olivocochlear system olivocochlear system the olivocochlear system is a component of the auditory system involved with the descending control of the cochlea. its nerve fibres, the olivocochlear bundle (ocb), form part of the vestibulocochlear nerve (viiith cranial nerve, also known as the auditory-vestibular nerve), and project from the superior olivary complex in the brainstem (pons) to the cochlea. anatomy of the olivocochlear system cell bodies of origin the mammalian olivocochlear bundle, divided into medial (red) and lateral (green) systems. both contain crossed and uncrossed fibres. the predominant fibres are represented by a thicker line. the insert (far left) shows the position of the cell bodies of the mocs and locs relative to the msoc and lsoc respectively, as observed in mammals. the olivocochlear bundle (ocb) originates in the superior olivary complex in the brainstem. the vestibulocochlear anastomosis carries the efferent axons into the cochlea, where they innervate the organ of corti (oc). the ocb contains fibres projecting to both the ipsilateral and contralateral cochleae, prompting an initial division into crossed (cocb) and uncrossed (ucocb) systems. more recently, however, the division of the ocb is based on the cell bodies’ site of origin in the brainstem relative to the medial superior olive (mso). the medioventral periolivary (mvpo) region, also known as the ventral nucleus of the trapezoid body, a diffuse region of neurons located medial to the mso, gives rise to the medial olivocochlear system (mocs). the lateral superior olive (lso), a distinct nucleus of neurons located lateral to the mso, gives rise to the lateral olivocochlear system (locs). the mocs neurons are large multipolar cells, while the locs are classically defined as composed of small spherical cells. this division is viewed as being more meaningful with respect to ocb physiology. in addition to these classically defined olivocochlear neurons, advances in tract tracing methods helped reveal a third class of olivocochlear neurons, termed shell neurons, which surround the lso. thus, locs class cell bodies within the lso are referred to as intrinsic locs neurons, while those surrounding the lso are referred to as shell, or extrinsic, locs neurons. shell neurons are typically large, and morphologically are very similar to mocs neurons. olivocochlear fibers the locs (originating from both the intrinsic and shell neurons) contains unmyelinated fibres that synapse with the dendrites of the type i spiral ganglion cells projecting to the inner hair cells. while the intrinsic locs neurons tend to be small (~10 to 15 µm in diameter), and the shell oc neurons are larger (~25 µm in diameter), it is the intrinsic oc neurons that possess the larger axons (0.77 µm compared to 0.37 µm diameter for shell neurons). in contrast, the mocs contains myelinated nerve fibres which innervate the outer hair cells directly. although both the locs and mocs contain crossed (contralateral) and uncrossed (ipsilateral) fibres, in most mammalian species the majority of locs fibres project to the ipsilateral cochlea, whilst the majority of the mocs fibres project to the contralateral cochlea. the proportion of fibres in the mocs and locs also varies between species, but in most cases the fibres of the locs are more numerous. in humans, there are an estimated (average) 1,000 locs fibres and 360 mocs fibres, however the numbers vary between individuals. the mocs gives rise to a frequency-specific innervation of the cochlea, in that moc fibres terminate on the outer hair cells at the place in the cochlea predicted from the fibres’ characteristic frequency, and are thus tonotopically organised in the same fashion as the primary afferent neurons. the fibres of the locs also appear to be arranged in a tonotopic fashion. however, it is not known whether the characteristic frequencies of the locs fibres coincide with the characteristic frequencies of the primary afferent neurons, since attempts to selectively stimulate the fibres of the locs have been largely unsuccessful. intrinsic locs derived axons travel only approximately 1 µm within the organ of corti, generally spiraling apically. they give off a small tuft of synaptic boutons that is compact in its extent, often involving less than 10 ihcs. in comparison, shell neurons spiral both apically and basally, and can cover large territories within the organ of corti. the shell axons often cover 1-2 octaves of tonotopic length. their terminal arbor is quite sparse, however. physiology of the olivocochlear system neurophysiology all currently known activity of the olivocochlear system is via a nicotinic class neurotransmitter receptor complex that is coupled with a calcium-activated potassium channel. together, these systems generate an unusual synaptic response to stimulation from the brain. the olivocochlear synaptic terminals contain various neurotransmitters and neuroactive peptides. the major neurotransmitter employed by the olivocochlear system is acetylcholine (ach), although gamma-aminobutyric acid (gaba) is also localized in the terminals. ach release from the olivocochlear terminals activates an evolutionarily ancient cholinergic receptor complex composed of the nicotinic alpha9 and alpha10 subunits. while these subunits create a ligand-gated ion channel that is especially permeable to calcium and monovalent cations the cellular response of the outer hair cells to ach activation is hyperpolarizing, rather than the expected depolarizing response. this comes about due to the rapid activation of an associated potassium channel. this channel, the apamin sensitive, small conductance sk2 potassium channel, is activated by calcium that is likely released into the cytoplasm via calcium-induced calcium release from calcium stores within the subsynaptic cisternae as a response to incoming calcium from the nicotinic complex. however, it has not been ruled out that some incoming calcium through the nicotinic alpha9alpha10 channel may also directly activate the sk channel. electrophysiological responses recorded from outer hair cells following ach stimulation therefore show a small inward current (carried largely by incoming calcium via the acetylcholine receptor) that is immediately followed by a large outward current, the potassium current, that hyperpolarizes the outer hair cell. when the olivocochlear bundle is surgically transected prior to the onset of hearing, auditory sensitivity is compromised. however, upon genetic ablation of either the alpha9 or alpha10 genes, such effects are not observed. this may be due to the different nature of the lesions- the surgical