Unifying the Midbrain: The Commissure of the Inferior Colliculus
Abstract and Keywords
Commissural fibres that interconnect the two sides of the brain are found at several points along the auditory pathway, thus suggesting their fundamental importance for the analysis of sound. This chapter presents an overview of what is currently known about the anatomy, physiology, and behavioral influences of the commissure of the inferior colliculus (CoIC)—the most prominent brainstem auditory commissure—that reciprocally interconnects the principal nuclei of the auditory midbrain, the inferior colliculi (IC). The primary contribution to the CoIC originates from neurons projecting from one inferior colliculus to the other, with the dorsal cortex and central nucleus providing the most extensive connections. In addition, many ascending and descending auditory centers send projections to IC via the CoIC, together with a diverse range of sources located outside the classically defined auditory pathway. The degree of interconnection between the two ICs suggests they function as a single entity. Recent in vivo evidence has established that CoIC projections modulate the neural representation of sound frequency, level, and location in IC, thus indicating an important role for the CoIC in auditory processing. However, there is limited evidence for the influence of the CoIC on auditory behavior. This, together with the diversity of sources projecting via CoIC, suggest unknown roles that warrant further exploration.
The auditory system is unique among mammalian sensory systems in having pre-cortical commissural connections that interconnect homologous structures on either side of the brain. In the somatosensory and visual systems, crossing fibers occur at the spinal cord and optic chiasm, respectively, but these are decussations, where fibers travel obliquely to terminate in structures at a level above their origin. True commissural interactions in most sensory and motor systems are found in the cerebral cortex, where the two hemispheres are interconnected by the corpus callosum and the other major commissures. However, as in several aspects of its functional organization, the auditory system proves to be the maverick among sensory systems, operating according to its own distinct requirements.
The first commissural connections in the auditory pathway occur between the cochlear nuclei, the direct recipients of input from the cochlea. There are two systems: one glycinergic that originates mainly in the core of the ventral cochlear nucleus (VCN) and another, excitatory, which arises from neurons in the small cell cap of the VCN (Alibardi, 1998; Arnott, Wallace, Shackleton, & Palmer, 2004; Brown, Drottar, Benson, & Darrow, 2013; Cant & Gaston, 1982; Doucet, Lenihan, & May, 2009; Schofield & Cant, 1996; Shore, Godfrey, Helfert, Altschuler, & Bledsoe, 1992). Given their different organization, these two systems likely serve several functions, including balancing binaural interactions between the cochlear nuclei (Doucet et al., 2009; Needham & Paolini, 2006).
Commissural projections are absent between the nuclei of the superior olivary complex, and next occur near the head of the brainstem where the commissure of Probst, a primarily GABAergic pathway, interconnects the binaurally responsive neurons of the dorsal nucleus of the lateral lemniscus (Adams & Mugnaini, 1984; Chen, Kelly, & Wu, 1999; Shneiderman, Oliver, & Henkel, 1988; van Adel, Kidd, & Kelly, 1999). Interestingly, the mainly monaural neurons in the ventral nucleus of the lateral lemniscus, which receive inputs predominantly from the contralateral cochlear nucleus, are not commissurally interconnected—an observation again consistent with the idea that commissural connections are important in binaural processing.
Of all the subcortical auditory commissures, the most substantial interconnects the inferior colliculi. The significance of this reciprocal innervation is evidenced by the fact that the commissure of the inferior colliculus (CoIC) is likely the largest single external source of input received by the IC (Moore, 1988). This chapter explores what is currently known about the organisation and function of the CoIC, and speculates about its role in sound analysis.
Structure of the Review
The chapter begins by considering the anatomy of the CoIC, including the sources and connections of its fiber. These sections are followed by a discussion of experiments that have investigated the function of the CoIC, and we conclude with a consideration of the putative role of the CoIC, and identify the major gaps in our knowledge. The aim is not to be historically exhaustive, but rather to highlight the major principles of CoIC organisation.
Anatomical Organization of the CoIC
The CoIC principally interconnects neurons in the two ICs, although, as discussed later, some of its fibers originate in, or target, other structures in the auditory pathway. In appearance, the CoIC is a curvilinear tract composed of heavily myelinated fibers that interconnect the ICs dorsal to the cerebral aqueduct (Figure 1A; Faye Lund & Osen, 1985; Saldaña & Merchán, 2005). The number of CoIC fibers increases dorsally, medially and rostrally as they coalesce to cross the midline, forming the caudal part of the tectal commissure, a fiber bundle that also contains the commissural fibers of the superior colliculus (Faye Lund & Osen, 1985). The CoIC courses symmetrically about the midline, forming a direct projection from neurons in one IC to those opposite. Intermingled between the commissural fibers are neurons that form a commissural nucleus, located between the dorsal cortex of the IC (ICd) and the periaqueductal grey in cat (Morest & Oliver, 1984) and rat (Faye Lund & Osen, 1985). This structure is now considered to be the caudal portion of a more extensive, tectal longitudinal column that receives collaterals of commissural fibers (Aparicio, Viñuela, & Saldaña, 2010; Saldaña, Viñuela, Marshall, Fitzpatrick, & Aparicio, 2007). Lateral to the commissural nuclei, CoIC fibers splay across the entirety of the IC where their fascicles decrease in density as they project toward their targets.
