Neuromodulatory Feedback to the Inferior Colliculus
Abstract and Keywords
The inferior colliculus (IC) receives prominent projections from centralized neuromodulatory systems. These systems include extra-auditory clusters of cholinergic, dopaminergic, noradrenergic, and serotonergic neurons. Although these modulatory sites are not explicitly part of the auditory system, they receive projections from primary auditory regions and are responsive to acoustic stimuli. This bidirectional influence suggests the existence of auditory-modulatory feedback loops. A characteristic of neuromodulatory centers is that they integrate inputs from anatomically widespread and functionally diverse sets of brain regions. This connectivity gives neuromodulatory systems the potential to import information into the auditory system on situational variables that accompany acoustic stimuli, such as context, internal state, or experience. Once released, neuromodulators functionally reconfigure auditory circuitry through a variety of receptors expressed by auditory neurons. In addition to shaping ascending auditory information, neuromodulation within the IC influences behaviors that arise subcortically, such as prepulse inhibition of the startle response. Neuromodulatory systems therefore provide a route for integrative behavioral information to access auditory processing from its earliest levels.
The inferior colliculus (IC) is an auditory crossroads. It receives ascending and descending inputs from auditory regions, contains functional domains defined by projections from specific auditory brainstem nuclei or by particular neurotransmitters, and responds to non-auditory events (Bajo & King, 2012; Bulkin & Groh, 2012; Choy Buentello et al., 2015; Lesicko et al., 2016; Loftus et al., 2010; Patel et al,. 2017; Zhou & Shore 2006). Projections from these different sources converge at the level of the IC to create or refine responses to acoustic stimuli. The IC further stages ascending and descending projections to auditory as well as non-auditory targets (Bartlett, 2013; Coomes & Schofield, 2004; Ito et al., 2009; Peruzzi et al., 1997; Schofield & Cant, 1999). Because of its centrality to these converging and diverging pathways, the IC is an important site for regulatory control.
There is a growing appreciation that regulation of the excitatory-inhibitory circuitry in the IC and other auditory regions can allow auditory processing to dynamically adjust to behavioral context, internal state, or experience (Charitidi & Canlon, 2010; Hurley & Hall, 2011; Weinberger, 2015). One important mechanism underlying this type of regulation is neuromodulation (Schofield & Hurley, 2018). The process of neuromodulation has been defined in different ways. Definitions are based on the identity and source of modulatory neurochemicals, the structure of synapses releasing neuromodulators, or the action of neuromodulatory receptors through second messenger systems (Maley et al., 1990; Marder, 2012; Nadim & Bucher, 2014). A useful functional perspective is based on a longstanding view of neuromodulators as reconfiguring the neural circuitry mediated by excitatory and inhibitory amino acid neurotransmitters like glutamate, GABA, and glycine. This chapter will focus on four types of neurochemicals that can fit one or more of these definitions: acetylcholine and the monoamines serotonin, norepinephrine, and dopamine. The effects of these neuromodulators in the auditory system follow basic principles that have been intensively studied for some time in motor systems (Marder, 2012), and are becoming more widely understood as an integral component of auditory processing (see Schofield & Beebe, this volume; Schofield & Hurley, 2018).
For the most part, this chapter will deal with neuromodulation by discrete groups of neurons that are extrinsic to the auditory system. It is important to note, however, that sources of neurochemical signals like acetylcholine and dopamine are also intrinsic components of auditory circuitry in the brainstem, which underlie feedback to early stages of auditory processing (Elgoyhen & Katz, 2012; Mulders & Robertson, 2004; Sherriff & Henderson, 1994). Auditory-extrinsic neuromodulatory centers show some striking functional similarities. One of these is their broad interaction with other neural sites. Neuromodulatory centers interconnect extensively with many other brain regions, including sensory, motor, and integrative sites (Benarroch, 2013; Lee et al., 2003; Luppi et al., 1995; Pollak Dorocic et al., 2014; Reese et al., 1995b; Retson & Van Bockstaele, 2013; Wang et al., 2006). These connections place neuromodulatory centers in position to instruct the auditory system on events in nonauditory brain regions.
All of the neuromodulatory regions discussed here also receive input from the auditory system, or possess populations of neurons that respond to acoustic stimuli (Aston-Jones & Bloom, 1981; Yasui et al., 1990; Reese et al., 1995a; Rasmussen et al., 1986; Heym et al., 1982). This reciprocity suggests that neuromodulatory systems could present a type of feedback to auditory neurons. A useful parallel model consists of descending pathways from the auditory cortex and IC, which are prominent features of auditory circuitry that provide feedback to the IC and auditory brainstem (e.g., Caicedo & Herbert, 1993); Schofield & Beebe, this volume). By virtue of their extensive connectivity with integrative brain regions that “interpret” external events, neuromodulatory systems could import information into the auditory system on situational variables that accompany acoustic stimuli, such as context, state, or salience (Petersen & Hurley, 2017).
The following sections present established and recent findings on neuromodulation in the IC and brainstem auditory nuclei in the framework of a feedback model. These sections emphasize major characteristics of auditory neuromodulation that are consistent with a feedback model, starting with the sources of neuromodulatory input, which originate in a diversity of neuron groups. In many cases, modulatory neurons are sensitive to acoustic stimuli, but represent “value-added” versions of these stimuli. The topography of terminal fields of neuromodulatory projections in the IC and brainstem auditory nuclei are specific and functionally suggestive. Once released from these projections, neuromodulatory signals within auditory regions encode information on behavioral salience. These neuromodulatory signals further multiplex information on external and internal events that occur on different time scales. Finally, neuromodulators functionally reconfigure auditory circuitry and alter behavioral responses to auditory stimulation.
