Bats possess the anatomical substrate for a laryngeal motor cortex.

Cortical neurons that make direct connections to motor neurons in the brainstem and spinal cord are specialized for fine motor control and learning [1, 2]. Imitative vocal learning, the basis for human speech, requires the precise control of the larynx muscles [3]. While much knowledge on vocal learning systems has been gained from studying songbirds [4], an accessible laboratory model for mammalian vocal learning is highly desirable. Evidence indicative of complex vocal repertoires and dialects suggests that bats are vocal learners [5, 6], however the circuitry that underlies vocal control and learning in bats is largely unknown. A key feature of vocal learning animals is a direct cortical projection to the brainstem motor neurons that innervate the vocal organ [7]. A recent study [8] described a direct connection from the primary motor cortex to medullary nucleus ambiguus in the Egyptian fruit bat (Rousettus aegyptiacus). Here we show that a distantly related bat, Seba's short-tailed bat (Carollia perspicillata) also possesses a direct projection from the primary motor cortex to nucleus ambiguus. Our results, in combination with Wirthlin et al. [8], suggest that multiple bat lineages possess the anatomical substrate for cortical control of vocal output. We propose that bats would be an informative mammalian model for vocal learning studies to better understand the genetics and circuitry involved in human vocal communication.

On the value of diverse organisms in auditory research: From fish to flies to humans.

Historically, diverse organisms have contributed to our understanding of auditory function. In recent years, the laboratory mouse has become the prevailing non-human model in auditory research, particularly for biomedical studies. There are many questions in auditory research for which the mouse is the most appropriate (or the only) model system available. But mice cannot provide answers for all auditory problems of basic and applied importance, nor can any single model system provide a synthetic understanding of the diverse solutions that have evolved to facilitate effective detection and use of acoustic information. In this review, spurred by trends in funding and publishing and inspired by parallel observations in other domains of neuroscience, we highlight a few examples of the profound impact and lasting benefits of comparative and basic organismal research in the auditory system. We begin with the serendipitous discovery of hair cell regeneration in non-mammalian vertebrates, a finding that has fueled an ongoing search for pathways to hearing restoration in humans. We then turn to the problem of sound source localization - a fundamental task that most auditory systems have been compelled to solve despite large variation in the magnitudes and kinds of spatial acoustic cues available, begetting varied direction-detecting mechanisms. Finally, we consider the power of work in highly specialized organisms to reveal exceptional solutions to sensory problems - and the diverse returns of deep neuroethological inquiry - via the example of echolocating bats. Throughout, we consider how discoveries made possible by comparative and curiosity-driven organismal research have driven fundamental scientific, biomedical, and technological advances in the auditory field.

Distribution and co-expression of adrenergic receptor-encoding mRNA in the mouse inferior colliculus.

Adrenergic receptors are mediators of adrenergic and noradrenergic modulation throughout the brain. Previous studies have provided evidence for the expression of adrenergic receptors in the midbrain auditory nucleus, the inferior colliculus (IC), but have not examined the cellular patterns of expression in detail. Here, we utilize multichannel fluorescent in situ hybridization to detect the expression of adrenergic receptor-encoding mRNA in the inferior colliculus of male and female mice. We found expression of α1 , α2A , and ß2 receptor-encoding mRNA throughout all areas of the IC. While we observed similar levels of expression of α1 receptor-encoding mRNA across the subregions of the IC, α2A and ß2 receptor-encoding mRNA was expressed differentially. To account for developmental changes in noradrenergic receptor expression, we measured expression levels in mice aged P15, P20, and P60. We observed little change in levels of expression across these ages. To ascertain the modulatory potential of multiple adrenergic receptor subtypes in a single IC cell, we measured co-expression of α1 , α2A , and ß2 receptor-encoding mRNA. We found greater proportions of cells in the IC that expressed no adrenergic receptor-encoding mRNA, α1 and α2A adrenergic receptor-encoding mRNA, and α1, α2A, and ß2 receptor-encoding mRNA than would be predicted by independent expression of each receptor subtype. These data suggest a coordinated pattern of adrenergic receptor expression in the IC and provide the first evidence for adrenergic receptor expression and co-expression in the subregions of the mouse auditory midbrain.