Connectivity of Commissural Fibers Between the ICs
The overall of schema of intercollicular connectivity is highly conserved across mammalian species. The patterns of connections formed by the intercollicular fibers were first demonstrated in a variety of species using degeneration techniques (Moore & Goldberg, 1966; Powell & Hatton, 1969; van Noort, 1969; Woollard & Harpman, 1940). More recent studies using anterograde and retrograde tracers have added detail and clarity to those earlier findings, demonstrating that there are commissural neurons in IC that project contralaterally to all its subdivisions (Adams, 1980; Coleman & Clerici, 1987; Gonzalez Hernandez, Meyer, & Ferres-Torres, 1986; Malmierca, Hernández, Antunes, & Rees, 2009; Malmierca, Rees, Lebeau, & Bjaalie, 1995; Saldana & Merchan, 1992).
The first detailed study of commissural projections, using the anterograde tracer Phaseolus vulgaris-leucoagglutinin, was conducted in rat (Saldana & Merchan, 1992). Tracer deposits in ICc labelled, in the coronal plane, two bands of fibers that coursed through rostral part of the ipsilateral IC; one through the dorsal cortex (ICd) and central nucleus (ICc), the other through the lateral cortex (ICl; save for the most superficial layer). Caudally, the two bands converged to form one continuous laminar plexus. A mirror symmetric, though less extensive, distribution of axon terminal fibers was revealed in the contralateral IC. Intercollicular connections therefore follow a reciprocal topographic pattern, with terminals distributed throughout the contralateral fibrodendritic lamina in all subdivisions (Saldaña & Merchán, 2005; Saldana & Merchan, 1992).
A similar distribution of intercollicular projections was demonstrated in guinea pig using biocytin injections combined with electrophysiological recording (Malmierca et al., 1995). This approach allowed the injection sites and the resulting labelled laminae to be characterized with respect to the frequency organisation of the IC. In the IC contralateral to the tracer injection, electrolytic lesions placed at sites with the same best frequency as the tracer injection confirmed the precise symmetry of these intercollicular connections.
Thus, the consistent finding from studies using anterograde tracers is a mirror symmetric pattern of labelling in each IC defining the arc of the fibrodendritic laminae (Figure 1B and C; Saldana and Merchan 1992; Malmierca et al. 1995; Malmierca et al. 2009). These laminae are the structural substrate underlying the tonotopic representation of sound frequency in the IC (Merzenich & Reid, 1974; Rose, Greenwood, Goldberg, & Hind, 1963).
Although these studies show the general organisation of commissural connections between the ICs, they do not address the intricacies of the circuitry involved. Particularly pertinent is whether the ipsilateral and contralateral laminae are connected in a point-to-point fashion, or whether neurons at a single location on a lamina send divergent connections across the lamina surface? A partial answer to this question was obtained using retrograde labelling from small injections of two dextran tracers. Malmierca et al. (2009) placed tracers at different frequency locations and subdivisions in rat IC and reconstructed in 3D the locations of retrograde labelled neurons on the contralateral side. Labelled somata were distributed throughout the contralateral lamina from an injection in ICc, but the number of labelled somata in the contralateral IC was maximal at a point mirror symmetric to the injection site (Figure 1B–E).
The caveats of tracer studies notwithstanding, the observed pattern of labelling suggests that commissural neurons make divergent connections. Thus a single point on a lamina receives convergent connections from neurons distributed over the surface of the homologous lamina in the contralateral side, but the greater weight of connections occurs between homotopic points (Figure 2A). Such an organisation may provide the basis for complex convergent and divergent information processing between the ICs. However, we do not know whether different classes of neurons contribute to these different projection patterns. The answer to this question awaits the detailed connectivity mapping of individual commissural neurons.
In addition to interconnecting neurons in the contralateral ICc, neurons in the ICc also receive projections from the contralateral ICd. An injection in ICc retrogradely labelled neurons in contralateral ICd whose distribution followed the axis of the lamina in ICc. In contrast, an injection in ICd resulted in a diffuse pattern of labelled somata in contralateral ICd (Malmierca et al., 2009). These distributions suggest there are two distinct populations of neurons within ICd giving rise to commissural connections: neurons in the ventral part of ICd, a region into which the frequency band laminae extend, project to the contralateral ICc and ventral ICd, whereas neurons in the dorsal part of ICd connect more widely throughout the contralateral ICd (Figure 2B). Neurons in ICl were rarely labelled following injections in ICc or ICd, indicating that although commissural projections terminate in this subdivision, it is not a source of commissural connections.
Together, these findings suggest that different populations of commissural neurons interconnect the two ICs in distinct ways, perhaps in a manner analogous to the functional zones identified for the multiple sources of afferent input to the IC (Cant, 2013; Cant & Benson, 2006; Loftus, Bishop, & Oliver, 2010). The search for the organizing principles of interactions within and between the fibrodendritic laminae of the IC remains an important, but unanswered, challenge.
