Granule Cell Domain Research Articles

Descending Axonal Projections from the Inferior Colliculus Target Nearly All Excitatory and Inhibitory Cell Types of the Dorsal Cochlear Nucleus.

The dorsal cochlear nucleus (DCN) integrates auditory nerve input with nonauditory sensory signals and is proposed to function in sound source localization and suppression of self-generated sounds. The DCN also integrates activity from descending auditory pathways, including a particularly large feedback projection from the inferior colliculus (IC), the main ascending target of the DCN. Understanding how these descending feedback signals are integrated into the DCN circuit and what role they play in hearing requires knowing the targeted DCN cell types and their postsynaptic responses. In order to explore these questions, neurons in the DCN that received descending synaptic input from the IC were labeled with a trans-synaptic viral approach in male and female mice, which allowed them to be targeted for whole-cell recording in acute brain slices. We tested their synaptic responses to optogenetic activation of the descending IC projection. Every cell type in the granule cell domain received monosynaptic, glutamatergic input from the IC, indicating that this region, considered an integrator of nonauditory sensory inputs, processes auditory input as well and may have complex and underappreciated roles in hearing. Additionally, we found that DCN cell types outside the granule cell regions also receive descending IC signals, including the principal projection neurons, as well as the neurons that inhibit them, leading to a circuit that may sharpen tuning through feedback excitation and lateral inhibition.SIGNIFICANCE STATEMENT Auditory processing starts in the cochlea and ascends through the dorsal cochlear nucleus (DCN) to the inferior colliculus (IC) and beyond. Here, we investigated the feedback projection from IC to DCN, whose synaptic targets and roles in auditory processing are unclear. We found that all cell types in the granule cell regions, which process multisensory feedback, also process this descending auditory feedback. Surprisingly, all except one cell type in the entire DCN receive IC input. The IC-DCN projection may therefore modulate the multisensory pathway as well as sharpen tuning and gate auditory signals that are sent to downstream areas. This excitatory feedback loop from DCN to IC and back to DCN could underlie hyperexcitability in DCN, widely considered an etiology of tinnitus.

Morphological and molecular correlates of altered hearing sensitivity in the genetically audiogenic seizure-prone hamster GASH/Sal

Rodent models of audiogenic seizures, in which seizures are precipitated by an abnormal response of the brain to auditory stimuli, are crucial to investigate the neural bases underlying ictogenesis. Despite significant advances in understanding seizure generation in the inferior colliculus, namely the epileptogenic nucleus, little is known about the contribution of lower auditory stations to the seizure-prone network. Here, we examined the cochlea and cochlear nucleus of the genetic audiogenic seizure hamster from Salamanca (GASH/Sal), a model of reflex epilepsy that exhibits generalized tonic–clonic seizures in response to loud sound. GASH/Sal animals under seizure-free conditions were compared with matched control hamsters in a multi-technical approach that includes auditory brainstem responses (ABR) testing, histology, scanning electron microscopy analysis, immunohistochemistry, quantitative morphometry and gene expression analysis (RT-qPCR). The cochlear histopathology of the GASH/Sal showed preservation of the sensory hair cells, but a significant loss of spiral ganglion neurons and mild atrophy of the stria vascularis. At the electron microscopy level, the reticular lamina exhibited disarray of stereociliary tufts with blebs, loss or elongated stereocilia as well as non-parallel rows of outer hair cells due to protrusions of Deiters’ cells. At the molecular level, the abnormal gene expression patterns of prestin, cadherin 23, protocadherin 15, vesicular glutamate transporters 1 (Vglut1) and -2 (Vglut2) indicated that the hair-cell mechanotransduction and cochlear amplification were markedly altered. These were manifestations of a cochlear neuropathy that correlated to ABR waveform I alterations and elevated auditory thresholds. In the cochlear nucleus, the distribution of VGLUT2-immunolabeled puncta was differently affected in each subdivision, showing significant increases in magnocellular regions of the ventral cochlear nucleus and drastic reductions in the granule cell domain. This modified inputs lead to disruption of Vglut1 and Vglut2 gene expression in the cochlear nucleus. In sum, our study provides insight into the morphological and molecular traits associated with audiogenic seizure susceptibility in the GASH/Sal, suggesting an upward spread of abnormal glutamatergic transmission throughout the primary acoustic pathway to the epileptogenic region.

