The natural history of sound localization in mammals--a story of neuronal inhibition

Abstract

Our concepts of sound localization in the vertebrate brain are widely based on the general assumption that both the ability to detect air-borne sounds and the neuronal processing are homologous in archosaurs (present day crocodiles and birds) and mammals. Yet studies repeatedly report conflicting results on the neuronal circuits and mechanisms, in particular the role of inhibition, as well as the coding strategies between avian and mammalian model systems. Here we argue that mammalian and avian phylogeny of spatial hearing is characterized by a convergent evolution of hearing air-borne sounds rather than by homology. In particular, the different evolutionary origins of tympanic ears and the different availability of binaural cues in early mammals and archosaurs imposed distinct constraints on the respective binaural processing mechanisms. The role of synaptic inhibition in generating binaural spatial sensitivity in mammals is highlighted, as it reveals a unifying principle of mammalian circuit design for encoding sound position. Together, we combine evolutionary, anatomical and physiological arguments for making a clear distinction between mammalian processing mechanisms and coding strategies and those of archosaurs. We emphasize that a consideration of the convergent nature of neuronal mechanisms will significantly increase the explanatory power of studies of spatial processing in both mammals and birds.

Keywords: GABA; LSO; MSO; archosaurs; binaural hearing; birds; evolution; glycine.

FIGURE 1

Parallel evolution of vertebrate ears. Tympanic middle-ears capable of receiving air-borne sound evolved separately among the ancestors of mammals (blue), modern frogs (“Anura,” green), “reptiles” (yellow), and birds (“Archosaurs,” orange/red) in the Triassic ∼210–230 million years ago (indicated by black closed circles/oval). Note that no common ancestor with tympanic ears had existed.

FIGURE 2

Binaural cues for sound localization depend on sound frequency and head size. Upper left: interaural time differences (ITDs): for frequencies below ∼2 kHz, the difference in the arrival time (Δt) of a sound wave (gray lines) at the two ears is used to localize a sound-source in the horizontal plane. ITDs depend on the angle of the sound-source relative to the head axis and the interaural distance (i.e., head size) of the individual. Upper right: interaural level differences (ILDs): for frequencies higher than ∼2 kHz, the shadowing effect of the head creates differences in the intensity of the sounds at the two ears (ΔI) that are utilized for sound localization in the horizontal plane. ILDs for a particular sound-source position increase with increasing frequencies. Lower: range of ILDs (inner hemicycle) and ITDs (middle hemicycle) are illustrated across the range of azimuthal sound-source positions (outer hemicycle) for a small mammal (the bat Molussus ater). While ITDs are minute even for the most lateralized sound-source positions (±50 μs), sizable ILDs are generated by the relatively small head already at moderately high frequencies (35 kHz for this example). Modified with permission from Harnischfeger et al. (1985).

FIGURE 3

Mammalian hearing originated in the ILD-dominated range. A hallmark of mammalian audiograms is that they are centered in the high-frequency range (>10 kHz), where ILDs are the dominant cue for sound localization. Many recent mammalian species like mice (Mus m.), bats (Eptesicus f.), rats (Rattus n.) and short-tailed opossums (Monodelphis d.) even expanded the high-frequency hearing compared to early mammals (Tachyglossus), allowing for an increase in obtainable ILDs. Only few species including Gerbils (Meriones u.) and man (Homo s.) expanded their hearing range into the low-frequency range, where ITD is an attainable sound localization cue (<2 kHz). Audiograms modified from: Echidna/Tachyglossus: Mills and Shepherd (2001); Monodelphis: Reimer (1995); Mouse: Heffner and Masterton (1980), Radziwon et al. (2009); Bat (Eptesicus fuscus): Koay et al. (1997); Rat (hooded rat): Heffner et al. (1994); Gerbil: Ryan (1976).

FIGURE 4

The coincidence mechanism of LSO neurons allows both as ILD and ITD detection. (A) LSO neurons receive excitatory inputs from SBCs in the ipsilateral AVCN and inhibitory inputs from the MNTB that is innervated from by GBCs from the contralateral AVCN. (B) The spatial tuning functions of LSO neurons take a hemispheric shape with the slope of the functions crossing frontal azimuthal positions. Upper and lower panels show normalized tuning functions for LSO neurons in cat with CFs below and above 10 kHz, respectively, recorded under virtual acoustic space stimulation that incorporates the HRTFs. Re-printed with permission from Tollin and Yin (2002). (C) Low CF neurons in the LSO are both ILD and ITD sensitive: upper panel shows ILD tuning function of a cat LSO neuron (CF = 566Hz), while the lower two panels illustrate the ITD-sensitivity of the same neuron. Note that the characteristic delay (CD) for this neuron, i.e., the delay of coincidence of excitatory and inhibitory inputs, results in a minimal response rate. Re-printed with permission from Tollin and Yin (2005).

