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. 2008 May 22;586(Pt 14):3479–3491. doi: 10.1113/jphysiol.2008.153254

Tonic inhibition and ponto-geniculo-occipital-related activities shape abducens motoneuron discharge during REM sleep

Miguel Escudero 1, Javier Márquez-Ruiz 1
PMCID: PMC2538812  PMID: 18499728

Abstract

Eye movements, ponto-geniculo-occipital (PGO) waves, muscular atonia and desynchronized cortical activity are the main characteristics of rapid eye movement (REM) sleep. Although eye movements designate this phase, little is known about the activity of the oculomotor system during REM sleep. In this work, we recorded binocular eye movements by the scleral search-coil technique and the activity of identified abducens (ABD) motoneurons along the sleep–wake cycle in behaving cats. The activity of ABD motoneurons during REM sleep was characterized by a tonic decrease of their mean firing rate throughout this period, and short bursts and pauses coinciding with the occurrence of PGO waves. We demonstrate that the decrease in the mean firing discharge was due to an active inhibition of ABD motoneurons, and that the occurrence of primary and secondary PGO waves induced a pattern of simultaneous but opposed phasic activation and inhibition on each ABD nucleus. With regard to eye movements, during REM sleep ABD motoneurons failed to codify eye position as during alertness, but continued to codify eye velocity. The pattern of tonic inhibition and the phasic activations and inhibitions shown by ABD motoneurons coincide with those reported in other non-oculomotor motoneurons, indicating that the oculomotor system – contrary to what has been accepted until now – is not different from other motor systems during REM sleep, and that all motor systems are receiving similar command signals during this period.

Mammalian sleep is not a homogeneous state. In 1953, Aserinsky and Kleitman (Aserinsky & Kleitman, 1953) described the existence of periods of fast and jerky eye movements during sleep in humans, and coined the term rapid eye movement (REM) sleep to differentiate this phase from other sleep periods. Besides these eye movements, REM sleep is characterized by other phasic signs, such as high-amplitude spiky potentials that are mainly recorded at pontine, geniculate and occipital areas (PGO) (Jeannerod et al. 1965), and spontaneous twitches in the antigravity musculature (Chase & Morales, 1983). These phasic activities are seen throughout this period, along with an absence of muscular tonus (Jouvet & Michel, 1959) and the presence of a high-frequency and low-amplitude electroencephalographic activity (Dement, 1958).

Of these cardinal signs, rapid eye movements are probably the poorest known – despite their designating this phase – and the oculomotor system during REM sleep remains almost unexplored. By contrast, the oculomotor system in alert animals is perhaps one of the most studied. Each eye is rotated by the action of six extraocular muscles: the medial and lateral recti are exclusively involved in horizontal eye movements, while the superior and inferior recti and the superior and inferior oblique control vertical and torsional eye movements. Abducting and adducting eye movements are controlled by motoneurons located in abducens (ABD) and oculomotor nuclei, respectively. Internuclear interneurons in the ABD nucleus project to the contralateral medial rectus motoneurons, and are responsible for conjugated eye movements (Highstein et al. 1982).

In alert animals, spontaneous eye movements consist of saccades that move the eyes to a visual target, and eye fixations that keep the eyes on the target, enabling visual acquisition. During these movements, extraocular motoneurons display phasic and tonic activities related to eye velocity and position, respectively (Fuchs & Luschei, 1970; Delgado-García et al. 1986). In the horizontal plane, velocity and position signals are generated at premotor levels (Escudero & Delgado-García, 1988) by burst neurons in the paramedial reticular formation (Hikosaka et al. 1978; Yoshida et al. 1982; Strassman et al. 1986a) and tonic neurons in the prepositus hypoglossi nucleus (Escudero et al. 1992; McFarland & Fuchs, 1992), respectively.

In a companion paper (Márquez-Ruiz & Escudero, 2008), we have characterized eye movements during the sleep–wake cycle in cats, and demonstrated the existence of a tonic nasal and downward maintained rotation of the two eyes, interrupted by complex rapid eye movements during REM sleep. Rapid eye movements coincided with the occurrence of PGO waves at the lateral geniculate nucleus (LGN), and consisted of back-and-forth movements in which abducting movements were faster. These tonic and phasic characteristics in eye movements recall some aspects of the tonic inhibition and phasic activations and inhibitions described in other motor system during REM sleep (Nakamura et al. 1978; Glenn et al. 1978). Notwithstanding, the full establishment of this parallelism requires knowing the activity of extraocular motoneurons during REM sleep.

In this work, we recorded and analysed the movement of both eyes and the activity of the same ABD motoneurons during alertness and REM sleep. The results allow us to disclose the tight coupling between eye movements, PGO waves and motoneuron activity, and to establish the similarity between the mechanisms operating on extraocular motoneurons and other motor neurons during REM sleep.

Methods

Subjects

Nine adult female cats (2.4–3.7 kg) of European strains, obtained from an authorized supplier (University of Córdoba, Spain), were used as experimental subjects. Experiments were performed in accordance with the European Union directive 609/86/EU, the current Spanish legislation (RD 1201/2005), and the Animal Experimentation Ethics Committee of the University of Seville for the use of laboratory animals. Every effort was made to minimize the number of animals used and their suffering.

