Differences related to aging in sensorimotor knowledge: Investigation of perceptual strength and body object interaction.

Embodied approach postulates that knowledge and conceptual representations are grounded in action and perception. In order to investigate the involvement of sensorimotor information in conceptual and cognitive processing, researchers have collected various norms in young adults. For instance, the perceptual strength (PS) assesses perceptual experience (i.e. visual, auditory, haptic, gustatory, olfactory) associated with a concept and the body-object-interaction (BOI) assesses the ease with which a human body can interact with the referent of a word. The importance of both BOI and PS in the multimodal composition of word meaning is today well recognized. However, given the sensorimotor development of the individual from childhood to later life, it is likely that different age periods are associated with different perceptual experience and capacity to interact with objects. The purpose of this research is to investigate exploratory the effect of age on PS and BOI by comparing the evaluation of 270 French language words by young adults and healthy older people. The results showed that older adults presented similar or even higher PS for some modalities (e.g. gustatory and olfactory) and in particular for certain categories of words, while the BOI decreases. In addition to the importance of adjusting the verbal stimuli used in aging studies when dealing with multimodal representations, our results will lead us to discuss the evolution of sensorimotor representations with age.

Neural progenitor fate decision defects, cortical hypoplasia and behavioral impairment in Celsr1-deficient mice.

The development of the cerebral cortex is a tightly regulated process that relies on exquisitely coordinated actions of intrinsic and extrinsic cues. Here, we show that the communication between forebrain meninges and apical neural progenitor cells (aNPC) is essential to cortical development, and that the basal compartment of aNPC is key to this communication process. We found that Celsr1, a cadherin of the adhesion G protein coupled receptor family, controls branching of aNPC basal processes abutting the meninges and thereby regulates retinoic acid (RA)-dependent neurogenesis. Loss-of-function of Celsr1 results in a decreased number of endfeet, modifies RA-dependent transcriptional activity and biases aNPC commitment toward self-renewal at the expense of basal progenitor and neuron production. The mutant cortex has a reduced number of neurons, and Celsr1 mutant mice exhibit microcephaly and behavioral abnormalities. Our results uncover an important role for Celsr1 protein and for the basal compartment of neural progenitor cells in fate decision during the development of the cerebral cortex.

GSK3beta, a centre-staged kinase in neuropsychiatric disorders, modulates long term memory by inhibitory phosphorylation at serine-9.

Accumulating evidence implicates deregulation of GSK3ss as a converging pathological event in Alzheimer's disease and in neuropsychiatric disorders, including bipolar disorder and schizophrenia. Although these neurological disorders share cognitive dysfunction as a hallmark, the role of GSK3ss in learning and memory remains to be explored in depth. We here report increased phosphorylation of GSK3ss at Serine-9 following cognitive training in two different hippocampus dependent cognitive tasks, i.e. inhibitory avoidance and novel object recognition task. Conversely, transgenic mice expressing the phosphorylation defective mutant GSK3ss[S9A] show impaired memory in these tasks. Furthermore, GSK3ss[S9A] mice displayed impaired hippocampal L-LTP and facilitated LTD. Application of actinomycin, but not anisomycin, mimicked GSK3ss[S9A] induced defects in L-LTP, suggesting that transcriptional activation is affected. This was further supported by decreased expression of the immediate early gene c-Fos, a target gene of CREB. The combined data demonstrate a role for GSK3ss in long term memory formation, by inhibitory phosphorylation at Serine-9. The findings are fundamentally important and relevant in the search for therapeutic strategies in neurological disorders associated with cognitive impairment and deregulated GSK3ss signaling, including AD, bipolar disorder and schizophrenia.

Deregulation of NMDA-receptor function and down-stream signaling in APP[V717I] transgenic mice.