Commissural Fibers Originating or Terminating Outside the IC
Not all fibers passing through the commissure originate in the IC. A subset of ascending lemniscal fibers cross via the commissure to the contralateral IC (Barnes, Magoun, & Ranson, 1943; Hutson, Glendenning, & Masterton, 1991). These originate from the ventral (Whitley & Henkel, 1984), intermediate (Hutson et al., 1991), and dorsal nuclei of the lateral lemniscus (Bajo, Merchan, Lopez, & Rouiller, 1993), as well as the sagulum (Henkel & Shneiderman, 1988). Some neurons in the paraolivary nucleus of the superior olivary complex similarly send collaterals to dorsal cortex of the contralateral colliculus via the commissure (Saldaña, Aparicio, Fuentes-Santamaría, & Berrebi, 2009). A recent report finds evenfibers originating from a location as peripheral as the DCN canreach the ipsilateral IC by traversing the brainstem to the contralateral IC before crossing back through the CoIC to terminate in ipsilateral ICd (Milinkeviciute, Muniak, Pongstaporn, Cho, & Ryugo, 2015). Thus, it seems projections taking this circuitous route contribute to the relatively sparse input described from the ipsilateral dorsal cochlear nucleus to the IC (see Cant 2005 for review).
The CoIC also likely contains ascending projections from IC to the superior colliculus (Moore & Goldberg 1966) and to the ventral nucleus of the contralateral MGB (Coomes & Schofield, 2004; González-Hernández, Galindo-Mireles, Castañeyra-Perdomo, & Ferres-Torres, 1991; Kudo & Niimi, 1978; Oliver, 1984). Double labelling experiments suggest that as many as 30% of IC neurons projecting to the ipsilateral MGB also project to the contralateral MGB (González-Hernández et al., 1991). Such projections may provide a means for further bilateral integration within MGB.
In addition to conveying ascending and laterally directed fibers, the CoIC also mediates descending connections. While cortico-collicular, and thalamo-collicular connections are predominantly ipsilateral, a small proportion reach the contralateral IC directly via the commissure. Most terminals of such cortico-collicular fibers are found medially and dorsally, and in contrast to their ipsilateral counterparts, labeled terminals in the contralateral ICc only extend into its most dorsal part, and are absent in ICl (Adams & Wenthold, 1979; Rockel & Jones, 1973; Saldana, Feliciano, & Mugnaini, 1996). After tracer injections in both ICs, around 5% of cortico-collicular neurons were found to be double labelled in guinea pig and opossum (Coomes, Schofield, & Schofield, 2005; Willard & Martin, 1984). In contrast, Bajo and Moore (2005) failed to find any double-labelled cells in auditory cortex after large tracer injections in both left and right IC in gerbil. Nevertheless, it seems that, at least in some species, cortical neurons may send collateralized inputs to both ICs.
We do not know the exact proportion of commissural fibers that either originate or terminate outside the IC, but they are likely a small proportion of the total. It is also interesting, that, in contrast to the weight of intercollicular connections between the ICcs, commissural connections to the IC from extra-collicular sources are predominantly restricted to ICd.
There are a few reports of non-auditory projections to IC which project through the CoIC. Higher order areas such as the insula (Winer, Chernock, Larue, & Cheung, 2002) and orbitofrontal cortex (Mizuno, Sauerland, & Clemente, 1968) innervate IC via CoIC, while subcortical sources include the substantia nigra pars lateralis, a tonically firing GABAergic output of the basal ganglia (Afifi & Kaelber, 1965; Olazabal & Moore, 1989), the cholinergic basolateral amygdala (Marsh, Fuzessery, Grose, & Wenstrup, 2002), and bilateral projections from the hypothalamus (Adams, 1980). These little considered sources of input suggest processing in the IC goes beyond the analysis of sound per se.
The Neurochemistry of Commissural Fibers
Studies concur that the CoIC comprises both excitatory and inhibitory fibers. Saint Marie (1996) demonstrated an glutamatergic, excitatory, component based on the synaptic uptake and retrograde transport of tritiated D-aspartate. But combining retrograde labeling with immunohistochemistry for GABA or its synthesizing enzyme GAD67 reveals a substantial minority of labeled neurons are GABAergic (González-Hernández, Mantolán-Sarmiento, González-González, & Pérez-González, 1996; Nakamoto, Sowick, & Schofield, 2013). In rat, 18% of retrogradely labeled commissural neurons in the IC were GABA positive (González-Hernández et al., 1996; Hernández, Rees, & Malmierca, 2006). Given that around 20–25% of neurons in the IC of rat are GABAergic (Merchán, Aguilar, Lopez-Poveda, & Malmierca, 2005) the percentage of inhibitory commissural projections suggests the commissural projection is representative of the population of GABAergic neurons in the IC. In guinea pig, co-labelling of commissurally identified neurons with GAD67 found that approximately 10% of intercollicular projections were GABAergic, but the number differed between subdivisions from only 4% in ICc, to between 12–21% in the different cortical subdivisions (Nakamoto et al., 2013). Species differences probably go some way to explain the differences between reports, but there also appears to be a dorsal to ventral gradient through ICd and ICc with respect to the number of GABAergic neurons that contribute to the commissure. In ICd, up to 68% of commissural neurons are GABAergic, but there are many fewer in the more ventral parts of ICc (González-Hernández et al., 1996). Such a gradient may, therefore, explain why (Zhang, Li, Kelly, & Wu, 1998) failed to find any GABAergic labeled cells among commissural neurons labelled with fluorogold following injections placed ventrally in ICc. The contribution of different proportions of GABAergic neurons between different regions of IC indicates disparate roles of fibers with the CoIC, related to their afferent sources and efferent targets.
