Principal cells of the brainstem's interaural sound level detector are temporal differentiators rather than integrators.

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.

Active integration of glutamatergic input to the inferior olive generates bidirectional postsynaptic potentials.

KEY POINTS: We establish experimental preparations for optogenetic investigation of glutamatergic input to the inferior olive. Neurones in the principal olivary nucleus receive monosynaptic extra-somatic glutamatergic input from the neocortex. Glutamatergic inputs to neurones in the inferior olive generate bidirectional postsynaptic potentials (PSPs), with a fast excitatory component followed by a slower inhibitory component. Small conductance calcium-activated potassium (SK) channels are required for the slow inhibitory component of glutamatergic PSPs and oppose temporal summation of inputs at intervals ≤ 20 ms. Active integration of synaptic input within the inferior olive may play a central role in control of olivo-cerebellar climbing fibre signals. ABSTRACT: The inferior olive plays a critical role in motor coordination and learning by integrating diverse afferent signals to generate climbing fibre inputs to the cerebellar cortex. While it is well established that climbing fibre signals are important for motor coordination, the mechanisms by which neurones in the inferior olive integrate synaptic inputs and the roles of particular ion channels are unclear. Here, we test the hypothesis that neurones in the inferior olive actively integrate glutamatergic synaptic inputs. We demonstrate that optogenetically activated long-range synaptic inputs to the inferior olive, including projections from the motor cortex, generate rapid excitatory potentials followed by slower inhibitory potentials. Synaptic projections from the motor cortex preferentially target the principal olivary nucleus. We show that inhibitory and excitatory components of the bidirectional synaptic potentials are dependent upon AMPA (GluA) receptors, are GABAA independent, and originate from the same presynaptic axons. Consistent with models that predict active integration of synaptic inputs by inferior olive neurones, we find that the inhibitory component is reduced by blocking large conductance calcium-activated potassium channels with iberiotoxin, and is abolished by blocking small conductance calcium-activated potassium channels with apamin. Summation of excitatory components of synaptic responses to inputs at intervals ≤ 20 ms is increased by apamin, suggesting a role for the inhibitory component of glutamatergic responses in temporal integration. Our results indicate that neurones in the inferior olive implement novel rules for synaptic integration and suggest new principles for the contribution of inferior olive neurones to coordinated motor behaviours.

Directional hearing by linear summation of binaural inputs at the medial superior olive.

Neurons in the medial superior olive (MSO) enable sound localization by their remarkable sensitivity to submillisecond interaural time differences (ITDs). Each MSO neuron has its own "best ITD" to which it responds optimally. A difference in physical path length of the excitatory inputs from both ears cannot fully account for the ITD tuning of MSO neurons. As a result, it is still debated how these inputs interact and whether the segregation of inputs to opposite dendrites, well-timed synaptic inhibition, or asymmetries in synaptic potentials or cellular morphology further optimize coincidence detection or ITD tuning. Using in vivo whole-cell and juxtacellular recordings, we show here that ITD tuning of MSO neurons is determined by the timing of their excitatory inputs. The inputs from both ears sum linearly, whereas spike probability depends nonlinearly on the size of synaptic inputs. This simple coincidence detection scheme thus makes accurate sound localization possible.

Human interaural time difference thresholds for sine tones: the high-frequency limit.

The smallest detectable interaural time difference (ITD) for sine tones was measured for four human listeners to determine the dependence on tone frequency. At low frequencies, 250-700 Hz, threshold ITDs were approximately inversely proportional to tone frequency. At mid-frequencies, 700-1000 Hz, threshold ITDs were smallest. At high frequencies, above 1000 Hz, thresholds increased faster than exponentially with increasing frequency becoming unmeasurably high just above 1400 Hz. A model for ITD detection began with a biophysically based computational model for a medial superior olive (MSO) neuron that produced robust ITD responses up to 1000 Hz, and demonstrated a dramatic reduction in ITD-dependence from 1000 to 1500 Hz. Rate-ITD functions from the MSO model became inputs to binaural display models-both place based and rate-difference based. A place-based, centroid model with a rigid internal threshold reproduced almost all features of the human data. A signal-detection version of this model reproduced the high-frequency divergence but badly underestimated low-frequency thresholds. A rate-difference model incorporating fast contralateral inhibition reproduced the major features of the human threshold data except for the divergence. A combined, hybrid model could reproduce all the threshold data.

