David T. Larue

Auditory cortical projections to the cat inferior colliculus

The projection from 11 auditory cortical areas onto the subdivisions of the inferior colliculus was studied in adult cats by using two different anterograde tracers to label corticocollicular (CC) axon terminals. The main results were that: 1) a significant CC projection arose from every field; 2) the principal inferior collicular targets were the dorsal cortex, lateral nucleus, caudal cortex, and intercollicular tegmentum, with only a sparse projection to the central nucleus; 3) the input was usually bilateral, with the ipsilateral side by far the most heavily labeled, and the contralateral projection was a symmetrical subset of the ipsilateral input; 4) the CC system is both divergent and convergent, with single cortical areas projecting to six or more collicular subdivisions, and each auditory midbrain subdivision receiving a convergent projection from two to ten cortical areas; 5) cortical areas devoid of tonotopic organization have topographic projections to collicular target nuclei; 6) the heaviest CC projection terminated in the caudal half of the inferior colliculus; and finally, 7) the relative strength of the corticocollicular labeling was far less than that of the corresponding corticothalamic projection in the same experiments.

Projections of Auditory Cortex to the Medial Geniculate Body of the Cat

The corticofugal projection from 12 auditory cortical fields onto the medial geniculate body was investigated in adult cats by using wheat germ agglutinin conjugated to horseradish peroxidase or biotinylated dextran amines. The chief goals were to determine the degree of divergence from single cortical fields, the pattern of convergence from several fields onto a single nucleus, the extent of reciprocal relations between corticothalamic and thalamocortical connections, and to contrast and compare the patterns of auditory corticogeniculate projections with corticofugal input to the inferior colliculus. The main findings were that (1) single areas showed a wide range of divergence, projecting to as few as 5, and to as many as 15, thalamic nuclei; (2) most nuclei received projections from approximately five cortical areas, whereas others were the target of as few as three areas; (3) there was global corticothalamic‐thalamocortical reciprocity in every experiment, and there were also significant instances of nonreciprocal projections, with the corticothalamic input often more extensive; (4) the corticothalamic projection was far stronger and more divergent than the corticocollicular projection from the same areas, suggesting that the thalamus and the inferior colliculus receive differential degrees of corticofugal control; (5) cochleotopically organized areas had fewer corticothalamic projections than fields in which tonotopy was not a primary feature; and (6) all corticothalamic projections were topographic, focal, and clustered, indicating that areas with limited cochleotopic organization still have some internal spatial arrangement. The areas with the most divergent corticothalamic projections were polysensory regions in the posterior ectosylvian gyrus. The projection patterns were indistinguishable for the two tracers. These findings suggest that every auditory thalamic nucleus is under some degree of descending control. Many of the projections preserve the relations between cochleotopically organized thalamic and auditory areas, and suggest topographic relations between nontonotopic areas and nuclei. The collective size of the corticothalamic system suggests that both lemniscal and extralemniscal auditory thalamic nuclei receive significant corticofugal input. J. Comp. Neurol. 430:27–55, 2001.

Descending projections to the inferior colliculus from the posterior thalamus and the auditory cortex in rat, cat, and monkey.

Projections from the posterior thalamus and medial geniculate body were labeled retrogradely with wheat germ agglutinin conjugated to horseradish peroxidase injected into the rat, cat, and squirrel monkey inferior colliculus. Neurons were found ipsilaterally in the (1) medial division of the medial geniculate body, (2) central gray, (3) posterior limitans nucleus, and the (4) reticular part of the substantia nigra. Bilateral projections involved the (5) peripeduncular/suprapeduncular nucleus, (6) subparafascicular and posterior intralaminar nuclei, (7) nucleus of the brachium of the inferior colliculus, (8) lateral tegmental/lateral mesencephalic areas, and (9) deep layers of the superior colliculus. The medial geniculate projection was concentrated in the caudal one-third of the thalamus; in contrast, the labeling in the subparafascicular nucleus, substantia nigra, and central gray continued much further rostrally. Robust anterograde labeling corresponded to known patterns of tectothalamic projection. Biotinylated dextran amine deposits in the rat inferior colliculus revealed that (1) many thalamotectal cells were elongated multipolar neurons with long, sparsely branched dendrites, resembling neurons in the posterior intralaminar system, and that other labeled cells were more typical of thalamic relay neurons; (2) some cells have reciprocal projections. Similar results were seen in the cat and squirrel monkey. The widespread origins of descending thalamic influences on the inferior colliculus may represent a phylogenetically ancient feedback system onto the acoustic tectum, one that predates the corticocollicular system and modulates nonauditory centers and brainstem autonomic nuclei. Besides their role in normal hearing such pathways may influence behaviors ranging from the startle reflex to the genesis of sound-induced seizures.