While glutamate or GABA are the neurotransmitters of most commissural neurons, a small number of neuropeptide Y and encephalin-labelled commissural neurons have been identified in the cortical subdivisions of the IC (Nakagawa et al., 1995). Further investigation of the diversity of the neurotransmitters expressed by CoIC fibers is required.
Neuronal Morphologies in IC Contributing to Commissural Connections
There is no systematic study of the neuronal types in IC that form the commissural projection. However, several reports using retrograde tracers or intracellular labeling show that IC neurons of widely differing morphologies are sources of commissural input (Adams, 1980; Coleman & Clerici, 1987; Druga & Syka, 1984; González-Hernández et al., 1996; Gonzalez Hernandez et al., 1986; Moore, 1988; Okoyama, Ohbayashi, Ito, & Harada, 2006; Saint Marie, 1996). The task of comparing these studies is somewhat hampered by the different terminologies applied to naming the neuronal types. However, it appears safe to say that the two major classes of neurons that feature in cytoarchitecture of the frequency-band laminae of the ICc (neurons with flattened disc shaped dendritic fields and stellate neurons—also termed flat and less flat types (Malmierca, Blackstad, Osen, Karagulle, & Molowny, 1993; Malmierca & Hackett, 2010; Oliver, 2005; Oliver & Morest, 1984) are both found in the commissural population in the central nucleus, together with mainly stellate types in ICd.
In one of the few quantitative studies, Okoyama et al. (2006) report that the most frequently encountered types were small- and medium-sized disc-shaped neurons (ca 10 and 15 µm soma diameter respectively) together with medium-sized stellate neurons. Neurons of both categories with large diameter soma (>20 µm) were observed, but much less frequently. These two major morphological classes are also present in studies that targeted the excitatory (Saint Marie, 1996) or inhibitory (GABAergic; González-Hernández et al., 1996; Nakamoto et al., 2013) components of the commissural projection. Following injection of tritiated aspartate to retrogradely label glutamatergic neurons, Saint Marie (1996) reported labelled neurons in ICc and ICd of the contralateral IC, including “fusiform” cells lying parallel to the orientation of the frequency band laminae, thus presumed disc-shaped neurons. Gonzalez-Hernandez et al. (1996) and Nakamoto et al. (2013) combined retrograde labelling with immunohistochemistry to identify GABAergic neurons projecting from one IC to the other. Labelling was most pronounced in ICd and the dorsal part of ICc. The labelled neurons constituted a heterogeneous population of morphologies and diameters with multipolar (stellate) and fusiform types representing soma diameters from 12 µm to over 20 µm. Comparison of these findings with the population analysis of GABAergic neuron size in the IC by Ito et al (Ito, Bishop, & Oliver, 2009), suggests that GABAergic of all sizes contribute to the commissural projection.
Intracellular and juxtacellular labelling techniques in vivo or in vitro produce smaller samples of neurons than retrograde studies, but have the advantage that labelling of dendritic arbors is more complete, and axons can often be traced along at least part of their length. Such studies have described labelled neurons with axons directed towards or into the commissure (Reetz & Ehret, 1999; Smith, 1992; Wallace, Shackleton, & Palmer, 2012). Consistent with the retrograde studies discussed previously, in ICd, most of these neurons are “multipolar” (putative stellate or less flat) cells (Smith 1992), but in the central nucleus, some have flattened dendritic arbors characteristic of neurons that aligned to form the frequency-band laminae (Reetz & Ehret, 1999; Wallace et al., 2012).
Inputs and Outputs of Commissural Neurons
Knowledge of the inputs and outputs of commissural neurons is essential to delineate their microcircuitry. Although we know relatively little about their sources of inputs, given their number and distribution in IC, it would be surprising if commissural neurons were not the recipients of extensive input from both intrinsic and external sources.
One significant source of input to commissural neurons comes from the auditory cortex. Nakamoto et al. (2013) in guinea pig used anterograde and retrograde tracers in combination to demonstrate that commissurally projecting neurons receive extensive input from the ipsilateral auditory cortex. These contacts were seen on neurons in ICd and ICc, and cortico-collicular endings were found on both presumed excitatory and identified inhibitory commissural neurons. Intriguingly, as suggested by Nakamoto et al. (2013), cortical input to commissural neurons might be the primary route whereby the IC is influenced by the contralateral auditory cortex.
In support of this hypothesis, spontaneous and sound-evoked firing in IC were found to be influenced by electrical stimulation of either contralateral or ipsilateral auditory cortex, but the latency of the contralateral effect was longer than that for ipsilateral stimulation (11.4 vs. 7.2 ms; Torterolo, Zurita, Pedemonte, & Velluti, 1998). The longer latency of the contralateral response is consistent with the possibility that the auditory cortex influences the contralateral IC indirectly via the commissure.