Último minuto en atrofia multisistémica / Latest update on multiple system atrophy

Introducción. La Atrofia Multisistémica (AMS) es un trastorno neurodegenerativo, rápidamente progresivo, esporádico, que se presenta con una combinación de síntomas disautonómicos, parkinsonianos, cerebelosos, y corticospinales. La etiopatogenia es desconocida, pero parece existir un papel genético subyacente que implica a la α-sinucleína. El diagnóstico temprano de la enfermedad ha mejorado con los nuevos criterios clínicos de 2008, apoyados por técnicas de neuroimagen estructural y funcional. El tratamiento sigue siendo sintomático, pero se han publicado recientes ensayos clínicos con opciones terapéuticas que intentan frenar la progresión natural de la enfermedad. Objetivo. Revisar los avances más notorios publicados en la literatura científica en los últimos 5 años en la AMS. Desarrollo. Se ha revisado la literatura de los últimos años y se presentan los avances más significativos en la patogenia, diagnóstico, y tratamiento de la AMS, así como las principales perspectivas futuras en dichos campos. Conclusiones. La patogenia de la AMS sigue siendo desconocida, aunque las variaciones en el locus SNCA del cromosoma 4q22.1 que codifica la α-sinucleína juegan un papel destacado. Los nuevos criterios diagnósticos han permitido mejorar la precisión diagnóstica en los estadios iniciales de la enfermedad. Existen diversos ensayos clínicos con prometedoras terapias modificadoras de la enfermedad, aunque son necesarios más estudios futuros para determinar el verdadero alcance clínico de las mismas (AU)

Introduction. Multiple System Atrophy (MSA) is a neurodegenerative, quickly progressive, sporadic disorder that presents with a combination of dysautonomic, parkinsonian, cerebellar and corticospinal symptoms. The aetiopathogenesis is unknown, but there seems to be an underlying genetic role involving a-synuclein. Early diagnosis of the disease has improved with the new clinical criteria of 2008, backed by structural and functional neuroimaging techniques. Treatment continues to be symptomatic, but recent clinical trails have been conducted with therapeutic options that attempt to curb the natural progression of the disease. www.neurologia.com Rev Neurol 2012; 54 (Supl 4): S45-S51 S51 PONENCIA Aims. The purpose of this study is to review the most significant advances in MSA reported in the scientific literature in the last 5 years. Development. The literature from the last few years was reviewed and we report on the most significant advances in the pathogenesis, diagnosis and treatment of MSA, as well as the main future perspectives in those fields. Conclusions. The pathogenesis of MSA remains unknown, although variations in the SNCA locus of chromosome 4q22.1, which codes for a synuclein, play an important role. The new diagnostic criteria have allowed diagnosis to become more accurate in the early stages of the disease. Several clinical trials have been carried out with promising disease-modifying therapies, although further studies will be needed in the future to determine their true clinical scope (AU)

Effects of ketamine on response properties of neurons in the superior paraolivary nucleus of the mouse.

The superior paraolivary nucleus (SPON; alternative abbreviation: SPN for the same nucleus in certain species) is a prominent brainstem structure that provides strong inhibitory input to the auditory midbrain. Previous studies established that SPON neurons encode temporal sound features with high precision. These earlier characterizations of SPON responses were recorded under the influence of ketamine, a dissociative anesthetic agent and known antagonist of N-methyl-d-aspartate glutamate (NMDA) receptors. Because NMDA alters neural responses from the auditory brainstem, single unit extracellular recordings of SPON neurons were performed in the presence and absence of ketamine. In doing so, this study represents the first in vivo examination of the SPON of the mouse. Herein, independent data sets of SPON neurons are characterized that did or did not receive ketamine, as well as neurons that were recorded both prior to and following ketamine administration. In all conditions, SPON neurons exhibited contralaterally driven spikes triggered by the offset of pure tone stimuli. Ketamine lowered both evoked and spontaneous spiking, decreased the sharpness of frequency tuning, and increased auditory thresholds and first-spike latencies. In addition, ketamine limited the range of modulation frequencies to which neurons phase-locked to sinusoidally amplitude-modulated tones.