Sources of Neuromodulatory Input to the IC and Auditory Brainstem
Ways to trace neuromodulatory sources
As prominent neuroanatomical features of the auditory system, neuromodulators in the IC and auditory brainstem have been studied for decades. Descriptions of modulatory projections to auditory brainstem nuclei based on histochemical reactions predate the use of selective labels for specific neurochemical pathways (Dahlstrom & Fuxe, 1964; Kromer & Moore, 1976; Levitt & Moore, 1979). The development of antibodies directed against specific monoamines, their synthetic enzymes, or selective transporters used in combination with tract tracing or selective neurotoxins has allowed for the sources of specific neuromodulatory inputs to the IC and many auditory brainstem nuclei to be identified (Hormigo et al., 2012; Klepper & Herbert, 1991; Motts & Schofield, 2009; Mulders & Robertson, 2005a). These studies portray a diverse set of neuromodulatory sources to the auditory system that in some cases have defied assumptions regarding their identity (Nevue et al., 2016a). This diversity is suggestive of a rich functional capability.
The extrinsic sources of neuromodulatory inputs to the IC and auditory brainstem have been extensively reviewed, for either single modulatory pathways (Schofield et al., 2011) or multiple pathways (Schofield & Hurley, 2018); this literature is therefore only briefly summarized here. Identifying modulatory sources typically involves retrograde or anterograde anatomical tracing, often accompanied by neurochemical identification of modulatory fibers or cell bodies (Klepper & Herbert, 1991; Motts & Schofield, 2009; Nevue et al., 2016a). Neurochemical identification has proven especially crucial, because most neuromodulatory nuclei house non-modulatory neurons that also project to the IC and auditory brainstem but use GABA or other neurotransmitters (Boucetta & Jones, 2009; Klepper & Herbert, 1991; Motts & Schofield, 2009; Nevue et al., 2016a; Vasudeva et al. 2011).
Where are auditory neuromodulators from?
There are multiple sources of cholinergic inputs to the IC and auditory brainstem nuclei. The cochlear nucleus receives inputs from cholinergic neurons in the auditory ventral nucleus of the trapezoid body, as well as tegmental cholinergic neurons in the pontomesencephalic tegmentum (Mellott et al., 2011). The IC itself receives projections from the pontomesencephalic cholinergic groups (Dautan et al., 2016; Motts & Schofield, 2009). An additional group of non-auditory cholinergic neurons projecting to the IC is found in the rostral ventrolateral medullary region (Stornetta et al., 2013). As a comparison, cholinergic innervation of the primary auditory cortex arises mainly from the basal forebrain (Bajo et al., 2014; Kamke et al., 2005). Thus, although many auditory sites receive cholinergic terminals, acetylcholine could be released under very different circumstances across auditory regions, depending on the source.
For other neuromodulatory pathways, the IC shares a dominant source with brainstem auditory nuclei. The IC and cochlear nucleus receive a majority of serotonergic projections from the dorsal raphe nucleus, with smaller although still substantial contributions from other raphe groups (Klepper & Herbert, 1991). The IC, cochlear nucleus, and superior olivary complex all receive noradrenergic input from the locus coeruleus (Klepper & Herbert, 1991; Mulders & Robertson, 2001). The understanding of dopaminergic innervation of the IC has changed with the addition of selective co-labels for the synthetic enzyme for dopamine. Although the dopaminergic substantia nigra projects to the IC (Olazábal & Moore, 1989), these projections may not be from dopaminergic neurons (Nevue et al., 2016a). Instead, some authors have suggested that the projections from substantia nigra to the IC are GABAergic (Maisonnette et al., 1996; Nobre et al., 2004). The IC and regions within the superior olivary complex receive dopaminergic projections from the subparafascicular nucleus (Nevue et al., 2016a, 2016b).
Hidden diversity within neuromodulatory sources
These findings together suggest that sources of cortical versus subcortical modulatory input are different for acetylcholine and dopamine, but similar for serotonin and norepinephrine. Even for seemingly universal modulatory sources like the dorsal raphe nucleus and locus coeruleus, however, there may be hidden variability, because these large modulatory centers are far from homogeneous (Calizo et al., 2011; Chandler et al., 2014a; Chandler et al., 2014b). In the dorsal raphe nucleus, subgroups of serotonergic neurons are distinguished by their position along rostrocaudal, mediolateral, and dorsoventral axes. Neurons in these different groups have afferent, efferent, and intrinsic distinctions (Calizo et al., 2011; Jacobs et al., 1978; Janusonis et al., 1999; Kirifides et al., 2001; Lee et al., 2003; Peyron et al., 1998; Van Bockstaele et al., 1993). For example, overlapping but distinct groups of dorsal raphe and locus coeruleus neurons project to cortical versus subcortical sensory sites (Kirifides et al., 2001; Waterhouse et al., 1993). In the locus coeruleus, subsets of noradrenergic neurons with distinct terminal fields show differential gene expression and electrophysiological characteristics (Chandler et al., 2014a).
Subpopulations of modulatory neurons may also be defined by their receptivity to other neurochemicals and their functional projections. For example, Pet1-positive dorsal raphe neurons expressing dopamine D2 receptors are involved in regulating aggressive behavior and project to a specific set of targets, sending strong projections to the IC and other auditory regions (Niederkofler et al., 2016). In general, although there is ample evidence that neuromodulatory centers have functionally distinct subsets of neurons, and of topographic organization of projections from neuromodulatory centers (Waterhouse et al., 1993; Waterhouse et al., 1986), the functional topographies of modulatory projections to the auditory system have not yet been well characterized.
