Descending Auditory Pathways and Plasticity
Abstract and Keywords
Descending auditory pathways originate from multiple levels of the auditory system and use a variety of neurotransmitters, including glutamate, GABA, glycine, acetylcholine, and dopamine. Targets of descending projections include cells that project to higher or lower centers, setting up circuit loops and chains that provide top-down modulation of many ascending and descending circuits in the auditory system. Descending pathways from the auditory cortex can evoke plasticity in subcortical centers. Such plasticity relies, at least in part, on brainstem cholinergic systems that are closely tied to descending cortical projections. Finally, the ventral nucleus of the trapezoid body, a component of the superior olivary complex, is a major target of descending projections from the cortex and midbrain. Through its complement of different neurotransmitter phenotypes, and its wide array of projections, the ventral nucleus of the trapezoid body is positioned to serve as a hub in the descending auditory system.
How can organisms attend to salient sounds, while ignoring unimportant ones? How can a sound that was previously unimportant to an organism, such as a harmless tone, become salient when paired with another stimulus? How can a reflexive response, such as a startle resulting from a loud sound, be inhibited by preceding auditory cues? Questions like these have led to discoveries of plasticity at many levels of the auditory system, from the cochlear nucleus to the cortex (e.g., Irvine, 2010; Zhao & Tzounopoulos, 2011; Miranda et al., 2014). A particularly exciting development over the past few decades has been the recognition of a role for descending pathways in modulating, or even driving, such plasticity (e.g., Bajo & King, 2013). Descending pathways are important in many listening conditions and are currently being investigated as a contributor to clinical deficits associated with aging or damage to the system (e.g., Boyen et al., 2014; Markovitz et al., 2015). In this chapter, we will attempt to summarize the literature surrounding the descending auditory pathways and consider some specific areas of recent progress.
Our review focuses on three areas that have advanced significantly in recent years. First, continued physiological studies have extended our understanding of corticofugal effects in the inferior colliculus (IC; where the majority of early studies were conducted) and have expanded our view to corticofugal effects in other areas, both within and outside the traditional ascending auditory pathway. A second area of work involves the modulatory systems and their close relationships with descending auditory pathways. Recent work has begun to examine the interactions between descending auditory pathways and neuromodulatory system, which will lead to advances in the understanding of plasticity in the normal auditory brainstem. Finally, there has been a resurgence of interest in neurotransmitter phenotypes associated with the descending pathways. This results in part from the general interest in neuromodulators and also from the advent of techniques that allow selective manipulation of neurotransmitter-specific circuits. While neurotransmitter phenotypes have long been a focus of studies in the ascending pathways, their roles in descending systems have been comparatively understudied. We begin with an update on the anatomy of the descending pathways to incorporate recent data and to review the associated neurotransmitters.
Previous reviews describe descending pathways within the auditory brainstem (Schofield, 2010, 2011; Malmierca & Ryugo, 2011). Here, we highlight new information, emphasizing neurotransmitter phenotype. Information about neurotransmitters is incomplete; confirmation with appropriate physiological approaches is limited to a small subset of pathways, but selective immunostains allow us to make tentative statements about the most likely neurotransmitters in many pathways. In some cases, the nucleus of origin may be largely homogenous in terms of neurotransmitter content, so the neurotransmitter present in the pathway can be inferred. Our discussion focuses on five neurotransmitters: glutamate, GABA, glycine, dopamine, and acetylcholine (ACh).
Subcortical Descending Projections to Auditory Brainstem Nuclei
Descending projections originate from a variety of subcortical auditory regions and, in contrast to projections from the auditory cortex, exhibit a variety of neurotransmitter phenotypes.
Glutamatergic descending projections.
Glutamate is the dominant excitatory neurotransmitter in both ascending and descending auditory pathways. Glutamate has been implicated in descending projections from the medial geniculate body (MG), the nucleus of the brachium of the IC (NBIC), the ventral tectal longitudinal column (TLCv), and the IC (Figure 1A).
Descending projections from the thalamus (MG and surrounding regions) terminate in numerous areas, including the IC, superior olivary complex (SOC) and cochlear nucleus (CN). Projections to the ipsilateral IC have been demonstrated in numerous species, including cats, rats, squirrel monkeys, gerbils, and mice (Adams, 1980; Frisina et al., 1998; Kuwabara & Zook, 2000; Patel et al., 2017; Senatorov & Hu, 2002; Winer et al., 2002). They originate from the medial and suprageniculate subdivisions of the medial geniculate body (included in the multisensory “paralaminar thalamus” in Figure 1A) and, in some species, also from the dorsal or ventral subdivisions (MGd, MGv). In rodents, the MG contains almost exclusively glutamatergic neurons, so the MG-IC pathway must be largely glutamatergic (Patel et al., 2017; Winer & Larue, 1996). Projections from the auditory thalamus target the lateral cortex of the IC (IClc), and, to a lesser extent, the central nucleus of the IC (ICc) and the dorsal cortex of the IC (ICd) (Frisina et al., 1998; Kuwabara & Zook, 2000; Patel et al., 2017).
The NBIC, situated along the brachial pathway between the IC and the MG, also sends a descending projection to the IC (Senatorov & Hu, 2002; Patel et al., 2017). Glutamatergic cells are likely to contribute to this projection, although more direct experiments are needed to confirm this point (Patel et al., 2017).