GABAA receptors contribute more to rate than temporal coding in the IC of awake mice.

Speech is our most important form of communication, yet we have a poor understanding of how communication sounds are processed by the brain. Mice make great model organisms to study neural processing of communication sounds because of their rich repertoire of social vocalizations and because they have brain structures analogous to humans, such as the auditory midbrain nucleus inferior colliculus (IC). Although the combined roles of GABAergic and glycinergic inhibition on vocalization selectivity in the IC have been studied to a limited degree, the discrete contributions of GABAergic inhibition have only rarely been examined. In this study, we examined how GABAergic inhibition contributes to shaping responses to pure tones as well as selectivity to complex sounds in the IC of awake mice. In our set of long-latency neurons, we found that GABAergic inhibition extends the evoked firing rate range of IC neurons by lowering the baseline firing rate but maintaining the highest probability of firing rate. GABAergic inhibition also prevented IC neurons from bursting in a spontaneous state. Finally, we found that although GABAergic inhibition shaped the spectrotemporal response to vocalizations in a nonlinear fashion, it did not affect the neural code needed to discriminate vocalizations, based either on spiking patterns or on firing rate. Overall, our results emphasize that even if GABAergic inhibition generally decreases the firing rate, it does so while maintaining or extending the abilities of neurons in the IC to code the wide variety of sounds that mammals are exposed to in their daily lives.NEW & NOTEWORTHY GABAergic inhibition adds nonlinearity to neuronal response curves. This increases the neuronal range of evoked firing rate by reducing baseline firing. GABAergic inhibition prevents bursting responses from neurons in a spontaneous state, reducing noise in the temporal coding of the neuron. This could result in improved signal transmission to the cortex.

Dopamine Acts via D2-Like Receptors to Modulate Auditory Responses in the Inferior Colliculus.

The ability to understand speech relies on accurate auditory processing of complex sounds. Individuals with Parkinson's disease suffer from speech perception deficits, suggesting that dopamine is involved in the encoding of complex sounds. Recent studies have demonstrated that dopamine has heterogeneous effects on the responses of many neurons in the inferior colliculus (IC) of mice, although the strongest effect is to suppress neural activity. However, it was previously unknown which dopamine receptors are involved in modulating neuronal responses, and whether the observed preponderance of depressive effects reflects the endogenous dopamine system in the IC. In this study, we tested whether dopamine acts via D1- and/or D2-like receptors to alter responses of IC neurons in female and male mice. We also tested the effect of optogenetically induced dopamine release on auditory responses in the IC. We found that the effects of dopamine in the IC occur via D2-like receptors. In iontophoretic and freely behaving experiments, the single-unit and multi-unit effects of dopamine and a D2-like agonist were heterogeneous as both either increased or decreased responses of IC neurons to tones, while a D2-like antagonist had opposite effects. We also found that optogenetic activation of the endogenous dopamine system in the IC alters responses of auditory neurons. Similar to the effects of exogenous dopamine application, optogenetic induction of endogenous dopamine release heterogeneously altered auditory responses in the majority of cells in mice expressing channelrhodopsin-2 (ChR2). Understanding how dopamine modulates auditory processing will ultimately inform therapies targeting mechanisms underlying auditory-related communication disorders.

Nicotinic acetylcholine receptor subunit α7-knockout mice exhibit degraded auditory temporal processing.