Neuromodulatory Neurons Receive Auditory and Nonauditory Inputs
The connectivity and firing patterns of modulatory neurons provide one way of assessing the conditions that could trigger the release of neuromodulators within the auditory system. Consistent with a feedback model, all of the neuromodulatory regions relevant to this chapter either receive input from auditory regions (Figure 1), or respond to simple auditory stimuli like clicks and tones. Projections from different auditory regions to the pontomesencephalic tegmental nuclei or the subparafascicular nucleus have been well-documented (inferior colliculus: Wang et al., 2006; Yasui et al., 1990; medial geniculate body: LeDoux et al., 1985; auditory cortex: Schofield & Motts, 2009; Schofield, 2010; Yasui et al., 1990); some of these are described in detail in the chapter by Schofield and Beebe, in this volume. Pontomesencephalic tegmental neurons further show extremely short latency responses to clicks (< 10 ms) as well as longer-latency responses, although the auditory-responsive neurons have not been chemically identified (Reese et al., 1995a). Responses of neurons in the serotonergic dorsal raphe nucleus and noradrenergic locus coeruleus to auditory stimuli have been reported for decades (Aston-Jones & Bloom, 1981; Foote et al., 1980; Heym et al., 1982; Shima et al., 1986), and serotonergic dorsal raphe neurons receive monosynaptic inputs from the external subregion of the IC (Pollak Dorocic et al., 2014).
Auditory inputs constitute only a subset of the inputs into neuromodulatory nuclei, however. These nuclei typically receive extensive projections from a wide range of brain regions. The pontomesencephalic tegmental cholinergic nuclei are notably interconnected with motor control regions, as well as with hypothalamic regions involved in sleep/wake regulation (Benarroch, 2013). The subparafascicular nucleus, which contains dopaminergic neurons, is interconnected with regions that regulate reproductive behavior (Wang et al., 2006). The dorsal raphe nucleus and locus coeruleus likewise receive afferents from a wide range of brain regions representing many different functional domains, including areas important to cognitive function, social behavior, affective state, and stress (e.g., Lee et al., 2003; Luppi et al., 1995; Pollak Dorocic et al., 2014; Retson & Van Bockstaele, 2013).
Diverse inputs create integrative responses
Corresponding to this wide range of afferents, the auditory responsiveness of neurons in modulatory areas does not simply indicate the presence of auditory stimuli, but corresponds to additional factors such as internal state. Behavioral arousal is a state often associated with neuromodulators of all types. This includes arousal associated with phases of the sleep-wake cycle. The activity patterns of modulatory neurons are frequently tied to the sleep-wake cycle (Boucetta & Jones, 2009; Foote et al., 1980; Lorincz & Adamantidis, 2017; Motts & Schofield, 2009). Higher tonic firing rates typically occur during waking states, although firing rates may vary among modulatory systems during different sleep states. Internal states other than arousal are also represented within neuromodulatory axes, in that neuromodulatory activity depends on factors like social status and reproductive state (Challis et al., 2013; Hall et al., 2012; Hanson & Hurley, 2016; Korzan & Summers, 2007; Matragrano et al., 2012a; Matragrano et al., 2012b). Neuromodulatory systems may therefore not only modulate the tone of neural activity in sensory systems according to the level of behavioral arousal, but also promote optimal processing as it relates to specific internal states.
Across internal states, it is clear that neuromodulatory neurons integrate auditory and nonauditory sources of information about specific events. Modulatory neurons are often polysensory, responding to stimuli in multiple modalities (e.g., Aston-Jones & Bloom, 1981; Heym et al., 1982). Modulatory neurons also represent the salience of acoustic stimuli, a phenomenon that is well demonstrated by the responsiveness of modulatory neurons to reward contingencies. Extrinsic reward or the natural salience associated with acoustic stimuli affect the responses of neurons in multiple modulatory centers (Fischer & Ullsperger, 2017; Maney, 2013). In the locus coeruleus, for example, pairing tones with foot shock can create frequency-selective responses to tones alone even when tones do not initially evoke responses at all (Martins & Froemke, 2015). The responses of neuromodulatory neurons to acoustic stimuli therefore often represent the behavioral significance of these stimuli.
Neuromodulatory Inputs Broadly Innervate the IC and Auditory Brainstem
What does it mean to project diffusely?
Modulatory neurons are often described as projecting diffusely. This is true in the sense that modulatory fibers take apparently nondirect pathways through neural tissue and typically have many release sites along their length (Janusonis, 2017). These release sites may contain synaptic specializations, or be asynaptic. The latter configuration has been associated with the volume release of neuromodulators. In this mode, neuromodulators may diffuse some distance from their release sites before binding to receptors or transporters (Bunin & Wightman, 1998; Eid et al., 2013; Fuxe et al., 2015; but see Sarter et al., 2009 for a discussion of the controversy surrounding the concepts of volume versus synaptic transmission of acetylcholine). Although the synaptic configurations of neuromodulatory release sites have not been examined ultrastructurally in the IC, many serotonergic varicosities that form basket terminals around GABAergic neurons in the auditory cortex show only weak synaptic specializations (DeFelipe et al., 1991).
Neuromodulatory fiber patterns are selective
At the same time, modulatory fibers selectively innervate different subregions of the IC and auditory brainstem nuclei, or even specific layers, neural subgroups, or functionally distinct domains. On the broadest scale, some auditory brainstem nuclei seem to be relatively devoid of particular types of neuromodulatory inputs. For example, in the superior olivary complex of mice, the lateral superior olive does not receive dopaminergic innervation from the subparafascicular nucleus (Nevue et al., 2016b), and the guinea pig superior olivary complex as a whole receives few dopaminergic fibers (Mulders & Robertson, 2005a). The densities of serotonergic and noradrenergic fibers are generally higher in periolivary regions than in olivary nuclei themselves, although some fibers are present within olivary nuclei (e.g., Mulders & Robertson, 2005a; Thompson & Schofield, 2000; Wynne & Robertson, 1996). The MNTB shows a species-specific pattern of innervation by serotonergic fibers, which are present in bat but very scattered in mouse and cat (Hurley & Thompson, 2001; Thompson & Hurley, 2004; Thompson & Schofield, 2000).
