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Based on the auditory periphery and the small head size, Etruscan shrews ( Suncus etruscus ) approximate ancestral mammalian conditions. The auditory brainstem in this insectivore has not been investigated. Using labelling techniques, we assessed the structures of their superior olivary complex (SOC) and the nuclei of the lateral lemniscus (NLL). There, we identified the position of the major nuclei, their input pattern, transmitter content, expression of calcium binding proteins (CaBPs) and two voltage-gated ion channels. The most prominent SOC structures were the medial nucleus of the trapezoid body (MNTB), the lateral nucleus of the trapezoid body (LNTB), the lateral superior olive (LSO) and the superior paraolivary nucleus (SPN). In the NLL, the ventral (VNLL), a specific ventrolateral VNLL (VNLLvl) cell population, the intermediate (INLL) and dorsal (DNLL) nucleus, as well as the inferior colliculus’s central aspect were discerned. INLL and VNLL were clearly separated by the differential distribution of various marker proteins. Most labelled proteins showed expression patterns comparable to rodents. However, SPN neurons were glycinergic and not GABAergic and the overall CaBPs expression was low. Next to the characterisation of the Etruscan shrew’s auditory brainstem, our work identifies conserved nuclei and indicates variable structures in a species that approximates ancestral conditions.

The brainstem’s lateral superior olive (LSO) is thought to be crucial for localizing high-frequency sounds by coding interaural sound level differences (ILD). Its neurons weigh contralateral inhibition against ipsilateral excitation, making their firing rate a function of the azimuthal position of a sound source. Since the very first in vivo recordings, LSO principal neurons have been reported to give sustained and temporally integrating ‘chopper’ responses to sustained sounds. Neurons with transient responses were observed but largely ignored and even considered a sign of pathology. Using the Mongolian gerbil as a model system, we have obtained the first in vivo patch clamp recordings from labeled LSO neurons and find that principal LSO neurons, the most numerous projection neurons of this nucleus, only respond at sound onset and show fast membrane features suggesting an importance for timing. These results provide a new framework to interpret previously puzzling features of this circuit.

This review summarizes recent work in auditory brainstem nuclei to demonstrate that developing brain stem circuits are subject to experience-dependent synaptic refinement. This is in contrast to the traditional view, which interprets the early development of brain stem tonotopy as indicative of a 'hard-wired' mechanism. A fundamental organizing principle of auditory brain circuits is tonotopy, the orderly representation of the sound frequency to which neurons are most sensitive. Tonotopy arises from the coding of frequency along the cochlea and the topographic organization of auditory pathways. The mechanisms that underlie the establishment of tonotopy are poorly understood. In auditory brainstem pathways, topographic precision is present at very early stages in development, which may suggest that synaptic reorganization contributes little to the construction of precise tonotopic maps. Accumulating evidence from several brainstem nuclei, however, is now changing this view by demonstrating that developing auditory brainstem circuits undergo a marked degree of refinement on both a subcellular and circuit level.

The reflexological view of brain function (Sherrington, 1906) has played a crucial role in defining both the nature of connectivity and the role of the synaptic interactions among neuronal circuits. One implicit assumption of this view, however, has been that CNS function is fundamentally driven by sensory input. This view was questioned as early as the beginning of the last century when a possible role for intrinsic activity in CNS function was proposed by Thomas Graham Brow (Brown, 1911, 1914). However, little progress was made in addressing intrinsic neuronal properties in vertebrates until the discovery of calcium conductances in vertebrate central neurons leading dendritic electroresponsiveness (Llinás and Hess, 1976; Llinás and Sugimori, 1980a,b) and subthreshold neuronal oscillation in mammalian inferior olive (IO) neurons (Llinás and Yarom, 1981a,b). This happened in parallel with a similar set of findings concerning invertebrate neuronal system (Marder and Bucher, 2001). The generalization into a more global view of intrinsic rhythmicity, at forebrain level, occurred initially with the demonstration that the thalamus has similar oscillatory properties (Llinás and Jahnsen, 1982) and the ionic properties responsible for some oscillatory activity were, in fact, similar to those in the IO (Jahnsen and Llinás, 1984; Llinás, 1988). Thus, lending support to the view that not only motricity, but cognitive properties, are organized as coherent oscillatory states (Pare et al., 1992; Singer, 1993; Hardcastle, 1997; Llinás et al., 1998; Varela et al., 2001).

Morphological studies of inner hair cell (IHC) synapses with cochlear nerve terminals have suggested that high- and low-threshold fibers differ in the sizes of their pre- and postsynaptic elements as well as the position of their synapses around the hair cell circumference. Here, using high-power confocal microscopy, we measured sizes and spatial positions of presynaptic ribbons, postsynaptic glutamate receptor (GluR) patches, and olivocochlear efferent terminals at eight locations along the cochlear spiral in normal and surgically de-efferented mice. Results confirm a prior report suggesting a modiolar > pillar gradient in ribbon size and a complementary pillar > modiolar gradient in GluR-patch size. We document a novel habenular < cuticular gradient in GluR patch size and a complementary cuticular < habenular gradient in olivocochlear innervation density. All spatial gradients in synaptic elements collapse after cochlear de-efferentation, suggesting a major role of olivocochlear efferents in maintaining functional heterogeneity among cochlear nerve fibers. Our spatial analysis also suggests that adjacent IHCs may contain a different synaptic mix, depending on whether their tilt in the radial plane places their synaptic pole closer to the pillar cells or to the modiolus.