The CHRNA7 gene that encodes the α7-subunit of the nicotinic acetylcholine receptor (α7-nAChR) has been associated with some autism spectrum disorders and other neurodevelopmental conditions characterized, in part, by auditory and language impairment. These conditions may include auditory processing disorders that represent impaired timing of neural activity, often accompanied by problems understanding speech. Here, we measure timing properties of sound-evoked activity via the auditory brainstem response (ABR) of α7-nAChR knockout mice of both sexes and wild-type colony controls. We find a significant timing delay in evoked ABR signals that represents midbrain activity in knockouts. We also examine spike-timing properties of neurons in the inferior colliculus, a midbrain nucleus that exhibits high levels of α7-nAChR during development. We find delays of evoked responses along with degraded spiking precision in knockout animals. We find similar timing deficits in responses of neurons in the superior paraolivary nucleus and ventral nucleus of the lateral lemniscus, which are brainstem nuclei thought to shape temporal precision in the midbrain. In addition, we find that other measures of temporal acuity including forward masking and gap detection are impaired for knockout animals. We conclude that altered temporal processing at the level of the brainstem in α7-nAChR-deficient mice may contribute to degraded spike timing in the midbrain, which may underlie the observed timing delay in the ABR signals. Our findings are consistent with a role for the α7-nAChR in types of neurodevelopmental and auditory processing disorders and we identify potential neural targets for intervention.NEW & NOTEWORTHY Disrupted signaling via the α7-nicotinic acetylcholine receptor (α7-nAChR) is associated with neurodevelopmental disorders that include impaired auditory processing. The underlying causes of dysfunction are not known but a common feature is abnormal timing of neural activity. We examined temporal processing of α7-nAChR knockout mice and wild-type controls. We found degraded spike timing of neurons in knockout animals, which manifests at the level of the auditory brainstem and midbrain.

Black Jacobin hummingbirds vocalize above the known hearing range of birds.

Hummingbirds are a fascinating group of birds, but some aspects of their biology are poorly understood, such as their highly diverse vocal behaviors. We show here that the predominant vocalization of black jacobins (Florisuga fusca), a hummingbird prevalent in the mountains of the Brazilian Atlantic Forest, consists of a triplet of syllables with high fundamental frequency (mean F0 ∼11.8 kHz), rapid frequency oscillations and strong ultrasonic harmonics and no detectable elements below ∼10 kHz. These are the most common vocalizations of these birds, and their frequency range is above the known hearing range of any bird species recorded to date, including hearing specialists such as owls. These observations suggest that black jacobins either have an atypically high frequency hearing range, or alternatively their primary vocalization has a yet unknown function unrelated to vocal communication. Black jacobin vocalizations challenge current notions about vocal communication in birds.

Subcortical pathways: Towards a better understanding of auditory disorders.

Hearing loss is a significant problem that affects at least 15% of the population. This percentage, however, is likely significantly higher because of a variety of auditory disorders that are not identifiable through traditional tests of peripheral hearing ability. In these disorders, individuals have difficulty understanding speech, particularly in noisy environments, even though the sounds are loud enough to hear. The underlying mechanisms leading to such deficits are not well understood. To enable the development of suitable treatments to alleviate or prevent such disorders, the affected processing pathways must be identified. Historically, mechanisms underlying speech processing have been thought to be a property of the auditory cortex and thus the study of auditory disorders has largely focused on cortical impairments and/or cognitive processes. As we review here, however, there is strong evidence to suggest that, in fact, deficits in subcortical pathways play a significant role in auditory disorders. In this review, we highlight the role of the auditory brainstem and midbrain in processing complex sounds and discuss how deficits in these regions may contribute to auditory dysfunction. We discuss current research with animal models of human hearing and then consider human studies that implicate impairments in subcortical processing that may contribute to auditory disorders.

Adaptive sequence convergence of the tumor suppressor ADAMTS9 between small-bodied mammals displaying exceptional longevity.