With respect to the output connections of commissural neurons, studies in vitro show that the majority of ICc neurons activated by stimulating the commissure are also driven by stimulation of the lateral lemniscus (Moore, Kotak, & Sanes, 1998; Reetz & Ehret, 1999). In contrast, neurons in ICd receiving commissural input were not, or only weakly, driven by stimulation of the lateral lemniscus (Smith, 1992). These data support the notion of different populations of commissural neurons suggested by the anatomical findings discussed earlier (see Figure 2).
GABAergic neurons projecting to GABAergic neurons in the contralateral IC have been demonstrated (Lee, Yanagawa, & Imaizumi, 2015), and cell-dependent monosynaptic tracing in mouse has extended this finding. Chen, Cheng, Ito, and Song (2018) reported differences in the proportions of inhibitory neurons projecting to glutamatergic and GABAergic neurons in the other IC. About a third of GABAergic neurons projected to glutamatergic neurons, and this proportion was similar for GABAergic neurons located in either ICc or ICd. However, there was a marked, location-dependent difference in the proportion of GABAergic neurons projecting to GABAergic neurons, with about 60% of those in ICd projecting to GABAergic neurons compared with only 20% of those in ICc. These data suggest that commissural connections predominantly drive dis-inhibitory circuits in ICd.
Among the GABAergic neurons targeted by commissural connections are the large GABAergic neurons with diameters >16.5 µm. These neurons, characterized by their dense axosomatic synapses associated with terminals expressing vesicular glutamate transporter 2 (VGLuT2; Altschuler, Tong, Holt, & Oliver, 2008; Ito et al., 2009), constitute the inhibitory connection from the IC to MGB (Ito et al., 2009; Winer, Saint Marie, Larue, & Oliver, 1996). These neurons receive excitatory inputs from several external and intrinsic sources, including from the contralateral IC, although these inputs are considerably sparser than from ipsilateral intrinsic neurons (Ito et al., 2015; Ito & Oliver, 2014).
Intracellular labeling demonstrates that some neurons that send axons toward the commissure also make axon collaterals that head towards the brachium or the lateral lemniscus. Although it was not possible to trace them to their terminals, this observation is consistent with commissural neurons also making ascending or descending connections external to the IC (Reetz & Ehret, 1999). More definitive double labelling tracer studies have also addressed this question. González-Hernández et al. (1991) observed that around 10% of neurons that project to MGB also project to the contralateral IC in rat, but this rose to 25–30% in some regions where the two tracers most overlapped. In contrast, Okoyama et al. (2006), also in rat, reported only about 1% of IC neurons were double labelled following injections into the contralateral IC and the ipsilateral MGB. Furthermore, the latter study showed a complete absence of neurons that contribute to both the commissural and the descending pathways from the IC to the cochlear nucleus or the superior olive. These conflicting findings are yet to be resolved.
Overview of Anatomical Findings
The sources and projections of commissural fibers are summarized in Figure 3. Together, the anatomical findings discussed emphasize several points about the organisation of the commissure. Commissural connections are responsible for extensive interaction between the two ICs. The commissure mediates excitatory and inhibitory connections roughly in proportion to the percentages in which those neuronal types are found in the IC, and cells with a wide variety of morphologies project from one side to the other. These projections, if not connecting point-to-point, are at least weighted towards the interconnection of homologous points on the fibrodendritic laminae of the ICc, while in ICd there appears to be two populations of commissural neurons with distinct patterns of connections.
Our knowledge of the micro-circuitry of the IC is rudimentary. The extent to which commissural neurons also project to the main external targets of the IC, the brainstem and the thalamus, is controversial, but within the IC their projections to output neurons converge with other inputs. It is not known if commissural neurons are directly reciprocal, though this seems likely. Commissural neurons receive feedback from the auditory cortex, providing a route for the contralateral auditory cortex to influence the IC, over and above the relatively sparse direct projections from the contralateral cortex.
Overall, the anatomical findings reveal the ICs so intimately bound to one another by the commissure, it is hard to avoid the conclusion that they function as a single entity.
Functional Properties of Commissural Projections
What is the function of these interconnections? In comparison to our knowledge of the anatomical organisation of the CoIC, our understanding of its function is far more limited. The interconnection of the left and right sides of the brain points to a commissural role in binaural interactions, including the neural representation of sounds in azimuth. However, the extent of coupling between the two ICs suggests equally extensive and wide-ranging effects on auditory processing. What knowledge we have about the functional role of commissural connections derives primarily from electrophysiological studies in vitro, and in vivo.
In Vitro Studies
Electrical stimulation in brain slices, has been used to study the effects of commissural fibers on their contralateral neuronal targets. Interestingly, for neurons recorded in the central nucleus, the predominant response of stimulating the commissure was a short latency EPSP followed by a short or, more often, a long latency IPSP (Moore et al., 1998; Reetz & Ehret, 1999). In contrast, although some neurons in ICd and ICl showed only a short latency EPSP or IPSP, the dominant pattern was a short latency IPSP followed by an EPSP, often accompanied by a second, long latency, IPSP (Li, Evans, & Faingold, 1999; Smith, 1992). The short latency responses are consistent with monosynaptic excitatory and inhibitory connections, while the longer latency inhibitory effects indicate at least a di-synaptic pathway. Admittedly, the number of neurons studied in this way was relatively small, but these findings support the suggestion made earlier that there are different patterns of synaptic organisation for commissural connections between the cortices of the IC, and those of the central nucleus.
