitation of signal transmission in the local circuits of the rat superior colliculus. Soc. Neurosci. Abstr., 24: 60.13. Isa, T., Endo, T. and Saito, Y. (1998b). The visuo-motor pathway in the local circuit of the rat superior colliculus. J. Neurosci., 18: 8496–8504. Jeon, C.J., Spencer, R.F. and Mize, R.R. (1993). Organization and synaptic connections of cholinergic fibers in the cat superior colliculus. J. Comp. Neurol., 333: 360–374. Kawagoe, R., Takikawa, Y. and Hikosaka, O. (1998). Expectation of reward modulates cognitive signals in the basal ganglia. Nat. Neurosci., 1: 411–416. Kobayashi, Y., Inoue, Y., Yamamoto, M., Isa, T. and Aizawa, H. (2002). Contribution of pedunculopontine tegmental nucleus neurons to performance of visually guided saccade tasks in monkeys. J. Neurophysiol., 88: 715–731. Koyama, Y. and Kayama, Y. (1993). Mutual interactions among cholinergic, noradrenergic and serotonergic neurons studied by ionophoresis of these transmitters in rat brainstem nuclei. Neuroscience, 55: 1117–1126. Koyama, Y., Jodo, E. and Kayama, Y. (1994). Sensory responsiveness of ‘broad-spike’ neurons in the laterodorsal tegmental nucleus, locus coeruleus and dorsal raphe of awake
445 rats: implications for cholinergic and monoaminergic neuronspecific responses. Neuroscience, 63: 1021–1031. Kustov, A.A. and Robinson, D.L. (1996). Shared neural control of attentional shifts and eye movements. Nature, 384: 74–77. Lavoie, B. and Parent, A. (1994). Pedunculopontine nucleus in the squirrel monkey: projections to the basal ganglia as revealed by anterograde tract-tracing methods. J. Comp. Neurol., 344: 210–231. Lindsley, D.B. (1958). The reticular system and perceptual discrimination. In: Jasper H.H. (Ed.), The Reticular Formation of the Brain. Little Brown & Co, Boston, pp. 513–534. Lokwan, S.J., Overton, P.G., Berry, M.S. and Clark, D. (1999). Stimulation of the pedunculopontine tegmental nucleus in the rat produces burst firing in A9 dopaminergic neurons. Neuroscience, 92: 245–254. Ma, T.P., Graybiel, A.M. and Wurtz, R.H. (1991). Location of saccade-related neurons in the macaque superior colliculus. Exp. Brain Res., 85: 21–35. Matsumura, M., Watanabe, K. and Ohye, C. (1997). Singleunit activity in the primate nucleus tegmenti pedunculopontinus related to voluntary arm movement. Neurosci. Res., 28: 155–165. Matsumura, M., Nambu, A., Yamaji, Y., Watanabe, K., Imai, H., Inase, M., Tokuno, H. and Takada, M. (2000). Organization of somatic motor inputs from the frontal lobe to the pedunculopontine tegmental nucleus in the macaque monkey. Neuroscience, 98: 97–110. May, P.J. and Porter, J.D. (1992). The laminar distribution of macaque tectobulbar and tectospinal neurons. Vis. Neurosci., 8: 257–276. McDonald, C.T., McGuinness, E.R. and Allman, J.M. (1993). Laminar organization of acetylcholinesterase and cytochrome oxidase in the lateral geniculate nucleus of prosimians. Neuroscience, 54: 1091–1101. Pare, M. and Munoz, D.P. (1996). Saccadic reaction time in the monkey: advanced preparation of oculomotor programs is primarily responsible for express saccade occurrence. J. Neurophysiol., 76: 3666–3681. Perry, E., Walker, M., Grace, J. and Perry, R. (1999). Acetylcholine in mind: a neurotransmitter correlate of consciousness?. Trends Neurosci., 22: 273–280. Redgrave, P., Mitchell, I.J. and Dean, P. (1987). Descending projections from the superior colliculus in rat: a study using
orthograde transport of wheatgerm-agglutinin conjugated horseradish peroxidase. Exp. Brain Res., 68: 147–167. Scarnati, E. and Florio, T. (1997). The pedunculopontine nucleus and related structures. Functional organization. Adv. Neurol., 74: 97–110. Schnurr, B., Spatz, W.B. and Illing, R.B. (1992). Similarities and differences between cholinergic systems in the superior colliculus of guinea pig and rat. Exp. Brain Res., 90: 291–296. Schultz, W. (1998). Predictive reward signal of dopamine neurons. J. Neurophysiol., 80: 1–27. Semba, K. and Fibiger, H.C. (1992). Afferent connections of the laterodorsal and the pedunculopontine tegmental nuclei in the rat: a retro- and antero-grade transport and immunohistochemical study. J. Comp. Neurol., 323: 387– 410. Shouse, M.N. and Siegel, J.M. (1992). Pontine regulation of REM sleep components in cats: integrity of the pedunculopontine tegmentum (PPT) is important for phasic events but unnecessary for atonia during REM sleep. Brain Res., 571: 50–63. Sparks, D.L. and Hartwich-Young, R. (1989). The deep layers of the superior colliculus. Rev. Oculomot. Res., 3: 213–255. Steckler, T., Keith, A.B. and Sahgal, A. (1994a). Lesions of the pedunculopontine tegmental nucleus do not alter delayed non-matching to position accuracy. Behav. Brain Res., 61: 107–112. Steckler, T., Inglis, W., Winn, P. and Sahgal, A. (1994b). The pedunculopontine tegmental nucleus: a role in cognitive processes?. Brain Res. Brain Res. Rev., 19: 298–318. Steriade, M. (1996a). Awakening the brain. Nature, 383: 24–25. Steriade, M. (1996b). Arousal: revisiting the reticular activating system. Science, 272: 225–226. Steriade, M., Datta, S., Pare, D., Oakson, G. and Curro Dossi, R.C. (1990). Neuronal activities in brain-stem cholinergic nuclei related to tonic activation processes in thalamocortical systems. J. Neurosci., 10: 2541–2559. Takakusaki, K., Shiroyama, T., Yamamoto, T. and Kitai, S.T. (1996). Cholinergic and noncholinergic tegmental pedunculopontine projection neurons in rats revealed by intracellular labeling. J. Comp. Neurol., 371: 345–361. Uhlrich, D.J., Tamamaki, N., Murphy, P.C. and Sherman, S.M. (1995). Effects of brain stem parabrachial activation on receptive field properties of cells in the cat’s lateral geniculate nucleus. J. Neurophysiol., 73: 2428–2447.