In some species, neuromodulatory fiber densities correspond to tonotopic organization. Serotonergic fibers are denser in the regions corresponding to low-frequency responses than to high-frequency responses in the bat lateral and medial superior olives (Hurley & Thompson, 2001). Catecholaminergic fibers similarly are denser in the low-frequency regions of bat cochlear nucleus (Kössl et al., 1988). This pattern suggests that serotonin and norepinephrine or dopamine may modulate responses of low-frequency neurons more than high frequency neurons. Interestingly, although the same frequency-variable pattern of fibers is not observed in mice (Kössl et al., 1988; Thompson & Hurley, 2004), the mouse auditory brainstem response is generally more sensitive to serotonergic perturbation when stimuli consist of low-frequency tones compared to high-frequency tones, providing some functional support for frequency-selective modulatory effects (Papesh & Hurley, 2016).
Another type of pattern is for neuromodulatory inputs to be densest in integrative multimodal regions of auditory nuclei. Of the major subdivisions of the IC, serotonergic, noradrenergic, and dopaminergic fibers are denser in some pericentral subregions than in the central subdivision, although modulatory fibers are also clearly found within the central nucleus (Fyk-Kolodziej et al., 2015; Hormigo et al., 2012; Hurley & Thompson, 2001; Klepper & Herbert, 1991; Nevue et al. 2016a; Papesh and Hurley 2012; Figure 2). This pattern is also seen in the cochlear nucleus, in which the dorsal cochlear nucleus has denser serotonergic and catecholaminergic inputs than ventral subdivisions in some species (Klepper & Herbert, 1991; Kössl et al., 1988; Thompson & Thompson, 2001). These findings suggest that one role of multiple types of neuromodulators is to regulate the convergence of ascending auditory input with descending auditory input or nonauditory inputs (Hurley & Thompson, 2001; Klepper & Herbert, 1991). This hypothesis has received functional support in the case of serotonin, which alters the balance of auditory versus polysensory input at the level of fusiform neurons of the dorsal cochlear nucleus (Tang & Trussell, 2017).
Modulatory fibers even selectively innervate specific cellular layers or groups. In both the pericentral IC and the dorsal cochlear nucleus, noradrenergic fibers are sparsest in the outermost layer and denser in other layers, while serotonergic fibers show a reversed pattern; that is, are densest in the most external layer (Klepper & Herbert. 1991). These patterns are suggestive of layer-specific, complementary functions of different types of neuromodulators. Layer 2 of the lateral subregion of the IC exhibits a particularly intriguing structure of repeated neurochemical modules that co-localize acetylcholinesterase as well as cytochrome oxidase, NADPH, and glutamic acid decarboxylase (Chernock et al., 2004; Lesicko et al., 2016). Cholinergic inputs may therefore participate in a distinct neurochemical complex in these domains, which are the termination sites for somatosensory inputs (Lesicko et al., 2016). Specific neuron types also show selective anatomical targeting and functional effects of neuromodulation. In the ventral cochlear nucleus, T-stellate cells, but not D-stellate cells, are sensitive to cholinergic agonists (Fujino & Oertel, 2001). Olivocochlear neurons within the superior olivary complex are also particular targets of multiple types of neuromodulators including norepinephrine, serotonin, and peptide transmitters (Behrens et al., 2002; Mulders & Robertson, 2005a; 2000; Thompson & Schofield, 2000; Woods & Azeredo, 1999). Functionally, neurons in olivocochlear regions are responsive to application of norepinephrine and serotonin, with complementary effects on their descending targets (Mulders & Robertson, 2005b; Wang & Robertson, 1997).
All of these patterns are consistent with neuromodulatory systems targeting different kinds of anatomical domains. Although some evidence supports the functional hypotheses that arise from these patterns, these hypotheses have not been tested in many cases.
Neuromodulatory Activity in the IC and Auditory Brainstem
How is neuromodulatory activity in the auditory system measured?
The broad responsiveness of neurons within modulatory centers, combined with the prominent projections from these areas to auditory regions, creates the confusing potential for many different types of information to be imported into the auditory system. A way to resolve this ambiguity is to directly measure neuromodulatory activity under different behavioral circumstances. These types of measurements have been accomplished by microdialysis or localized tissue collection followed by HPLC measurement of neuromodulators and their major metabolites (Cransac et al., 1998; Matragrano et al., 2012b). Additionally, antibodies specific for activated forms of modulatory synthetic enzymes, or carbon fiber voltammetry, can capture neuromodulatory activity (Hall et al., 2010; Matragrano et al., 2012a). Most of the studies in this area have assessed either serotonergic or noradrenergic activity on relatively broad spatial and temporal scales rather than on the scale of synaptic events.
Acoustic and nonacoustic stimuli influence neuromodulatory activity
Absolute changes in the levels of serotonin and norepinephrine and their major metabolites have been measured following exposure to noise in the cochlear nucleus, IC, and auditory cortex. These show activation of modulatory pathways that is specific to particular auditory nuclei and their subregions, and that varies with sound level. For example, noise alters the ratios of serotonin and norepinephrine relative to their metabolites in tissue containing both the dorsal and posteroventral cochlear nuclei, but not in the anteroventral cochlear nucleus (Cransac et al., 1998). These ratios are generally interpreted as an indication of modulatory release and subsequent metabolism, termed “turnover.” Modulatory turnover is dependent on the intensity of noise; noradrenergic turnover in the cochlear nucleus and serotonergic turnover in the auditory cortex are only seen at relatively low intensities. Voltammetric measurements suggest that serotonergic activity increases modestly in the IC with moderate noise levels (Hall et al., 2010). In neither of these studies was the relationship of noise exposure to levels of systemic stress explored. However, nonauditory stressors including confinement to a small arena also increase serotonergic activity in the IC (Hall et al., 2010; Hall et al., 2012; Hanson & Hurley, 2014). Glucocorticoids do not directly evoke this release, since the systemic injection of corticosterone has no effect on serotonergic activity (Hall et al., 2012). Not all purported inducers of stress influence auditory serotonin, however. The presentation of an olfactory stressor, a chemical component of fox urine that induces strong aversive responses in mice, does not significantly alter serotonergic activity in the IC (Hall et al., 2010). Thus, increases in neuromodulatory activity in the IC in response to simple stimuli, even stimuli that share threatening qualities, are quite selective.