Maximum lifespan varies by two orders of magnitude across mammals. How such divergent lifespans have evolved remains an open question, with ramifications that may potentially lead to therapies for age-related diseases in humans. Several species of microbats as well as the naked mole-rat live much longer than expected given their small sizes, show reduced susceptibility to neoplasia, and largely remain healthy and reproductively capable throughout the majority of their extended lifespans. The convergent evolution of extreme longevity in these two groups allows for the opportunity to identify potentially important aging related genes that have undergone adaptive sequence convergence in these long-lived, yet small-bodied species. Here, we have tested 4,628 genes for evidence of convergence between the microbats and naked mole-rat. We find a strong signal of adaptive sequence convergence in the gene A disintegrin-like and metalloprotease with thrombospondin type 1 motifs 9 (ADAMTS9). We also provide evidence that the shared substitutions were driven by selection. Intriguingly, ADAMTS9 is a known inhibitor of the mTor pathway and has been implicated in several aging related processes.

Serotonin modulates response properties of neurons in the dorsal cochlear nucleus of the mouse.

The neurochemical serotonin (5-hydroxytryptamine, 5-HT) is involved in a variety of behavioral functions including arousal, reward, and attention, and has a role in several complex disorders of the brain. In the auditory system, 5-HT fibers innervate a number of subcortical nuclei, yet the modulatory role of 5-HT in nearly all of these areas remains poorly understood. In this study, we examined spiking activity of neurons in the dorsal cochlear nucleus (DCN) following iontophoretic application of 5-HT. The DCN is an early site in the auditory pathway that receives dense 5-HT fiber input from the raphe nuclei and has been implicated in the generation of auditory disorders marked by neuronal hyperexcitability. Recordings from the DCN in awake mice demonstrated that iontophoretic application of 5-HT had heterogeneous effects on spiking rate, spike timing, and evoked spiking threshold. We found that 56% of neurons exhibited increases in spiking rate during 5-HT delivery, while 22% had decreases in rate and the remaining neurons had no change. These changes were similar for spontaneous and evoked spiking and were typically accompanied by changes in spike timing. Spiking increases were associated with lower first spike latencies and jitter, while decreases in spiking generally had opposing effects on spike timing. Cases in which 5-HT application resulted in increased spiking also exhibited lower thresholds compared to the control condition, while cases of decreased spiking had no threshold change. We also found that the 5-HT2 receptor subtype likely has a role in mediating increased excitability. Our results demonstrate that 5-HT can modulate activity in the DCN of awake animals and that it primarily acts to increase neuronal excitability, in contrast to other auditory regions where it largely has a suppressive role. Modulation of DCN function by 5-HT has implications for auditory processing in both normal hearing and disordered states.

Contrasting patterns of adaptive sequence convergence among echolocating mammals.

Several recent studies have described genes demonstrating adaptive sequence convergence between echolocating bats and dolphin, suggesting that common selective pressures can induce common molecular changes, even in distantly related species. However, in the case of the auditory genes Otoferlin (Otof), Cadherin 23 (Cdh23) and Protocadherin 15 (Pcdh15), the reported sequence convergence was supported only by incongruent gene and species trees and counts of convergent substitutions. Therefore, it remains unclear whether echolocating bats and dolphin really do demonstrate evidence of adaptive sequence convergence, or whether there is simply a high level of random background convergence in these genes. To address this question, we estimated the number of convergent and divergent amino acid substitutions along all independent branches of a sufficiently deep phylogeny containing between 22 and 32 mammals for each gene, and compared convergence between the two proposed suborders of bat, Yangochiroptera and Yinpterochiroptera, and dolphin. We find no support for convergence between bats and dolphin in the gene Pcdh15. For the gene Otof we report minimal evidence for convergent evolution only between the Yinpterochiroptera and dolphin. Cdh23 displayed a high level of convergence between dolphin and the Yinpterochiroptera. In addition, dolphin and certain members of the Yangochiroptera that emit high frequency echolocation calls shared several unique convergent substitutions. These results indicate that the convergent evolution of Cdh23 was likely driven by selection for hearing above a certain frequency threshold. Moreover, the contrasting patterns of convergence between the two bat suborders and dolphin in all auditory genes studied thus far suggest echolocation may have evolved independently in the Yinpterochiroptera and Yangochiroptera.

