A cholinergic mechanism underlies persistent neural activity necessary for eye fixation

https://doi.org/10.1016/S0079-6123(06)54011-7Get rights and content

Abstract

It is generally accepted that the prepositus hypoglossi (PH) nucleus is the site where horizontal eye-velocity signals are integrated into eye-position ones. However, how does this neural structure produce the sustained activity necessary for eye fixation? The generation of the neural activity responsible for eye-position signals has been studied here using both in vivo and in vitro preparations. Rat sagittal brainstem slices including the PH nucleus and the paramedian pontine reticular formation (PPRF) rostral to the abducens nucleus were used for recording intracellularly the synaptic activation of PH neurons from the PPRF. Single electrical pulses applied to the PPRF showed a monosynaptic projection on PH neurons. This synapse was found to be glutamatergic in nature, acting on alpha-amino-3-hydroxy-5-methylisoxazole propionate (AMPA)/kainate receptors. Train stimulation (100 ms, 50–200 Hz) of the PPRF evoked a depolarization of PH neurons, exceeding (by hundreds of ms) the duration of the stimulus. Both duration and amplitude of this long-lasting depolarization were linearly related to train frequency. The train-evoked sustained depolarization was demonstrated to be the result of the additional activation of cholinergic fibers projecting onto PH neurons, because it was prevented by slice superfusion with atropine sulfate and pirenzepine (two cholinergic antagonists), and mimicked by carbachol and McN-A-343 (two cholinergic agonists). These results were confirmed in alert behaving cats. Microinjections of atropine and pirenzepine evoked an ipsilateral gaze-holding deficit consisting of an exponential-like, centripetal eye movement following saccades directed toward the injected site. These findings suggest that the sustained activity present in PH neurons carrying eye-position signals is the result of the combined action of PPRF neurons and the facilitative role of cholinergic terminals, both impinging on PH neurons. The present results are discussed in relation to other proposals regarding integrative properties of PH neurons and/or related neural circuits.

Introduction

The eye moves in the horizontal plane under the action of two antagonist extraocular muscles: the lateral and medial recti. The lateral rectus muscle is innervated by motoneurons located in the pontine abducens nucleus, while the medial rectus muscle is innervated by motoneurons located in the mesencephalic oculomotor complex (Büttner-Ennever and Horn, 1997). As illustrated in Fig. 1, Fig. 2, these extraocular motoneurons are capable of evoking phasic firing (i.e., high-frequency bursts of action potentials lasting ≈100 ms) that will produce a strong muscular contraction which is able to generate a fast eye displacement — that is, a saccade or a fast phase of the vestibulo-ocular or opto-kinetic reflexes (Robinson, 1981; Moschovakis et al., 1996; Delgado-García, 2000). This fast muscular activation is necessary to overcome the viscous drag of the orbit. In order to maintain a stable position of the eye in the orbit, extraocular motoneurons are also capable of a sustained tonic firing, necessary to counteract the restoring elastic components of orbital tissues (Robinson, 1981; Escudero et al., 1992; Fukushima et al., 1992; Moschovakis, 1997; Delgado-García, 2000; Major and Tank, 2004). Thus, horizontal motoneurons encode the necessary velocity and position signals to rotate the eye toward the appropriate visual target and to hold the eye stable in the orbit. In fact, the firing properties of ocular motoneurons can be precisely represented by a first-order linear model (Robinson, 1981). In cats, horizontal motoneurons increase their mean firing rate by ≈7 spikes/s per degree of eye position, and by 1 spike/s per degree/s of eye velocity in the pulling direction of the involved muscle (see references in Delgado-García, 2000).

In the next few pages we will concentrate on experiments carried out by our group regarding the firing activities of prepositus hypoglossi (PH) neurons during eye movements, and on recent in vitro studies on the functional properties of reticular afferents to these neurons. More-detailed and comparative reviews regarding the integrative properties of PH neurons for the generation of eye-position signals can be found elsewhere (Robinson, 1981; Cannon and Robinson, 1987; Fukushima et al., 1992; Moschovakis et al., 1996; Moschovakis, 1997; Delgado-García, 2000; Major and Tank, 2004).

Section snippets

The final common pathway for horizontal eye movements

Abducens and medial rectus motoneurons represent the final common neural pathway interposed between eye-movement-related brainstem centers and extraocular muscles in the horizontal plane. Thus, abducens and medial rectus motoneurons must be able to translate to the lateral and medial recti muscles the precise neural motor commands corresponding to each type of eye movement (Robinson, 1981; Escudero and Delgado-García, 1988; Fukushima et al., 1992; Büttner-Ennever and Horn, 1997; Moschovakis,

Firing properties of prepositus hypoglossi neurons

Neurons located in the paramedian pontine reticular formation (PPRF), in particular those called excitatory burst neurons (EBN; Fig. 2), are able to generate bursts of action potentials that encode the amplitude, peak velocity, and duration of eye saccades and fast phases of the vestibulo-ocular and opto-kinetic reflexes (Igusa et al., 1980; Escudero and Delgado-García, 1988; Fukushima et al., 1992; Moschovakis et al., 1996). These neurons project monosynaptically onto abducens motoneurons and