Origins of medial geniculate body projections to physiologically defined zones of rat primary auditory cortex.

Medial geniculate body neurons projecting to physiologically identified subregions of rat primary auditory cortex (area 41, Te1) were labeled with horseradish peroxidase in adult rats. The goals were to determine the type(s) of projection neuron and the spatial arrangement of these cells with respect to thalamic subdivisions. Maps of best frequency were made with single neuron or unit cluster extracellular recording at depths of 500-800 microm, which correspond to layers III-IV in Nissl preparations. Tracer injections were made in different cortical isofrequency regions (2, 11, 22, or 38 kHz, respectively). Labeled neurons were plotted on representative sections upon which the architectonic subdivisions were drawn independently. Most of the cells of origin lay in the ventral division in every experiment. Injections at low frequencies labeled bands of neurons laterally in the ventral division; progressively more rostral deposits at higher frequencies labeled bands or clusters more medially in the ventral division, and through most of its caudo-rostral extent. Medial division labeling was variable. Labeled cells were always in the lateral half of the nucleus and were often scattered. There were few labeled cells in the dorsal division. Seven types of thalamocortical neuron were identified: ventral division cells had a tufted branching pattern, while medial division neurons have heterogeneous shapes and sizes and were larger. Dorsal division neurons had a radiate branching pattern. The size range of labeled neurons spanned that of Nissl stained neuronal somata. Area 41 may receive two types of thalamic projection: ventral division input is strongly convergent, highly topographic, spatially focal, and restricted to one type of neuron only, while the medial division projection is more divergent, coarsely topographical, involves multiple cortical areas, and has several varieties of projection neuron. Despite species differences in local circuitry, many facets of thalamocortical organization are conserved in phylogeny.

Neural architecture of the rat medial geniculate body

The rat medial geniculate body was subdivided using Nissl preparations to establish nuclear boundaries, with Golgi-Cox impregnations to identify projection and local circuit neurons, and in fiber stained material to delineate the fiber tracts and their distribution. Three divisions were recognized (ventral, dorsal and medial): the first two had subdivisions. The ventral division had lateral and medial parts. The main cell type had bushy tufted dendrites which, with the afferent axons, formed fibrodendritic laminae oriented from dorso-lateral to ventro-medial; such laminae were not as regular medially, in the ovoid nucleus. The dorsal division contained several nuclei (dorsal superficial, dorsal, deep dorsal, suprageniculate, and ventrolateral) and neurons with radiating or bushy dendrites; the nuclear subdivisions differed in the concentration of one cell type or another, and in packing density. A laminar organization was present only in the dorsal superficial nucleus. Medial division neurons were heterogeneous in size and shape, ranging from tiny cells to magnocellular neurons; the various cell types intermingled. so that no further subdivision could be made. This parcellation scheme was consistent with, and supported by, the findings from plastic embedded or fiber stained material. There were very few small neurons with locally ramifying axons and which could perform an intrinsic role like that of Golgi type II cells. Their rarity was consistent with the small number of such profiles in plastic embedded or Nissl material and the few GABAergic medial geniculate body neurons seen in prior immunocytochemical work. While similar neuronal types and nuclear subdivisions are recognized in the rat and cat, there may be major interspecific differences with regard to interneuronal organization in the auditory thalamus whose functional correlates are unknown.

A multisensory zone in rat parietotemporal cortex: intra- and extracellular physiology and thalamocortical connections.

