Inhibitory Neural Circuits in the Mammalian Auditory Midbrain

Abstract

The auditory midbrain is the critical integration center in the auditory pathway of vertebrates. Synaptic inhibition plays a key role during information processing in the auditory midbrain, and these inhibitory neural circuits are seen in all vertebrates and are likely essential for hearing. Here, we review the structure and function of the inhibitory neural circuits of the auditory midbrain. First, we provide an overview on how these inhibitory circuits are organized within different clades of vertebrates. Next, we focus on recent findings in the mammalian auditory midbrain, the most studied of the vertebrates, and discuss how the mammalian auditory midbrain is functionally coordinated.

Keywords: Auditory pathway; inhibitory neural circuits; midbrain; synaptic inputs.

Figure 1.

Schematic drawings of ascending auditory pathways to the vertebrate midbrain. Red and blue lines indicate excitatory and inhibitory pathways, respectively. The black lines indicate pathways in which the cell types of the projection neurons have not been identified. Thus, pathways indicated by the black lines are potentially either excitatory or inhibitory, or may contain both excitatory and inhibitory projections. We created these drawings based on the following literatures: (A) fish,^,– (B) anuran,^,– (C) reptile/bird,^– and (D) mammals.^– To emphasize the similarity in the basic organization of the auditory system, we used the terms CN, SO, NLL, and IC for first-, second-, third-order nuclei, and midbrain nucleus. CN indicates cochlear nucleus; DCN, dorsal cochlear nucleus; DLL, dorsal nucleus of lateral lemniscus; IC, inferior colliculus; ILL, intermediate nucleus of lateral lemniscus; NA, nucleus angularis; NM, nucleus magnocellularis; NL, nucleus laminaris; PLN, perilemniscal nucleus; SO, superior olive; SOC, superior olivary complex; VCN, ventral cochlear nucleus; VLL, ventral nucleus of lateral lemniscus.

Figure 2.

The combination of input sources is cell-type dependent. (A) The IC is composed of synaptic domains, which receive specific combinations of input nuclei. A cell type–specific monosynaptic tracing study suggests that glutamatergic neurons (GLU, red) receive domain-specific inputs, whereas GABAergic neurons (LG and SG, blue) receive similar combinations of inputs which are unrelated to the location of cell bodies. However, excitatory axosomatic inputs to LG neurons are location-dependent. Consistent with this fact, GABAergic neurons show a responsiveness to sound that is similar to the responsiveness of adjacent GLU neurons. Both LG and SG neurons have a large dendritic field that covers several synaptic domains, whereas GLU neurons have a smaller dendritic field (Ito, unpublished observation). Out-of-domain neurons may receive different input nuclei, and as a consequence, the net inputs to GABAergic neurons would be similar and unrelated to the location of the somata. The out-of-domain inputs may contribute subthreshold responses to sound and make GABAergic neurons state-dependent. (B) The combination of input nuclei is location-dependent inside the central nucleus of the IC (ICC) for GLU neurons (top), whereas it is always similar and unrelated to the location inside the ICC for GABAergic neurons (bottom). Cre-dependent monosynaptic retrograde tracing was examined for VGLUT2-Cre and VGAT-Cre mice, which express Cre in GLU and GABAergic neurons, respectively, in the IC. Inputs per starter neurons were calculated for each input nuclei; a correlation of the ratios between input nuclei was obtained for all pairs of input nuclei, and heat maps of correlations were shown on the left. Dendrograms of the dissimilarity of correlation were made to examine the presence of clusters of similarity. In GLU neurons, 3 clusters of correlated nuclei were visible, namely, the cluster composed of auditory brainstem nuclei, composed mainly of neuromodulatory nuclei, and those composed of the contralateral (c) dorsal cochlear nucleus (DCN) and ipsilateral (i) auditory cortex (Cortex). This suggests that the combination of input nuclei is related to the injection sites of the tracer. However, GABAergic neurons exhibited a high correlation among all pairs of input nuclei, suggesting that the combination of input nuclei is always the same. IC indicates inferior colliculus; LC, locus coeruleus; LDTg/PPTg, laterodorsal and peduculopontine tegmental nuclei; LG, large GABAergic; PP/PIL, peripeduncular and posterior intralaminar thalamic nuclei; SG, small GABAergic; SPF, subparafascicular nucleus; VCN, ventral cochlear nucleus. Adapted from Chen et al., with permission from the Journal of Neuroscience.

Figure 3.

The sound response organization in the microdomain. (A) The FRAs of closely located GABAergic (left) and glutamatergic (right) neurons. (B) The correlation coefficient of the FRAs of paired neurons was plotted against the distance between the neurons. Closely located neurons had higher correlation coefficients of the FRAs, regardless of the cell types. (C) The schematic drawing of the FRA organization in the microdomains. The different frequency channels might be shaped by different microdomains, in which the excitatory and inhibitory neurons shared similar FRAs. (D) The correlation coefficients of peristimulus time histograms (PSTHs) of closely located neurons. The correlation coefficient was plotted against the distance between the pair. Each panel represents the response to a different sound intensity (10 and 30 dB above threshold). The schematic drawings of the outputs from the microdomains in the response to sounds: (E) Sound 1 (low-frequency sound) evokes responses in the low- and middle-frequency regions (MD1 and MD2), but not in the high-frequency region (MD3). Both excitatory and inhibitory outputs from the microdomains contain diverse temporal spike sequences. The red and blue traces in the right panels represent excitatory and inhibitory PSTHs of neurons in a microdomain. (F) Sound 2 (low-frequency sound) evokes responses in the middle- and high-frequency regions (MD2 and MD3), but not in the low-frequency region (MD1). FRA indicates frequency response area. Adapted from Ono et al., with permission from the Journal of Neuroscience.