Dopaminergic projections of the subparafascicular thalamic nucleus to the auditory brainstem.

Neuromodulators can alter the response properties of sensory neurons, including those in the auditory system. Dopamine, which plays a major role in reward and movement, has been shown to alter neural responses in the auditory brainstem and midbrain. Recently we identified the subparafascicular thalamic nucleus (SPF), part of the A11 dopaminergic cell group, as the source of dopamine to the inferior colliculus (IC). The superior olivary complex (SOC) is also a likely target of dopaminergic projections from the SPF because it receives projections from the SPF and contains fibers and terminals immunoreactive for tyrosine hydroxylase, the rate limiting enzyme in dopamine synthesis. However, it is unknown if the projections from the SPF to SOC are dopaminergic, and if single neurons in the SPF project to both the IC and SOC. Using anterograde tracing combined with fluorescent immunohistochemistry, we found that the SPF sends dopaminergic projections to the superior paraolivary nucleus and the medial nucleus of the trapezoid body, but not the lateral superior olive. We confirmed these projections using a retrograde tracer. By making dual retrograde deposits in the IC and SOC, we found that individual dopaminergic cells innervate both the IC and SOC. These results suggest dopaminergic innervation, likely released in a context dependent manner, occurs at multiple levels of the auditory pathway.

16p11.2 Deletion Syndrome Mice Display Sensory and Ultrasonic Vocalization Deficits During Social Interactions.

Recurrent deletions and duplications at chromosomal region 16p11.2 are variably associated with speech delay, autism spectrum disorder, developmental delay, schizophrenia, and cognitive impairments. Social communication deficits are a primary diagnostic symptom of autism. Here we investigated ultrasonic vocalizations (USVs) in young adult male 16p11.2 deletion mice during a novel three-phase male-female social interaction test that detects vocalizations emitted by a male in the presence of an estrous female, how the male changes its calling when the female is suddenly absent, and the extent to which calls resume when the female returns. Strikingly fewer vocalizations were detected in two independent cohorts of 16p11.2 heterozygous deletion males (+/-) during the first exposure to an unfamiliar estrous female, as compared to wildtype littermates (+/+). When the female was removed, +/+ emitted calls, but at a much lower level, whereas +/- males called minimally. Sensory and motor abnormalities were detected in +/-, including higher nociceptive thresholds, a complete absence of acoustic startle responses, and hearing loss in all +/- as confirmed by lack of auditory brainstem responses to frequencies between 8 and 100 kHz. Stereotyped circling and backflipping appeared in a small percentage of individuals, as previously reported. However, these sensory and motor phenotypes could not directly explain the low vocalizations in 16p11.2 deletion mice, since (a) +/- males displayed normal abilities to emit vocalizations when the female was subsequently reintroduced, and (b) +/- vocalized less than +/+ to social odor cues delivered on an inanimate cotton swab. Our findings support the concept that mouse USVs in social settings represent a response to social cues, and that 16p11.2 deletion mice are deficient in their initial USVs responses to novel social cues.

Responses to Social Vocalizations in the Dorsal Cochlear Nucleus of Mice.