Sound rhythms are encoded by postinhibitory rebound spiking in the superior paraolivary nucleus.

The superior paraolivary nucleus (SPON) is a prominent structure in the auditory brainstem. In contrast to the principal superior olivary nuclei with identified roles in processing binaural sound localization cues, the role of the SPON in hearing is not well understood. A combined in vitro and in vivo approach was used to investigate the cellular properties of SPON neurons in the mouse. Patch-clamp recordings in brain slices revealed that brief and well timed postinhibitory rebound spiking, generated by the interaction of two subthreshold-activated ion currents, is a hallmark of SPON neurons. The I(h) current determines the timing of the rebound, whereas the T-type Ca(2+) current boosts the rebound to spike threshold. This precisely timed rebound spiking provides a physiological explanation for the sensitivity of SPON neurons to sinusoidally amplitude-modulated (SAM) tones in vivo, where peaks in the sound envelope drive inhibitory inputs and SPON neurons fire action potentials during the waveform troughs. Consistent with this notion, SPON neurons display intrinsic tuning to frequency-modulated sinusoidal currents (1-15Hz) in vitro and discharge with strong synchrony to SAMs with modulation frequencies between 1 and 20 Hz in vivo. The results of this study suggest that the SPON is particularly well suited to encode rhythmic sound patterns. Such temporal periodicity information is likely important for detection of communication cues, such as the acoustic envelopes of animal vocalizations and speech signals.

The sound of silence: ionic mechanisms encoding sound termination.

Offset responses upon termination of a stimulus are crucial for perceptual grouping and gap detection. These gaps are key features of vocal communication, but an ionic mechanism capable of generating fast offsets from auditory stimuli has proven elusive. Offset firing arises in the brainstem superior paraolivary nucleus (SPN), which receives powerful inhibition during sound and converts this into precise action potential (AP) firing upon sound termination. Whole-cell patch recording in vitro showed that offset firing was triggered by IPSPs rather than EPSPs. We show that AP firing can emerge from inhibition through integration of large IPSPs, driven by an extremely negative chloride reversal potential (E(Cl)), combined with a large hyperpolarization-activated nonspecific cationic current (I(H)), with a secondary contribution from a T-type calcium conductance (I(TCa)). On activation by the IPSP, I(H) potently accelerates the membrane time constant, so when the sound ceases, a rapid repolarization triggers multiple offset APs that match onset timing accuracy.

Slow build-up of cochlear suppression during sustained contralateral noise: central modulation of olivocochlear efferents?

The strength of the medial olivocochlear (OC) reflex is routinely assayed by measuring suppression of ipsilateral responses such as otoacoustic emissions (OAEs) by a brief contralateral noise, e.g., (Berlin, C.I., Hood, L.J., Cecola, P., Jackson, D.F., Szabo, P. 1993. Does type I afferent dysfunction reveal itself through lack of efferent suppression. Hear. Res. 65, 40-50). Here, we show in anesthetized guinea pigs, that the magnitude of OC-mediated suppression of ipsilateral cochlear responses (i.e., compound actions potentials (CAPs), distortion product (DP) OAEs and round-window noise) slowly builds over 2-3 min during a sustained contralateral noise. The magnitude of this build-up suppression was largest at low ipsilateral stimulus intensities, as seen for suppression measured at contra-noise onset. However, as a function of stimulus frequency, build-up suppression magnitude was complementary to onset suppression, i.e., largest at the lowest and highest frequencies tested. Both build-up and onset suppression were eliminated by cutting the OC bundle. In contrast to "slow effects" of shock-evoked medial OC activity (Sridhar, T.S., Liberman, M.C., Brown, M.C., Sewell, W.F. 1995. A novel cholinergic "slow effect" of efferent stimulation on cochlear potentials in the guinea pig. J. Neurosci. 15, 3667-3678), which are mediated by slow intracellular changes in Ca concentration in OHCs, build-up effects of contralateral noise are immediately extinguished upon OC bundle transection and are likely mediated by central modulation of the response rates in MOC fibers due to the sustained noise. Results suggest that conventional tests of OC reflex strength may underestimate its magnitude in noisy environments.