Multisensory integration is essential for the expression of complex behaviors in humans and animals. However, few studies have investigated the neural sites where multisensory integration may occur. Therefore, we used electrophysiology and retrograde labeling to study a region of the rat parietotemporal cortex that responds uniquely to auditory and somatosensory multisensory stimulation. This multisensory responsiveness suggests a functional organization resembling multisensory association cortex in cats and primates. Extracellular multielectrode surface mapping defined a region between auditory and somatosensory cortex where responses to combined auditory/somatosensory stimulation were larger in amplitude and earlier in latency than responses to either stimulus alone. Moreover, multisensory responses were nonlinear and differed from the summed unimodal responses. Intracellular recording found almost exclusively multisensory cells that responded to both unisensory and multisensory stimulation with excitatory postsynaptic potentials (EPSPs) and/or action potentials, conclusively defining a multisensory zone (MZ). In addition, intracellular responses were similar to extracellular recordings, with larger and earlier EPSPs evoked by multisensory stimulation, and interactions suggesting nonlinear postsynaptic summation to combined stimuli. Thalamic input to MZ from unimodal auditory and somatosensory thalamic relay nuclei and from multisensory thalamic regions support the idea that parallel thalamocortical projections may drive multisensory functions as strongly as corticocortical projections. Whereas the MZ integrates uni‐ and multisensory thalamocortical afferent streams, it may ultimately influence brainstem multisensory structures such as the superior colliculus. J. Comp. Neurol. 460:223–237, 2003.

Two Systems of Giant Axon Terminals in the Cat Medial Geniculate Body: Convergence of Cortical and GABAergic Inputs

The thalamus plays a critical role in processing sensory information that involves interactions between extrinsic connections and intrinsic circuitry. Little is known regarding how these different systems might interact. We found an unexpected nuclear convergence of two types of giant axon terminals, each of which must have independent origins, in the dorsal division of the cat medial geniculate body. The first class of giant terminal was labeled after injections of biotinylated dextran amines (BDA) in seven auditory cortical areas. A second type was found in sections immunostained for γ‐aminobutyric acid (GABA); these endings had the same nuclear distribution, and they were numerous. The origin of this GABAergic terminal is unknown. The giant corticothalamic terminals were presumably those described in prior accounts using different tracers (Rouiller and de Ribaupierre [1990] Neurosci. Lett. 208:29–35; Ojima [1994] Cerebral Cortex 6:646–663), but with BDA they are labeled more fully. Clusters of such endings were often linked, and hundreds may occur in a single section. Their boutons formed a substantial proportion of the corticothalamic population. Other types of corticogeniculate axon terminals were also labeled, including two kinds that are much smaller and that match closely the classical descriptions of corticothalamic axons. The giant GABAergic endings were found in all dorsal division nuclei and in thalamic visual nuclei such as the lateral posterior nucleus. Like the giant cortical endings, the giant GABAergic terminals often encircled large, pale, immunonegative profiles that may be dendritic. This implies a close spatial, and perhaps a close functional, relationship between the populations of giant axon terminals. Insofar as physiological studies found that pharmacological inactivation of rat somatic sensory cortex suppresses peripheral information transmission through the posterior thalamus, corticofugal input may be essential for normal processing (Diamond et al. [1992] J. Comp. Neurol. 319:66–84). Our findings suggest that the giant corticothalamic endings could play an important role in descending control. Perhaps they are counterbalanced by a GABAergic system and affect thalamic oscillations implicated in shifts in vigilance and attention. J. Comp. Neurol. 413:181–197, 1999.

A periodic network of neurochemical modules in the inferior colliculus

A new organization has been found in shell nuclei of rat inferior colliculus. Chemically specific modules with a periodic distribution fill about half of layer 2 of external cortex and dorsal cortex. Modules contain clusters of small glutamic acid decarboxylase-positive neurons and large boutons at higher density than in other inferior colliculus subdivisions. The modules are also present in tissue stained for parvalbumin, cytochrome oxidase, nicotinamide adenine dinucleotide phosphate-diaphorase, and acetylcholinesterase. Six to seven bilaterally symmetrical modules extend from the caudal extremity of the external cortex of the inferior colliculus to its rostral pole. Modules are from approximately 800 to 2200 microm long and have areas between 5000 and 40,000 microm2. Modules alternate with immunonegative regions. Similar modules are found in inbred and outbred strains of rat, and in both males and females. They are absent in mouse, squirrel, cat, bat, macaque monkey, and barn owl. Modules are immunonegative for glycine, calbindin, serotonin, and choline acetyltransferase. The auditory cortex and ipsi- and contralateral inferior colliculi project to the external cortex. Somatic sensory influences from the dorsal column nuclei and spinal trigeminal nucleus are the primary ascending sensory input to the external cortex; ascending auditory input to layer 2 is sparse. If the immunopositive modular neurons receive this input, the external cortex could participate in spatial orientation and somatic motor control through its intrinsic and extrinsic projections.