Chronic preparation

Animals were prepared for chronic recording of eye movements and for simultaneous recording of identified ABD motoneurons, as previously described (Escudero et al. 1992). Briefly, animals were anaesthetized with sodium pentobarbitone (35 mg kg−1, i.p.) following a protective injection of atropine (0.5 mg kg−1, i.m.) aimed at preventing vagal reflexes. Under aseptic conditions, the cats were implanted bilaterally with Teflon-coated stainless-steel coils sutured to the scleral margin of the eye (Fig. 1). In the same surgical act, a 6 mm × 6 mm hole was drilled through the occipital bone to allow access to the posterior brainstem via the cerebellum. Bipolar silver stimulating electrodes were implanted bilaterally on the VIth nerve (Fig. 1) at its exit from the brainstem (stereotaxic coordinates, lateral 3.5 and posterior 1, according to Berman, 1968). The final location of the stimulating electrodes was adjusted to evoke the maximum abducting eye movement with the minimum electrical stimulation (50 μs, cathodic square pulses of < 0.1 mA of current intensity) (CS-220A, Cibertec, Madrid, Spain). Screw electrodes were implanted bilaterally over the frontal cortex for electroencephalography (EEG), bipolar stainless-steel wires (Cooner Wire, Chatsworth, CA, USA) in the trapezius muscles for electromyography (EMG), and bipolar silver electrodes (A-M Systems, Everett, WA, USA) in the lateral LGN (lateral 8.6 and anterior 5.5, according to Berman, 1968) for the recording of PGO waves during REM sleep. The final location of each LGN bipolar electrode was adjusted by recording the neuronal activity in response to light flashes. A head-holding system, consisting of three bolts cemented to the skull perpendicular to the stereotaxic plane, was also implanted. Eye coils and polysomnographic recording electrodes were connected to a socket attached to the holding system. The animal received post-operative systemic treatment with antibiotics, and anti-inflammatory and analgesic drugs. During the complete experimental period, antibiotics, local anaesthetics and corticoids were topically applied to the eyes and the cranial window.

Figure 1. Schematic representation of the experimental design and arrangement of the horizontal oculomotor system.

Figure 1

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The abducens (ABD) nucleus is composed of motoneurons (Mn, caged circle) that innervate the ipsilateral lateral rectus (LR) muscle through the VIth nerve, and internuclear interneurons that cross the midline and project via the medial longitudinal fasciculus (MLF) to the contralateral oculomotor (OCM) nucleus, reaching the Mn that innervate the medial rectus (MR) muscle. Teflon-coated stainless-steel coils were fixed to the scleral margin of both eyes. A bipolar stimulating electrode (St) was implanted on each VIth nerve to stimulate Mn antidromically in the ABD nucleus. A glass micropipette was introduced into each ABD nucleus to record the activity of identified Mn. The recording activity of each ABD Mn began during alertness and was maintained to the end of the next rapid eye movement sleep phase.

Recording sessions

One to two weeks later, when there was a total recovery from surgery, animals were habituated to the experimental set-up. Every 2–4 days, for 2–3 h per day, animals were lightly restrained by elastic bandages, with their head fixed to the recording table by means of the head-holding system. The head of the cat was fixed 21 deg nose-down to maintain the horizontal semicircular canal in the horizontal plane. After one to five sessions, animals remained quiet, their heart and respiratory rates not different from those of free animals, showing no signs of discomfort or stress. Recording sessions were carried out for a maximum of 8–12 weeks. A glass micropipette (1–3 μm in diameter) filled with 2 m NaCl was advanced through the cerebellum towards either the left or the right ABD nucleus, which was identified by the recording of the antidromic field potential induced by electric stimulation of the ipsilateral VIth nerve. Recorded neurons were identified as motoneurons by antidromic activation and collision test from the ipsilateral VIth nerve electrical stimulation. Spontaneous eye movements and unitary activity of ABD motoneurons were recorded continuously during the alert state and during spontaneous REM sleep. Eye movements were recorded with the search-coil technique (CNC-Engineering, Seattle, CA, USA) (Fuchs & Robinson, 1966), and were calibrated at the beginning of each experimental session by rotating (± 10 deg) the magnetic field frame about both the horizontal and vertical planes. Eye position, field and unitary electrical activities were stored using an eight-channel video tape recording system (Neurocorder, Neurodata Instruments, NY, USA), and fed into a computer for off-line analysis (Power 1401, Cambridge Instruments, Cambridge, UK). Eye-position signals and unitary electrical activity were sampled at 500 Hz and 17 kHz, respectively. Neural activity signals were filtered at 1 Hz high-pass and 10 kHz low-pass filter, allowing the recording of PGO waves at ABD level. At the end of the experimental period, animals were anaesthetized with sodium pentobarbitone (50 mg kg−1i.p.), and transcardially perfused with saline and 4% paraformaldehyde, to anatomically confirm the location of the implanted electrodes and the recording zone.

