Differential effects of inferior olive lesion on vestibulo-ocular and optokinetic motor learning.

The combined operation of optokinetic reflex (OKR) and vestibular-ocular reflex (VOR) is essential for image stability during self-motion. Retinal slip signals, which provide neural substrate for OKR and VOR plasticity, are delivered to the inferior olive. Although it has been assumed that the neural circuitry and mechanisms underlying OKR and VOR plasticity are shared, differential role of the inferior olive in the plasticity of OKR and VOR has not been clearly established. To investigate the differential effect of inferior olive lesion on OKR and VOR plasticity, we examined the change of OKR and VOR gains after gain-up and gain-down VOR training. The results demonstrated that inferior olive-lesion differentially affected cerebellum-dependent motor learning. In control mice, OKR gain increased after both gain-up and gain-down VOR training, and VOR gain increased after gain-up VOR training and decreased after gain-down VOR training. In inferior olive-lesioned mice, OKR gain decreased after both gain-up and gain-down VOR training, and while VOR gain did not significantly change after gain-up VOR training, VOR gain decreased after gain-down VOR training. We suggest that multiple mechanisms of plasticity are differentially involved in VOR and OKR adaptation, and gain-up and gain-down VOR learning rely on different plasticity mechanisms.

Effects of inferior olive lesion on fear-conditioned bradycardia.

The inferior olive (IO) sends excitatory inputs to the cerebellar cortex and cerebellar nuclei through the climbing fibers. In eyeblink conditioning, a model of motor learning, the inactivation of or a lesion in the IO impairs the acquisition or expression of conditioned eyeblink responses. Additionally, climbing fibers originating from the IO are believed to transmit the unconditioned stimulus to the cerebellum in eyeblink conditioning. Studies using fear-conditioned bradycardia showed that the cerebellum is associated with adaptive control of heart rate. However, the role of inputs from the IO to the cerebellum in fear-conditioned bradycardia has not yet been investigated. To examine this possible role, we tested fear-conditioned bradycardia in mice by selective disruption of the IO using 3-acetylpyridine. In a rotarod test, mice with an IO lesion were unable to remain on the rod. The number of neurons of IO nuclei in these mice was decreased to ∼40% compared with control mice. Mice with an IO lesion did not show changes in the mean heart rate or in heart rate responses to a conditioned stimulus, or in their responses to a painful stimulus in a tail-flick test. However, they did show impairment of the acquisition/expression of conditioned bradycardia and attenuation of heart rate responses to a pain stimulus used as an unconditioned stimulus. These results indicate that the IO inputs to the cerebellum play a key role in the acquisition/expression of conditioned bradycardia.

Microlesions of the inferior olive reduce vestibular modulation of Purkinje cell complex and simple spikes in mouse cerebellum.

Cerebellar Purkinje cells have two distinct action potentials: complex spikes (CSs) are evoked by single climbing fibers that originate from the contralateral inferior olive. Simple spikes (SSs) are often ascribed to mossy fiber-granule cell-parallel fiber inputs to Purkinje cells. Although generally accepted, this view lacks experimental support. Vestibular stimulation independently activates primary afferent mossy fibers and tertiary afferent climbing fibers that project to the uvula-nodulus (folia 8-10). CSs and SSs normally discharge antiphasically during sinusoidal roll-tilt. When CSs increase, SSs decrease. We tested the relative independence of these pathways in mice by making electrolytic microlesions of the two inferior olivary nuclei from which vestibular climbing fibers originate; the ß-nucleus and dorsomedial cell column. This reduced vestibular climbing fiber signaling to the contralateral folia 8-10, while leaving intact vestibular primary and secondary afferent mossy fibers. We recorded from Purkinje cells and interneurons in folia 8-10, identified by juxtacellular labeling with Neurobiotin. Microlesions of the inferior olive increased the spontaneous discharge of SSs in contralateral folia 8-10, but blocked their modulation during vestibular stimulation. The vestibularly evoked discharge of excitatory cerebellar interneurons (granule cells and unipolar brush cells) was not modified by olivary microlesions. The modulated discharge of stellate cells, but not Golgi cells, was reduced by olivary microlesions. We conclude that vestibular modulation of CSs and SSs depends on intact climbing fibers. The absence of vestibularly modulated SSs following olivary microlesions reflects the loss of climbing fiber-evoked stellate cell discharge.