Pharmacological approaches in these studies showed that the long latency component of the inhibition was blocked by the perfusion of AMPA glutamatergic-receptor antagonists, confirming that the long-latency inhibitory component is mediated by di- or poly-synaptic pathways in which GABAergic neurons are driven by excitatory commissural fibers (Moore et al., 1998; Smith, 1992). Thus, although excitatory fibers in the commissure outnumber inhibitory fibers by around 4:1, inhibitory effects arising from commissural activation could occur more frequently than expected from this ratio. For some commissurally activated neurons in ICd, it was also possible to uncover an NMDA-receptor mediated component, suggesting that these inputs may play a role in processing that involves learning and plasticity (Li et al., 1999; Smith, 1992), as might be expected given the role of ICd in learning-induced auditory plasticity (Bajo, Nodal, Moore, & King, 2010).
In Vivo Studies
The main advantage of in vivo recording for auditory studies is that it can be combined with physiologically relevant sound stimulation. In the current context, such recordings have been combined with stimulating or inactivating the commissural pathway.
In principle, inactivating commissural inputs, and thus removing their normative influence, might be more informative for understanding the physiology of commissural connections. Two approaches have been used: the application of drugs, either by pressure injection (Malmierca et al., 2003; Malmierca, Hernandez, & Rees, 2005), or microdialysis (Orton, Papasavvas, & Rees, 2016; Orton & Rees, 2014) into one IC, or local cooling of one IC (Orton et al., 2016; Orton, Poon, & Rees, 2012; Orton & Rees, 2014). A limitation of pressure injection is the proximity of the recording site to the site of injection and the mechanical instability that often accompanies the injection. This is a particular problem for single unit studies where the recording is highly sensitive to mechanical disturbance. Micro-iontophoresis avoids these issues, but the volume of drug delivered, and therefore the region of influence of the drug, is small, and, given the organisation of commissural connections, requires positioning the pipette to match the location of the recording site in the other IC. A better combination of mechanical stability and extended region of influence is obtained by delivering a drug via a microdialysis cannula (Orton et al., 2016; Orton & Rees, 2014). An alternative to blocking commissural activity is to activate the commissure via electrical stimulation of the contralateral IC (Mei, Cheng, Tang, Fu, Wang, et al., 2012). This method allows direct activation of commissural fibers with control over the pattern of stimulation. However, it may not mimic physiological activity, and could result in effects arising from the antidromic activation of neurons in the contralateral IC.
In vivo studies demonstrate that modulating commissural input has wide-ranging effects on neurons in the contralateral IC, with evidence for effects on frequency response areas, rate-level functions and the processing binaural cues.
Frequency response areas or receptive fields in the IC can be subdivided into several categories according to their shape. Many neurons have a V-shaped response area, redolent of auditory nerve fibers (LeBeau, Malmierca, & Rees, 2001; Palmer, Shackleton, Sumner, Zobay, & Rees, 2013). The other broad group, termed non-V, contains several patterns, some of which appear to have been sculpted by inhibition from a V-type shape (Alkhatib, Biebel, & Smolders, 2006; Egorova, Ehret, Vartanian, & Esser, 2001; LeBeau et al., 2001; Palmer et al., 2013). While distinct sub-types appear to occur within this group, detailed analysis of thousands of response areas suggest they do not constitute discrete classes, but lie on a continuum (Palmer et al., 2013). Experiments where recording is combined with iontophoresis of GABAergic antagonists shows differential effects on these two groups: V-shaped response areas show increased firing rate over the whole response area, with little change in receptive field area or shape. In contrast, neurons in the non-V group show changes in receptive field shape, often reverting to a more V-like appearance (LeBeau et al., 2001).
Interestingly, inactivation of the commissural connections produces changes in frequency response areas reminiscent of those seen with inhibitory blockade (LeBeau et al., 2001; Malmierca et al., 2003; Orton & Rees, 2014). V-shaped response areas typically showed an increase or reduction in firing over the whole response area, whereas in non-V type responses changes in firing rate were accompanied by an increase or decrease in receptive field area and shape (Figure 4; Orton & Rees, 2014). The parallels between these observations and those in which inhibitory inputs to the recorded neuron are blocked by GABAergic antagonists, suggest that commissural connections contribute to the inputs defining receptive field shape, and these can be excitatory or inhibitory in their action.
Electrical stimulation of one IC leads to changes in firing rate and broadening or narrowing of V-shaped tuning curves for neurons in the other IC, in some cases accompanied by a change in best frequency (Cheng et al., 2013; Mei, Cheng, Tang, Fu, Jen, et al., 2012). The direction of such changes depended on the difference between the frequency represented by the stimulation site in one IC and the recording site in the other. Where such a difference existed, the best frequency shifted towards that of the stimulation site (Cheng et al., 2013; Mei, Cheng, Tang, Fu, Wang, et al., 2012). These effects appear to involve plasticity, since they are sustained for 1–2 hours following 30 mins of stimulation. It is not clear to what extent these effects implicate commissural interactions between different frequency-band laminae.