Analysis of ABD motoneuronal sensitivity to eye position and velocity

In order to study the relationship between the firing rate of ABD motoneurons and the position and velocity of the ipsilateral eye during alertness and REM sleep, each identified ABD motoneuron was recorded during alertness and sleep states. To calculate the sensitivity of each motoneuron to eye position, the mean firing rate during fixations was plotted as a function of the mean eye position in the horizontal plane during the same intervals. In order to avoid interference with saccadic velocity signals, the first 300 ms after saccades were not considered in the analysis. The slope of the regression line for this relationship – ‘k’ (spikes s−1 deg−1) – represents the sensitivity of the neuron to eye position. This process was carried out for each ABD motoneuron recorded in each of the phases, and the values obtained were compared later.

In order to calculate the sensitivity of ABD motoneurons to eye velocity, a theoretical firing rate was calculated, applying the equation obtained for eye position sensitivity analysis to the actual eye position, and subtracting it from the firing discharge of the motoneuron; thus, the new firing rate was independent of the eye position. To characterize the sensitivity of ABD motoneurons to eye velocity during saccadic eye movements, the maximum firing frequency was plotted as a function of the peak velocity of the eye during each saccade. The slope of the regression line for this relationship – ‘r’ (spikes s−1 deg−1 s) – defined the sensitivity of the neuron to eye velocity.

In order to describe the behaviour of recorded motoneurons, collected data were included in a first-order linear model (Robinson, 1970): FR = F0 + kP + rP′, where FR is the firing rate, F0 the firing rate at eye position zero, k the sensitivity to eye position (P), and r the sensitivity to eye velocity (P′). The position threshold of motoneurons (Th) was calculated as −F0k−1.

Relationship between the firing rate of ABD motoneurons, eye movements and PGO wave activities

In order to establish the relationship between PGO waves, eye movements and motoneuronal activity, the position and velocity of both eyes and the firing rate of identified ABD motoneurons (n = 100), using triphasic PGO waves recorded at the ABD nucleus as a trigger, were averaged. The histogram for ABD motoneuronal activities was constructed with a bin size of 5 ms.

Results

The position of both eyes, PGO wave activity at the LGN and ABD nuclei, and the behaviour of 26 identified ABD motoneurons were recorded during alertness and REM sleep.

Relationship between PGO waves at the LGN and ABD nuclei and their relation with eye movements

Figure 2 displays an example of recording of EEG, right trapezius EMG, field activity in the LGN and ABD nuclei, and horizontal and vertical eye movements during a representative transition from non-REM (NREM) to REM sleep. As NREM sleep ended, muscle activity decreased progressively and high-amplitude spiky potentials (PGO waves) developed at the LGN. At the beginning of the transition from NREM to REM sleep, PGO waves were isolated, but as the trapezius muscle activity disappeared, they tended to cluster. At that time, the eyes were slowly rotating nasally (oblique straight arrows), and tended to maintain a convergent position during the whole REM sleep period (Márquez-Ruiz & Escudero, 2008). This eccentric position was interrupted by rapid eye movements that coincided with the presence of PGO waves. In the horizontal plane, abducting eye movements were always faster than adducting ones.

Figure 2. Binocular eye movements in the horizontal plane and electrographic activities during sleep in the cat.

Figure 2

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From top to bottom, representative recording of the electroencephalography (EEG), right trapezius rectified electromyography (EMG), ponto-geniculo-occipital (PGO) waves at the lateral geniculate (LGN) and abducens (ABD) nuclei, and eye position and velocity of the left (LH, LH′) and right (RH, RH′) eyes during non-rapid (NREM), rapid eye movement (REM) sleep, and the transition (T) in between. The T period was identified by the occurrence of the first rapid eye movements in association with isolated PGO waves, the decrease in amplitude and increase in frequency of the EEG, and the loss of tonic discharge of the neck muscle. During the T period, both eyes tended to rotate nasally (oblique arrows) and to maintain this visual convergence along REM sleep. During REM sleep, the most-vigorous and -complex rapid eye movements developed, always in coincidence with bursts of PGO waves. These movements were characteristically faster in the abducting direction, as shown by the opposite directions in the velocity traces of the two eyes. Calibrations are indicated at the right side of the figure.