Degeneração olivar hipertrófica após ressecção de metástase cerebelar: relato de caso e revisão da literatura / Hypertrophic olivary degeneration secondary to resection of cerebellar metastasis: case report and literature review

Degeneração olivar hipertrófica resulta de lesão no circuito formado pelos núcleos denteado, rubro e olivar inferior (triângulo de Guillain e Mollaret). Pode ser secundária a hemorragias, trauma, neoplasias, entre outras causas que lesem estruturas desse circuito. Destaca-se a relevância deste relato de caso por apresentar um caso de degeneração olivar hipertrófica bilateral, secundária a insulto em ambos os núcleos denteados após ressecção de metástase.

Hypertrophic olivary degeneration represents the results of a lesionthat damages the neuronal connections between the dentate nucleus of the cerebellum, the red nucleus, and the inferior olivary nucleus (Guillain Mollaret triangle). This entity can occur secondary to hemorrhage, trauma, neoplasm and other causes that candamage structures of this pathway. This is an important case report because of its description of a bilateral hypertrophic olivary degeneration, secondary to injuries in both dentate nucleous after metastatic resection.

Olivocochlear efferent control in sound localization and experience-dependent learning.

Efferent auditory pathways have been implicated in sound localization and its plasticity. We examined the role of the olivocochlear system (OC) in horizontal sound localization by the ferret and in localization learning following unilateral earplugging. Under anesthesia, adult ferrets underwent olivocochlear bundle section at the floor of the fourth ventricle, either at the midline or laterally (left). Lesioned and control animals were trained to localize 1 s and 40 ms amplitude-roved broadband noise stimuli from one of 12 loudspeakers. Neither type of lesion affected normal localization accuracy. All ferrets then received a left earplug and were tested and trained over 10 d. The plug profoundly disrupted localization. Ferrets in the control and lateral lesion groups improved significantly during subsequent training on the 1 s stimulus. No improvement (learning) occurred in the midline lesion group. Markedly poorer performance and failure to learn was observed with the 40 ms stimulus in all groups. Plug removal resulted in a rapid resumption of normal localization in all animals. Insertion of a subsequent plug in the right ear produced similar results to left earplugging. Learning in the lateral lesion group was independent of the side of the lesion relative to the earplug. Lesions in all reported cases were verified histologically. The results suggest the OC system is not needed for accurate localization, but that it is involved in relearning localization during unilateral conductive hearing loss.

Short-term pathophysiologic changes and histopathologic findings of the auditory pathway after closed head injury, using a rabbit model.

Hearing impairment is a well-known consequence of closed head injury (CHI). The aim of this study was to elucidate the pathogenesis of CHI-induced hearing loss, using a rabbit model. Twelve New Zealand white rabbits were divided into two groups of 6. In the first group, CHI was induced mechanically, whereas the rabbits of the second group served as controls. Baseline distortion product otoacoustic emissions (DPOAEs), contralateral suppression (CS) of the DPOAEs and auditory brainstem response (ABR) were obtained. The same measurements were performed in the first group after CHI. Three hours later, the animals were sacrificed and their brain was excised and subjected to histopathologic examination. Mean I-III ABR latencies were increased and DPOAE amplitudes and CS values were reduced in the trauma group after CHI, at a statistically significant level. Histopathologic examination of the temporal lobe and brainstem showed multiple hemorrhagic and necrotic areas, with edema in the surrounding region. The vestibulocochlear nerve was severely damaged at its emerging site at the brainstem. In conclusion, both peripheral and central involvement of the auditory pathway was found after CHI. Otoacoustic emissions in conjunction with ABR may provide significant information on both peripheral and central auditory function.

Memory trace of motor learning shifts transsynaptically from cerebellar cortex to nuclei for consolidation.