Experience-dependent refinement of the inhibitory axons projecting to the medial superior olive.

Neurons in the medial superior olive (MSO) analyze interaural time differences (ITDs) by comparing the arrival times of the two excitatory inputs from each ear using a coincidence detection mechanism. They also receive a prominent inhibitory, glycinergic projection from the ipsilateral medial nucleus of the trapezoid body (MNTB), which contributes to the fine-tuning of ITD analysis. Here, we investigated developmental changes of the axonal arborisation pattern of single Microruby-labeled MNTB neurons projecting to the MSO region. During the first 2 weeks after hearing onset, the axonal arborisation of MNTB neurons was significantly refined resulting in a narrowed projection area across the tonotopic axis of the MSO and a redistribution of the axonal endsegments to a mostly somatic location. Rearing the animals in omnidirectional noise prevented the structural changes of single MNTB projections. These results indicate that the functional elimination of inhibitory inputs on MSO neurons after hearing onset, as described previously, is paralleled by a structural, site-specific refinement of the inputs and is dependent on the normal acoustic experience of the animal.

Interaural level difference discrimination thresholds for single neurons in the lateral superior olive.

The lateral superior olive (LSO) is one of the earliest sites in the auditory pathway that is involved in processing acoustical cues to sound location. Here, we tested the hypothesis that LSO neurons can signal small changes in interaural level differences (ILDs), a cue to horizontal sound location, of pure tones based on discharge rate consistent with psychophysical performance in the discrimination of ILDs. Neural thresholds for ILD discrimination were determined from the discharge rates and associated response variability of single units in response to 300 ms tones in the LSO of barbiturate-anesthetized cats using detection theory. Neural response variability was well described by a power function of the mean rate, both in individual neurons and collectively; LSO neurons were less variable than expected from a Poisson process. Compared with psychophysical data, the best-threshold ILDs of single LSO neurons were comparable with or better than behavior over the full range of frequencies (0.3-35 kHz) and pedestal ILDs (+/-25 dB) explored in this study. With a pedestal ILD of 0 dB, ILD increments of 1 dB could be discriminated by some neurons, with a median of 4.35 dB across neurons. For pedestal ILDs away from 0 dB, the best-threshold ILDs were as low as 0.5 dB, with a median of 2.3 dB. These findings support the hypothesis that the LSO plays a role in the extraction of ILD, and that the representation of ILD by LSO neurons may set a lower bound on the behavioral sensitivity to ILDs.

Subclinical dysfunction of cochlea and cochlear efferents in migraine: an otoacoustic emission study.

Otoacoustic emission (OAE) testing enables us to identify the cochlear component of a hearing disorder and to monitor objectively minute changes in cochlear status undetectable by other audiological methods. Contralateral sound-induced suppression is mediated by medial superior olivary complex efferents which induce hyperpolarization counteracting the amplifying effects of outer hair cell (OHC) activity. The aim of this study was to assess functions of cochlea and its efferents in migraine using OAE testing and contralateral suppression of transiently evoked OAEs (TEOAE). Fifty-three migraineurs (106 ears) and 41 healthy subjects (82 ears) were included and pure tone audiometry (PTA), speech discrimination scores (SDS), distortion product OAE (DPOAE), TEOAE and contralateral suppression of TEOAEs were tested. PTA and SDS of migraineurs and controls were not different (P > 0.05). DPOAEs were tested between 1 and 6 kHz and a significant difference was detected only at 5 kHz frequency, where DPOAE amplitudes in migraine with aura (MA) were lower than in controls (P < 0.03). The mean amplitudes of TEOAEs were statistically insignificant between controls and migraine groups. Contralateral sound stimulus induced significant decrease in amplitudes of TEOAE (P = 0.005) in controls. In patients with migraine without aura and MA, mean amplitudes of TEOAEs were not suppressed by contralateral sound stimulus (P > 0.05). As PTA, SDS and DPOAE tests demonstrate normal functioning of inner ear between 1 and 4 kHz, absence of suppression of the TEOAEs by contralateral sound stimulation indicates the presence of dysfunction either in the medial olivocochlear complex in the brainstem or at the synaptic transmission between olivocochlear efferents and OHCs in the cochlea. Disruption in the contralateral suppression may be one of the mechanisms predisposing to the phonophobia symptom associated with migraine headache.