To characterize the relationship between PGO waves at the LGN and those at the ABD nucleus, and their association with eye movements, PGO waves were recorded bilaterally and simultaneously in each of these structures (Fig. 3A). When PGO waves were recorded at the LGN, there was always one that was bigger and occurred slightly earlier in one LGN (primary) than in the other (secondary). The mean latency between the negative peaks of primary and secondary wave was 7.5 ± 2.0 ms (N = 273). At the ABD nucleus, a biphasic wave was recorded ipsilateral to the LGN in which the primary PGO occurred, and a triphasic wave of higher amplitude in the contralateral side. The latency between triphasic and biphasic ABD-PGO waves, measured at the first negative and positive peak, respectively, was 3.2 ± 1.7 ms (N = 133). These different ABD-PGO waves determined the movement of each eye. The ABD-PGO wave always preceded the movement of the eyes. The triphasic ABD-PGO wave induced a fast short ipsilateral eye movement that was more prominent in the ipsilateral eye. The mean latency between the negative peak of the triphasic ABD-PGO wave and the peak velocity of the ipsilateral eye was 13.4 ± 1.7 ms (N = 157). The biphasic wave, developed at the contralateral ABD nucleus, also induced a rapid ipsilateral movement that was bigger in the ipsilateral eye. The mean latency between the negative peak of the biphasic ABD-PGO wave and the peak velocity of the ipsilateral eye was 18.3 ± 3.6 ms (N = 113). Taking together the type of ABD-PGO wave and its temporal occurrence (Fig. 3B), the movement of the eyes comprised a very short first component (C1 in Fig. 3A) directed ipsilaterally to the side in which the triphasic ABD-PGO wave was recorded, followed by a bigger contralateral movement (C2 in Fig. 3A) directed to the side in which the biphasic ABD-PGO wave occurred. The complexity of these eye movements will be better understood after the behaviour of the ABD motoneurons during REM sleep is described.

Figure 3. Eye movements and ponto-geniculo-occipital (PGO) waves during rapid eye movement (REM) sleep.

Figure 3

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A, simultaneous recordings of the left (L, grey) (LH) and right (R, black) (RH) eye position and velocity (LH′ and RH′) in the horizontal plane during a burst of PGO waves recorded at the lateral geniculate (LGN) and abducens (ABD) nuclei, in which primary – bigger and earlier – PGO waves occurred at the LGNR. B, averaging (n = 50) of the activities displayed in A triggered by the positive peak of the PGO wave recorded at the left ABD nucleus. During the occurrence of a primary PGO wave at the LGNR, a secondary one was recorded at the LGNL, and a biphasic and a triphasic wave were recorded at the ABDR and ABDL, respectively. Eye movements comprised two consecutive movements: a small one (C1) that was bigger and faster in the contralateral eye and directed contralateral to the side of occurrence of the primary PGO, followed by a larger one (C2) that was bigger and faster in the ipsilateral eye and directed in the contralateral direction.

Qualitative behaviour of ABD motoneurons during alertness and REM sleep

When the animal was awake, identified ABD motoneurons (inset in Fig. 4A and D) showed a firing rate that increased as the eyes moved ipsilateral to the recorded side (Fig. 4A and D). During eye fixations, ABD motoneurons showed a tonic discharge that was proportional to the degree of rotation of the ipsilateral eye in the abducting direction. During saccades directed to the recorded side (on-direction), ABD motoneurons produced a burst of action potentials whose maximum firing rate was proportional to the peak eye velocity. During saccades in the off-direction, ABD motoneurons displayed a pause in their firing discharge.

Figure 4. Activity of abducens motoneurons during wakefulness and rapid eye movement (REM) sleep.

Figure 4

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Examples of the activity of two identified abducens (ABD) motoneurons (A–C and D–F) recorded in the left ABD nucleus during alertness and REM sleep. During alertness (A and D), ABD motoneurons showed a burst, and a tonic firing rate (FR) that was proportional to the velocity and position of the ipsilateral eye during movements in the abducting direction. During REM sleep, 62.5% of ABD motoneurons displayed some tonic activity (B and C), while others did not (E and F), but in all cases the activities were dependent on the occurrence of ponto-geniculo-occipital (PGO) waves. During triphasic PGO waves (B and E) recorded at the ABD nucleus (filled arrowheads), motoneurons produced a very short burst followed by a pause in their discharge (visible only in motoneurons with some tonic discharge during REM sleep, B). This short burst produced a short ipsilateral movement of high velocity in the ipsilateral eye (C1). During biphasic PGO waves (C and F) (open arrowheads), motoneurons paused in their firing discharge (also visible only in motoneurons with tonic discharge, C), followed by a burst and tonic discharge. This activity induced an ipsilateral movement of the ipsilateral eye (C2) which tended to maintain the position reached. By contrast, the contralateral eye tended to drift to its initial position before the rapid eye movement. For easy comparison of the temporal relationship between PGO wave activities at the ABD nucleus, the activity of ABD motoneurons, and eye movements, an average (n = 100) triggered by the peak eye velocity is shown at the right side of the panels B, C, E and F. Calibrations for B, E and F are shown in C, except if another value is indicated.

Although the level of excitability of different ABD motoneurons was variable, the qualitative behaviour of all identified ABD motoneurons (n = 26) recorded during REM sleep was similar. All of them decreased their mean firing discharge, and 37.5% did not show any tonic discharge, producing action potentials exclusively during the presence of PGO waves. Figure 4 shows an example of a neuron that displayed tonic activity during REM sleep (Fig. 4B and C), and another that discharged only during the occurrence of PGO waves (Fig. 4E and F).

