Cortical development dynamics across autism spectrum disorder mouse models.

The auditory efferent system comprises descending connections from higher- to lower-level auditory brain areas and the auditory periphery (; ). These include connections from cortical to subcortical neurons, from subcortical to other subcortical neurons, and from subcortical neurons to various targets in the cochlea, such as outer hair cells (OHCs) and auditory-nerve fibers (ANs). This final set of circuits—the olivocochlear (OC) system—is of principal interest here. The OC system consists of neurons located in or nearby the superior olivary complex that send projections to targets in the cochlea. In mammals, the OC system is differentiated into two sub-pathways, named for the positions of their constituent cell bodies relative to the superior olivary complex: the medial olivocochlear (MOC) system and the lateral olivocochlear (LOC) system (; ). We defer further consideration of the LOC system to and focus our attention on the MOC system. MOC neurons receive excitatory ascending input from the cochlear nucleus (, ; ) and send myelinated projections to the cochlea to form synapses on OHCs (), Type I AN dendrites (), and Type II AN dendrites (). The influence of MOC neurons on OHCs, which is the focus here, is much better understood than their direct influence on AN fibers. When MOC neurons are stimulated, they release acetylcholine, hyperpolarizing OHCs via α9α10 cholinergic receptors and reducing cochlear gain (). This “fast” mechanism for efferent gain control appears to operate on a time scale of ~100 ms and coexists with another less well understood “slow” mechanism that allows MOC neurons to alter cochlear sensitivity over time scales of ~10–100 seconds (); the focus of our modeling effort is the “fast” MOC effects. The consequences of this gain reduction have been observed invasively in basilar-membrane vibration (; ), inner-hair-cell potentials (; ), and afferent-fiber activity (, , ; ; , ). Non-invasively, the consequences have been observed via otoacoustic emissions (; ; , ) and psychophysics (; ; , ; ; , ; ), and simulated via computational models (; ; ; ; ; ). Because MOC neurons respond to sound, increase their firing rate with increasing sound level, and reduce cochlear gain (; ), the MOC system has often been described as a sound-driven “reflex”, and there is great curiosity about the possible role(s) of this reflex in auditory perception (). In this paper, we present a new auditory computational model that includes a brainstem-level MOC reflex (MOCR) circuit. To motivate the design of our MOC model, we first highlight several key anatomical and physiological characteristics of the MOC system. The number of MOC neurons varies significantly among species (e.g., with as few as ~150 MOC neurons innervating one cochlea in mouse and as many as ~1100 in guinea pig), while the number of MOC synaptic terminals per OHC varies significantly among species, OHC row, and characteristic frequency (CF) location (e.g., with as few as 1–2 MOC terminals per OHC in mouse to over 10 per OHC in cat at some CFs) (, ; ; ; ; ). Individual MOC neurons branch in the cochlea, innervating OHCs spanning 5–10% of cochlear distance on average, but sometimes as little as 1% or as much as 25% of cochlear distance (, ; ). This synaptic patterning is depicted schematically in . MOC neurons with a given CF tend to innervate regions of the cochlea tuned to the same frequency or somewhat higher frequencies, but rarely regions tuned to lower frequencies (). When contralateral sound is used to elicit the MOCR, sounds lower in frequency than the probe tend to be more effective elicitors (), although this effect may be relatively more pronounced for probes near 1–2 kHz than at other frequencies (). MOC neurons respond to sound, exhibit “chopping” type responses, have sharp frequency tuning (comparable to or slightly broader than afferent tuning, depending on the species and study), have dynamic ranges exceeding 40 dB for pure-tone stimulation, and adapt weakly compared to AN fibers (, ; ; ). Limited data suggests that MOC neurons are also tuned to amplitude-modulation frequency (), but generally little is known about how they respond to other higher order features of sound.