Evidence is accumulating for a role for amyloid peptides in impaired synaptic plasticity and cognition, while the underlying mechanisms remain unclear. We here analyzed the effects of amyloid peptides on NMDA-receptor function in vitro and in vivo. A synthetic amyloid peptide preparation containing monomeric and oligomeric A beta (1-42) peptides was used and demonstrated to bind to synapses expressing NMDA-receptors in cultured hippocampal and cortical neurons. Pre-incubation of primary neuronal cultures with A beta peptides significantly inhibited NMDA-receptor function, albeit not by a direct pharmacological inhibition of NMDA-receptors, since acute application of A beta peptides did not change NMDA-receptor currents in autaptic hippocampal cultures nor in xenopus oocytes expressing recombinant NMDA-receptors. Pre-incubation of primary neuronal cultures with A beta peptides however decreased NR2B-immunoreactive synaptic spines and surface expression of NR2B containing NMDA-receptors. Furthermore, we extended these findings for the first time in vivo, demonstrating decreased concentrations of NMDA-receptor subunit NR2B and PSD-95 as well as activated alpha-CaMKII in postsynaptic density preparations of APP[V717I] transgenic mice. This was associated with impaired NMDA-dependent LTP and decreased NMDA- and AMPA-receptor currents in hippocampal CA1 region in APP[V717I] transgenic mice. In addition, induction of c-Fos following cued and contextual fear conditioning was significantly impaired in the basolateral amygdala and hippocampus of APP[V717I] transgenic mice. Our data demonstrate defects in NMDA-receptor function and learning dependent signaling cascades in vivo in APP[V717I] transgenic mice and point to decreased surface expression of NMDA-receptors as a mechanism involved in early synaptic defects in APP[V717I] transgenic mice in vivo.

Modulation of synaptic plasticity and Tau phosphorylation by wild-type and mutant presenilin1.

The function of presenilin1 (PS1) in intra-membrane proteolysis is undisputed, as is its role in neurodegeneration in FAD, in contrast to its exact function in normal conditions. In this study, we analyzed synaptic plasticity and its underlying mechanisms biochemically in brain of mice with a neuron-specific deficiency in PS1 (PS1(n-/-)) and compared them to mice that expressed human mutant PS1[A246E] or wild-type PS1. PS1(n-/-) mice displayed a subtle impairment in Schaffer collateral hippocampal long-term potentiation (LTP) as opposed to normal LTP in wild-type PS1 mice, and a facilitated LTP in mutant PS1[A246E] mice. This finding correlated with, respectively, increased and reduced NMDA receptor responses in PS1[A246E] mice and PS1(n-/-) mice in hippocampal slices. Postsynaptically, levels of NR1/NR2B NMDA-receptor subunits and activated alpha-CaMKII were reduced in PS1(n-/-) mice, while increased in PS1[A246E] mice. In addition, PS1(n-/-) mice, displayed reduced paired pulse facilitation, increased synaptic fatigue and lower number of total and docked synaptic vesicles, implying a presynaptic function for wild-type presenilin1, unaffected by the mutation in PS1[A246E] mice. In contrast to the deficiency in PS1, mutant PS1 activated GSK-3beta by decreasing phosphorylation on Ser-9, which correlated with increased phosphorylation of protein tau at Ser-396-Ser-404 (PHF1/AD2 epitope). The synaptic functions of PS1, exerted on presynaptic vesicles and on postsynaptic NMDA-receptor activity, were concluded to be independent of alterations in GSK-3beta activity and phosphorylation of protein tau.

Calcium/calmodulin kinase kinase beta has a male-specific role in memory formation.

The calcium/calmodulin (CaM) kinase cascade regulates gene transcription, which is required for long-term memory formation. Previous studies with Camkk2 null mutant mice have shown that in males calcium/calmodulin kinase kinase beta (CaMKKbeta) is required for spatial memory formation and for activation of the transcription factor cyclic AMP-responsive element binding protein (CREB) in the hippocampus by spatial training. Here we show that CaMKKbeta is not required for spatial memory formation in female mice as female Camkk2 null mutants were not impaired in spatial memory formation and they had the same level of hippocampal CREB phosphorylation after spatial training as female wild-type mice. Furthermore, we show that male but not female Camkk2 null mutants were impaired in long-term potentiation (LTP) at hippocampal CA1 synapses. Finally, a transcriptional analysis of male Camkk2 null mutants led to the identification of a gene, glycosyl phosphatidyl-inositol anchor attachment protein 1 (GAA1), whose hippocampal mRNA expression was up-regulated by spatial and contextual training in male but not in female wild-type mice. Taken together, we conclude that CaMKKbeta has a male-specific function in hippocampal memory formation and we have identified male-restricted transcription occurring during hippocampal memory formation.