GABAergic organization of the cat medial geniculate body.

A study of neurons and processes (puncta) immunolabeled by antibodies to γ‐aminobutyric acid (GABA) or glutamic acid decarboxylase was undertaken in the medial geniculate body of the adult cat. The proportion and types of GABAergic cells were determined with high resolution methods, including postembbedding immunocytochemistry on semithin plastic sections. A second goal was to draw parallels and differences between the auditory thalamus and other thalamic nuclei. Finally, the types of GABAergic puncta and their concentration in the three major subdivisions of the medial geniculate body were analyzed. The results were that (1) each division had many GABAergic neurons, averaging approximately 26% of the neuronal population; (2) the ventral division had the highest proportion of these cells (33%), the medial division the fewest (18%), and the dorsal division was intermediate (26%); (3) there was a gradient in the proportion of GABAergic neurons, i.e., the ventral and medial division values increased caudorostrally, whereas the value in the dorsal division declined; (4) the predominant GABAergic cell type in each division was a small neuron with a soma approximately 10–12 μm in diameter; (5) a small population of much larger GABAergic neurons was present mainly in the dorsal division; (6) in addition to the fine, granular puncta in each division, a type of giant GABAergic puncta was found only in the dorsal division nuclei. The results obtained with the two antibodies were essentially identical. These findings suggest a structural basis for qualitative differences in the distribution of GABAergic processing within the medial geniculate complex. The GABAergic arrangement in the ventral division was stereotyped, with only one type of putative GABAergic interneuron, and the puncta were correspondingly homogeneous. In contrast, the dorsal division had two types of GABAergic neurons, and the giant GABAergic puncta represent a new substrate for inhibitory interactions. The medial division also had more than one type of GABAergic neuron and a slightly lower concentration of puncta. These qualitative and quantitative distinctions suggest a morphologic basis for possible differences in inhibitory processing among medial geniculate body subdivisions. J. Comp. Neurol. 415:368–392, 1999.

Auditory Connections and Neurochemistry of the Sagulum

We studied the cytoarchitecture, neurochemical organization, and connections of the sagulum. The goal was to clarify its role in midbrain, lateral tegmental, and thalamic auditory processing. On cytoarchitectonic grounds, ventrolateral (parvocellular) and dorsomedial (magnocellular) subdivisions were recognized. The patterns of immunostaining for γ‐aminobutyric acid (GABA) and glycine were distinct. Approximately 5–10% of the neurons were GABAergic, and more than one type was identified; GABAergic axon terminals were abundant in number and varied in form. Glycinergic neurons were much rarer, <1% of the population, and glycinergic axon terminals were correspondingly sparse. Wheat germ agglutinin conjugated to horseradish peroxidase was used for purposes of connectional mapping, and biotinylated dextran amines revealed the structure of corticosagular axons. All nine cortical areas injected project to the ipsilateral sagulum. Five (areas AI, AII, SF, EPD, and Te) had heavier projections than the others. Areas AI and AII projected throughout the rostrocaudal sagulum. Labeling from AI was moderate in density and concentrated in the central sagulum, whereas the input from AII was heavier and ended more laterally. Suprasylvian fringe input was light, especially caudally, and was chiefly in the central sagulum. The projection from the dorsal region of the posterior ectosylvian gyrus was comparatively stronger and was in the dorsolateral sagulum. Finally, the temporal cortex sent axons to the most lateral sagulum, spanning the dorsoventral extent, whereas insular cortex axons ended diffusely in the dorsolateral sagulum. Corticofugal axons ranged from fine boutons en passant to larger globular terminals. The sagulum may represent the earliest significant opportunity in the ascending auditory pathway for corticofugal modulation. The most extensive input arises from the polymodal association areas. The sagulum then projects divergently to the dorsal cortex of the inferior colliculus and the dorsal division of the medial geniculate body. The projection from the dorsal division of the auditory thalamus to nonprimary auditory cortex completes this circuit between the forebrain and the midbrain and represents a nexus in the ascending and descending auditory systems. Such circuits could play a critical role in auditory‐motor adjustments to sound. J. Comp. Neurol. 401:329–351, 1998.