The TLCv is an auditory-responsive nucleus located near the dorsal midline of the superior colliculi and rostral part of the inferior colliculi (Saldaña et al., 2007). A defining feature of the TLCv is a large descending projection to the SOC, which targets, at least in part, the superior paraolivary nucleus (SPN; Viñuela et al., 2011). A majority of TLCv neurons express vesicular glutamate transporters (a marker of glutamatergic cells), so the descending projection is likely to be at least partly glutamatergic, although this has not been demonstrated directly (Aparicio & Saldaña, 2014).
The IC is the origin of descending projections to the CN, the SOC, and regions in or around the nuclei of the lateral lemniscus (NLL; reviewed by Malmierca & Ryugo, 2011). Most, perhaps all, of the descending projections from the IC are glutamatergic (Milinkeviciute et al., 2017; Saint Marie, 1996).
Projections from the IC to the dorsal nucleus of the lateral lemniscus (DNLL) originate primarily from the ipsilateral ICc and are topographically organized (Caicedo & Herbert, 1993). Projections to the ipsilateral sagulum originate primarily from the IClc and ICd, and are not topographic.
Descending pathways from the IC to the SOC originate from the ICc and IClc (Faye-Lund, 1986; Hashikawa & Kawamura, 1983; Hashikawa, 1983; Okoyama et al., 2006) and primarily target the ventral nucleus of the trapezoid body (VNTB) and its rostral extension, the rostral periolivary area (Caicedo & Herbert, 1993; Faye-Lund, 1986; Malmierca et al., 1996; Schofield & Cant, 1999; Thompson & Thompson, 1993; Vetter et al., 1993). The projection terminates tonotopically and bilaterally with an ipsilateral dominance. Targets of IC projections include medial olivocochlear neurons (Suthakar & Ryugo, 2017; Vetter et al., 1993) and olivary cells that project to the CN ipsilaterally, contralaterally, or bilaterally (Gómez-Nieto et al., 2008; Schofield & Cant, 1999). Many olivary cells have projections to other nuclei within the SOC (reviewed in Thompson & Schofield, 2000), and it seems very likely that descending pathways contact some of these cells; however, there are very few data published on this issue.
Projections from the IC to the CN originate mostly in the IClc and the ICc (Caicedo & Herbert, 1993; Milinkeviciute et al., 2017; Schofield, 2001; Shore et al., 1991) and largely target the dorsal CN (DCN) bilaterally and tonotopically (Caicedo & Herbert, 1993; Malmierca et al., 1996; Milinkeviciute et al., 2017). Cellular targets within the DCN include fusiform and giant cells in the fusiform cell layer and the inner molecular layer, at least some of which make projections to the IC (Alibardi, 1999; Milinkeviciute et al., 2017). The IC–DCN projection is glutamatergic (Saint Marie, 1996; Ostapoff et al., 1997; Milinkeviciute et al., 2017).
GABAergic and glycinergic descending projections.
Three areas of the auditory pathways give rise to substantial GABAergic or glycinergic descending projections (Figure 1A). These arise from the subparafascicular nucleus of the thalamus (SPF), the NBIC, and the SOC. The NLL contain large numbers of GABAergic and glycinergic neurons, but there is scant evidence for descending projections from these cells.
The SPF is a thalamic nucleus located medial to the MG. It has extensive connections with auditory nuclei, including reciprocal connections with auditory cortex (AC) and inputs from the IC (reviewed in Schofield, 2011). It also gives rise to descending projections to several auditory regions, including the IC, SOC, and CN. Projections to the IC terminate bilaterally, with an ipsilateral dominance, primarily in the IClc and ICd (Yasui et al., 1992). GABAergic cells in the SPF contribute to these projections, although their precise termination patterns are unknown (Moriizumi & Hattori, 1992).
As described earlier, the NBIC sends a descending projection to the IC. About half of the cells participating in this projection are GABAergic (Patel et al., 2017). The NBIC projections terminate primarily in the IClc and the ICd, but the characteristics of the target cells are otherwise unknown.
The SOC can be divided into principal nuclei (the medial and lateral superior olivary nuclei, MSO and LSO) and periolivary nuclei (the remaining nuclei, including the medial nucleus of the trapezoid body [MNTB], which others have sometimes called a principal SOC nucleus). The MSO has exclusively ascending projections. The LSO has ascending projections that arise from glutamatergic and glycinergic cells and descending projections to the cochlea (lateral olivocochlear cells) that are cholinergic. The periolivary nuclei vary across species in size, location and nomenclature (see discussions in Schwartz, 1992; Thompson & Schofield, 2000); nonetheless, there are generalizations that apply broadly to the periolivary projections to the CN.
The periolivary nuclei are the main source of extrinsic GABAergic and glycinergic inputs to CN cells. While periolivary cells can use a variety of neurotransmitter phenotypes (GABA, glycine, glutamate, acetylcholine as well as several neuropeptides), cells that use GABA or glycine constitute a majority (74–92%) of olivary cells that project to the CN (Ostapoff et al., 1997). Glycinergic projections arise from each of the ipsilateral periolivary nuclei; there are few glycinergic inputs from the contralateral SOC. Periolivary projections terminate throughout the CN, and a majority of CN cell types receive glycinergic inputs (Kolston et al., 1992; Altschuler et al., 1993; Oertel & Young, 2004), but rarely have the inputs been related to a specific source outside the CN. One exception is a glycinergic projection from principal cells of the MNTB, which project to the ipsilateral CN where their targets appear to include multipolar (stellate) cells and globular bushy cells (Schofield, 1994).