Sexual dimorphisms in the effect of low-level p25 expression on synaptic plasticity and memory.

p25, a degradation product of p35, has been reported to accumulate in the forebrain of patients with Alzheimer's disease. p25 as well as p35 are activators of cyclin-dependent kinase 5 (Cdk5) although p25/Cdk5 and p35/Cdk5 complexes have distinct properties. Several mouse models with high levels of p25 expression exhibit signs of neurodegeneration. On the contrary, we have shown that low levels of p25 expression do not cause neurodegeneration and are even beneficial for particular types of learning and memory [Angelo et al., (2003) Eur J. Neurosci., 18, 423-431]. Here, we have studied the influence of low-level p25 expression in hippocampal synaptic plasticity and in learning and memory for each sex separately in two different genetic backgrounds (129B6F1 and C57BL/6). Surprisingly, we found that low-level p25 expression had different consequences in male and female mutants. In the two genetic backgrounds LTP induced by a strong stimulation of the Schaffer's collaterals (four trains, 1-s duration, 5-min interval) was severely impaired in male, but not in female, p25 mutants. Furthermore, in the two genetic backgrounds spatial learning in the Morris water maze was faster in female p25 mutants than in male transgenic mice. These results suggest that, in women, the production of p25 in Alzheimer's disease could be a compensation for some early learning and memory deficits.

Resonance of spike discharge modulation in neurons of the guinea pig medial vestibular nucleus.

The modulation of action potential discharge rates is an important aspect of neuronal information processing. In these experiments, we have attempted to determine how effectively spike discharge modulation reflects changes in the membrane potential in central vestibular neurons. We have measured how their spike discharge rate was modulated by various current inputs to obtain neuronal transfer functions. Differences in the modulation of spiking rates were observed between neurons with a single, prominent after hyperpolarization (AHP, type A neurons) and cells with more complex AHPs (type B neurons). The spike discharge modulation amplitudes increased with the frequency of the current stimulus, which was quantitatively described by a neuronal model that showed a resonance peak >10 Hz. Modeling of the resonance peak required two putative potassium conductances whose properties had to be markedly dependent on the level of the membrane potential. At low frequencies (< or =0.4 Hz), the gain or magnitude functions of type A and B discharge rates were similar relative to the current input. However, resting input resistances obtained from the ratio of the membrane potential and current were lower in type B compared with type A cells, presumably due to a higher level of active potassium conductances at rest. The lower input resistance of type B neurons was compensated by a twofold greater sensitivity of their firing rate to changes in membrane potential, which suggests that synaptic inputs on their dendritic processes would be more efficacious. This increased sensitivity is also reflected in a greater ability of type B neurons to synchronize with low-amplitude sinusoidal current inputs, and in addition, their responses to steep slope ramp stimulation are enhanced over the more linear behavior of type A neurons. This behavior suggests that the type B MVNn are moderately tuned active filters that promote high-frequency responses and that type A neurons are like low-pass filters that are well suited for the resting tonic activity of the vestibular system. However, the more sensitive and phasic type B neurons contribute to both low- and high-frequency control as well as signal detection and would amplify the contribution of both irregular and regular primary afferents at high frequencies.

Modification of the pacemaker activity of vestibular neurons in brainstem slices during vestibular compensation in the guinea pig.

In the guinea pig, unilateral labyrinthectomy causes an immediate and severe depression of the spontaneous activity of the ipsilateral central vestibular neurons, which subsequently recovers completely within one week. A possible underlying mechanism could be an increase in the endogenous activity of the neurons deprived of their labyrinthine input. Here, we addressed this hypothesis. The endogenous activity of the neurons was assessed by their spontaneous activity recorded extracellularly in brainstem slices in the presence of a cocktail of neurotransmitter blockers (CNQX, D-APV, bicuculline and strychnine) which freed them from their main synaptic influences. The left medial vestibular nucleus (MVN) was explored in a very systematic way and strict methodological precautions were taken in order to validate comparisons between the numbers of spontaneously active neurons recorded in the MVN of distinct slices. In the presence of neurotransmitter antagonists, the mean number of spontaneously active neurons detected in a single MVN increased dramatically from 9.5 in slices from control guinea pigs to 26.3 in slices from animals labyrinthectomized on the left side one week beforehand. The mean firing rate of the recorded neurons also increased from 7.5 +/- 5.6 spikes/s in slices from control animals to 12.3 +/- 7.6 spikes/s in slices from guinea pigs labyrinthectomized one week beforehand. These results show that deprivation of the vestibular neurons of their labyrinthine input caused a change in the deprived neurons themselves. They suggest that an increase in pacemaker activity might be a factor responsible for the restoration of spontaneous activity in the vestibular neurons after labyrinthectomy.