The presence of each type of ABD-PGO wave not only was related to the movement of the eyes as indicated above, but also seemed to change the behaviour of ABD motoneurons. Triphasic ABD-PGO waves (filled black arrowheads in Fig. 4B and E) induced a very short burst – usually one to three action potentials – followed by a pause in ABD motoneurons. This burst induced the small ipsilateral movement of the eyes, faster in the ipsilateral eye, which we designated above as component C1. During the occurrence of biphasic waves (open arrowheads in Fig. 4C and F), ABD motoneurons displayed a pause in their firing rate (Fig. 4C) – visible only in neurons that remained active during REM sleep – followed by a burst and tonic discharge. The tonic discharge after the burst, also more lasting in motoneurons that remained active, was independent of the position of the eye in the orbit. This burst and tonic discharge induced an ipsilateral movement (component C2) that was bigger in the ipsilateral eye. At the end of this rapid eye movement, the tonic discharge tended to maintain the ipsilateral eye at the position reached, whereas the contralateral eye did not maintain the position reached, but tended to drift to a position close to which it was before the execution of the rapid eye movement.

To completely understand the movement of the two eyes during REM sleep and to establish the temporal relationship between the firing discharges and ABD-PGO waves, simultaneous bilateral recording was performed at both ABD nuclei. Figure 5 shows the average (N = 100) of PGO wave activities, the firing rate of two ABD motoneurons recorded in each ABD nucleus, and the position and velocity of the eyes. As indicated, when one type of PGO wave was recorded in one ABD nucleus, the other PGO wave was recorded in the other ABD nucleus (Fig. 5A). ABD motoneurons displayed opposed firing discharge profiles. The activity of the motoneurons (grey histogram in Fig. 5B) in the same ABD nucleus in which the biphasic PGO wave was recorded was characterized by a pause followed by a burst and tonic discharge. The pause and the maximum firing discharge occurred at the same time as the positive and negative peaks of the PGO wave, respectively. During the recording of the triphasic PGO wave, the ABD motoneurons (black histogram in Fig. 5B) displayed a short burst of activity followed by a pause, and the subsequent recovery of the background activity. The burst and the pause coincided with the first negative and positive peaks of the triphasic PGO wave, respectively.

Figure 5. Temporal relationship between ponto-geniculo-occipital (PGO) waves, abducens (ABD) motoneuronal activities and horizontal eye movements.

Figure 5

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Average (n = 100) of simultaneous recording (left side in grey; right side in black) of PGO waves in both ABD nuclei and the corresponding firing rate (FR) of identified ABD motoneurons and horizontal left (LH) and right (RH) eye position and velocity (LH′ and RH′). The average was triggered by the triphasic PGO wave. The peri-stimulus histogram for the firing discharge of identified ABD motoneurons was constructed with a bin size of 5 ms. When a biphasic PGO wave was recorded in one ABD nucleus, a triphasic PGO wave was recorded in the other, and vice versa. During the recording of biphasic PGO waves, ABD motoneurons were firstly inhibited and thereafter activated, whereas during the triphasic waves, motoneurons were briefly activated and then inhibited. This push–pull response of the two ABD nuclei shaped a conjugated eye movement directed firstly to the side on which the triphasic PGO wave (C1, black arrows) occurred, followed by another to the contralateral side (C2, grey arrows). In both cases, the velocity of each eye was higher for abducting movements, inducing a divergence between the visual axes of the two eyes.

Thus, considering the opposed activities in the two ABD nuclei, it is easier to interpret the dynamics of the eye movements during REM sleep. The movements of the two eyes are determined by the activity of the ABD nuclei in such a way that movements to the right is carried out by the right ABD nucleus and that to the left by the activity of the left ABD nucleus. When motoneurons in one ABD nucleus produced a short burst during the first peak of the triphasic PGO wave, the contralateral ABD motoneurons paused, and consequently both eyes moved ipsilaterally (black arrows in Fig. 5C). The movement of the ipsilateral eye (right eye in Fig. 5D) was faster and bigger than that of the contralateral one, as shown by the black arrows. As the activity of this ABD nucleus was absent after the short burst – while the contralateral ABD motoneurons showed a burst and tonic activity – now both eyes moved in the opposite direction (grey arrows in Fig. 5C). Again, the movement of the ipsilateral eye was bigger and faster (grey arrows in Fig. 5D). Due to the higher tonic activity of the ABD motoneurons at the end of the biphasic PGO, the ipsilateral eye tended to maintain the position reached.