GABAergic inputs to the CN, in contrast, originate mainly from the VNTB and the SPN. Moreover, GABAergic inputs originate bilaterally from the VNTB. Some VNTB cells have axons that branch to innervate both left and right CN (Schofield & Cant, 1999); while the neurotransmitter phenotype was not identified in that study, the available evidence suggests that this bilateral projection is GABAergic. Although GABAergic boutons are found widely in the CN, there are few data relating extrinsic sources of GABA to specific CN cell types.
Dopaminergic descending projections.
Figure 1B illustrates dopaminergic descending projections within the auditory brainstem. The paralaminar thalamus was mentioned earlier as a source of descending glutamatergic and GABAergic projections. The SPF, one of the paralaminar nuclei, also sends dopaminergic projections to lower centers, including the IC, where the projections terminate bilaterally with an ipsilateral dominance in the IClc and the ICd (Nevue et al., 2016a). Additional dopaminergic projections from the SPF terminate in the SOC (Nevue et al., 2016b). These projections are also bilateral with an ipsilateral dominance, and target primarily the SPN and MNTB. Individual dopaminergic cells in the SPF can send collateral projections to both the ipsilateral IC and SOC, suggesting that dopamine can be released nearly simultaneously in these two targets (Nevue et al., 2016b). The projections of the cells that are targeted by the dopaminergic axons are not known.
There are also projections from the SPF to the CN (Yasui et al., 1992). There is evidence for dopaminergic innervation of the CN, but it has yet to be determined whether the SPF is the source of the dopamine (reviewed in Altschuler & Shore, 2010; note that dopaminergic cells have been identified in several auditory regions and some in the SOC are known to project to the cochlea, but the projections of others are unknown).
Cholinergic descending projections.
The SOC is the only auditory structure that contains a substantial number of cholinergic neurons. These cells have been associated exclusively with descending pathways. The best-known cholinergic projections are those of the olivocochlear system, which consists of medial and lateral subsystems (see Elgoyhen et al, this volume). The SOC is also a source of cholinergic projections to the CN (Figure 1B). Some of these projections arise as collaterals of olivocochlear axons. The medial olivocochlear cells can project to the ipsilateral or contralateral cochlea, and most of these cells have axon collaterals that terminate in the CN on same side as the targeted cochlea. The medial olivocochlear axons contact large dendrites in the granule cell area (Benson & Brown, 1990; Brown et al., 1988). At least some of these dendrites belong to ventral CN multipolar cells; however, other ventral CN cell types with dendrites present in the granule cell area may be contacted as well (Benson & Brown, 1990). Reports differ on whether lateral olivocochlear cells, most of which are cholinergic, also send collaterals into the CN (Brown et al., 1988; Horváth et al., 2000; Ryan et al., 1990).
A second group of cholinergic cells in the SOC projects to the CN but does not project to the cochlea (Sherriff & Henderson, 1994). This group of small cells, located in the VNTB, projects into the CN bilaterally with a contralateral dominance. Some of these cholinergic projections contact cells of the auditory nerve nucleus (Gómez-Nieto et al., 2008); whether there are other targets within the CN is unknown.
Cortical Descending Projections to Auditory Brainstem Nuclei
It has been known for decades that higher functions can affect early auditory processing, including effects in the cochlea (reviewed in Delano & Elgoyhen, 2016). For much of that time, the underlying circuitry was assumed to be a three-neuron descending chain: (1) AC projects to the IC; (2) the IC projects to the SOC; (3) the SOC projects to the cochlea. The seminal discovery in 1995 of extensive projections from AC to subcollicular regions, including the CN, the SOC, and regions near the NLL, ushered in a renewed interest in corticofugal systems and top-down modulation of the auditory brainstem (Feliciano et al., 1995). Cortically driven plasticity has now been observed in several brainstem auditory nuclei; understanding the advantages (and possible disadvantages) of such plasticity requires a clear picture of the underlying circuitry.
AC projections to subcollicular targets appear to arise exclusively from layer V pyramidal cells and could be expected to be glutamatergic and to excite their targets. A major step toward characterizing the circuits is to identify the brainstem cells targeted by AC axons. In some areas, such as the cochlear nucleus, the targeted cell types have been identified. However, in many areas, most aspects of the target cells’ phenotype, including the neurotransmitters used by target cells, are just beginning to be identified.
The AC projects directly to many of the brainstem auditory nuclei (Figure 2, gray shading). These projections are usually bilateral with an ipsilateral dominance. Additional details, particularly regarding the distribution of cortical terminals within a target area, are omitted from the figure but carry important implications about the circuits that are targeted (Malmierca & Ryugo, 2011; see Schofield, 2010). For example, projections to the CN terminate heavily in the granule cell areas and, at least in guinea pigs, less densely in other regions of the CN. As its name implies, the SOC is particularly complex in this regard, with many distinguishable nuclei that vary from no cortical input (e.g., the medial superior olivary nucleus) to especially dense cortical inputs (e.g., the VNTB). The SOC as a whole gives rise to numerous ascending and descending auditory projections, and also contains substantial intra-olivary circuits, providing a rich array of targets for cortical axons. Work is continuing to dissect these circuits and their functions. Cortical projections to the IC terminate very densely in the outer shell areas, and less densely in the central nucleus (ICc). As we shall discuss, cortical effects can be observed in numerous IC subdivisions, where they are likely to play different functional roles. Finally, a number of cortical projections have been identified but not addressed in terms of target cell/circuit or function; many of these, such as projections to areas near the lateral lemniscus, are omitted from Figure 2.