Identifying sounds is critical for an animal to make appropriate behavioral responses to environmental stimuli, including vocalizations from conspecifics. Identification of vocalizations may be supported by neuronal selectivity in the auditory pathway. The first place in the ascending auditory pathway where neuronal selectivity to vocalizations has been found is in the inferior colliculus (IC), but very few brainstem nuclei have been evaluated. Here, we tested whether selectivity to vocalizations is present in the dorsal cochlear nucleus (DCN). We recorded extracellular neural responses in the DCN of mice and found that fusiform cells responded in a heterogeneous and selective manner to mouse ultrasonic vocalizations. Most fusiform cells responded to vocalizations that contained spectral energy at much higher frequencies than the characteristic frequencies of the cells. To understand this mismatch of stimulus properties and frequency tuning of the cells, we developed a dynamic, nonlinear model of the cochlea that simulates cochlear distortion products on the basilar membrane. We preprocessed the vocalization stimuli through this model and compared responses to these distorted vocalizations with responses to the original vocalizations. We found that fusiform cells in the DCN respond in a heterogeneous manner to vocalizations, and that these neurons can use distortion products as a mechanism for encoding ultrasonic vocalizations. In addition, the selective neuronal responses were dependent on the presence of inhibitory sidebands that modulated the response depending on the temporal structure of the distortion product. These findings suggest that important processing of complex sounds occurs at a very early stage of central auditory processing and is not strictly a function of the cortex.

Dopaminergic Input to the Inferior Colliculus in Mice.

The response of sensory neurons to stimuli can be modulated by a variety of factors including attention, emotion, behavioral context, and disorders involving neuromodulatory systems. For example, patients with Parkinson's disease (PD) have disordered speech processing, suggesting that dopamine alters normal representation of these salient sounds. Understanding the mechanisms by which dopamine modulates auditory processing is thus an important goal. The principal auditory midbrain nucleus, the inferior colliculus (IC), is a likely location for dopaminergic modulation of auditory processing because it contains dopamine receptors and nerve terminals immunoreactive for tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis. However, the sources of dopaminergic input to the IC are unknown. In this study, we iontophoretically injected a retrograde tracer into the IC of mice and then stained the tissue for TH. We also immunostained for dopamine beta-hydroxylase (DBH), an enzyme critical for the conversion of dopamine to norepinephrine, to differentiate between dopaminergic and noradrenergic inputs. Retrogradely labeled neurons that were positive for TH were seen bilaterally, with strong ipsilateral dominance, in the subparafascicular thalamic nucleus (SPF). All retrogradely labeled neurons that we observed in other brain regions were TH-negative. Projections from the SPF were confirmed using an anterograde tracer, revealing TH-positive and DBH-negative anterogradely labeled fibers and terminals in the IC. While the functional role of this dopaminergic input to the IC is not yet known, it provides a potential mechanism for context dependent modulation of auditory processing.

The role of ultrasonic vocalizations in mouse communication.

Human speech and language underlie many aspects of social behavior and thus understanding their ultimate evolutionary function and proximate genetic and neural mechanisms is a fundamental goal in neuroscience. Mouse ultrasonic vocalizations have recently received enormous attention as possible models for human speech. This attention has raised the question of whether these vocalizations are learned and what roles they play in communication. In this review, we first discuss recent evidence that ultrasonic vocalizations are not learned. We then review current evidence addressing how adult vocalizations may communicate courtship, territorial and/or other information. While there is growing evidence that these signals play key roles in communication, many important questions remain unanswered.

Inhibition does not affect the timing code for vocalizations in the mouse auditory midbrain.