Quantitative analysis of the firing rate of ABD motoneurons during alertness and REM sleep

To compare the characteristics of ABD motoneuronal discharge during wakefulness and REM sleep, the sensitivity to the position (k) and velocity (r) of 10 identified ABD motoneurons recorded continuously through both states was analysed. During alertness, ABD motoneurons produced a tonic firing discharge that was proportional to eye position (Fig. 6A). The mean slope of the relationship between firing rate and eye position was 6.0 ± 2.0 spikes s−1 deg−1 (Table 1). During REM sleep (Fig. 6B), those ABD motoneurons that maintained some tonic activity between PGO waves displayed a high variability in their codification and a poor relationship with eye position (Fig. 6B and Table 1). With this fuzzy behaviour of ABD motoneurons, it was difficult to find significant correlation between their firing rate and the position of the eye. In those few motoneurons in which a significant correlation (P < 0.05) was found, the value of R2 was always less than 0.5, and their sensitivity to eye position (k in Table 1) around 25% of the value obtained during alertness. By contrast, eye velocity sensitivity of ABD motoneurons was similar during alertness and REM sleep. During both states, ABD motoneurons produced a burst of spikes, whose maximum firing discharge was proportional to the velocity of movement of the ipsilateral eye in the abducting direction. The mean slope of the relationship between firing rate and eye velocity during REM sleep (r = 0.8 ± 0.4 spikes s−1 deg−1 s; Fig. 6D, Table 1) was not different from that during alertness (r = 0.6 ± 0.3 spikes s−1 deg−1 s; Fig. 6C; Table 1).

Figure 6. Codification of the eye position and velocity by abducens motoneurons during wakefulness and rapid eye movement (REM) sleep.

Figure 6

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Identified abducens motoneurons (n = 10) were recorded along the sleep–wake cycle to compare their behaviour during alertness and REM sleep. During alertness (A), abducens motoneurons displayed a tonic discharge that correlated with eye position. During REM sleep (B), only some motoneurons showed a tonic activity, and their activity correlated poorly with eye position (R2 < 0.5, Table 1). Motoneuron bursting discharges during rapid eye movements correlated with eye velocity during wakefulness (C) and REM sleep (D), with no statistical differences in the codification of eye velocity during the two states. Data for a representative abducens motoneuron and their corresponding regression line are plotted in black in A, B, C and D. Grey lines correspond to regression lines for the other nine motoneurons. Statistical values for each motoneuron are shown in Table 1.

Table 1.

Eye position and velocity sensitivity for 10 identified abducens motoneurons recorded during alertness and rapid eye movement (REM) sleep

Alertness REM sleep
Mn Th k R2 r R2 Th k R2 r R2
1 6.6 10.8 0.7 0.9 0.6 — — — 1.0 0.6
2 −7.6 6.9 0.8 0.4 0.8 −16.7 1.6 0.3 0.4 0.5
3 −4.5 3.8 0.9 0.3 0.8 −20.0 1.3 0.5 0.3 0.8
4 −7.6 5.0 0.8 0.4 0.8 – – – 0.4 0.7
5 −9.1 6.2 0.9 1.0 0.7 – – – 0.8 0.6
6 −12.0 5.3 0.8 0.9 0.8 −25.7 1.8 0.3 1.1 0.8
7 −6.6 4.0 0.7 0.5 0.5 — — — 0.5 0.8
8 −9.5 6.7 0.9 0.4 0.8 — — — 1.0 0.7
9 −3.1 5.8 0.6 0.6 0.9 — — — 1.7 0.8
10 −12.9 5.7 0.8 0.7 0.7 −15.9 2.0 0.3 0.7 0.6
Mean −6.6 6.0 — 0.6 — −19.6 1.7 — 0.8 —
   ± s.d.    ± 5.5    ± 2.0 —    ± 0.3 —    ± 4.5    ± 0.3 —    ± 0.4 —
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To describe the behaviour of identified abducens motoneurons, collected data were included in a first-order linear model (Robinson, 1970): FR = Fo + kP + rP′, where FR represents the firing rate of the motoneuron, Fo the rate at eye position zero, k the sensitivity to the position (P), and r the sensitivity to eye velocity (P′). The position of the eye at which ABD motoneurons started to discharge (Th) was calculated as − fo/k. During REM sleep, some motoneurons did not show tonic discharge (−), or their fitted regression line was not significant (—).

Inhibition of ABD motoneurons during REM sleep

The absence of tonic activity in 37.5% of ABD motoneurons during REM sleep and the poor codification of the eye position in those that remained active posed the question of whether ABD motoneurons were disfacilitated or inhibited during REM sleep. To answer this question, we performed continuous electric stimulation (1 Hz) of the VIth nerve along the sleep cycle in order to quantify the latency of the antidromic field potential at the ABD nucleus. Figure 7A shows the EEG, PGO wave activity, trapezius EMG and the latency of the antidromic field potential during one of these experiments. During alertness, the mean latency of the antidromic field potential was 0.7 ± 0.01 ms. At the transition between NREM and REM sleep, a slow, progressive increase in latency was observed, tending to stop at 0.8 ± 0.02 ms during REM sleep. Similarly, the amplitude of the antidromic field potential decreased to 48% with respect to alertness. During REM sleep, the latency and amplitude of the antidromic field potential varied depending on the coincidence between the electrical stimulus in the nerve and the occurrence of biphasic or triphasic ABD-PGO waves. When the stimulus coincided with the negative peak of the ABD-PGO wave – i.e. during the activation of ABD motoneurons – the latency decreased to 0.7 ms, whereas when it coincided with the positive peak – during the inhibition of the ABD motoneurons – the latency increased to 0.8 ms (Fig. 7A and B). To compare these results with another well-known physiological condition in which ABD motoneurons are activated or inhibited, we performed the same electrical stimulation during vestibular sinusoidal rotation when the animal woke after sleep. Figure 7C shows an average of the latency of the antidromic field potential during vestibular stimulation at 0.5 Hz and 50 deg s−1 of peak velocity. During vestibular stimulation, mean values during maximum inhibition and activation were 0.8 ± 0.02 and 0.7 ± 0.02 ms, respectively. Comparing these results with those during REM sleep, it could be concluded that during REM sleep, the ABD motoneuron pool is tonically inhibited, whereas during the occurrence of ABD-PGO waves, they receive phasic activation and inhibition.