As expected given changes in frequency response areas, stimulation or inactivation in the IC also influences the relationship between firing rate and sound level of neurons in the opposite side, as exemplified by rate-level functions (RLFs). Electrical stimulation can elicit increases or decreases in firing rate, although the majority of neurons were inhibited by stimulation of the contralateral IC (Cheng 2016; Mei 2012). Facilitation was generally only observed with small BF differences whereas inhibition occurred over a wider range of best frequency differences, again raising the possibility of interactions between within and between laminae. In general, rate level responses were suppressed by electrical stimulation with increased slope, and a reduction in dynamic range, but no change in the degree of monotonicity. As with the effects on frequency responses, there was evidence for the involvement of short-term plasticity.
Blockade of commissural inputs, either by cooling or microdialysis of procaine, in guinea pig resulted in shifts in RLFs towards higher sound levels and reduced non-monotonicity, effects that were, in the main, due to changes in responsivity at supra-threshold sound levels (Orton & Rees, 2014). As a consequence of these changes, there was an overall reduction in the ability of neurons to discriminate sound levels, suggesting that physiologically commissural input enhances the neural representation of sound level.
Although in all these studies there was evidence for both excitatory and inhibitory commissural effects, inhibitory effects appear to occur disproportionately to the known distribution of glutamatergic and GABAergic fibers in the commissure (see The Neurochemistry of Commissural Fibers Malmierca et al., 2005; Mei, Cheng, & Chen, 2013; Orton & Rees, 2014). This finding concurs with the findings of in vitro studies (see In Vitro Studies) demonstrating that inhibitory effects are mediated not only mono-synaptically, but also by di- or poly-synaptic circuits in which excitatory commissural fibers target local inhibitory neurons in the contralateral IC.
As we suggested earlier, it seems intuitive that commissural interactions might impact binaural processing. Physiological studies in vivo lend some support to this view (Malmierca et al 2005; Orton et al 2016). Orton et al (2016) addressed this issue by inactivating the IC by cooling or procaine infusion while recording neuronal responses to stimuli of varying interaural time or level difference (ITD, ILD) in the opposite IC. The dominant effect of IC inactivation was a reversible reduction or increase in firing rate at all values ITD or ILD. Across the population of recorded neurons, there was no evidence that the range of ITD or ILDs encoded changed on removal of commissural input. Nevertheless, analysis of firing rates for the control and inactivated conditions (Figure 5) indicated, both for ITD and ILD, that response gain was reduced following commissural inactivation. Commensurate with this reduction in gain, discriminability of these binaural cues was also reduced. Taken together, these findings suggest that in normal operation, commissural inputs enhance the ability of IC neurons to discriminate changes in the position of sounds in azimuthal space.
An important caveat that applies to all the methodologies used thus far to manipulate commissural inputs is that they might influence the contralateral IC via routes other than the commissure. These alternative pathways could go via the auditory cortex, given that both ipsilateral and contralateral cortices influence the IC, the latter, in part, via a commissural projection (Nakamoto et al., 2013). Alternatively, the descending projections from the IC to the superior olivary complex or the cochlear nucleus could also modulate the ascending input into the IC. The possibility seems less likely in view of the fact that when the IC is inactivated through cooling, the effect on sound-evoked local field potentials recorded in the opposite IC is predominantly on the later potentials rather than on the initial afferent volley (Orton et al 2012).
Some of the technical limitations of the methods used to investigate commissural function thus far could be surmounted with the application of optogenetics, which confers the possibility of targeting only those neurons that contribute to the commissural projection, a feat not possible with methods that globally modulate IC function. Furthermore, given evidence that commissural neurons may be a distinct subset of IC neurons (Okoyama et al., 2006), the ability to manipulate them in the absence of influencing IC neurons that project to upstream or downstream targets would be a distinct advantage.
If commissural inputs are important for sound processing in the IC, then the loss of commissural input might be expected to lead to behavioral deficits in sound processing. Transecting the commissure is difficult and not reversible, and there is only one study in the literature where this has been reported (Moore, Casseday, & Neff, 1974). In this behavioral study of sound localization in cat, transection of the commissure of the IC was either performed alone, or preceded or followed by transections of the trapezoid body and/or the corpus callosum to demonstrate their cumulative effects. Only a lesion to the trapezoid body was reported to impact sound localization. Unfortunately, the study has limited utility since only two sound sources were used, situated either side of the animal’s midline, thus it tested lateralization rather than localization. Subsequent studies have confirmed that following unilateral lesions within various structures in the ascending auditory pathway, animals can retain the ability to lateralize sound sources, but may not be able to localize them (Jenkins & Masterton, 1982).
In the absence of studies involving commissural transection, we can look to studies in animals or human where there is a lesion in one IC. These reports vary in the tests conducted and the effects observed, but are consistent in reporting deficits in sound localization in the spatial hemifield contralateral to the lesion (Kelly & Kavanagh, 1994; Litovsky, Fligor, & Traino, 2002) (Champoux et al., 2007; Jenkins & Masterton, 1982). The extent of the lesion varied from study to study, but the most marked deficits occurred where damage extended to the nuclei of the lateral lemniscus (Kelly & Kavanagh, 1994).