Glutamatergic Projections to the Cochlear Nucleus are Redistributed in Tinnitus

Tinnitus alters auditory–somatosensory plasticity in the cochlear nucleus (CN). Correspondingly, bimodal auditory–somatosensory stimulation treatment attenuates tinnitus, both in animals and humans (Marks et al., 2018). Therefore, we hypothesized that tinnitus is associated with altered somatosensory innervation of the CN. Here, we studied the expression of vesicular glutamate transporters 1 and 2 (VGLUT1 and VGLUT2) in the CN, which reveals glutamatergic projections from the cochlea as well as somatosensory systems to this brainstem auditory center.Guinea pigs were unilaterally exposed to narrowband noise and behaviorally tested for tinnitus using gap-prepulse inhibition of the acoustic startle. Following physiological and behavioral measures, brain sections were immunohistochemically stained for VGLUT1 or VGLUT2. Puncta density was determined for each region of the ipsilateral and contralateral CN.Tinnitus was associated with an ipsilateral upregulation of VGLUT2 puncta density in the granule cell domain (GCD) and anteroventral CN (AVCN). Furthermore, there was a tinnitus-associated interaural asymmetry for VGLUT1 expression in the AVCN and deep layer of the dorsal CN (DCN3), due to contralateral downregulation of VGLUT1 expression. These tinnitus-related glutamatergic imbalances were reversed upon bimodal stimulation treatment.Tinnitus-associated ipsilateral upregulation of VGLUT2-positive projections likely derives from somatosensory projections to the GCD and AVCN. This upregulation may underlie the neurophysiological hallmarks of tinnitus in the CN. Reversing the increased ipsilateral glutamatergic innervation in the CN is likely a key mechanism in treating tinnitus.

All the way from the cortex: a review of auditory corticosubcollicular pathways.

Enrico Mugnaini has devoted part of his long and fruitful neuroscientific career to investigating the structural similarities between the cerebellar cortex and one of the first relay stations of the mammalian auditory pathway: the dorsal cochlear nucleus. The hypothesis of the cerebellar-like nature of the superficial layers of the dorsal cochlear nucleus received definitive support with the discovery and extensive characterization in his laboratory of unipolar brush cells, a neuron type unique to certain regions of the cerebellar cortex and to the granule cell domains of the cochlear nuclei. Paradoxically, a different line of research carried out in his laboratory revealed that, unlike the mammalian cerebellar cortex, the dorsal cochlear nucleus receives direct projections from the cerebral cortex, a fact that constitutes one of the main differences between the cerebellum and the dorsal cochlear nucleus. In an article published in 1995, Mugnaini's group described in detail the novel direct projections from the rat auditory neocortex to various subcollicular auditory centers, including the nucleus sagulum, the paralemniscal regions, the superior olivary complex, and the cochlear nuclei (Feliciano et al., Auditory Neuroscience 1995; 1:287-308). This review gives Enrico Mugnaini credit for his seminal contribution to the knowledge of auditory corticosubcollicular projections and summarizes how this growing field has evolved in the last 20years.

Ultrastructural Study of the Synaptic Glomeruli in the Rat’s Cochlear Nucleus

Summary The granule cell domain of the cochlear nuclear complex contains interneurons, which are the targets for nonprimary auditory inputs from the superior olivary complex, inferior colliculus, auditory cortex, cuneate and trigeminal nuclei of the somatosensory system. The cellular targets of the non-primary projections are unknown due to a lack of information regarding postsynaptic profiles in the granule cell areas. In the present paper, we examined the synaptic relationships between a heterogeneous class of large synaptic terminals, called mossy fibers and their targets within subdivisions of the granule cell domain. During the late stage of postnatal development, we observed heterogenous groups of complex synaptic glomeruli. Using electron microscopy, we provide evidence for ultrastructural features of dendrites that receive input from the mossy fibers. The distinct synaptic relations between mossy fibers and dendrites of microneurons further imply fundamentally separate roles in processing of acoustic signals.