Neuromodulatory activity during social interaction
A more complex context that increases serotonergic activity in the IC is presentation of a social partner. Serotonergic increases occur across a range of different types of encounters: in males interacting with males or with females (Hall et al., 2011; Hurley & Hall, 2011; Keesom & Hurley, 2016) and in females interacting with males (Hanson & Hurley, 2014). Within each of these types of encounters, across-individual variation in serotonergic activity corresponds to variation in behavior. In male-male interactions, for example, serotonergic activity correlates with social investigation by the experimental subjects, and with overall movement (Hall et al., 2011). Males that are more active and more socially investigative show the largest serotonergic increases. In contrast, serotonergic activity in males interacting with females correlates inversely with the rejection behaviors of the female partners, but not with behaviors of the subject males (Keesom & Hurley, 2016). Individual males that experience the most rejection, including female-produced broadband vocalizations (“squeaks”), do not show serotonergic increases. In this case, serotonin levels inversely correspond to a specific type of auditory stimulus (female-produced squeaks) and are more representative of the valence, or positive versus negative behavioral value, of the situation for individual males.
Internal state and experience play a role
Serotonergic pathways within the IC are also capable of multiplexing information about behaviorally relevant events that occur on different timescales. This is accomplished through plasticity at different levels of the serotonergic system. For example, internal state is one factor that is encoded by serotonin release. Serotonergic activity in the IC increases as animals recover from anesthesia (Hall et al., 2010). This may be due to increased firing rates of neurons in the dorsal raphe nucleus (Sakai & Crochet, 2001). Reproductive cycles may also induce long-term changes in the infrastructure of serotonin in the auditory midbrain. Implanting female white-throated sparrows with estradiol, which would normally increase during their breeding season, augments the density of serotonergic fibers in an avian auditory midbrain nucleus that is a homolog of the IC (Matragrano et al., 2012b). In a parallel study in males, treatment with testosterone to mimic breeding levels results in a decrease in both serotonergic and noradrenergic fibers in the auditory midbrain (Matragrano et al., 2013). Seasonally breeding fish also experience neuromodulatory plasticity in both the auditory periphery and central auditory system (Forlano & Sisneros, 2016). Reproductively related changes in neuromodulation are not limited to seasonally reproducing animals. In female lab mice, the effects of manipulating serotonin levels on immediate early gene activity in the IC depends on the naturally cycling estrous phase (Hanson & Hurley, 2016). This result suggests change at the level of responsiveness to serotonin release, potentially in the expression of serotonin receptors by IC neurons. Neuromodulatory systems are therefore regulated at times when acoustic social signals have particular significance for reproduction.
Experience of multiple kinds also alters serotonergic infrastructure. Monaural acoustic trauma alters the bilateral balance of serotonergic fibers in the IC, decreasing fibers in the IC contralateral to trauma relative to the ipsilateral side (Papesh & Hurley, 2012). Bilateral cochlear ablation likewise decreases the density of fibers immunoreactive for tyrosine hydroxylase, a synthetic enzyme for dopamine and norepinephrine (Tong et al., 2005). Binaural acoustic trauma or ablation, as well as age-associated hearing loss, upregulate or downregulate the expression of several types of serotonin receptors in the IC relative to controls (Holt et al., 2005; Smith et al., 2014; Tadros et al., 2007). This includes at least one type of receptor that is expressed strongly in the IC as measured both immunohistochemically and by ligand binding studies, the 5-HT1A receptor (Peruzzi & Dut, 2004; Smith et al., 2014; Thompson et al., 1994). This evidence suggests that serotonin receptor expression by auditory neurons is altered following hearing loss. The effects of acoustic trauma and hearing loss on modulatory systems therefore occur at levels that are both presynaptic and postsynaptic to modulatory fibers within the IC.
Postweaning social isolation is another class of experience that alters serotonergic activity in the IC (Keesom et al., 2017). Male mice housed in same-sex social groups versus in isolation for a period of weeks after the time of weaning show two key differences when acutely challenged with an unfamiliar social partner. Individually housed mice have more sluggish serotonergic responses that peak later than those of socially housed mice, although their relative amplitudes do not differ. Individually housed mice also do not exhibit the correlations between serotonergic activity and behavior that are typical for socially housed mice (Hall et al., 2011; Keesom et al., 2017). Thus, serotonin release may be dysregulated relative to variation in the social context for mice with less social experience.
Together, these types of studies illustrate that neuromodulatory activity in auditory regions does not faithfully represent acoustic stimuli, but instead may encode the value of particular situations, internal state, and different kinds of experience. These factors may be represented at multiple levels of modulatory systems, including in the level of modulatory release and responsiveness, and in neuromodulatory infrastructure including the density of fibers and receptor expression (Figure 3)
Neuromodulators Functionally Reconfigure Auditory Circuitry
Once released in the IC and auditory brainstem, neuromodulators have profound effects; all four neurochemicals discussed in this chapter influence the firing patterns or response properties of substantial proportions of IC neurons. These effects fit a classic model of neuromodulators as reconfiguring neural circuitry by targeting specific aspects of cellular function (Harris-Warrick & Johnson, 2010; Marder & Bucher, 2007).