Auditory brainstem neural activation patterns are altered in EphA4- and ephrin-B2-deficient mice.

Auditory processing requires proper formation of tonotopically ordered projections. We have evaluated the role of an Eph receptor tyrosine kinase and an ephrin ligand in the development of these frequency maps. We demonstrated expression of EphA4 and ephrin-B2 in auditory nuclei and found expression gradients along the frequency axis in neonates. We tested the roles of EphA4 and ephrin-B2 in development of auditory projections by evaluating whether mutations result in altered patterns of expression of the immediate early gene c-fos after exposure to pure tone stimuli. We evaluated two nuclei, the dorsal cochlear nucleus (DCN) and the medial nucleus of the trapezoid body (MNTB), which project in two distinct auditory pathways. The mean number of c-fos-positive neurons in EphA4(-/-) DCN after 8-kHz pure tone stimulation was 42% lower than in wild-type DCN. Along the dorsoventral, tonotopic axis of DCN, the mean position of c-fos-positive neurons was similar for mutant and wild-type mice, but the spread of these neurons along the tonotopic axis was 35% greater for ephrin-B2(lacZ/+) mice than for wild-type mice. We also examined these parameters in MNTB after exposure to 40-kHz pure tones. Both EphA4(-/-) and ephrin-B2(lacZ/+) mice had significantly fewer c-fos-positive cells than wild-type littermates. The labeled band of cells was narrower and laterally shifted in EphA4(-/-) mice compared with wild-type mice. These differences in cell number and distribution suggest that EphA4 and ephrin-B2 signaling influence auditory activation patterns.

Early appearance of inhibitory input to the MNTB supports binaural processing during development.

Despite the peripheral and central immaturities that limit auditory processing in juvenile animals, they are able to lateralize sounds using binaural cues. This study explores a central mechanism that may compensate for these limitations during development. Interaural time and level difference processing by neurons in the superior olivary complex depends on synaptic inhibition from the medial nucleus of the trapezoid body (MNTB), a group of inhibitory neurons that is activated by contralateral sound stimuli. In this study, we examined the maturation of coding properties of MNTB neurons and found that they receive an inhibitory influence from the ipsilateral ear that is modified during the course of postnatal development. Single neuron recordings were obtained from the MNTB in juvenile (postnatal day 15-19) and adult gerbils. Approximately 50% of all recorded MNTB neurons were inhibited by ipsilateral sound stimuli, but juvenile neurons displayed a much greater suppression of firing as compared with those in adults. A comparison of the prepotential and postsynaptic action potential indicated that inhibition occurred at the presynaptic level, likely within the cochlear nucleus. A simple linear model of level difference detection by lateral superior olivary neurons that receive input from MNTB suggested that inhibition of the MNTB may expand the response of LSO neurons to physiologically realistic level differences, particularly in juvenile animals, at a time when these cues are reduced.

The distribution and the modulation of tyrosine hydroxylase immunoreactivity in the lateral olivocochlear system of the guinea-pig.