Given the large number of pathways that are directly targeted by cortical axons, Figure 3 separates them into those pathways that project to higher centers (ascending pathways, Figure 3A) and those that project to lower centers (descending pathways, Figure 3B). A commissural pathway connecting the two ICs is also a target of AC projections (Figure 3A). Although the ascending and descending pathways are depicted separately, a simple examination shows that AC axons in a given target area (e.g., the IC) can contact ascending or descending pathways (e.g., IC–MG cells or IC–CN cells). An interesting question that has yet to be examined is whether single cortical axons contact both ascending and descending pathways, implying co-activation of the pathways. Perhaps the most striking aspect of Figure 3 is the large number of ascending and descending pathways, originating from almost all levels of the system, that are targeted directly by AC axons. Most of the pathways identified here were reviewed previously (Malmierca & Ryugo, 2011; Schofield, 2010, 2011); newer findings are described next.
AC projections to the NBIC.
The NBIC has long been known as a target of AC projections, but the output pathways of the NBIC that are targeted have been unknown (Andersen et al., 1980; Budinger et al., 2006, 2013; Saldaña et al., 1996; Winer et al., 1998). The NBIC receives auditory input from the IC and is probably best known as the primary source of auditory projections to the superior colliculus, where it presumably contributes to orienting or avoidance responses to sounds (Mellott et al., 2018). The NBIC also projects directly to the MG, and is thus a component of ascending pathways to the AC. The projections to the MG originate from both GABAergic and non-GABAergic NBIC cells, suggesting inhibitory and excitatory effects on MG cells. Axons from the AC have now been identified as contacting both GABAergic and non-GABAergic NBIC cells that project to the thalamus (Mellott et al., 2014a). Whether AC axons contact NBIC cells that make descending projections to the IC is unknown.
AC projections to the IC.
Bajo & King (2013) reviewed the corticocollicular pathway recently, and this topic continues to be a popular focus of research. The AC sends a dense projection to the ipsilateral IC and a sparse projection to the contralateral IC. The ipsilateral projections terminate densely in the IC shell areas and sparsely in the ICc; projections to the contralateral IC terminate only in the shell areas. Most physiological studies of the corticocollicular pathway have focused on the ICc, presumably because of its key role in the lemniscal pathway. Anatomical studies indicate that ascending and descending pathways from the IC originate from different, but intermingled, populations of IC cells (Coomes & Schofield, 2004; Okoyama et al., 2006; Schofield, 2001). Furthermore, AC axons appear to make direct contact with both ascending and descending IC output pathways (Coomes Peterson & Schofield, 2007; Schofield & Coomes, 2006). Unfortunately, very few physiological studies include information on the projections of the IC cells that are modulated by AC inputs, so it is unknown whether the effects observed in the study apply to ascending or descending pathways from the IC.
The IC commissural pathway is a recently discovered target of AC projections. Such a pathway could allow the AC on one side to affect the contralateral IC. While there is a direct projection from the AC to the contralateral IC, the large size of the ipsilateral AC-IC projection (roughly 10 times the size of the contralateral projection) along with the large size of the IC commissural pathway (Moore, 1988), suggests that a commissural route could play a significant role in corticofugal effects. Physiological studies indicate that the AC can affect activity in the contralateral IC (Ma & Suga, 2001). Nakamoto et al. (2013b; Torterolo et al., 1998) showed that AC axons that terminate in the ipsilateral IC appear to contact many IC commissural cells. Moreover, the commissural pathway originates from both excitatory glutamatergic neurons and inhibitory GABAergic IC neurons, both of which appear to be contacted directly by the AC axons (Nakamoto et al. 2013b). Thus, the large IC commissural pathway could provide a route for AC-evoked excitation and inhibition in the contralateral IC. Overall, the AC has multiple pathways by which it could potentially modulate ascending, descending and commissural pathways from the IC.
Corticocollicular cells form synapses in all IC subdivisions, where they release glutamate and excite their collicular targets (Feliciano & Potashner, 1995; Saldaña et al. 1996; Xiong et al., 2015). Corticocofugal projections activate both excitatory and inhibitory circuits in the IC (Gao et al., 2015; Mitani et al., 1983; Popelár et al., 2016; Peng et al., 2017). Cortical activation of inhibitory circuits has been assumed to result from cortical boutons contacting GABAergic cells in the IC. Nakamoto et al., (2013a) combined electron microscopy with immunochemistry to provide the first anatomical evidence for cortical inputs to IC GABAergic cells. The synaptic contacts were observed in the cortical regions of the IC (dorsal cortex and lateral cortex), where AC axons terminate densely. GABAergic cells in these regions project to the ICc, to the contralateral IC, or to the MG, and thus could distribute cortically driven inhibition to numerous target areas (González-Hernández et al., 1996; Jen et al., 2001; Mellott et al., 2014b).