FIGURE 5

The MSO coincidence mechanism is derived from the LSO coincidence mechanism. The schematic depicts temporal relationships of EPSPs and IPSPs, (red and blue traces, respectively) during ipsi-favoring (1, gray), slightly contra-favoring (2, magenta) and strongly contra-favoring (3, green) input combinations. The left-hand and middle column illustrates processing of these synaptic inputs in the LSO for ILDs and ITDs respectively, and ITD processing in the MSO is shown in the right-hand panel. Note that the MSO integrates EPSPs and IPSPs from both the ipsi- and contralateral side, because of the additional excitatory (contralateral) and inhibitory (ipsilateral) inputs compared to the LSO. The panel in the lower row explains how conditions 1–3 affect spatial tuning functions in the respective nuclei.

FIGURE 6

Binaural excitation and inhibition of the MSO circuit allows fine-tuning of the coincidence mechanism. (A) MSO neurons receive binaural excitatory inputs from SBCs in the AVCN of either side and binaural inhibitory inputs from LNTB and MNTB, which are innervated by GBCs of the ipsilateral and contralateral AVCN, respectively. (B) ITD tuning function of a gerbil MSO neuron (CF = 683Hz). Note that the peak of the function (“best ITD”) is positioned at a contralateral leading ITD outside of the range of physiological ITDs (gray area), while the slope spans the entire range of physiological ITDs. (C) Upper panel: blocking inhibition in MSO cells in vivo shifts the best ITD toward 0 ITD. Thus, inhibitory inputs tune the ITD of coincidence in MSO cells. Taken from Pecka et al. (2008). Lower panel: combination of ipsi- and contralateral inhibitory inputs (right-sided box) allow for both larger shifts of the best ITD (color-coded) than contralateral inhibition alone (left-sided box). Modified from Myoga et al. (2014).

FIGURE 7

Both the ILD and ITD code is based on hemispheric tuning functions. The azimuthal tuning function of both LSO and MSO span a wide range of azimuthal space. (A) LSO neurons respond best to ipsilateral sound-source positions (compare Figure 4B). This ipsi-preference is flipped to a contra-preference upstream of the LSO because of the contralateral projections of LSO neurons to the midbrain. (B) MSO neurons respond best to contralateral sound-source positions. This contra-preference is maintained upstream of the LSO because of the ipsilateral projections of MSO neurons to the midbrain.

FIGURE 8

LSO and MSO responses are modulated by prior activity and thus encode relative sound-source positions. The firing rates of both LSO and MSO neurons are controlled in an activity-dependent manner via GABAergic inhibition. (A) In the LSO, GABA is released retrogradly by dendritic release from LSO neurons onto their synaptic partners. (B) In the MSO, GABA is released via a di-synaptic feedback loop including the SPN (superior para-olivary nucleus). Both mechanisms generate levels of GABA-mediated inhibition that are proportional to the prior activity of the respective LSO/MSO neuron. In both cases, the firing activity is modulated by GABA_B-receptors, resulting in a divisive gain control mechanism. Data modified from Magnusson et al. (2008) (A) and Stange et al. (2013) (B). (C) In vivo recordings in gerbils showed that upon prolonged presentation of an Adapter stimulus from a very lateralized sound-source position (stimulus paradigm is schematized in upper left), the GABAergic gain control results in asymmetric changes in the two coding channels (ipsi- and contralateral MSOs or LSOs) due to the asymmetric activity profile between the two channels and the activity dependence of the gain control mechanism. Particularly, the cross-point between left and right coding channel is shifted away from the actual midline (indicated by red horizontal arrows) and toward the location of the Adapter location (indicated by black vertical arrow). In accordance with the hypothesis of hemispheric coding channels of sound localization, this stimulation paradigm leads to systematic shifts of the perception of test tone positions in human listeners (right column). The result from a single subject is shown in the upper panel, the average from four subjects is shown in the lower panel. A difference score of 5 approximates a shift in lateral perception of 30°. As predicted from the activity-dependence of the GABAergic gain control circuit, the presentation of an Adapter stimulus at a different frequency than the test tone (green line) did not affect the localization percept. Data taken from Stange et al. (2013)

FIGURE 9

Physical prerequisites shaped distinct binaural processing and coding strategies in mammals and birds. Head size (abscissa) and hearing range (ordinate) during the time of the middle-ear development define the binaural cue (gray scale: white = ILD; gray = ITD) that is most easily exploitable for horizontal sound localization by mammals (blue) and archosaurs/birds (brown). The binaural cue in turn shaped the emergence of distinct neuronal mechanisms that are optimized for the processing and encoding of the particular cue (boxes on right-hand side of panel). Early mammals (Morganucodon, dark blue) were very small and had high-frequency hearing. Therefore, they used ILDs as original binaural cue. Subsequent evolutionary changes in head size and/or hearing range (e.g., cats or humans, light blue) allowed the use of ITDs. However, the neuronal mechanisms (precise temporal integration of excitatory and inhibitory inputs) and coding principles (population code) remained similar to early, high-frequency hearing mammals (dark and light blue boxes on right-hand side of panel). Early archosaurs (brown) were very large and had low-frequency hearing. Therefore, they used ITDs as original binaural cue. Subsequent evolutionary changes in head size and/or hearing range in birds (e.g., chicks or barn owls, brown) allowed the continued use of ITDs. Thus, the neuronal mechanisms (delay-lines) and coding principles (labeled line) remained the same as in early archosaurs (brown box on right-hand side of panel).