Figure 7. Tonic inhibition and phasic activations and inhibitions of the ABD nucleus during REM sleep.

Figure 7

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A, representative electroencephalography (EEG), ponto-geniculo-occipital waves at the lateral geniculate nucleus (LGN), right trapezius electromyography (EMG), and abducens antidromic field potential (AFP) latency during a representative period of non-REM (NREM) sleep, the transition period (T), REM sleep, and alertness (A). AFP was induced by continuous electrical stimulation (at 1 Hz) of the ipsilateral VIth nerve. The AFP latency increased tonically from the end of NREM and during the T period, tending to maintain a latency longer during REM sleep than during alertness. In coincidence with PGO waves, AFP latency was shorter or longer depending on its coincidence with the activation or inhibition of abducens motoneurons. B, examples of abducens antidromic field potentials recorded at the time marked by the grey and black dots in A. C, mean ± standard deviation of the AFP latency during 10 cycles of sinusoidal vestibular stimulation at 0.5 Hz just after the animal woke from the sleep shown in A.

Discussion

Despite our knowing for more than 50 years the existence of periods of vigorous rapid eye movements during sleep (Aserinsky & Kleitman, 1953), the neural activity of the oculomotor system has long been surmised. Only a few authors have measured eye movements with appropriate techniques that allow knowing the position of the eye in the orbit (Fuchs & Ron, 1968; Bon et al. 1980; Herman et al. 1983; Aserinsky et al. 1985; Vanni-Mercier et al. 1994; Escudero & Vidal, 1996; Zhou & King, 1997; Márquez-Ruiz & Escudero, 2008), but none have examined the behaviour of oculomotor motoneurons. The present study shows for the first time the behaviour of ABD motoneurons during REM sleep and, on the basis of their firing discharge, offers a comprehensive view of eye movement generation.

Tonic and phasic activities of ABD motoneurons underlying eye movements during REM sleep

It has been shown that eye movements during REM sleep are characterized by the presence of tonic and phasic components (Márquez-Ruiz & Escudero, 2008). Tonic components produce a strong downward (Bon et al. 1980) and convergent movement of the two eyes that develops from the beginning of REM sleep and lasts throughout it. In the horizontal plane, this convergence means a loss of the binocular alignment (Zhou & King, 1997; Márquez-Ruiz & Escudero, 2008) that characterizes the position of the eyes during alertness. Such convergence requires a relaxation of the lateral recti muscles and a tonic contraction of the medial ones. In accordance with this, the present results have shown the existence of a tonic inhibition of the ABD nucleus during REM sleep and a decrease in the tonic firing discharge of identified ABD motoneurons with respect to alertness.

Phasic components during REM sleep consist of rapid eye movements that are either isolated or in bursts (Herman et al. 1983; Escudero & Vidal, 1996), occurring simultaneously with PGO waves (Vanni-Mercier et al. 1994; Márquez-Ruiz & Escudero, 2008). Linkage between rapid eye movements and PGO waves has been proposed previously (Dement & Kleitman, 1957; Jouvet, 1972). Two types of PGO wave – primary and secondary – have been described at the LGN (Sakai & Cespuglio, 1976; Sakai et al. 1976), and primary waves have been associated with rapid eye movements directed ipsilaterally to the recorded side (Nelson et al. 1983; Vanni-Mercier et al. 1994). The meticulous detection of the movement of both eyes (using the scleral search-coil technique), and the simultaneous recording of the field potentials in both ABD nuclei and of the activity of identified ABD motoneurons, enable us to establish the occurrence of eye movements during both types of PGO wave. Primary and secondary PGO waves recorded at the LGN corresponded with biphasic and triphasic waves at the ABD nucleus, respectively (Sakai & Cespuglio, 1976; Sakai et al. 1976). Each type of PGO wave was present simultaneously in each ABD nucleus. During biphasic PGO waves, ABD motoneurons displayed a pause followed by a burst and tonic behaviour, whereas during triphasic waves, motoneurons showed a brief burst followed by a pause in their firing discharge. This antagonist behaviour of the two ABD nuclei is not surprising, because the premotor system is also organized as pairs of antagonist excitatory and inhibitory terminals in each ABD nucleus (Escudero & Delgado-García, 1988). However, the successive phasic activations of the two ABD nuclei at short latency are exclusive to REM sleep. There is no known oculomotor mechanism able to activate one ABD nucleus and then the other as happens during the occurrence of the PGO waves.