Despite the fact that the AC projections terminate most heavily in the IC shell regions, the majority of physiologic data on corticocollicular effects has been collected from cells in the ICc. In a series of studies, Suga and colleagues demonstrated that AC activation can modulate the response of an IC cell to an acoustic stimulus (reviewed in Suga, 2012). The nature of the modulation depends on the similarity of tuning for the cortical and collicular sites. In brief, a cortical site can enhance the responses of collicular cells that have response properties similar to the cortical site and can shift the responses of nearby cells so that they respond more similarly to the cortical site. The responses of a collicular cell with more distant tuning properties are unaffected by the cortical stimulation. Suga referred to this as “egocentric” selection, whereby a cortical site can shift subcortical responses toward the inputs that would activate that cortical region. A remarkable level of specificity can be maintained in these effects; retuning can affect a neuron’s response to stimulus duration, intensity, or location, in addition to the frequency effects described earlier. A particularly interesting aspect to these effects is that they can outlast, by minutes to hours, the period of cortical stimulation (Suga, 2012). If atropine was applied to block muscarinic receptors in the IC, a collicular cell’s responses were retuned during cortical stimulation, but this retuning ceased once cortical stimulation ended. Thus, the cortically driven plasticity was dependent on cholinergic muscarinic receptors in the IC. This interplay between cortical projections and cholinergic systems will be discussed.
Recent work has also shown top-down effects on collicular cell responses to binaural cues. Nakamoto et al., (2010) showed that corticocollicular projections modulate IC responses to binaural cues. Such modulation may contribute to stream segregation, allowing a listener to distinguish sounds from different locations. The descending pathways may further contribute to filtering of different sounds by selectively enhancing or suppressing a sound based on its salience. Gao et al., (2015) suggested that corticocollicular projections enhance responses to biologically relevant vocalizations. Top-down modulation of binaural processing in the brainstem, with a role in stream segregation and the ability to hear one sound source in the presence of others, may be particularly relevant in the context of human hearing and age-related deficits.
Evidence for corticocollicular effects on IC responses to binaural cues led King and colleagues to investigate the ability of ferrets to localize sounds after selectively lesioning corticocollicular cells (Bajo et al., 2010). An adult ferret can normally be trained to localize sounds quite accurately and, with additional training, can recover that ability after localization cues are altered by placing an earplug in one ear. If the corticocollicular pathway is lesioned selectively, the ferret can localize sounds but is unable to adapt to an earplug. Thus, the corticocollicular pathway is critical for adaptation to the altered sensory input. The site, or more likely sites, of cellular plasticity that underlie these changes have not yet been determined; while the study manipulated corticocollicular projections, the targeted IC cells could project to higher centers (e.g., MG or superior colliculus) or lower centers (e.g., olivocochlear cells; see discussion in Bajo & King, 2013).
Many of the effects we have discussed demonstrate, or at least imply, frequency-specific effects of the corticocollicular pathway. To what extent are these pathways tonotopically organized? Corticocollicular projections arise from a wide array of auditory cortical fields, only some of which are tonotopically organized (reviewed by Malmierca & Ryugo, 2011; Bajo & King, 2013). Anatomical studies suggest that the projection from primary AC (A1) to the ICc is tonotopically organized (Saldaña et al., 1996; Budinger et al., 2013). Physiological studies now confirm such an arrangement (Markovitz et al., 2013). Another tonotopically organized projection to the ICc has been identified from a cortical area known in guinea pigs as the ventrorostral belt (Straka et al., 2015). The tonotopic organization of ventrorostral belt terminations in the ICc appears less precise than the organization of projections from A1. The two cortical areas also have different termination patterns: A1 projections terminate throughout the ICc iso-frequency laminae, whereas the ventrorostral belt projections terminate preferentially in the caudo-medial part of the laminae. Thus, different parts of a lamina receive input from different combinations of AC areas. The authors note that the ventrorostral belt may be specialized for processing vocalizations (Grimsley et al., 2012), but otherwise little is known about the functions of these two different projections.
Additional studies support the idea that corticofugal projections can have different effects on different parts of the IC. Anderson and Malmierca (2013) showed that inactivation of the AC affects stimulus specific adaptation of many cells located in the IC shell areas (see also Malmierca, this volume). In a different study, bilateral ablation of the AC increased the response (fMRI BOLD signal) to noise and decreased response selectivity to vocalizations in the IC (Gao et al., 2015). Interestingly, the effect on noise responses was seen primarily in the ICc whereas the effect on vocalization selectivity was seen primarily in the IC shell. These data provide further support for differential effects of AC projections on different IC regions. The same study also showed that ablation of visual cortex had smaller but still differential effects on the IC regions.
Zhang and colleagues have added the pathway from the IC to the dorsolateral periaqueductal gray to the list of brainstem auditory pathways directly affected by AC projections (Xiong et al., 2015). Activation of this IC projection leads to flight behavior, and the authors speculate that the AC input to this pathway enhances the likelihood of an animal taking flight when the forebrain (i.e., AC and amygdala) detects a threatening stimulus. Of additional significance is that the authors attribute the main effects to the IC shell areas and conclude that the ICc plays, at most, a minor role in these defensive responses. This is one of the few studies that address the contributions of IC shell areas to corticofugal functions.
AC projections to the SOC (and effects on the cochlea).