Receptors determine modulatory effects
The effects of neuromodulatory release on the intrinsic properties and sound-evoked responses of auditory neurons depend upon the types of receptors expressed by target neurons (Hurley & Sullivan, 2012). For example, many neuromodulators have suppressive effects on neural firing for some IC neurons, and facilitatory effects for others (e.g., acetylcholine: Habbicht & Vater, 1996; serotonin: Hurley & Pollak, 1999; dopamine: Gittelman et al., 2013). In some cases, these differences are positively attributable to the activation of different receptor types. For acetylcholine, a nicotinic antagonist increases neural activity while a broad-spectrum muscarinic antagonist generally decreases activity (Habbicht & Vater, 1996). There is further diversity even among muscarinic receptor subtypes, since m1 and m2 muscarinic acetylcholine receptor antagonists have different effects. For serotonin, selective agents for receptors in at least three of the seven receptor families have characteristic suppressive or facilitatory physiological effects on sound-evoked responses (Bohorquez & Hurley, 2009; Hurley, 2007, 2006). This general phenomenon of multiple types of effects of single neuromodulators is widespread, and is also observed in a number of auditory brainstem nuclei (e.g., Ebert, 1996; Ebert & Ostwald, 1992; Kössl & Vater, 1989; Wang & Robertson, 1997). Rather than canceling each other out, such opposing effects may result in greater selectivity for specific inputs at the level of auditory microcircuitry, may shape temporal responses, or may stabilize new circuit configurations (Harris-Warrick & Johnson, 2010; Kössl & Vater, 1989; Tang & Trussell, 2017).
Neural phenotypes influence modulatory effects
The effects of neuromodulators also depend on the identities of neurons expressing the relevant receptors. Given the importance of inhibitory inputs in the IC to the response properties of IC neurons (Pollak, 2013; Pollak et al., 2002; Pollak et al., 2011), neuromodulation of inhibition has been a particular focus for some studies. There is robust evidence for modulation of GABAergic and glycinergic inputs to IC neurons by both acetylcholine and serotonin. In slice preparations, activation of muscarinic receptors or 5-HT2 receptors creates a dramatic increase in the frequency of spontaneous GABAergic inhibitory postsynaptic currents, and a 5-HT2 agonist also increases their amplitude (Wang et al., 2008; Yigit et al., 2003). Serotonin also increases the frequency of glycinergic postsynaptic currents, although not as dramatically (Obara et al., 2014). Because some of these effects can be prevented by blocking action potentials with tetrodotoxin, these increases in inhibitory activity are thought to represent enhanced spontaneous firing of presynaptic inhibitory neurons. It is not clear whether these effects are limited to a specific developmental phase, as are similar effects of serotonin in the lateral superior olive (Fitzgerald & Sanes, 1999).
The 5-HT1B receptor may also act through inhibitory neurons. This receptor increases sound-evoked activity of many IC neurons (Baldan Ramsey et al., 2010; Hurley, 2006; Hurley et al., 2008). In other brain regions, the 5-HT1B receptor generally acts by limiting synaptic transmission, and its effects in the IC are reduced in the presence of a GABAA receptor agonist, consistent with effects of the 5-HT1B receptor on presynaptic GABAergic neurons (Hurley et al., 2008; Sari, 2004). Likewise, although the D2 receptor is the predominant dopamine receptor type in the IC, dopamine application to the IC has heterogeneous effects, potentially by influencing presynaptic GABAergic neurons (Gittelman et al., 2013). Although inhibition is clearly an important functional target of neuromodulation in the IC, neuromodulators likely influence the activity of non-GABAergic neurons too (Hurley & Sullivan, 2012; Peruzzi & Dut, 2004).
Neuromodulators selectively target specific subcellular compartments; this type of selectivity has been most thoroughly explored in different auditory brainstem nuclei. At the Calyx of Held, both norepinephrine acting via α2 adrenergic receptors and serotonin acting via 5-HT1B receptors limit calcium influx presynaptically at early developmental stages, resulting in reduced release of glutamate (Leão & Von Gersdorff, 2002; Mizutani et al., 2006). Neuromodulators can also alter intrinsic excitability by changing the membrane potential (Goyer et al., 2016; Miko & Sanes, 2009). Further, neuromodulators selectively alter neural output. For cartwheel cells in the dorsal cochlear nucleus, dopaminergic D3 receptors shift firing patterns from a bursting to a regular-firing mode by decreasing T-type calcium current selectively in the axon initial segment (Bender et al., 2010, 2012). For MSO neurons, activation of 5-HT1A receptors hyperpolarizes the membrane potential in the axon initial segment and decreases spike threshold (Ko et al., 2016). These selective effects occur partly through targeting particular types of ion currents. For example, the activation curve of the hyperpolarization-activated, cyclic nucleotide- gated cation current is shifted by norepinephrine in the MNTB and the avian nucleus laminaris (Banks et al., 1993; Yamada et al., 2005), and by serotonin in the MSO and DCN (Ko et al., 2016; Tang & Trussell, 2015).
Functional outcomes of targeted effects
In the IC, this range of selective modulatory mechanisms results in the transformation of functional response properties. Neuromodulators commonly alter the spontaneous or evoked firing rates of IC neurons in response to stimuli (Curtis & Koizumi, 1961; Gittelman et al., 2013; Hurley et al., 2004; Hurley & Pollak, 1999). Neuromodulators also alter firing patterns (Gittelman et al., 2013; Habbicht & Vater, 1996), latency or latency jitter (Felix et al., 2017; Gittelman et al., 2013; Hurley, 2007; Hurley & Pollak, 2005b), or selectively alter frequency tuning (Hurley & Pollak, 2001). These types of changes can contribute to shifts in neural selectivity for spectrotemporally divergent sounds, such as tones versus FM sweeps (Hurley & Pollak, 1999), sounds of different frequency (Hurley et al., 2004; Hurley & Pollak, 2001) or different species-specific vocalizations (Hurley & Pollak, 2005a).
Responses of IC neurons to temporally complex stimuli are also altered by neuromodulation. Ionotropic 5-HT3 receptors are responsible for a seconds-long depolarization of a few millivolts in baseline membrane potential following stimulus barrage to lemniscal inputs. This depolarization increases the gain of the neural response to a single stimulus of the input fibers (Miko & Sanes, 2009). In vivo, the same receptor type causes responses to different acoustic stimulus rates to become more similar (Bohorquez & Hurley, 2009). For neurons that show stimulus-specific adaptation, acetylcholine equalizes responses between rare and common stimuli by decreasing adaptation to the common stimulus (Ayala & Malmierca, 2015; Ayala et al., 2016). These types of effects demonstrate that neuromodulators regulate the responses to local auditory context.