It was previously shown that tyrosine hydroxylase (TH) immunoreactivity in the terminals of the lateral efferents of the cochlea is decreased by acoustic trauma and that sound preconditioning counteracted this decrease [Hear Res 174 (2002) 124]. Here we identify those neurons in the lateral olivocochlear system (LOC) in the brainstem that regulates the peripheral expression of TH in the cochlea. By employing retrograde tracing techniques, dextran-labeled neurons were found predominantly in the ipsilateral LOC system including lateral superior olive (LSO), and the surrounding periolivary regions (dorsal periolivary nucleus [DPO], dorsolateral periolivary nucleus [DLPO], lateral nucleus of trapezoid body [LNTB]). Employing immunocytochemistry, it was found that a control group had 35% of the ipsilateral LOC neurons positively stained with TH. Of the total population of TH neurons, 77% were double-stained (TH and dextran) in the LOC system. Acoustic trauma decreased the number of TH positive neurons in the LSO and the surrounding DLPO, and caused a reduction of TH fiber immunolabeling in these regions. Changes were not found in the DPO or the LNTB after acoustic trauma. Sound conditioning protected against the decrease of TH immunolabeling by acoustic trauma and increased the fiber staining for TH in the LSO and DLPO, but not in the DPO or the LNTB. These results provide evidence that TH positive neurons are present in the LOC system in the guinea-pig. It is now demonstrated that protection against acoustic trauma by sound conditioning has a central component that is governed by TH in the LSO and the surrounding periolivary DLPO region.

Responses of medial olivocochlear neurons. Specifying the central pathways of the medial olivocochlear reflex.

Medial olivocochlear (MOC) neurons project to outer hair cells (OHC), forming the efferent arm of a reflex that affects sound processing and offers protection from acoustic overstimulation. The central pathways that trigger the MOC reflex in response to sound are poorly understood. Insight into these pathways can be obtained by examining the responses of single MOC neurons recorded from anesthetized guinea pigs. Response latencies of MOC neurons are as short as 5 ms. This latency is consistent with the idea that type I, but not type II, auditory-nerve fibers provide the major inputs to the reflex interneurons in the cochlear nucleus. This short latency also implies that the cochlear-nucleus interneurons have rapidly conducting axons. In the cochlear nucleus, lesions of the posteroventral subdivision (PVCN), but not the anteroventral (AVCN) or dorsal (DCN) subdivisions, produce permanent disruption of the MOC reflex, based on a metric of adaptation of the distortion-product otoacoustic emission (DPOAE). This finding supports earlier anatomical results demonstrating that some PVCN neurons project to MOC neurons. Within the PVCN, there are two general types of units when classified according to poststimulus time histograms: onset units and chopper units. The MOC response is sustained and cannot be produced solely by inputs having an onset pattern. The MOC reflex interneurons are thus likely to be chopper units of PVCN. Also supporting this conclusion, chopper units and MOC neurons both have sharp frequency tuning. Thus, the most likely pathway for the sound-evoked MOC reflex begins with the responses of hair cells, proceeds with type I auditory-nerve fibers, PVCN chopper units, and MOC neurons, and ends with the MOC terminations on OHC.

Topography of interaural temporal disparity coding in projections of medial superior olive to inferior colliculus.

Neurons in the medial superior olive encode interaural temporal disparity, and their receptive fields indicate the location of a sound source in the azimuthal plane. It is often assumed that the projections of these neurons transmit the receptive field information about azimuth from point to point, much like the projections of the retina to the brain transmit the position of a visual stimulus. Yet this assumption has never been verified. Here, we use physiological and anatomical methods to examine the projections of the medial superior olive to the inferior colliculus for evidence of a spatial topography that would support transmission of azimuthal receptive fields. The results show that this projection does not follow a simple point-to-point topographical map of receptive field location. Thus, the representation of sound location along the azimuth in the inferior colliculus most likely relies on a complex, nonlinear map.

Physiological response properties of neurons in the superior paraolivary nucleus of the rat.