Somatosensory Projections to Cochlear Nucleus Are Upregulated after Unilateral Deafness

The cochlear nucleus (CN) receives innervation from auditory and somatosensory structures, which can be identified using vesicular glutamate transporters, VGLUT1 and VGLUT2. VGLUT1 is highly expressed in the magnocellular ventral CN (VCN), which receives auditory nerve inputs. VGLUT2 is predominantly expressed in the granule cell domain (GCD), which receives nonauditory inputs from somatosensory nuclei, including spinal trigeminal nucleus (Sp5) and cuneate nucleus (Cu). Two weeks after unilateral deafening VGLUT1 is significantly decreased in ipsilateral VCN while VGLUT2 is significantly increased in the ipsilateral GCD (Zeng et al., 2009), putatively reflecting decreased inputs from auditory nerve and increased inputs from nonauditory structures in guinea pigs. Here, we wished to determine whether the upregulation of VGLUT2 represents increases in the number of somatosensory projections to the CN that are maintained for longer periods of time. Thus, we examined concurrent changes in VGLUT levels and somatosensory projections in the CN using immunohistochemistry combined with anterograde tract tracing three and six weeks following unilateral deafening. The data reveal that unilateral deafness leads to increased numbers of VGLUT2-colabeled Sp5 and Cu projections to the ventral and dorsal CN. These findings suggest that Sp5 and Cu play significant and unique roles in cross-modal compensation and that, unlike after shorter term deafness, neurons in the magnocellular regions also participate in the compensation. The enhanced glutamatergic somatosensory projections to the CN may play a role in neural spontaneous hyperactivity associated with tinnitus.

Cuneate and spinal trigeminal nucleus projections to the cochlear nucleus are differentially associated with vesicular glutamate transporter-2

There are distinct distributions and associations with vesicular glutamate transporters (VGLUTs) for auditory nerve and specific somatosensory projections in the cochlear nucleus (CN). Auditory nerve fibers project primarily to the magnocellular areas of the ventral cochlear nucleus and deepest layer of the dorsal cochlear nucleus and predominantly colabel with VGLUT1; whereas the spinal trigeminal nucleus (Sp5) projections terminate primarily in the granule cell domains (GCD) of CN and predominantly colabel with VGLUT2. Here, we demonstrate that the terminals of another somatosensory pathway, originating in the cuneate nucleus (Cu), also colabel with VGLUT2. Cu projections in cochlear nucleus exhibited a bilateral distribution pattern with ipsilateral dominance, with 30% of these classified as putative mossy fibers (MFs) and 70% as small boutons (SBs). Cu anterograde endings had a more prominent distribution in the GCD than Sp5, with a higher percentage of MF terminals throughout the CN and higher MF/SB ratio in GCD. 56% of Cu endings and only 25% of Sp5 endings colabeled with VGLUT2. In both cases these were mostly MFs with only 43% of Cu SBs and 18% of Sp5 SBs colabeled with VGLUT2. The few Cu and Sp5 terminals that colabeled with VGLUT1 (11% vs. 1%), were evenly distributed between MFs and SBs. The high number of VGLUT2-positive Cu MFs predominantly located in the GCD, may reflect a faster-acting pathway that activates primarily dorsal cochlear nucleus cells via granule cell axons. In contrast, the higher percentage of Sp5-labeled SB terminals and a greater number of projections outside the GCD suggest a slower-acting pathway that activates both dorsal and ventral cochlear nucleus principal cells. Both projections, with their associations to VGLUT2 likely play a role in the enhancement of VGLUT2 after unilateral deafness [Zeng C, Nannapaneni N, Zhou J, Hughes LF, Shore S (2009) J Neurosci 29:4210–4217] that may be associated with tinnitus.