Adaptation of ocular reflexes is a prototype of motor learning. While the cerebellum is acknowledged as the critical site for motor learning, the functional differences between the cerebellar cortex and nuclei in motor memory formation are not precisely known. Two different views are proposed: one that the memory is formed within the cerebellar flocculus, and the other that the memory is formed within vestibular nuclei. Here we developed a new paradigm of long-term adaptation of mouse horizontal optokinetic response eye movements and examined the location of its memory trace. We also tested the role of flocculus and inferior olive in long-term adaptation by chronic lesion experiments. Reversible bilateral flocculus shutdown with local application of 0.5 microl-5% lidocaine extinguished the memory trace of day-long adaptation, while it very little affected the memory trace of week-long adaptation. The responsiveness of vestibular nuclei after week-long adaptation was examined by measuring the extracellular field responses to the electrical stimulation of vestibular nerve under trichloroacetaldehyde anesthesia. The amplitudes and slopes of evoked monosynaptic field response (N1) of week-long adapted mice were enhanced around the medial vestibular nucleus compared with those of control mice. Chronic flocculus or inferior olive lesions abolished both day and week-long adaptations. These results suggest that the functional memory trace of short-term adaptation is formed initially within the cerebellar cortex, and later transferred to vestibular nuclei to be consolidated to a long-term memory. Both day and week-long adaptations were markedly depressed when neural nitric oxide was pharmacologically blocked locally and when neuronal nitric oxide synthase was ablated by gene knockout, suggesting that cerebellar long-term depression underlies both acquisition and consolidation of motor memory.

Purkinje cell spinogenesis during architectural rewiring in the mature cerebellum.

Spines can grow and retract within hours of activity perturbation. We investigated the time course of spine formation in a model of plasticity involving changes in brain architecture where spines of a dendritic domain become innervated by a different neuronal population. Following a lesion of rat olivocerebellar axons, by severing the inferior cerebellar peduncle, new spines grow on the deafferented proximal dendrite of the Purkinje cells (PCs) and these new spines become innervated by parallel fibres (PFs) that normally contact only the distal dendrites. The varicosities of climbing fibre (CF) terminal arbors disappear within 3 days of the lesion. Spine density in the proximal dendritic domain begins to rise within 3 days and continues to increase towards a plateau at 6-8 days. In 'slow Wallerian degeneration' mice, in which axonal degeneration is delayed, climbing fibre varicosities virtually disappear at 14 rather than 3 days. Spine density in the proximal dendritic domain is similar to control Purkinje cells up to 14 days and increases significantly 18 days postlesion. The delayed spinogenesis in the latter mutant is the result of a persistence of the climbing fibre presynaptic structure in the absence of activity. Therefore, climbing fibre activity itself is not directly responsible for the suppression of spine formation, but suppression mechanisms tend to become weaker as long as the structural dismantling of the presynaptic varicosities proceeds. Thus, spinogenesis is guided by two different mechanisms; a rapid one related to changes in homotypic remodeling and a slower one, which requires the removal of a competitive afferent.

The superior olivary complex is necessary for the full expression of the acoustic but not tactile startle response in rats.

The acoustic startle response (ASR) in rats is mediated by an oligosynaptic pathway from the cochlea via the brainstem to spinal and cranial motoneurons. The present study tested whether the superior olivary complex (SOC) plays a role in the mediation of the ASR. The SOC receives auditory information from the ventral cochlear nuclei and projects to the caudal pontine reticular nucleus (PnC), the sensorimotor interface of the ASR. Axon-sparing excitotoxic lesions of the SOC strongly reduced the ASR amplitude and slightly prolonged ASR onset and peak latencies. The integrity of PnC which is adjacent to the SOC was confirmed by testing the tactile startle response which was not affected by SOC lesions. We suggest that the SOC is necessary for a full expression of the ASR and discuss possible auditory input structures involved in the mediation of the ASR.

Effects of bilateral olivocochlear lesions on vowel formant discrimination in cats.

Operant conditioning procedures were used to measure the effects of bilateral olivocochlear lesions on the cat's discrimination thresholds for changes in the second formant frequency (deltaF2) of the vowel /epsilon/. Three cats were tested with the formant discrimination task under quiet conditions and in the presence of continuous broadband noise at signal-to-noise ratios (S/Ns) of 23, 13, and 3 dB. In quiet, vowel levels of 50 and 70 dB produced average deltaF2s of 42 and 47 Hz, respectively, and these thresholds did not change significantly in low levels of background noise (S/Ns = 23 and 13 dB). Average deltaF2s increased to 94 and 97 Hz for vowel levels of 50 and 70 dB in the loudest level of background noise (S/N = 3 dB). Average deltaF2 thresholds in quiet and in lower noise levels were only slightly affected when the olivocochlear bundle was lesioned by making bilateral cuts into the floor of the IVth ventricle. In contrast, post-lesion deltaF2 thresholds in the highest noise level were significantly larger than pre-lesion values; the most severely affected subject showed post-lesion discrimination thresholds well over 200 Hz for both 50 and 70 dB vowels. These results suggest that olivocochlear feedback may enhance speech processing in high levels of ambient noise.