lesion results in complete loss of all olivocochlear innervation to the hair cells, while the genetic manipulations result in much more selective functional loss- that of the targeted gene only. any remaining neuroactive substances that can be released by the intact synaptic terminals can still activate the hair cells. indeed, upon genetic ablation of one of the neuroactive peptides present in the locs terminals, consequences similar to that following the surgical lesion were observed, demonstrating that the effects of the surgery were most likely due to loss of this peptide, and not the ach present in the synaptic terminals. effects of electrical stimulation in animals, the physiology of the mocs has been studied far more extensively than the physiology of the locs. this is because the myelinated fibres of the mocs are easier to electrically stimulate and record. consequently, relatively little is known about the physiology of the locs. many studies performed on animals in vivo have stimulated the olivocochlear bundle (ocb) using shock stimuli delivered by electrodes placed on the nerve bundle. these studies have measured the output of the auditory nerve (an), with and without ocb stimulation. in 1956, galambos activated the efferent fibres of the cat by delivering shock stimuli to the floor of the fourth ventricle (at the decussation of the cocb). galambos observed a suppression of the compound action potentials of the an (referred to as the n1 potential) evoked by low-intensity click stimuli. this basic finding was repeatedly confirmed (desmedt and monaco, 1961; fex, 1962; desmedt, 1962; wiederhold, 1970). an efferent suppression of n1 was also observed by stimulating the mocs cells bodies in the medial soc, confirming that the n1 suppression was the result of moc (not loc) stimulation. more recently, several researchers have observed a suppression of cochlear neural output during stimulation of the inferior colliculus (ic) in the midbrain, which projects to the superior olivary complex (soc) (rajan, 1990; mulders and robertson, 2000; ota et al., 2004; zhang and dolan, 2006). ota et al. (2004) also showed that the n1 suppression in the cochlea was greatest at the frequency corresponding to the frequency placement of the electrode in the ic, providing further evidence for tonotopic organisation of the efferent pathways. these findings led to the current understanding that moc activity decreases the active process of ohcs, leading to a frequency-specific reduction of cochlear gain. acoustically evoked responses of the mocs the basic moc acoustic reflex. the auditory nerve responds to sound, sending a signal to the cochlear nucleus. afferent nerve fibres cross the midline from the cochlear nucleus to the cell bodies of the mocs (located near the msoc), whose efferent fibres project back to the cochlea (red). in most mammals, the majority of the reflex is ipsilateral (shown as a thicker line), effectuated by the crossed mocs. electrical stimulation in the brainstem can result in (i) the entire mocs being stimulated, (ii) a discharge rate (up to 400 sec-1) much higher than is normally evoked by sound (up to 60 sec-1), and (iii) electrical stimulation of neurons other than mocs fibres. therefore, electrical stimulation of the mocs may not give an accurate indication of its biological function, nor the natural magnitude of its effect. the mocs’ response to sound is mediated through the moc acoustic reflex pathway (see inset), which had been previously investigated using anterograde and retrograde labelling techniques (aschoff et al., 1988; robertson and winter, 1988). acoustic stimulation of the inner hair cells sends a neural signal to the posteroventral cochlear nucleus (pvcn), and the axons of the neurons from the pvcn cross the brainstem to innervate the contralateral moc neurons. in most mammals, the moc neurons predominantly project to the contralateral side (forming the ipsilateral reflex), with the remainder projecting to the ipsilateral side (forming the contralateral reflex). the strength of the reflex is weakest for pure tones, and becomes stronger as the bandwidth of the sound is increased (berlin et al., 1993), hence the maximum mocs response is observed for broadband noise (guinan et al., 2003). researchers have measured the effects of stimulating the mocs with sound. in cats, liberman (1989) showed that contralateral sound (resulting in mocs stimulation) reduced the n1 potential, a suppression which was eliminated upon transection of the olivocochlear bundle (ocb). in humans, the largest amount of evidence for the action of efferents has come from the suppression of otoacoustic emissions (oaes) following acoustic stimulation. using acoustic stimuli to activate the moc reflex pathway, recordings have been made from single efferent fibres in guinea pigs and cats. both studies confirmed that moc neurons are sharply tuned to frequency, as previously suggested by cody and johnstone (1982), and robertson (1984). they also showed that the firing rate of moc neurons increased as the intensity of sound increased from 0 to 100 db spl, and have comparable thresholds (within ~15 db) to afferent neurons. furthermore, both studies showed that most moc neurons responded to sound presented in the ipsilateral ear, consistent with the majority of mammalian moc neurons being contralaterally located. no recordings have been made from moc fibres in humans. because invasive in vivo experiments are not possible. in other primate species however, it has been shown that about 50-60% of moc fibres are crossed (bodian and gucer, 1980; thompson and thompson, 1986). proposed functions of the mocs the hypothesised functions of the mocs fall into three general categories; (i) cochlear protection against loud sounds, (ii) development of cochlea function, and (iii) detection and discrimination of sounds in noise. cochlear protection against loud sounds cody and johnstone (1982) and rajan and johnstone (1988a; 1988b) showed that constant acoustic stimulation that in (which evokes a strong mocs response (brown et al., 1998)) reduced the severity of acoustic trauma. this protection was negated in the presence of a chemical known to suppress the action of the olivocochlear bundle (ocb) (strychnine), implicating the action of the mocs in protection of the cochlea from loud sounds. further evidence for the auditory efferents having a protective role was provided by rajan (1995a) and kujawa and liberman (1997). both studies showed that the hearing loss sustained by animals due to binaural sound exposure was more severe if the ocb was severed. rajan (1995b) also showed a frequency dependence