AC axons terminate throughout most of the ipsilateral SOC, with the densest terminations in the VNTB and moderate terminations in all remaining nuclei except the MSO (Figure 2; reviewed by Malmierca and Ryugo, 2011). A sparser termination exists in the contralateral SOC, with the VNTB again receiving the strongest projection. The ascending and descending pathways from the SOC appear to arise largely from different populations of cells, although these cells can be intermingled within individual nuclei (Schofield, 2002). Many of the SOC cells that give rise to the ascending projections to the IC or descending projections to the CN or cochlea can receive direct inputs from AC axons (reviewed by Malmierca & Ryugo, 2011; Schofield, 2010). There has not yet been any direct study of the cortical effects on olivary cells. However, AC projections to olivocochlear cells were reported years ago (Mulders & Robertson, 2000), and many studies have described modulation of cochlear function via top-down mechanisms (see chapter by Elgoyhen et al. in this volume for an update on cochlear innervation, and several recent reviews for descending influences on the cochlea, e.g., Terreros & Delano, 2015; Delano & Elgoyhen, 2016). These descending effects are likely mediated via multiple descending inputs to olivocochlear cells, including inputs from the AC, IC, and various modulatory systems.
The anatomical studies suggest that a large proportion of the cortico-olivary axons terminate on olivary cells that are not olivocochlear. As mentioned previously, some of these cells probably project to the cochlear nucleus or to the inferior colliculus. In addition, there are extensive intra-olivary circuits, connecting nearby nuclei as well as nuclei across the midline (Thompson & Schofield, 2000). Cortical inputs to these circuits could affect both monaural and binaural processing in the SOC, but new studies are needed to characterize such cortical effects.
AC projections to the CN.
AC projections terminate bilaterally in the CN in rats, mice, gerbils, and guinea pigs (Budinger et al., 2013; Malmierca & Ryugo, 2011). The majority of boutons are in the granule cell area and the DCN; in guinea pigs and gerbils, additional terminals have been observed in ventral CN. Physiological studies in mice have documented effects of A1 stimulation on CN responses bilaterally in the anteroventral CN and contralaterally in the DCN (e.g., Kong et al., 2014; Liu et al., 2010). The “egocentric” model described for corticofugal effects in the IC also applies in the CN. In other words, cortical stimulation tends to enhance responses of physiologically matched CN neurons and suppress responses in unmatched neurons. The study by Kong et al. (2014) also revealed that AC stimulation led to effects in the DCN that lasted for over an hour after cortical stimulation ended, showing cortically driven plasticity. While the direct projections from the AC to the CN likely play a key role in the observed effects, it is worth noting that there are several disynaptic pathways whereby the AC could affect the CN via relays in the IC or the SOC (reviewed in Schofield & Coomes, 2006). The extent to which these pathways interact is unknown.
Descending Pathways and Brainstem Modulatory Systems
Modulatory systems are increasingly recognized for their roles in subcortical auditory processing (Schofield and Hurley, 2018; see also Hurley, this volume). As mentioned earlier, recent discoveries have highlighted relationships between descending auditory pathways and neuromodulatory systems that use acetylcholine or dopamine. These connections probably serve a variety of important functions, including a role in top-down plasticity.
Circuits that Could Underlie AC-Driven Plasticity: Interactions between Descending and Cholinergic Systems
Auditory cortical projections to subcortical auditory nuclei likely control some details of how subcortical neurons are retuned for salient stimulus properties. At the same time, cortical projections to cholinergic centers in the midbrain tegmentum could determine whether ACh is also released in the auditory nuclei, and thus determine whether the retuning effects are sustained via long term plastic changes. Physiological evidence for a role of ACh in cortically driven plasticity predated the discovery of the underlying circuitry. The earliest studies focused on the IC, but evidence is accumulating for similar plasticity in other subcortical auditory centers.
Cortical and cholinergic inputs to the IC.
A hallmark of cortically driven plasticity in the IC has been the high degree of specificity in the effects on cellular responses; that is, a collicular cell can be finely re-tuned in its selectivity for a specific stimulus parameter (e.g., frequency, location, duration, or intensity; see reviews by Suga, 2012; Bajo & King, 2013). Re-tuning typically includes increased firing to some stimuli and decreased firing to other stimuli, with the result that the tuning of the IC neuron shifts toward the tuning of the cortical site that was stimulated. At a circuit level, both excitatory and inhibitory components are involved; the AC projections are glutamatergic and excite IC cells, presumably including direct synaptic activation of glutamatergic and GABAergic IC cells (Nakamoto et al., 2013a). Plasticity is exhibited in that the retuning can outlast the period of cortical stimulation. Moreover, this plasticity is blocked by application of atropine to the IC, demonstrating that the plasticity is dependent on muscarinic cholinergic receptors in the IC. Acetylcholine in the IC originates primarily from the pontomesencephalic tegmentum (PMT, consisting of the pedunculopontine tegmental nucleus and the laterodorsal tegmental nucleus; Motts & Schofield, 2009). This cholinergic group extends through the tegmentum of the pons and midbrain from a caudal point just medial to the dorsal nucleus of the lateral lemniscus to a rostral and ventral location nearing the substantia nigra. The AC, including primary auditory cortex, projects directly to the PMT, where the cortical axons contact cholinergic cells, including some that project to the IC (reviewed in Schofield et al., 2011). Thus, stimulation of the AC, as done to activate the corticocollicular pathway, could also activate PMT cholinergic cells and lead to release of ACh in the IC (Figure 4A). We suggest that the highly detailed re-tuning is accomplished by the corticocollicular projections in conjunction with intra-collicular circuitry. The role of PMT-derived ACh is to provide a permissive signal for plasticity. If the cholinergic system is not active, then the cortical effects on IC cells would be short-lived; if the cholinergic system is activated concurrently with the corticocollicular system, then plasticity could enhance and prolong the cortical effects.