Precise temporal and spatial sequences of synaptogenesis occur in the cerebellar system, as in other synaptic circuits of the brain. In postmortem brain sections of 172 human fetuses and neonates, synaptophysin immunoreactivity was studied in nuclei of the Guillain-Mollaret triangle: dentato-olivo-rubro-cerebellar circuit. Synaptophysin demonstrates not only progressive increase in synaptic vesicles in each structure, but also shows the development of shape from amorphous globular neuronal aggregates to undulated nuclei. Intensity of synaptophysin reactivity is strong before the mature shape of these nuclei is achieved. Accessory olivary and deep cerebellar nuclei are intensely stained earlier than the principal olivary and dentate nuclei. The dorsal blades of both form earlier than the ventral, with reactivity initially peripheral. Initiation of synaptophysin reactivity is at 13 weeks in the inferior olive (r6, r7) and at 16 weeks in the dentate (r2). Initial synaptic vesicles are noted at 13 weeks in the red nucleus (r0); synapses form initially on the small neurons at 13 weeks but thereafter simultaneously on small and large neurons. Form and reactivity follow caudorostral, dorsoventral and mediolateral gradients in the axes of the rhombencephalon. This study provides control data to serve as a basis for interpreting aberrations in synaptogenesis in malformations of the cerebellar system, genetic disorders and acquired insults to the cerebellum and brainstem during fetal life, applicable to tissue sections and complementing biochemical and molecular techniques.

The brain adapts to chronic ethanol intoxication by altering synaptic and ion-channel function to increase excitability, a homeostatic counterbalance to inhibition by alcohol. Delirium tremens occurs when those adaptations are unmasked during withdrawal, but little is known about whether the primate brain returns to normal with repeated bouts of ethanol abuse and abstinence. Here, we show a form of bidirectional plasticity of pacemaking currents induced by chronic heavy drinking within the inferior olive of cynomolgus monkeys. Intracellular recordings of inferior olive neurons demonstrated that ethanol inhibited the tail current triggered by release from hyperpolarization (I tail ). Both the slow deactivation of hyperpolarization-activated cyclic nucleotide-gated channels conducting the hyperpolarization-activated inward current and the activation of Ca v 3.1 channels conducting the T-type calcium current (I T ) contributed to I tail , but ethanol inhibited only the I T component of I tail . Recordings of inferior olive neurons obtained from chronically intoxicated monkeys revealed a significant up-regulation in I tail that was induced by 1 y of daily ethanol self-administration. The up-regulation was caused by a specific increase in I T which (i) greatly increased neurons' susceptibility for rebound excitation following hyperpolarization and (ii) may have accounted for intention tremors observed during ethanol withdrawal. In another set of monkeys, sustained abstinence produced the opposite effects: (i) a reduction in rebound excitability and (ii) a down-regulation of I tail caused by the down-regulation of both the hyperpolarization-activated inward current and I T . Bidirectional plasticity of two hyperpolarization-sensitive currents following chronic ethanol abuse and abstinence may underlie persistent brain dysfunction in primates and be a target for therapy.

The aims of this study were: (1) to test whether higher spatial resolution diffusion tensor images and a higher field strength (3 T) enable a more accurate delineation of the anatomical tract within the brainstem, and, in particular, (2) to try to distinguish the different components of the corticopontocerebellar paths in terms of their cortical origins. The main tracts of the brainstem of four volunteers were studied at 3 T using a probabilistic diffusion tensor imaging (DTI) axonal tracking. The resulting tractograms enabled anatomical well-delineated structures to be identified on the diffusion tensor coloured images. We tracked corticopontine, corticospinal, central tegmental, inferior and superior cerebellopeduncular, transverse, medial lemniscal and, possibly, longitudinal medial fibres. Moreover, DTI tracking allowed a broad delineation of the corticopontocerebellar paths. Diffusion tensor coloured images allow a rapid and reliable access to the white matter broad parcellation of the brainstem and of the cerebellum, which can be completed by fibre tracking. However, a more accurate and exhaustive depiction of the anatomical connectivity within the brainstem requires the application of more sophisticated techniques and tractography algorithms, such as diffusion spectrum imaging.

Few imaging studies have been devoted to the structural and functional connectivity of the red and inferior olivary nuclei although these two nuclei represent two main targets of the cerebellum within the brainstem. However, the RN is anatomically and functionally related to a widespread sensorimotor, limbic, and executive brain network. It projects massively onto the principal olive with which it contributes to a cerebello-rubro-olivo-cerebellar loop modulated by cortical and subcortical afferents. Despite a minor role in planning and execution of rhythmic movements, the red nucleus in conjunction with the inferior olive, more specifically involved in the detection of “unexpected” events, contributes to sensorimotor, sensory and, likely, cognitive higher functions.

Projections to the inferior colliculus (IC) from the lateral and medial superior olivary nuclei (LSO and MSO) were studied in the gerbil (Meriones unguiculatus) with neuroanatomical tract-tracing methods. The terminal fields of projecting axons were labeled via anterograde transport of biotinylated dextran amine (BDA) and were localized on series of horizontal sections through the IC. In addition, to make the results easier to visualize in three dimensions and to facilitate comparisons among cases, the data were also reconstructed into the transverse plane. The results show that the terminal fields from the low frequency parts of the LSO and MSO are concentrated in a dorsal, lateral, and rostral area that is referred to as the \"pars lateralis\" of the central nucleus by analogy with the cat. This region also receives substantial input from both the contralateral and ipsilateral cochlear nuclei (Cant and Benson, 2008) and presumably plays a major role in processing binaural, low frequency information. The basic pattern of organization in the gerbil IC is similar to that of other rodents, although the low frequency part of the central nucleus in gerbils appears to be relatively greater than in the rat, consistent with differences in the audiograms of the two species.