Mutant presenilins disturb neuronal calcium homeostasis in the brain of transgenic mice, decreasing the threshold for excitotoxicity and facilitating long-term potentiation.

Mutant human presenilin-1 (PS1) causes an Alzheimer's-related phenotype in the brain of transgenic mice in combination with mutant human amyloid precursor protein by means of increased production of amyloid peptides (Dewachter, I., Van Dorpe, J., Smeijers, L., Gilis, M., Kuiperi, C., Laenen, I., Caluwaerts, N., Moechars, D., Checler, F., Vanderstichele, H. & Van Leuven, F. (2000) J. Neurosci. 20, 6452-6458) that aggravate plaques and cerebrovascular amyloid (Van Dorpe, J., Smeijers, L., Dewachter, I., Nuyens, D., Spittaels, K., van den Haute, C., Mercken, M., Moechars, D., Laenen, I., Kuipéri, C., Bruynseels, K., Tesseur, I., Loos, R., Vanderstichele, H., Checler, F., Sciot, R. & Van Leuven, F. (2000) J. Am. Pathol. 157, 1283-1298). This gain of function of mutant PS1 is approached here in three paradigms that relate to glutamate neurotransmission. Mutant but not wild-type human PS1 (i) lowered the excitotoxic threshold for kainic acid in vivo, (ii) facilitated hippocampal long-term potentiation in brain slices, and (iii) increased glutamate-induced intracellular calcium levels in isolated neurons. Prominent higher calcium responses were triggered by thapsigargin and bradykinin, indicating that mutant PS modulates the dynamic release and storage of calcium ions in the endoplasmatic reticulum. In reaction to glutamate, overfilled Ca(2+) stores resulted in higher than normal cytosolic Ca(2+) levels, explaining the facilitated long-term potentiation and enhanced excitotoxicity. The lowered excitotoxic threshold for kainic acid was also observed in mice transgenic for mutant human PS2[N141I] and was prevented by dantrolene, an inhibitor of Ca(2+) release from the endoplasmic reticulum.

Pan-Thames survey of occupational exposure to HIV and the use of post-exposure prophylaxis in 71 NHS trusts.

OBJECTIVES: To review the management of occupational exposure to definite or suspected HIV-infected blood, following the introduction of the 1997 UK Department of Health guidelines on the use of post-exposure prophylaxis. METHODS: Cross-sectional telephone survey of protocols in 71 NHS Trusts in the Pan-Thames region. Retrospective postal survey of the management of each definite or suspected HIV blood exposure between 1 July 1997 and 30 June 1999. RESULTS: Sixty-two (93%) Trusts had a written protocol, with many specialties involved in exposure management. Twenty-four Trusts reported 171 occupational exposures to definite or suspected HIV-infected blood. Of 97 definite HIV exposures, eight (8%) were discovered on post-incident HIV testing of the source patient; to which most source patients agreed when approached. Seventy-two (74%) exposed health care workers started prophylaxis and 49 (68%) completed the recommended 4-week course. Only half of those whose exposures occurred more than 6 months ago were known to have had a follow-up HIV test. CONCLUSIONS: Although most Trusts have implemented the Department of Health's guidance, collecting data on individual exposures proved difficult. We suggest that a designated department in each Trust co-ordinates and records HIV exposure management. Routine HIV testing is acceptable to most source patients and is appropriate in areas with a high prevalence of HIV seropositivity.

Voltage-gated calcium channels contribute to the pattern of the resting discharge in guinea pig medial vestibular nucleus neurons.

In brainstem slices of guinea pigs perfused with artificial cerebro-spinal fluid (ACSF), the discharge of all the spontaneously active neurons of the medial vestibular nucleus (MVN) is regular. It has been reported that prolonged exposure to a low Ca(2+) medium could induce these neurons to fire bursts of spikes. In this study, we performed a systematic exploration of the spontaneous activity of the guinea pig MVN neurons by extracellular recordings in slices perfused either with a low Ca(2+)-high Mg(2+) medium, or with ACSF added with omega-agatoxin-IVA and with omega-conotoxin-GVIA. The percentage of recorded neurons which fired bursts, was 67% in low Ca(2+)-high Mg(2+) medium and 34% under the action of Ca(2+) channel blockers. These results show that the sensitivity of the firing properties to divalent cations is not shared by all of the MVN neurons and that the regularity of firing of a class of MVN neurons depends on the Ca(2+) channels they express in their membranes.