The superior paraolivary nucleus (SPON) is a prominent nucleus of the superior olivary complex. In rats, this nucleus is composed of a morphologically homogeneous population of GABAergic neurons that receive excitatory input from the contralateral cochlear nucleus and inhibitory input from the ipsilateral medial nucleus of the trapezoid body. SPON neurons provide a dense projection to the ipsilateral inferior colliculus and are thereby capable of exerting profound modulatory influence on collicular neurons. Despite recent interest in the structural and connectional features of SPON, little is presently known concerning the physiological response properties of this cell group or its functional role in auditory processing. We utilized extracellular, in vivo recording methods to study responses of SPON neurons to broad band noise, pure tone, and amplitude-modulated pure tone stimuli. Localization of recording sites within the SPON provides evidence for a medial (high frequency) to lateral (low frequency) tonotopic representation of frequencies within the nucleus. Best frequencies of SPON neurons spanned the audible range of the rat and receptive fields were narrow with V-shaped regions near threshold. Nearly all SPON neurons responded at the offset of broad band noise and pure tone stimuli. The vast majority of SPON neurons displayed very low rates of spontaneous activity and only responded to stimuli presented to the contralateral ear, although a small population showed binaural facilitation. Most SPON neurons also generated spike activity that was synchronized to sinusoidally amplitude-modulated tones. Taken together, these data suggest that SPON neurons may serve to encode temporal features of complex sounds, such as those contained in species-specific vocalizations.

Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice.

In the mammalian retina, a small subset of retinal ganglion cells (RGCs) are intrinsically photosensitive, express the opsin-like protein melanopsin, and project to brain nuclei involved in non-image-forming visual functions such as pupillary light reflex and circadian photoentrainment. We report that in mice with the melanopsin gene ablated, RGCs retrograde-labeled from the suprachiasmatic nuclei were no longer intrinsically photosensitive, although their number, morphology, and projections were unchanged. These animals showed a pupillary light reflex indistinguishable from that of the wild type at low irradiances, but at high irradiances the reflex was incomplete, a pattern that suggests that the melanopsin-associated system and the classical rod/cone system are complementary in function.

GABAergic and glutamatergic modulation of spontaneous and motor-cortex-evoked complex spike activity.

Olivocerebellar activity is organized such that synchronous complex spikes occur primarily among Purkinje cells located within the same parasagittally oriented strip of cortex. Previous findings have shown that this synchrony distribution is modulated by the release of GABA and glutamate within the inferior olive, which probably act by controlling the efficacy of the electrotonic coupling between olivary neurons. The relative strengths of these two neurotransmitters in modulating the patterns of synchrony were compared by obtaining multiple electrode recordings of spontaneous crus 2a complex spike activity during intraolivary injection of solutions containing a GABA(A) (picrotoxin) and/or AMPA [1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide disodium (NBQX)] receptor antagonist. Injection of either antagonist led to increased synchrony between cells located within the same parasagittally oriented approximately 250-microm-wide cortical strip. Picrotoxin also increased complex spike synchrony among cells located in different cortical strips, leading to a less prominent banding pattern, whereas injections of NBQX tended to decrease complex spike synchrony among such cells, enhancing the banding pattern. The relative strength of these two classes of olivary afferents was assessed by first injecting one of the antagonists alone and then in combination with the other. The enhanced banding pattern of complex spike synchrony following injection of NBQX alone remained during the subsequent combined injection of both antagonists. Furthermore, the widespread synchronization of complex spike activity following injection of picrotoxin alone was partially or completely reversed by combined injection of picrotoxin and NBQX. Changes in the climbing fiber reflex induced by the intraolivary injections paralleled the changes observed for spontaneous complex spike activity, indicating that the effects of picrotoxin and NBQX on the synchrony distribution reflect changes in the pattern of effective coupling of inferior olivary neurons and demonstrating that synchronous complex spike activity does not require simultaneous excitatory input to olivary cells. Finally the pattern of synchrony during motor cortical stimulation was examined. It was found that the patterns of synchrony for motor-cortex-evoked complex spike activity were similar to those of spontaneous activity, indicating an important role for electrotonic coupling in determining the response of the olivocerebellar system to afferent input. Moreover, intraolivary injections of picrotoxin increased the spatial distribution of the evoked response. In sum, the results provide evidence for the hypothesis that electrotonic coupling of inferior olivary neurons via gap junctions is the mechanism underlying complex spike synchrony and that this coupling plays an important role in determining the responses of the olivocerebellar system to synaptic input.