A superb example of how neuromodulatory effects at the level of multiple auditory neurons within a microcircuit combine to create functionally coherent change is seen for the effects of serotonin in the dorsal cochlear nucleus. Serotonin acts through multiple receptor types and multiple cell types converging on fusiform cells to enhance multisensory responses and dampen auditory-only responses (Tang & Trussell, 2017, 2015). These types of combinatorial processes also occur in the IC. For example, 5-HT1A and 5-HT1B receptors both influence the responses of high proportions of neurons, but in opposite ways. Activation of 5-HT1A receptors often reduces responses to acoustic stimuli and delays spikes, consistent with suppression of excitability in other brain regions by this receptor (Hurley, 2007; 2006; Ohno, 2010). In contrast, 5-HT1B activation usually increases the responses of IC neurons to acoustic stimuli, consistent with a presynaptic reduction of GABAergic transmission (Hurley et al., 2008; Sari, 2004). Some IC neurons respond to activation of both of these types of receptors (Baldan Ramsey et al., 2010). For these double-responsive neurons, the effects of activating both receptor types on spike rate is linear, in that large effects of a given receptor type alone correspond to large effects when applied in combination. However, effects on spike latency are dominated by the 5-HT1A receptor. Thus, different types of neuromodulatory receptor may combine in nonlinear ways to create distinct profiles of neural activity.
Neuromodulators do not act alone
Creating additional potential for complex regulatory effects, different neuromodulatory systems also interact with each other. In some auditory regions, neuromodulatory systems are activated during some of the same events, including associative training (dopamine and serotonin: Stark & Scheich, 1997) or exposure to noise (norepinephrine and serotonin: Cransac et al., 1998; Hall et al., 2010). In each of these cases, although multiple neuromodulators are activated in the same general stimulus paradigm, the patterns of neuromodulatory release across stimulus conditions or across auditory regions are distinct. Profiles of release across different neuromodulators could therefore be more informative than for any single neuromodulator. At the level of auditory neurons and the receptors that they express, specific neuron types in the auditory brainstem and midbrain are the targets of multiple neuromodulatory systems (e.g., cartwheel cells: (Bender et al., 2010; He et al., 2014; Kuo & Trussell, 2011), calyx of Held: (Leão & Von Gersdorff, 2002; Mizutani et al., 2006). A very few studies have also documented responsiveness of the same individual auditory neurons to multiple types of neuromodulators (Hurley et al., 2004; McCormick & Pape, 1990). Different neuromodulatory systems therefore are likely to collaborate in their influence on auditory circuitry.
Behavioral Functions of Neuromodulation in in the IC
Building and testing hypotheses for the perceptual outcomes of auditory neuromodulation requires reconciling the exceptional breadth of neuromodulatory capabilities with specific behavioral contexts and auditory circuits (Linster & Cleland, 2016). A well-explored and well-reviewed example of the influence of neuromodulators on auditory perception is plasticity in responses to the pairing of tones with aversive stimuli like shock. Multiple types of neuromodulators, including acetylcholine, dopamine, and norepinephrine, alter the representation of frequency in auditory cortex and may change behavior following associative learning in parallel (Bao et al., 2001; Martins & Froemke, 2015; Weinberger, 2015). In the auditory cortex, local modulation with a peptide neurotransmitter, oxytocin, also alters neural responses in step with maternal responses to pup calls (Marlin et al., 2015).
Neuromodulatory regulation of aversion
Through effects in the IC, neuromodulation influences several classes of behaviors. These include unconditioned and conditioned aversion. Electrical or chemical stimulation of the central subdivision of the IC induces a variety of unconditioned fearful or aversive behaviors, including arousal, freezing, and escape behaviors (Brandão et al., 1994; Brandão et al., 1999). IC stimulation can even serve as an unconditioned aversive stimulus in operant conditioning paradigms in which animals leave a chamber to discontinue the stimulus (Melo & Brandão, 1995). These findings have led to a model of the IC as part of a mesencephalic substrate for defensive behaviors, along with regions of the periaqueductal gray and superior colliculus (Brandão et al., 1999). Local injection of neuromodulators or their specific receptor agonists or antagonists into the IC can modify these defensive behaviors. Zimelidine, a serotonin reuptake inhibitor, reduces the number and increases the latency of conditioned aversive behaviors when it is injected into the IC (Brandão et al., 1993; Melo and Brandão 1995). Injection of 5-HT1A or 5-HT2A agonists have similar effects, consistent with the prevalence of each of these receptor types in the IC (Melo & Brandão, 1995; Peruzzi & Dut, 2004; Smith et al., 2014; Thompson et al., 1994; Wang et al., 2008). Injection of sulpiride, a D2 dopaminergic receptor antagonist, into the IC increases avoidance of open arms in the elevated plus maze as well as the amplitude of the auditory evoked potential recorded locally in the IC (de Oliveira et al., 2014). Thus, multiple neuromodulatory systems dampen aversive behavioral responses to stimulation of the IC.
Neuromodulatory regulation of prepulse inhibition
Auditory prepulse inhibition is another phenomenon in which the IC plays an important role (Gomez-Nieto et al., 2008; Li & Yue, 2002; Yeomans et al., 2006). The startle response to an acoustic stimulus can be reduced by a non-startling transient prepulse or by electrical stimulation of the IC, and is also disrupted by lesion of the IC (Leitner & Cohen, 1985; Li et al., 1998a; Li et al., 1998b). This suppression may protect the response to the initial sound (prepulse), and involves specific subcortical circuitry in which the IC contributes information about the prepulse (Carlson & Willott, 1998; Fendt et al., 2001; Leitner & Cohen, 1985; Li & Yue, 2002). Cholinergic pathways originating in the pontomesencephalic tegmentum are also important to this circuit (Fendt et al., 2001; Koch et al., 1993). Consistent with this model, local effects of neuromodulators in the IC alter prepulse inhibition. Unilateral injection of 2,5-Dimethoxy-4-iodoamphetamine, an agonist of 5-HT2 receptors, reduces prepulse inhibition but does not affect the amplitude of the acoustic startle response itself (de Oliveira et al., 2017). The injection of D2 agonists into the IC induces similar effects (Satake et al., 2012).