Changes in protein expression in the vestibular nuclei during vestibular compensation.

In the guinea pig, labyrinthectomy induces an immediate depression of the resting discharges in the neurons of the ipsilateral vestibular nuclei. Later on, in spite of the persistent deprivation of their ipsilateral labyrinthine input, a spontaneous restoration of activity, which is complete within 1 week, occurs in these neurons. Here, by using computer-assisted quantitative two-dimensional gel analysis, we have detected three proteins whose expressions were increased in the ipsilateral vestibular nuclei 1 week after unilateral labyrinthectomy. The spatio-temporal pattern of this phenomenon was compatible with a role for it in the restoration of activity in the vestibular neurons deprived of their ipsilateral labyrinthine input. Furthermore, the N-terminal amino acid sequences of two of these expressed proteins were obtained.

The subdivisions of the guinea pig vestibular complex revealed by acetylcholinesterase staining.

A detailed map of the vestibular nuclear complex of the guinea pig has been established by Gstoettner and Burian (1987), using cytoarchitectonic (cresyl violet staining) and fiberarchitectonic criteria. However, the exact borders between the different subdivisions are not always evident in Nissl stained sections. In the present study, serial sections of the vestibular nuclei of the guinea pig were stained to visualize acetylcholinesterase (AChE) activity, and compared with corresponding sections stained with cresyl violet. All of the subdivisions of the vestibular nuclear complex previously described are more readily distinguished in AChE than in Nissl preparations. The AChE reactivity also shows that the medial vestibular nucleus extends more rostrally than previously described. Furthermore, it questions whether the area classically referred to as the rostral pole of the descending vestibular nucleus belongs to the descending vestibular nucleus or to the lateral vestibular nucleus (LV). Finally, a morphometric analysis performed on cresyl violet stained sections shows that (1) in the caudal LV, the neurons of the ventromedial extension are smaller than those of the dorsolateral extension and that (2) in the rostral LV, the ventromedial division contains a larger ratio of smaller neurons than the dorsolateral one.

Neuronal correlates of vestibulo-ocular reflex adaptation in the alert guinea-pig.

The spiking behaviour of 66 second-order vestibular neurons was studied in alert, chronically prepared guinea-pigs during the horizontal vestibulo-ocular reflex (VOR). Among the 66 studied neurons, seven were held long enough (> 1 h) to compare their spiking behaviour before and after a training procedure inducing a decrease in the gain of the VOR. When tested in darkness following adaptation, five of them showed a significant decrease of their sensitivity to head rotation. However, the resting discharge of these five neurons remained unchanged. This suggests that VOR adaptation is mediated not only by changes in synaptic efficacities but also by modifications in the spike generator which transforms synaptic inputs into a pattern of action potentials.

Neck muscle activity after unilateral labyrinthectomy in the alert guinea pig.

In the guinea pig, lateral deviation of the head is a cardinal symptom of the vestibular syndrome caused by unilateral labyrinthectomy. In the course of recovery from this syndrome (vestibular compensation), lateral deviation of the head disappears completely in 2-3 days. Because this symptom is known to be due to the lesion of the horizontal semicircular canal system, and since obliquus capitis inferior (OCI) muscle is activated predominantly by yaw rotation (horizontal vestibulocollic reflex), we hypothesized that changes in the activity of this muscle could be at least in part responsible for the lateral head deviation caused by unilateral labyrinthectomy. In order to test this hypothesis, electromyographic (EMG) activities of the right and left OCI muscles, as well as eye movements, were recorded in 12 head-fixed alert guinea pigs at various times after left surgical labyrinthectomy (performed with the animals under halothane anesthesia). After the operation, a decrease in tonic EMG activity was observed in the right (contralateral to the lesion) OCI muscle while an increase in tonic EMG activity was detected in the left (ipsilateral) OCI muscle. In addition, phasic changes in EMG activity associated with ocular nystagmic beats occurred in the OCI muscles. These phasic changes were in the opposite direction to those of the tonic changes. There were bursts of activity in the right OCI and pauses in the left OCI. From measurements of rectified averaged EMG activities which took into account both parts (tonic and phasic) of the phenomenon, it was concluded that the labyrinthectomy-induced asymmetry between the activities of the left and right OCI muscles was high enough and lasted long enough to be an important mechanism in the lateral deviation of the head caused by unilateral labyrinthectomy.