Cellular generators of the binaural difference potential in cat.

In humans, lateralization and fusion of binaurally presented clicks are correlated with the latency and amplitude of the binaural difference potential (BDP) (e.g., Furst et al., 1985). The BDP is derived by subtracting the brainstem auditory evoked potential (BAEP) for binaural stimulation from the sum of the BAEPs for left and right monaural stimulation. Our aim in this work was to determine the cellular generators of the BDP and thus identify cells that may be crucial for specific types of binaural sound processing. To this end, we injected kainic acid into the superior olivary complex (SOC) or the cochlear nucleus (CN) in cats and examined the effects of the resulting lesions on the click-evoked BDP. Lesions confined to the anterior anteroventral CN (AVCNa) substantially reduced the BDP, while lesions primarily involving more posterior parts of the CN had little or no effect. BDP reductions occurred for lesions involving either high (> 10 kHz) or lower (< 10 kHz) characteristic frequency (CF) regions of the AVCNa (as well as the posterior CN). Lesions involving the SOC reduced the BDP and, in one case, eliminated the high-pass filtered (270 Hz cutoff) BDP. Combining these results with published information about the physiology and anatomy of auditory brainstem cells, we conclude that: (1) spherical cells in the AVCNa are essential for BDP production, (2) the earliest part of the BDP is generated by medial superior olive (MSO) principal cells which receive spherical cell inputs, (3) a later part is probably generated by the cellular targets of MSO principal cells and, (4) the cells involved in BDP generation have CFs above, as well as below, 10 kHz. Since humans, like cats, have a well-developed MSO, we suggest that the MSO may also be essential for BDP production in humans. Thus, perceptual correlates of the BDP, binaural fusion and click lateralization, apparently involve the MSO.

Chronic cochlear de-efferentation and susceptibility to permanent acoustic injury.

The question of whether olivocochlear (OC) efferent feedback can decrease permanent damage from acoustic overexposure was investigated by comparing the chronic threshold shifts and cochlear histopathology in guinea pigs either surgically de-efferented or sham-operated and then exposed (awake and unrestrained) to a 109- or 112-dB narrow-band noise centered at 10 kHz for 2 h. Threshold shifts were estimated using compound action potentials; hair cell loss and stereocilia condition were evaluated via light-microscopic examination of plastic-embedded surface preparations, and the degree of de-efferentation was assessed by measuring OC fascicles in the tunnel of Corti. Among animals exposed to 109-dB noise, the mean permanent threshold shift (PTS) was less than 25 dB, and there were no significant differences between normal and de-efferented animals with respect to either physiological or histological measures of acoustic injury. Among animals exposed to 112 dB, the mean peak PTS was roughly 50 dB. There was a small (but statistically significant) increase in PTS for de-efferented animals, especially at frequencies above the region of peak threshold shift; however, the patterns of hair cell loss and stereocilia damage were statistically indistinguishable. Thus, for these particular exposure conditions, sound-evoked activity in the OC system does not play a major protective role in the auditory periphery, except perhaps for the extreme basal regions of the cochlea.

MR-imaging of post-traumatic olivary hypertrophy.

We present clinical and magnetic resonance (MR) findings in 83 patients with inner cerebral trauma (ICT). In addition to the ICT-related lesions, uni- or bilateral enlargement and signal abnormalities of the inferior olivary nucleus were detected by MR in 9.6% of patients as a consequence of lesions within the dentato-rubro-olivary pathway. Clinically, segmental myoclonias were present in five patients. These observations suggest that MR imaging is highly sensitive in the detection of olivary hypertrophy and of causative traumatic lesions of the dentato-rubro-olivary pathway.

Post-traumatic segmental myoclonus associated with bilateral olivary hypertrophy.

We present clinical and magnetic resonance (MR) findings in three patients with segmental myoclonia occurring 11-18 months after severe brainstem injury. Palatal myoclonus and vertical ocular myorhythmia were present in all three patients and synchronous involuntary movements of the upper extremities ("wing beating") in two patients. MR-imaging showed multiple post-traumatic lesions within the dentato-rubro-olivary pathway ("myoclonic triangle"), associated with bilateral enlargement and increased signal intensity of the inferior olives. The signal abnormality was more prominent on proton density weighted images than on T2-weighted images, suggesting underlying pathological changes different from typical gliosis.