Cortical projections and cholinergic inputs to other auditory nuclei.
Two main cholinergic groups innervate the subcortical auditory system: the PMT and the cholinergic groups of the SOC. The SOC groups are focused, perhaps exclusively, on the auditory system, whereas the PMT has connections with many systems across the brainstem and thalamus. Cholinergic cells in both areas have branching axons, allowing individual cells to innervate multiple auditory targets. Many olivocochlear cells have collateral branches that terminate in the CN. As a group, the PMT cholinergic cells have more widespread projections than do the olivary cells (reviewed in Schofield et al., 2011). Moreover, individual PMT cholinergic cells have branching axons that can innervate targets on both sides of the brain, that innervate different hierarchical levels of the auditory system, or combinations of such (Figure 4B–D; Motts & Schofield, 2011; Schofield & Beebe, 2018). At the population level, this allows the relatively small PMT (it contains ~7000 cholinergic cells in guinea pigs; ~6000 in rats; ~40,000 in humans) to innervate much of the brainstem and thalamus (Jones, 1990; Leonard et al., 1995; Manaye et al., 1999). It also means that activation of a small number of cells could lead to widespread release of acetylcholine.
The auditory corticofugal system is in a position to trigger acetylcholine release in auditory targets extending from the cochlea to the thalamus (Figure 4E). AC axons contact olivocochlear cells (Mulders & Robertson, 2000). AC axons can also contact PMT cholinergic cells, including those that project to the CN, to the MG, and to various combinations (Schofield, 2011; Schofield & Beebe, 2018). Such top-down control of acetylcholine release could play a key role in plasticity of the sort described earlier (Luo et al., 2011). Acetylcholine has also been implicated in other functions, such as gain control, and the descending inputs to cholinergic cells may allow for top-down influences on these functions as well.
Descending Pathways and Other Neuromodulatory Systems
The past decade has seen increasing interest in the role of neuromodulators in auditory processing and plasticity (see Hurley, this volume). Significantly, these roles are being investigated at all levels of the auditory system, from cochlea to cortex. As discussed previously, dopamine appears to be a neurotransmitter in descending projections from the thalamus to the IC and to the SOC. These dopaminergic cells are located in the SPF, a region of the thalamus that receives ascending auditory input from the IC as well as descending input from the AC (reviewed in Schofield, 2010). It has not yet been determined whether the cortical axons directly contact SPF dopaminergic cells and, if so, where those cells project. Such a circuit could allow for auditory cortical projections to elicit dopamine release in the inferior colliculus and/or the superior olivary complex; new experiments will be needed to assess such a possibility.
Some Current Conceptual Issues
In this section, we touch briefly on the concepts of circuit loops and chains for understanding the descending auditory system. We then consider the ventral nucleus of the trapezoid body, a nucleus of the superior olivary complex and major component of the descending auditory system. We propose that this understudied nucleus serves as an inhibitory hub in the descending auditory pathways.
Loops and Chains
The concepts of feedback loops and multi-synaptic chains of neurons continue to be dominant themes for understanding the descending auditory pathways (Bajo & King, 2013; Malmierca & Ryugo, 2011; Schofield, 2010; Spangler & Warr, 1991; ). Much of the early work was based on anatomical findings, and work has continued to more fully characterize descending chains (e.g., Brown et al., 2013). Loops can be technically more challenging to study, but physiological studies have reinforced views of extended loops that cross multiple levels of the auditory system. One early example is the AC–IC–MG–AC loop discussed by Yan and colleagues (Xiong et al., 2009; Luo & Yan, 2013). This work focuses on the multilevel components that interact to support cortically driven plasticity. Specifically, activation of the AC (by acoustic or artificial means) can lead to changes in the way cortical and subcortical cells respond to sounds. The largest changes are typically seen in the cortex. A key advance has been the recognition that the large changes seen in cortical responses reflect cellular changes, that is, plasticity, in both cortical and subcortical cells.
More recent work has promoted the idea of multiple interacting loops that allow top-down mechanisms to influence an even greater expanse of the central nervous system. Marsh and Campbell (2016) propose a brainstem-centered filter that controls the processing of complex sounds prior to that information being sent to higher (i.e., thalamic and cortical) levels. This brainstem filter relies on top-down influences from the AC and prefrontal cortex as well as the forebrain cholinergic system (which acts on the cortical areas). The filter, centered in the brainstem and controlled by the forebrain, exerts effects throughout the auditory system, extending even to the cochlea. One intriguing aspect of this filter is that it allows higher functions—such as attention and expectancy—to play a key role in the perception of speech in a noisy or reverberant environment. Declining function of forebrain systems, as commonly occurs during aging, could affect processing the auditory brainstem through their effects on the brainstem filter.
The VNTB as an Inhibitory Hub in the Descending Auditory System
The VNTB stands out as a target of descending projections from both the AC and the IC. These latter regions project to numerous auditory regions below the IC, but their axons terminate most densely in the VNTB. The VNTB projects in turn to many auditory regions, including the cochlea, cochlear nucleus, other olivary nuclei, nuclei of the lateral lemniscus, inferior colliculus and auditory thalamus (Schofield et al., 2014; Warr & Beck, 1996). To date, there is direct evidence that descending pathways to the VNTB contact cells that project to the cochlea, cochlear nucleus or inferior colliculus. Specifically, projections from the IC contact VNTB cells that project contralaterally to the cochlea or contralaterally, ipsilaterally or bilaterally to the CN (Schofield & Cant, 1999). Projections from the AC contact VNTB cells that project to the cochlea or CN, and also VNTB cells that project to the IC (Coomes Peterson, & Schofield, 2007; Mulders & Robertson, 2000; Schofield & Coomes, 2006). Together, these facts suggest that the VNTB serves as a hub in the descending auditory system, distributing top-down influences from the AC and the IC to many parts of the subcortical auditory system (Figure 5).