Neuronal activity in the vestibular nuclei after contralateral or bilateral labyrinthectomy in the alert guinea pig.

In the guinea pig, a unilateral labyrinthectomy is followed by an initial depression and a subsequent restoration of the spontaneous activity in the neurons of the ipsilateral vestibular nuclei. In two previous works, we have established the time course of these changes in the alert guinea pig using electrical stimulation as a search stimulus to select the analyzed neurons. The latter criterion was important to capture the many ipsilateral neurons that are silent at rest during the immediate postlabyrinthectomy stage. Because it is known that a pathway originating from the vestibular nuclei on one side crosses the midline and functionally inhibits the activity of the vestibular nuclei on the other side, we investigated in the first part of this study the spiking behavior of the neurons in the vestibular nuclei contralateral to the labyrinthectomy using the same procedure as that used for the ipsilateral neurons. The spiking behavior of 976 neurons was studied during 4-h recording sessions in intact animals and 1 h, 1 day, 2 days, or 1 wk postlabyrinthectomy. Neurons selected according to the electrical activation criterion were classified further as type I (their firing rate increased during ipsilateral rotation), type II (their firing rate increased during contralateral rotation), or unresponsive. The resting activity of type I neurons, which was 38.1 +/- 20.9 spikes/s (mean +/- SD) in the control state, increased statistically significantly 1 h after the lesion (53.3 +/- 29.1 spikes/s) and remained at this level 1 wk later (56.0 +/- 20.3 spikes/s). The sensitivity of type I units, which was 0.80 +/- 0.46 spikes/s per deg/s in the control population, decreased to 0.49 +/- 0.26 spikes/s per deg/s 1 h after the lesion and remained at this level 1 wk later (0.50 +/- 0.39 spikes/s per deg/s). When all monosynaptically activated neurons (type I, type II, unresponsive) were pooled, the sensitivity to horizontal rotation fell from 0.58 +/- 0.51 spikes/s per deg/s in the control state to 0. 15 +/- 0.25 spikes/s per deg/s 1 h after the lesion and to 0.20 +/- 0.32 spikes/s per deg/s 1 wk later. The major findings of the first part of this study in the alert guinea pig are thus in accord with those of Curthoys et al. and Smith and Curthoys in anesthetized guinea pigs. In the second part of this work, we studied the spiking behavior of the neurons in the vestibular nuclei after bilateral labyrinthectomy. After unilateral labyrinthectomy, the resting discharge of the ipsilateral monosynaptically activated vestibular neurons fell from 36.9 +/- 21 spikes/s (basal activity) to 6.7 +/- 17.0 spikes/s 1 h after the lesion and then recovered, reaching 17.4 +/- 18.9 and 40.8 +/- 23.7 spikes/s 1 day and 1 wk after the lesion, respectively. These observations raise the two following questions. What are the relative contributions of the loss of the excitatory influence from the ipsilateral labyrinth (destroyed) and of the persistence of the inhibitory influence from the contralateral labyrinth (intact) in the labyrinthectomy-induced depression of activity? And are the left-right asymmetries caused by a unilateral labyrinthectomy the driving force for restoration of activity? Here, we addressed these two questions by studying the spiking behavior of 473 second-order vestibular neurons in the alert guinea pig after a bilateral labyrinthectomy. In the acute stage, 1 h after bilateral labyrinthectomy, the resting discharge of the second-order vestibular neurons was 16.2 +/- 22.4 spikes/s. From comparison with the results obtained in the acute stage after a unilateral labyrinthectomy, we inferred that the ipsilateral excitatory influence was between two and three times more powerful than the contralateral inhibitory influence. (ABSTRACT TRUNCATED)

Spike discharge regularity of vestibular neurons in labyrinthectomized guinea pigs.

Single unit activity of second-order vestibular neurons was recorded in alert guinea pigs. Here, we compared the spike discharge regularity (measured by calculating the coefficient of variation (CV)) of neurons from control animals with those from animals labyrinthectomized 1 week before. The mean CV (+/-SD) were the same in both groups (0.72+/-0.43 vs. 0.70+/-0.39). Furthermore, in both groups, the CV was related to the resting rate (RR) according to the same law (CV = 4/square root of RR). Because the discharge of a neuron is more regular when it is due to a pacemaker activity than when it is due to the synaptic drive, we conclude that restoration in the firing rate after labyrinthectomy is due to increase in the synaptic drive rather than to increase in the (intrinsic) pacemaker activity.