All together, these findings show that in addition to being a site for the modulation of ascending auditory information, the IC is involved in subcortical circuitry that modifies responses to potentially threatening stimuli. Multiple types of neuromodulators can influence these defensive behaviors through local effects within the IC.
Do Neuromodulatory Systems Really Provide Feedback to Auditory Circuits?
The previous sections illustrate that auditory and modulatory regions are anatomically interconnected. Despite this evidence, it would not be an accurate reflection of a broad body of literature to say that neuromodulatory systems simply channel instructive feedback to the auditory system. One reason for this is that modulatory systems are both downstream and upstream of integrative brain regions such as the prefrontal cortex, amygdala, hypothalamic nuclei, or bed nucleus of the stria terminalis (Benarroch, 2013; Lee et al., 2003; Luppi et al., 1995; Mena-Segovia & Bolam, 2017; Parent et al., 1981; Pollak Dorocic et al., 2014; Retson & Van Bockstaele, 2013). Modulatory systems may therefore play an important role in establishing, as well as distributing, information regarding stimulus salience.
A second way that neuromodulatory systems violate a linear model of auditory feedback circuitry is illustrated by a widely expressed anatomical feature of modulatory neurons: they often send collateral projections to divergent targets. These collaterals can potentially couple modulatory signals in different auditory regions. Dopaminergic neurons in the subparafascicular nucleus, cholinergic neurons in the pedunculopontine tegmental nucleus, and noradrenergic neurons in the locus coeruleus all send collaterals to multiple auditory targets (Klepper & Herbert, 1991; Nevue et al., 2016b; Schofield et al., 2011). As might be expected from this pattern of projections, the effects of neuromodulators at different levels interact. For example, acetylcholine applied locally to the IC influences auditory cortical plasticity, and vice versa (Ma & Suga, 2005). Many collaterals of modulatory neurons are even more divergently projecting, targeting not only sensory regions, but non-sensory regions too (e.g., Lee et al., 2009; Villar et al., 1988). This pattern could result in neuromodulatory release under the same conditions in functionally divergent brain regions. As an example, serotonin levels in both the IC and the preoptic area increase when male rodents interact with females, and depend on the females being sexually available (Fumero et al., 1994; Keesom & Hurley, 2016; Mas et al., 1995). Neuromodulatory systems are therefore capable of broadly coordinating neural activity across sensory, motor, and motivational systems.
Interactions among the IC, amygdala, and modulatory systems
The functional entanglement that arises from these types of interactions is highlighted by a series of studies illustrating the modulatory control of unconditioned aversive behavior evoked by stimulation of the IC. As described earlier, electrical stimulation of the IC evokes aversive behavior, and local injection of serotonergic and dopaminergic agents into the IC dampen some of these aversive behavioral responses. The amygdala is another site that regulates aversive behaviors and that interacts with the IC, in which neuromodulators influence behavioral output. Lesion of the central amygdala increases aversive thresholds to stimulation of the IC but lesion of the basolateral amygdala decreases them (Maisonnette et al., 1996). This finding is consistent with a model of the amygdala as downstream of the IC in the regulation of aversive behaviors. Modulatory nuclei may also act as functional intermediaries between the IC and amygdala, in that stimulation of the IC causes increased release of serotonin and dopamine within the basolateral amygdala, although less in the central amygdala (Macedo et al., 2005). The actions of serotonin and dopamine in the amygdala exert complex effects on defensive behavior. The local injection of serotonergic and dopaminergic antagonists within the basolateral amygdala dampens conditioned place aversion but enhances unconditioned aversion in response to chemical stimulation of the IC (Macedo et al., 2007). Likewise, selective neurochemical lesion of serotonergic fibers in the central amygdala increases thresholds for alertness, freezing, and escape behavior caused by IC stimulation, while neurochemical lesion within the basolateral complex decreases thresholds for these behaviors (Macedo et al., 2002). Finally, anatomical pathways from the amygdala to the IC suggest an additional route for direct amygdalo-collicular feedback (Marsh et al., 2002). Functionally, manipulation of inhibitory neurotransmission in the amygdala alters the amplitude of locally measured auditory evoked potentials in the IC (Nobre & Brandão, 2011). Arising from these somewhat complicated results is an important general point. It is not simply the case that the auditory system and neuromodulatory systems mutually influence each another, a point made at length in this chapter. Rather, recursive connections among auditory, interpretive, and modulatory systems all interact to regulate behavior (Figure 4)
Conclusion: Neuromodulators Are a Substrate for Auditory and Nonauditory IntegrationUnderstanding the actions of neuromodulatory pathways in the auditory system requires thinking about the auditory system from its earliest levels as anatomically and functionally interwoven with non-auditory regions of the brain. Neuromodulatory systems channel integrative information to the auditory system, providing the potential for auditory circuits to adjust their activity to conform to salient events, internal state, or experience. Auditory neuromodulation influences behavioral responses to sound, but the importance of modulatory pathways to behavior depends on the circuitry underlying specific behavioral tasks, the functional connectivity between modulatory subgroups and auditory regions, and the behavioral context. A circuit-based approach will therefore be crucial to better understanding auditory neuromodulation and the roles that modulatory processes play in perception and behavior.
The extensive interactions between auditory and modulatory regions also potentially give auditory neurons the power to mediate the transformation between external events and internal representations such as valence or salience (Petersen & Hurley, 2017). In part through the influence of modulatory systems, auditory neurons may be active participants in extracting information relevant to specific contexts, states, or histories of individuals, and consequently have a profound influence on behavioral output. Ultimately, mutual influence by auditory and interpretive systems may optimally shape behavior to best match the dynamics of an animal’s internal and external environments.
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