Vesicular Glutamate Transporter 2 Is Associated with the Cochlear Nucleus Commissural Pathway

The cochlear nucleus (CN) is the first auditory structure to receive binaural information via CN-commissural connections. In spite of an abundance of evidence that CN-commissural neurons are glycinergic and thus inhibitory, physiological, and anatomical evidence suggests that a small group of CN-commissural neurons are excitatory. In this study, we examined the excitatory portion of the CN-commissural pathway by combining anterograde tract tracing with immunohistochemistry of vesicular glutamate transporters (VGLUTs) and retrograde tract tracing with immunohistochemistry of glycine and GABA. VGLUTs accumulate glutamate in synaptic vesicles and are prime markers for glutamatergic neurons. The terminal endings of CN-commissural projections were typically en passant or small terminal boutons, but large, irregular swellings were also observed, confined to the granule cell domain (GCD). Both small and large terminal endings in the GCD colabeled with VGLUT2, but not VGLUT1. In addition, some CN-commissural cells themselves received VGLUT2-positive puncta on their somata. After large injections into the CN, 37% of the total number of retrogradely labeled commissural neurons was immunonegative to glycine or GABA. Retrograde labeling after a restricted GCD injection revealed a majority of putative excitatory CN-commissural neurons as multipolar, in the marginal regions of the ventral CN, medially as well as in the small cell cap region and deep dorsal CN. These results provide direct anatomical evidence that an excitatory commissural projection is present, and VGLUT2 is associated with this pathway both as its source and as a recipient.

Cytosolic calcium elevation induced by orexin/hypocretin in granule cell domain cells of the rat cochlear nucleus in vitro

Using rat brain slice preparations, we examined the effect of orexin on cytosolic Ca 2+ concentrations ([Ca 2+] i) in the granule cell domain (GCD) cells of the cochlear nucleus that carry non-auditory information to the dorsal cochlear nucleus. Application of orexin concentration-dependently increased [Ca 2+] i, and in two thirds of GCD cells these increases persisted in the presence of tetrodotoxin. There was no significant difference between the dose–response curve for orexin-A and that for orexin-B. Extracellular Ca 2+ removal abolished the [Ca 2+] i elevation induced by orexin-B, whereas depletion of intracellular Ca 2+ stores had no effect. The orexin-B-induced elevation of [Ca 2+] i was not blocked by inhibitors of reverse-mode Na +/Ca 2+ exchanger (NCX) and nonselective cation channel, whereas it was blocked by lowering the extracellular Na + or by applying inhibitors of forward-mode NCX and voltage-gated R- and T-type Ca 2+ channels. The ORX-B-induced increase in [Ca 2+] i was also blocked by inhibitors of adenylcyclase (AC) and protein kinase A (PKA), but not by inhibitors of phosphatidylcholine-specific and phosphatidylinositol-specific phospholipase C. In electrophysiological experiments using whole-cell patch clamp recordings, half of GCD cells were depolarized by orexin-B, and the depolarization was abolished by a forward-mode NCX inhibitor. These results suggest that orexin increases [Ca 2+] i postsynaptically via orexin 2 receptors, and the increase in [Ca 2+] i is induced via the AC–PKA–forward-mode NCX-membrane depolarization-mediated activation of voltage-gated R- and T-type Ca 2+ channels. The results further support the hypothesis that the orexin system participates in integrating neural systems that are involved in arousal, sensory processing, energy homeostasis and autonomic function.

Cytosolic calcium elevation induced by orexin/hypocretin in granule cell domain cells of the rat cochlear nucleus in vitro

Cytosolic calcium elevation induced by orexin/hypocretin in granule cell domain cells of the rat cochlear nucleus in vitro