The cascade model for the generation of eye-position signals

Using available data collected from extracellular recordings of firing activities of PH neurons during eye movements in alert cats, Delgado-García et al. (1989) have proposed a neural circuit in cascade to explain the generation of eye-position signals. In this circuit, the three neuronal types described above (velocity-position, position-velocity, and position neurons) were assumed to receive similar inputs from vestibular and reticular origins. This early proposal was modified following data

In search of a synaptic mechanism for eye fixation

As shown by Aksay et al. (2001), the sustained firing rate observed in the neural integrator subserving eye position does not depend on neuronal intrinsic properties, but has to be ascribed to the amplitude and rate of the synaptic inputs arriving at the integrator (brainstem area I, where position-related neurons are located in goldfish). It has also been proposed that synaptic feedback among neurons located in the brainstem area I is still necessary for temporal integration (Aksay et al., 2003

The cholinergic connection

The diagrams illustrated in Fig. 8, Fig. 9, Fig. 10 attempt to summarize the results obtained by our group in a recent series of in vitro and in vivo experiments (Navarro-López et al., 2004, Navarro-Lopez et al., 2005).

The electrical stimulation of the PPRF (i.e., of EBN; Fig. 8) by single pulses evokes a monosynaptic depolarization of PH neurons (Igusa et al., 1980). The PPRF synapse is glutamatergic in nature, acting on AMPA/kainate receptors. It has been shown (Navarro-López et al., 2004)

Abbreviations

    AMPA

    alpha-amino-3-hydroxy-5-methylisoxazole propionate

    NMDA

    N-methyl-d-aspartate

    PH

    prepositus hypoglossi

    PPRF

    paramedian pontine reticular formation

Acknowledgments

We acknowledge the editorial help of Mr. R. Churchill. The authors thank the help of Dr. Agnès Gruart in the edition of the figures. This work was supported by grant BFI2000-00939 from the Spanish Ministry of Science.

References (43)

  • A.K. Moschovakis et al.

    The microscopic anatomy and physiology of the mammalian saccadic system

    Prog. Neurobiol.

    (1996)
  • K. Semba et al.

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

    Neuroscience

    (1990)
  • E. Aksay et al.

    Correlated discharge among cell pairs within the oculomotor horizontal velocity-to-position integrator

    J. Neurosci.

    (2003)
  • E. Aksay et al.

    In vivo intracellular recording and perturbation of persistent activity in a neural integrator

    Nat. Neurosci.

    (2001)
  • R. Baker et al.

    Synthesis of horizontal conjugate eye movement signals in the abducens nucleus

    Jap. J. EEG EMG Suppl.

    (1981)
  • S.C. Cannon et al.

    Loss of the neural integrator of the oculomotor system from brain stem lesions in monkey

    J. Neurophysiol.

    (1987)
  • W.W. Chan et al.

    Integrator function in the oculomotor system is dependent on sensory context

    J. Neurophysiol.

    (2005)
  • G. Cheron et al.

    Disabling of the oculomotor neuronal integrator by kainic acid injections in the prepositus-vestibular complex of the cat

    J. Physiol. (Lond.)

    (1987)
  • R.R. De la Cruz et al.

    Behaviour of medial rectus motoneurons in the alert cat

    Eur. J. Neurosci.

    (1989)
  • A.V. Egorov et al.

    Graded persistent activity in entorhinal cortex neurons

    Nature

    (2002)
  • M. Escudero et al.

    Behavior of reticular, vestibular and prepositus neurons terminating in the abducens nucleus of the alert cat

    Exp. Brain Res.

    (1988)
  • Cited by (19)

    • Distinct response properties of rat prepositus hypoglossi nucleus neurons classified on the basis of firing patterns

      2017, Neuroscience Research
      Citation Excerpt :

      In the PHN, transient burst signals that are proportional to eye velocity are transformed into sustained signals that are proportional to eye position for gaze holding; therefore, the PHN is regarded as an oculomotor neural integrator. The function of the PHN is accomplished by heterogeneous neuronal populations that display distinct electrophysiological, morphological, and chemical profiles (Delgado-Garcia et al., 2006; McCrea and Horn, 2006). Preceding in vitro studies have indicated that PHN neurons can be classified into two discrete types based on their spike shapes, a type that exhibits monophasic afterhyperpolarization (AHP) (type A) and a type that exhibits biphasic AHP (type B), although an intermediate type (type C) and an additional type that exhibits monophasic AHP and clusters of action potentials intermingled with subthreshold membrane oscillations (type D) have also been found (Idoux et al., 2006, 2008; see also, Serafin et al., 1991; Beraneck et al., 2003).

    • The pharmacology of McN-A-343

      2012, Pharmacology and Therapeutics
    • New insights into feature and conjunction search: II. Evidence from Alzheimer's disease

      2010, Cortex
      Citation Excerpt :

      The noisier conjunction percepts would thus lead to more false positive signals in patients than controls and/or a reduced ability to distinguish these from genuine targets. ACh depletion may also contribute directly to patients' disrupted fixation patterns, given its reported role in the sustained neural activity needed for eye fixation (Delgado-Garcia et al., 2006; Navarro-Lopez et al., 2006). In more general terms, the pupil data fail to support suggestions that AD patients suffer from markedly depleted attentional resources (e.g., Foldi et al., 2002, 2005; Sebastian et al., 2006).

    View all citing articles on Scopus
    View full text