For the current discussion, the question is whether such unilateral lesions had any impact on responses to stimuli presented in the hemifield ipsilateral to the lesion, the “intact hemifield”? Such effects would be expected if signals to the IC, via the commissure, from the lesioned side, were ordinarily important. Although the other IC is not necessary for localization in the “intact hemifield,” there is evidence that performance in that hemifield is affected by a lesion to the other IC. Litovsky et al.’s (2002) patient showed impaired performance, relative to controls, when localizing targets close to the midline in the “intact hemifield,” and in animal studies, pre-lesion performance was consistently worse than post-lesion performance in the “intact hemifield” (Kelly & Kavanagh, 1994). Although these were small effects and could have alternative explanations, we should be cautious about ruling out the importance of the commissural pathway on the basis of these studies. Most behavioral studies tested localization using clicks or brief noise bursts, in which the main interaural cue is stimulus onset time, rather than on-going interaural time and level differences. Furthermore, tests were conducted in quiet conditions using constant intensity stimuli, and so did not fully reflect the more demanding conditions of real-world listening.
Speculations Regarding the Function of Commissural Projections
The anatomical and physiological evidence accumulated so far suggest the CoIC’s extensive connections exert wide-ranging effects on sound processing that encompass at least the encoding of frequency, level, and location.
Insights into why the colliculi are interconnected may be gained by considering why is it important for one colliculus to know about the responses of its twin in response to events in the acoustic environment? One possibility is that the signal in one IC alone is insufficient to define the properties of a sound source unambiguously. For example, consider how the location of a sound source is represented in the two ICs. Signals encoding interaural time and level differences reach the ICs having been extracted in the medial and lateral nuclei, respectively, of the superior olivary complex (Grothe, Pecka, & McAlpine, 2010). The neural representation of these azimuthal cues is organized in mirror symmetric hemispheric channels. As a sound source moves from one extreme of azimuth to the other, the firing rate of neurons in one IC increases while those in the other decrease in a negatively correlated manner. However, when considering the neural activity in one IC alone, such a rate-coded representation might not code the stimulus invariantly. As represented schematically in Figure 6, the change in firing rate of neurons in the right IC to a sound that moves from the midline to the left side (green arrow and green dot) would be indistinguishable from that to a sound on the midline that increases in overall level (blue arrow, blue dot). These stimulus changes are distinguishable, however, if the firing rates in both ICs are compared. The increase in level results in an increased firing rate in both ICs, whereas the change in azimuth leads to a reduction in firing in the left IC and an increase in the right. Although such an analysis is doubtless an oversimplification of reality, it serves to demonstrate how signals sent back and forth across the commissure signalling the mutual state of the ICs could be important for resolving such ambiguities.
Other roles for the commissure are suggested by anatomical and physiological findings. One important aspect of real-world hearing is the need to adjust response properties of neurons to keep them within their operating range as overall sound levels in the acoustic environment change. Stimulus-dependent gain control in the IC has been shown to keep neurons within their operating range so maintaining their responsiveness to tones as noise levels increase (Dean, Harper, & McAlpine, 2005; Rees & Palmer, 1988; Robinson & McAlpine, 2009). It is interesting that modulation of commissural activity leads to shifts in the operating ranges of rate-level functions (Mei, Cheng, Tang, Fu, Jen, et al., 2012; Mei, Tang, Fu, Cheng, & Chen, 2016; Orton & Rees, 2014).
Finally, there is increasing evidence of the important influence that corticofugal and other descending inputs have on auditory processing, including mediating various forms of plasticity (Bajo & King, 2013; Bajo et al., 2010; Suga & Ma, 2003). Such descending inputs might also mediate the types of feedback interactions postulated in predictive coding (Bastos et al., 2012). Particularly intriguing in this context is the evidence for a crossed cortical input to the contralateral IC mediated by commissural connections (Nakamoto et al., 2013).
This chapter has highlighted the extent to which the two inferior colliculi are tightly interconnected by commissural connections that closely integrate many aspects of their complex circuitry. The wide-ranging effects of the commissural system on the coding of fundamental parameters of sound: frequency, level and spatial location, is consistent with the possibility that responses of virtually all neurons in one IC are influenced by those in the other. Thus, functionally, the two ICs appear to operate as a single entity.
Existing studies have only scratched the surface in discovering the role of commissural connections, and it is important to avoid the fallacy of basing an understanding of commissural function on the answers to what might be the wrong questions! It is more than likely that the adequate stimulus (Sherrington, 1906) necessary to reveal the critical contribution of the CoIC has yet to be identified. Furthermore, it is increasingly evident that the inferior colliculus does much more than just integrate ascending sensory information. It receives a multitude of inputs from diverse sources, including those of corticofugal (Bajo & King, 2013) and neuromodulatory origin (Gittelman, Perkel, & Portfors, 2013; Hurley & Sullivan, 2012), that have thus far received little attention. A more complete understanding of the function of the CoIC may require experiments in an awake behaving preparation where the full impact of these diverse inputs can be assessed.
Some of our own work discussed in this chapter was supported by grants from the Wellcome Trust (066348) and BBSRC (BB/J0008680/1) to AR.
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