Urocortin Expression in Mouse Cochlear Nucleus and Scarpa's Ganglion

Clinical and basic studies have correlated tinnitus with stress. Although the etiology of tinnitus is unknown, the cochlear nucleus (CN) appears to play a role. To better understand the potential impact of stress on tinnitus and modulation of the central auditory system in general, the goal of the current study was to examine the presence and distribution of axon terminals containing urocortin in the CN of the mouse. Prospective description of histological findings. Three different forms of urocortin were labeled in brainstem sections collected from 10 wild-type mice by immunohistochemistry. Immunoreactive terminal fibers in the CN were digitally photographed, as well as reconstructed in the CN under a drawing tube attached to a light microscope. Specific staining was found in en passant type fibers scattered throughout the CN but situated mostly within the granule cell domains. Clusters of labeled fibers were observed in the nerve root. Labeled axons were observed in the three tracts known to carry olivocochlear fibers to the CN, as well as in the olivocochlear bundle itself. As the axons within the olivocochlear bundle departed the brainstem in the vestibular nerve, numerous labeled en passant fibers were observed among somata of the vestibular ganglion (Scarpa's). Centrally, labeled axons were followed from the CN to the lateral superior olive, an established source of urocortin-positive efferents to the cochlea. These findings indicate that lateral olivocochlear efferents innervate the CN and Scarpa's ganglion, and also that urocortin is likely a neuromodulator in particular CN circuits. The current study supports innervation of specific regions of the mouse CN and Scarpa's ganglion by neurons expressing urocortin. The innervation may be one substrate by which stress modulates particular CN processes. Further studies are necessary to establish the role of urocortin in CN models of tinnitus.

Projections of low spontaneous rate, high threshold auditory nerve fibers to the small cell cap of the cochlear nucleus in cats

The marginal shell of the anteroventral cochlear nucleus houses small cells that are distinct from the overlying microneurons of the granule cell domain and the underlying projection neurons of the magnocellular core. This thin shell of small cells and associated neuropil receives auditory nerve input from only the low (<18 spikes/s) spontaneous rate (SR), high threshold auditory nerve fibers; high SR, low threshold fibers do not project there. It should be noted, that most of these auditory nerve terminations reside in the neuropil and intermix with dendrites that originate outside the shell. Consequently, electron microscopy is necessary to determine the synaptic targets. For this report, the terminations of intracellularly labeled low SR auditory nerve fibers in the small cell of cats cap were mapped through serial sections using a light microscope. The terminals were then examined with an electron microscope and found to form synapses with the somata and dendrites of small cells. Moreover, the small cell dendrites were identifiable by an abundance of microtubules and the presence of polyribosomes that were free or associated with membranous cisterns. These data contribute to the concept of a high threshold feedback circuit to the inner ear, and reveal translational machinery for local control of activity-dependent synaptic modification.

Projections of the lateral reticular nucleus to the cochlear nucleus in rats

The lateral reticular nucleus (LRN) resides in the rostral medulla and caudal pons, is implicated in cardiovascular regulation and cranial nerve reflexes, and gives rise to mossy fibers in the cerebellum. Retrograde tracing data revealed that medium-sized multipolar cells from the magnocellular part of the LRN project to the cochlear nucleus (CN). We sought to characterize the LRN projection to the CN using BDA injections. Anterogradely labeled terminals in the ipsilateral CN appeared as boutons and mossy fibers, and were examined with light and electron microscopy. The terminal field in the CN was restricted to the granule cell domain (GCD), specifically in the superficial layer along the anteroventral CN and in the granule cell lamina. Electron microscopy showed that the smallest LRN boutons formed 1-3 synapses, and as boutons increased in size, they formed correspondingly more synapses. The largest boutons were indistinguishable from the smallest mossy fibers, and the largest mossy fiber exhibited 15 synapses. Synapses were asymmetric with round vesicles and formed against thin dendritic profiles characterized by plentiful microtubules and the presence of fine filopodial extensions that penetrated the ending. These structural features of the postsynaptic target are characteristic of the terminal dendritic claw of granule cells. LRN projections are consistent with known organizational principles of non-auditory inputs to the GCD.