Reappearance of activity in the vestibular neurones of labyrinthectomized guinea-pigs is not delayed by cycloheximide.

1. In mammals, unilateral labyrinthectomy induces an immediate depression of the resting discharges in the neurones of the ipsilateral vestibular nuclei. Later on, a spontaneous restoration of this activity occurs. The aim of the present study was to test the possibility that protein synthesis could be involved in the start of this process in the guinea-pig. 2. Cycloheximide (CHX), a protein synthesis inhibitor, was injected intramuscularly 1 h before (30 mg kg-1) and 5 h after (15 mg kg-1) labyrinthectomy. 3. In a first group of animals, CHX was found to induce an inhibition of protein synthesis at levels ranging from 71 to 93% for 9 h after labyrinthectomy. 4. In a second group of alert animals, we studied single unit activity of second-order vestibular neurones. It was found that, in the 12-16 h post-labyrinthectomy period, at a time when restoration began in guinea-pigs not treated with CHX, the discharges in the labyrinthectomized group treated with CHX were not different from those observed in a previous study in labyrinthectomized animals not treated with CHX. 5. We conclude that protein synthesis is not required for the start of restoration of activity in the vestibular neurones deprived of their ipsilateral labyrinthine input.

Dissociations between behavioural recovery and restoration of vestibular activity in the unilabyrinthectomized guinea-pig.

1. In the guinea-pig, a unilateral labyrinthectomy induces postural disturbances and an ocular nystagmus which abate or disappear over time. These behavioural changes are accompanied by an initial collapse and a subsequent restoration of the spontaneous activity in the neurones of the ipsilateral vestibular nuclei. Recently, it has been shown that the vestibular neuronal activity remained collapsed over at least 10 h whereas its restoration was complete 1 week after the lesion. The aims of this study were to determine when restoration of spontaneous activity in the partially deafferented vestibular neurones started and to compare the time courses of the behavioural and neuronal recoveries in guinea-pigs that had undergone a unilateral labyrinthectomy. 2. Neuronal discharge measurements were made using chronic extracellular recording of single unit activity. After a left labyrinthectomy, electrodes, were placed on the site of the destroyed labyrinth to enable stimulation of the left vestibular nerve. Behavioural measurements included chronic recording of eye movements by the scleral search coli technique. After a left labyrinthectomy, lateral deviation of the head, twisting of the head, and eye velocity of the slow phases of the nystagmus were measured. 3. The neuronal activity of the rostral part of the vestibular nuclear complex on the lesioned side was recorded in alert guinea-pigs over 4 h recording sessions between 12 and 72 h after the lesion. 4. The criterion used to select vestibular neurones for analysis was their recruitment by an electric shock on the vestibular nerve. In addition, in order to explore a uniform population, we focused on neurones recruited at monosynaptic latencies (0.85-1.15 ms). 5. For each recording period, the mean resting rate was calculated animal by animal and the grand mean of these individual resting rate means was calculated. Previously, a decline in the grand mean resting rate from 35.8 +/- 6.0 spikes s-1 (control state) to 7.1 +/- 4.2 spikes s-1 during the first 4 h after labyrinthectomy has been shown. In the present study, the first sign of recovery was observed during the 12-16 h recording period when the resting rate grand mean increased to 16.3 +/- 3.9 spikes s-1. This grand mean activity did not change significantly during the following 12 h. Thereafter, restoration of neuronal activity improved and was complete 1 week after the lesion. 6. Although the abatement of the vestibular symptoms roughly paralleled the restoration of neuronal activity in the vestibular nuclei, some discrepancies between the time courses of both phenomena emerged. An important step in postural recovery (the animals managed to stand up) and a major part of the abatement of the nystagmus occurred before the recovery of vestibular neuronal activity. In addition, lateral deviation of the head disappeared while restoration of the neuronal activity was incomplete, but significant head twisting was still evident when vestibular resting rates had recovered completely. 7. We conclude that restoration of neuronal activity in the ipsilateral vestibular nuclei starts 12 h after the lesion and that restoration of neuronal activity in the ipsilateral vestibular nuclei is not the only mechanism underlying behavioural vestibular compensation.