It is known that phasic inputs to ABD motoneurons come from excitatory (Strassman et al. 1986a) and inhibitory (Strassman et al. 1986b) burst neurons in the pons. These burst neurons are responsible for every rapid eye movement during alertness, independently of its origin, and it should not be surprising that these neurons are involved in rapid eye movement generation during REM sleep. Nevertheless, the similarities found between the behaviour of ABD and those reported in spinal motoneurons (Chase & Morales, 1983), seem to imply the existence of common inputs. A good candidate for this could be the reticulospinal neurons (Grantyn et al. 1987) that reach oculomotor and spinal motor systems and mediate the orienting response (Grantyn & Berthoz, 1987).

Eye position and velocity codification by ABD motoneurons during REM sleep

The activity of ABD motoneurons has been well characterized in alert animals (Fuchs & Luschei, 1970; Delgado-García et al. 1986; McCrea et al. 1986) and during the wake–sleep transition (Henn et al. 1984; De La Cruz et al. 1989). During alertness, ABD motoneurons displayed a tonic firing rate that was proportional to the position of the ipsilateral eye in the abducting direction, and a burst of action potentials whose maximum firing rate was proportional to eye velocity during ipsilateral-directed saccadic eye movements. During REM sleep, ABD motoneurons were less active and encoded eye position only fuzzily, but continued to codify eye velocity. The inhibition found at the ABD nuclei could be responsible for the loss in eye-position codification. Nevertheless, the weak maintenance of the eye position during REM sleep could also suggests a disfacilitation or inhibition at premotor levels – and more specifically at the prepositus hypoglossi, a nucleus responsible for eye-position generation in the horizontal plane (López-Barneo et al. 1982; Delgado-García et al. 1989; Escudero et al. 1992; McFarland & Fuchs, 1992). Loss of vertical position signals during REM sleep in neurons recorded at the interstitial nucleus of Cajal (Fukushima & Fukushima, 1990) – the eye-position generator for vertical eye movements (Fukushima et al. 1992) – supports this hypothesis.

By contrast, ABD motoneuronal sensitivity to eye velocity during REM sleep was not different from that during alertness, indicating that phasic activities are commanded to the extraocular muscles as during alertness. It has been shown that the slope of the eye velocity–amplitude relationship is greater during REM sleep (Vanni-Mercier et al. 1994; Escudero & Vidal, 1996; Márquez-Ruiz & Escudero, 2008). Since it is not thought that mechanical properties of extraocular muscles could change during REM sleep, an increase of this slope would suggest that ABD motoneurons are more synchronized during bursting activities in REM sleep than in alertness. All recorded motoneurons, even those that lost their tonic discharge, produced a burst during PGO waves that was related to eye velocity. If synchronicity is the mechanism that subtended the change in slope of the eye velocity–amplitude relationship, a greater slope would be attainable for the first – shorter – component of the eye movement (C1) than for the second (C2), as seems to be the case (Márquez-Ruiz & Escudero, 2008).

Comparisons between ABD and other motoneurons during REM sleep

Previous studies have firmly established the existence of tonic inhibition in trigeminal (Nakamura et al. 1978), spinal (Glenn et al. 1978; Glenn & Dement, 1981; Chase & Morales, 1983; Soja et al. 1995) and hypoglossal (Yamuy et al. 1999) motoneurons during REM sleep. We now show that the ABD motoneuron population must also be receiving a tonic inhibitory input during REM sleep. The increase in latency of the antidromic field potential during REM sleep suggests that ABD motoneurons are hyperpolarized, delaying the initial segment–soma–dendritic interval invasion of the antidromic volley (Lipski, 1981; Sakai & Crochet, 2001). A comparison of this increase in latency with that obtained during ipsilateral vestibular stimulation, when medial vestibular neurons are inhibiting ipsilateral ABD motoneurons (Escudero et al. 1992), strongly supports the existence of tonic inhibition during REM sleep.

Muscular twitches coinciding with rapid eye movements and PGO waves are also characteristic of REM sleep. During the occurrence of PGO waves, hyperpolarizing and depolarizing postsynaptic potentials have been recorded in antigravity motoneurons during REM sleep (Glenn et al. 1978; Chase & Morales, 1983; Glenn & Dement, 1985; Soja et al. 1995). Excitation–inhibition and inhibition–excitation patterns observed in ABD motoneurons during PGO waves were exclusive to REM sleep. Inhibitory–excitatory patterns observed during biphasic PGO waves were similar to those described in lumbar motoneurons during REM sleep in cats (Chase & Morales, 1983).

Whether tonic inhibition and high-frequency oscillations of synchronized neural populations have a physiological role during REM sleep remains to be determined, but it is interesting that all motoneurons recorded – extraocular or not – seem to be subject to the same principia.

Acknowledgments

This research was supported by grants MCYT-BFU2005-01579 and the Consejería de Innovación, Ciencia y Empresa of the Junta de Andalucía, Spain. The authors wish to acknowledge the editorial help of Mr R. Churchill.

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