Vessicular glutamate transporters 1 and 2 are differentially associated with auditory nerve and spinal trigeminal inputs to the cochlear nucleus

Projections of glutamatergic somatosensory and auditory fibers to the cochlear nucleus (CN) are mostly nonoverlapping: projections from the spinal trigeminal nucleus (Sp5) terminate primarily in the granule cell domains (GCD) of CN, whereas type I auditory nerve fibers (ANFs) project to the magnocellular areas of the VCN (VCNm) and deep layers of Dorsal CN (DCN). Vesicular glutamate transporters (VGLUTs), which selectively package glutamate into synaptic vesicles, have different isoforms associated with distinct subtypes of excitatory glutamatergic neurons. Here we examined the distributions of VGLUT1 and VGLU2 expression in the CN and their colocalization with Sp5 and ANF terminals following injections of anterograde tracers into Sp5 and the cochlea in the guinea pig. The CN regions that showed the most intense expression of VGLUT1 and VGLUT2 were largely nonoverlapping and were consistent with ANF and Sp5 projections, respectively: VGLUT1 was highly expressed in VCNm and the molecular layer of the DCN, whereas VGLUT2 was expressed predominantly in the GCD. Half (47% +/- 3%) of the Sp5 mossy fiber endings colabeled with VGLUT2, but few (2.5% +/- 1%) colabeled with VGLUT1. In contrast, ANFs colabeled predominantly with VGLUT1. The pathway-specific expression of VGLUT isoforms in the CN may be associated with the intrinsic synaptic properties that are unique to each sensory pathway.

Projections from auditory cortex to cochlear nucleus: A comparative analysis of rat and mouse

Mammalian hearing is a complex special sense that involves detection, localization, and identification of the auditory stimulus. The cerebral cortex may subserve higher auditory processes by providing direct modulatory cortical projections to the auditory brainstem. To support the hypothesis that corticofugal projections are a conserved feature in the mammalian brain, this article reviews features of the rat corticofugal pathway and presents new data supporting the presence of similar projections in the mouse. The mouse auditory cortex was localized with electrophysiological recording and neuronal tracers were injected into AI. The cochlear nucleus was dissected and examined for terminal fibers by light and electron microscopy. Bouton endings were found bilaterally forming synapses with dendrites of granule cells of the cochlear nucleus. This report provides evidence for direct auditory cortex projections to the cochlear nucleus in the mouse. The distribution of projections to the granule cell domain and the synapses onto granule cell dendrites are consistent with what has been reported for rats and guinea pigs. These findings suggest a general plan for corticofugal modulation of ascending auditory information in mammals. Corticobulbar inputs to the auditory brainstem likely provided a survival advantage by improving sound detection and identification, thus allowing the development of complex social behaviors and the navigation of varied environments.

Somatosensory influence on the cochlear nucleus and beyond

Interactions between somatosensory and auditory systems occur at peripheral levels in the central nervous system. The cochlear nucleus (CN) receives innervation from trigeminal sensory structures: the ophthalmic division of the trigeminal ganglion and the caudal and interpolar regions of the spinal trigeminal nucleus (Sp5I and Sp5C). These projections terminate primarily in the granule cell domain, but also in magnocellular regions of the ventral and dorsal CN. Additionally, new evidence is presented demonstrating that cells in the lateral paragiganticular regions of the reticular formation (RF) also project to the CN. Not unlike the responses obtained from electrically stimulating the trigeminal system, stimulating RF regions can also result in excitation/inhibition of dorsal CN neurons. The origins and central connections of these projection neurons are associated with systems controlling vocalization and respiration. Electrical stimulation of trigeminal and RF projection neurons can suppress acoustically driven activity of not only CN neurons, but also neurons in the inferior colliculus. Together with the anatomical observations, these physiological observations suggest that one function of somatosensory input to the auditory system is to suppress responses to “expected” body-generated sounds such as vocalization or respiration. This would serve to enhance responses to “unexpected” externally-generated sounds, such as the vocalizations of other animals.