What are the likely physiological effects in the descending system? The descending projections from the IC and the AC are glutamatergic and are expected to excite VNTB cells. The VNTB contains a multitude of neurotransmitter phenotypes, including cells that use GABA, glycine or acetylcholine. GABA and glycine are generally inhibitory whereas acetylcholine can be excitatory or inhibitory depending on the postsynaptic receptor. In guinea pigs, about 80% of the VNTB cells that project to the CN use GABA, glycine or both (Ostapoff et al., 1997). Accordingly, the VNTB is the primary source of inhibitory projections to the cochlear nucleus. As mentioned above, both AC and IC axons contact VNTB cells that project to the CN; if these cells use GABA or glycine, they could provide top-down inhibition to the CN. Assuming that the cortical and collicular projections excite their targets, the VNTB could serve as an inhibitory hub for higher order effects on the CN. Given the diverse projections from the VNTB (it projects to other olivary nuclei, to nuclei of the lateral lemniscus, to the IC and directly to the thalamus), the VNTB could possibly provide a route for AC and IC projections to exert effects throughout much of the subcortical auditory pathway. Future experiments will need to clarify the neurotransmitter phenotypes of VNTB cells targeted by descending axons and the projections of those VNTB cells.
How does a “hub” fit into the loops and chains organization? The VNTB is likely to contribute to multiple loops and chains. The “hub” characteristic emphasizes the spatial overlap of the dense descending inputs and the multitude of VNTB outputs, raising the possibility of interactions or even shared components between loops and chains. Future experiments should be directed at characterizing the VNTB cells, their response properties, inputs, outputs, intrinsic properties, neurotransmitter phenotypes, and so on, so that the circuits can be related to their functions.
Many questions remain to be addressed to understand the contributions of descending auditory pathways to hearing. We list here a few that appear particularly relevant to the current discussion.
1. What cell types give rise to descending pathways from a given area? The characterization of these cells must include their neurotransmitters, the inputs they receive, their intrinsic properties, the receptors they express, and their projection targets (again, at a resolution of cell type, not just brain area). The concept of different cell types implies different functions; correlating cell types with projection patterns will help in defining those functions and also contribute to distinguishing cell types (supporting existing schemes and/or suggesting their revision or refinement).
2. Do cells with descending projections have branched axonal projections to multiple targets? This is important for understanding function and also for designing and interpreting experiments. From a functional standpoint, do cells with descending projections send information (or commands) to multiple targets, or do those targets receive input from different populations of cells, allowing for independent effects on the targets? From the experimental perspective, it is critical for interpreting optogenetic experiments to know whether the axons making up a given pathway have collaterals that could lead to stimulation of additional (perhaps unintended) sites.
3. What are the roles of tonotopic vs. non-tonotopic descending projections? The IC gives rise to both types of projections. Moreover, the massive descending projections from the AC also includes both types. Much of the existing work on corticofugal physiology has involved stimulation or silencing of primary AC. What about projections from other cortical fields, including belt and parabelt areas, many of which are not tonotopically organized?
4. To what extent do descending systems interact with the classic neuromodulatory systems? There is growing evidence for close ties between corticofugal projections and the brainstem cholinergic systems. Do corticofugal projections activate, directly or indirectly, cells that use modulators like serotonin, dopamine, or noradrenaline (all of which are known to modulate brainstem auditory centers)? What functions are associated with such interactions?
5. What roles do the descending pathways play during aging or after damage to the nervous system? Marsh and Campbell (2016) suggest that top-down effects are critical for selecting signal from noise and represent a major site of failure in aging. Do descending pathways help compensate for diminishing input from an aging cochlea? Perhaps clinical symptoms arise after the descending systems have reached their limit of compensation. Or do some problems reflect dysfunction of the descending systems themselves?
This brief review has focused on the brainstem and descending inputs to it. Ongoing work is leading to better characterization of descending circuits. There remains a critical need for characterizing cell types/phenotypes of both the cells that give rise to descending projections and the cells and circuits they contact. This characterization must include neurotransmitters, the associated post-synaptic receptors and many other cellular properties that help to define function and distinguish cell types. Key advances are likely to include new insights into the relationships of descending auditory pathways with the various neuromodulatory systems. New experimental approaches, spurred by recent developments in chemogenetic and optogenetic methods, are expanding the range of functions associated with descending pathways. It will be of particular interest to learn the roles of descending pathways in contributing to the various forms of brainstem plasticity that play a role in hearing throughout the lifespan and in response to damage or degeneration in the auditory system.
The work described here that was completed in the authors’ laboratory was supported by grants from the National Institutes of Health (R01 DC004391, F31 DC08463, F32 DC012450, F32 DC010958, and F31 DC014228). Space limitations prevent citation of many original studies. The authors acknowledge those researchers here with gratitude for their understanding. Special thanks to Will Noftz, Dr. Matthew Smith, and Dr. Michael Roberts for comments on an earlier draft.
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