Many animals use a diverse repertoire of complex acoustic signals to convey different types of information to other animals. The information in each vocalization therefore must be coded by neurons in the auditory system. One way in which the auditory system may discriminate among different vocalizations is by having highly selective neurons, where only one or two different vocalizations evoke a strong response from a single neuron. Another strategy is to have specific spike timing patterns for particular vocalizations such that each neural response can be matched to a specific vocalization. Both of these strategies seem to occur in the auditory midbrain of mice. The neural mechanisms underlying rate and time coding are unclear, however, it is likely that inhibition plays a role. Here, we examined whether inhibition is involved in shaping neural selectivity to vocalizations via rate and/or time coding in the mouse inferior colliculus (IC). We examined extracellular single unit responses to vocalizations before and after iontophoretically blocking GABAA and glycine receptors in the IC of awake mice. We then applied a number of neurometrics to examine the rate and timing information of individual neurons. We initially evaluated the neuronal responses using inspection of the raster plots, spike-counting measures of response rate and stimulus preference, and a measure of maximum available stimulus-response mutual information. Subsequently, we used two different event sequence distance measures, one based on vector space embedding, and one derived from the Victor/Purpura D q metric, to direct hierarchical clustering of responses. In general, we found that the most salient feature of pharmacologically blocking inhibitory receptors in the IC was the lack of major effects on the functional properties of IC neurons. Blocking inhibition did increase response rate to vocalizations, as expected. However, it did not significantly affect spike timing, or stimulus selectivity of the studied neurons. We observed two main effects when inhibition was locally blocked: (1) Highly selective neurons maintained their selectivity and the information about the stimuli did not change, but response rate increased slightly. (2) Neurons that responded to multiple vocalizations in the control condition, also responded to the same stimuli in the test condition, with similar timing and pattern, but with a greater number of spikes. For some neurons the information rate generally increased, but the information per spike decreased. In many of these neurons, vocalizations that generated no responses in the control condition generated some response in the test condition. Overall, we found that inhibition in the IC does not play a substantial role in creating the distinguishable and reliable neuronal temporal spike patterns in response to different vocalizations.

Discrimination of ultrasonic vocalizations by CBA/CaJ mice (Mus musculus) is related to spectrotemporal dissimilarity of vocalizations.

The function of ultrasonic vocalizations (USVs) produced by mice (Mus musculus) is a topic of broad interest to many researchers. These USVs differ widely in spectrotemporal characteristics, suggesting different categories of vocalizations, although this has never been behaviorally demonstrated. Although electrophysiological studies indicate that neurons can discriminate among vocalizations at the level of the auditory midbrain, perceptual acuity for vocalizations has yet to be determined. Here, we trained CBA/CaJ mice using operant conditioning to discriminate between different vocalizations and between a spectrotemporally modified vocalization and its original version. Mice were able to discriminate between vocalization types and between manipulated vocalizations, with performance negatively correlating with spectrotemporal similarity. That is, discrimination performance was higher for dissimilar vocalizations and much lower for similar vocalizations. The behavioral data match previous neurophysiological results in the inferior colliculus (IC), using the same stimuli. These findings suggest that the different vocalizations could carry different meanings for the mice. Furthermore, the finding that behavioral discrimination matched neural discrimination in the IC suggests that the IC plays an important role in the perceptual discrimination of vocalizations.

Dopamine modulates auditory responses in the inferior colliculus in a heterogeneous manner.

Perception of complex sounds such as speech is affected by a variety of factors, including attention, expectation of reward, physiological state, and/or disorders, yet the mechanisms underlying this modulation are not well understood. Although dopamine is commonly studied for its role in reward-based learning and in disorders, multiple lines of evidence suggest that dopamine is also involved in modulating auditory processing. In this study, we examined the effects of dopamine application on neuronal response properties in the inferior colliculus (IC) of awake mice. Because the IC contains dopamine receptors and nerve terminals immunoreactive for tyrosine hydroxylase, we predicted that dopamine would modulate auditory responses in the IC. We recorded single-unit responses before, during, and after the iontophoretic application of dopamine using piggyback electrodes. We examined the effects of dopamine on firing rate, timing, and probability of bursting. We found that application of dopamine affected neural responses in a heterogeneous manner. In more than 80 % of the neurons, dopamine either increased (32 %) or decreased (50 %) firing rate, and the effects were similar on spontaneous and sound-evoked activity. Dopamine also either increased or decreased first spike latency and jitter in almost half of the neurons. In 3/28 neurons (11 %), dopamine significantly altered the probability of bursting. The heterogeneous effects of dopamine observed in the IC of awake mice were similar to effects observed in other brain areas. Our findings indicate that dopamine differentially modulates neural activity in the IC and thus may play an important role in auditory processing.