Synaptic influences of pontine nuclei on cochlear nucleus cells

Using the in vitro isolated whole brain preparation of the guinea pig, we tested the synaptic effects induced by the stimulation of pontine nuclei (PN) in intracellularly recorded and stained principal cells of the cochlear nucleus (CN). Twenty percent of the recorded cells in all CN subdivisions responded to stimulation of either ipsilateral or contralateral PN, and 12% of the cells exhibited convergence of inputs from both sides. The responses were recorded only in stellate cells of the ventral CN and in the pyramidal cells of the dorsal CN, whereas no responses were observed in bushy, octopus, and giant cells. PN stimulation produced excitatory and inhibitory postsynaptic potentials as well as mixed responses. The heterogeneous nature and the wide latency range (3.2-18 ms) of observed responses suggest significant variability in the underlying synaptic mechanisms and the implicated pathways. We propose that PN projections to the CN, terminating mainly in the granule cell domain (GCD), together with other non-auditory and auditory inputs contribute to multimodal convergence in the GCD leading ultimately to modulatory actions on the output activity of CN principal cells.

Projections from the spinal trigeminal nucleus to the cochlear nucleus in the rat

The integration of information across sensory modalities enables sound to be processed in the context of position, movement, and object identity. Inputs to the granule cell domain (GCD) of the cochlear nucleus have been shown to arise from somatosensory brain stem structures, but the nature of the projection from the spinal trigeminal nucleus is unknown. In the present study, we labeled spinal trigeminal neurons projecting to the cochlear nucleus using the retrograde tracer, Fast Blue, and mapped their distribution. In a second set of experiments, we injected the anterograde tracer biotinylated dextran amine into the spinal trigeminal nucleus and studied the resulting anterograde projections with light and electron microscopy. Spinal trigeminal neurons were distributed primarily in pars caudalis and interpolaris and provided inputs to the cochlear nucleus. Their axons gave rise to small (1-3 microm in diameter) en passant swellings and terminal boutons in the GCD and deep layers of the dorsal cochlear nucleus. Less frequently, larger (3-15 microm in diameter) lobulated endings known as mossy fibers were distributed within the GCD. Ventrally placed injections had an additional projection into the anteroventral cochlear nucleus, whereas dorsally placed injections had an additional projection into the posteroventral cochlear nucleus. All endings were filled with round synaptic vesicles and formed asymmetric specializations with postsynaptic targets, implying that they are excitatory in nature. The postsynaptic targets of these terminals included dendrites of granule cells. These projections provide a structural substrate for somatosensory information to influence auditory processing at the earliest level of the central auditory pathways.

Multimodal inputs to the granule cell domain of the cochlear nucleus

There is growing evidence that hearing involves the integration of many brain functions, including vision, balance, somatic sensation, learning and memory, and emotional state. Some of these integrative processes begin at the earliest stages of the central auditory system. In this review, we will discuss evidence that reveals multimodal projections into the granule cell domain of the cochlear nucleus.

The cellular origin of corticofugal projections to the superior olivary complex in the rat

Corticofugal pathways originating in auditory cortex innervate most subcortical auditory nuclei in the ascending pathway [ Auditory Neurosci. 1 (1995) 287–308; J. Comp. Neurol. 371 (1996) 15–40]. Our goal is to determine if these projections arise from the same neurons or if different neurons project to each of the separate structures. We also seek to identify the layers and fields of auditory cortex from which these neurons originate. In the present study, we answer these questions with respect to the projections to the superior olivary complex (SOC). Fluorescent retrograde tracers, Fast Blue (FB) or Diamidino Yellow (DiY), were injected into the SOC and the pattern of labeled cells was determined in temporal neocortex. We also injected FB into the granule cell domain (GCD) of the cochlear nucleus. Cortical projections to the GCD derive exclusively from layer V pyramidal cells in primary auditory cortex [ Brain Res. 706 (1996) 97–102]. Thus the pattern of labeling produced by injections in the GCD provided a reference for interpreting the labeling after SOC injections. Layer V pyramidal cells project to the SOC, and these neurons were distributed bilaterally in primary and secondary areas of auditory cortex. The projections to the SOC from primary auditory cortex are predominantly uncrossed, whereas those from secondary auditory cortex are nearly equal for the two hemispheres. In animals that received injections of FB in the GCD and DiY in the SOC, cells labeled by each injection had a different laminar distribution and very few cells were double labeled. These data suggest that the cortical pathways ending in the cochlear nucleus and SOC are largely independent. We discuss the implications of these findings with respect to the multifunctional nature of the SOC in brainstem auditory processing.