The excitation of muscle stretch receptors by suxamethonium

1. Changes in the response of cat soleus muscle spindle primary, secondary and "intermediate" sensory endings to ramp stretchin during intravenous and intra-arterial infusions of suxamethonium (SCh) in the intact anaesthetised animal have been studied. The effects of SCh on the spindle sensory endings have been related to the known action of SCh and ACh on the two nuclear bag intrafusal muscle fibres of isolated cat muscle spindles in vitio (Gladden 1976) 2. The application of repetitive short-duration ramp-and-hold test stretches to the soleus muscle during continuous slow infusion of SCh enabled the gradual activation of the spindle sensory endings to be studied in detail. Typical muscle spindle primary sensory endings were activated in three consecutive stages during infusion of SCh, which will be termed Phases I, II and III of excitation. In Phase I of excitation, a gradual facilitatory effect of SCh on tha discharge of the Ia sensory endings accompanied by a progressive reduction in the sensitivity of the endings to liuscle shortening was observed. This occurred without a potentiation of, and usually a decrease in, the dynamic and position sensitivities of the Ia endings to muscle stretch. The Phase I facilitatory effects of SCh on la endings appear not to be caused by the contraction of intrafusal muscle fibres, and are probably the result of a direct or indirect depolarising action of SCh on the sensory nerve terminals of the la afferent axon. In Phase II of excitation, the sensitivity of the Ia endings to the dynamic phase of the ramp stretch increased dramatically, and the response of the endings to stretch was very similar to that of la endings during strong dynamic fusimotor activation. This increase in the dynamic sensitivity is very likely the result of the recruitment of the dynamic nuclear bag (DNB) fibre, which has the lower threshold of SCh of the two nuclear bag fibres (Gladden 1976), and which is made to contract by dynamic fusi- motor axons (Boyd, Gladden, McWilliam&Ward 1977), In Phase III of excitation, a marked increase in the position sensitivity of the Ia endings was superimposed on the already enhanced dynamic sensitivity, and the response of the la endings to stretch became very similar to that during combined stimulation of powerful dynamic and static fusi-motor axons. The increase in the position sensitivity of the Ia endings in Phase III of activation no doubt reflects the contraction of the static nuclear bag (SNB) fibre, which has the higher threshold to SCh of the two nuclear bag fibres (Gladden 1976). The characteristic response to stretch of la endings in Phase III of excitation is thus the result of the combined activation of the dynamic and static nuclear bag fibres by SCh. 3. Unlike soleus muscle spindle primary sensory endings, secondary endings showed only a gradual facilitation of their discharge during infusion of SCh, and behaved in a similar way to Ia endings in Phase I of excitation. while Ia endings subsequently experienced large increases in their dynamic and position sensitivities following the recruitment of the two nuclear bag fibres, secondary sensory endings did not show similar effects. The activation of typical secondary sensory endings by SCh therefore appears to be entirely the result of a direct or indirect depolarising action of SCh on the afferent nerve terminals, without any apparent contribution from the contraction of the two nuclear bag fibres

Synaptic plasticity in medial vestibular nucleus neurons: comparison with computational requirements of VOR adaptation

Background: Vestibulo-ocular reflex (VOR) gain adaptation, a longstanding experimental model of cerebellar learning, utilizes sites of plasticity in both cerebellar cortex and brainstem. However, the mechanisms by which the activity of cortical Purkinje cells may guide synaptic plasticity in brainstem vestibular neurons are unclear. Theoretical analyses indicate that vestibular plasticity should depend upon the correlation between Purkinje cell and vestibular afferent inputs, so that, in gain-down learning for example, increased cortical activity should induce long-term depression (LTD) at vestibular synapses. Methodology/Principal Findings: Here we expressed this correlational learning rule in its simplest form, as an anti-Hebbian, heterosynaptic spike-timing dependent plasticity interaction between excitatory (vestibular) and inhibitory (floccular) inputs converging on medial vestibular nucleus (MVN) neurons (input-spike-timing dependent plasticity, iSTDP). To test this rule, we stimulated vestibular afferents to evoke EPSCs in rat MVN neurons in vitro. Control EPSC recordings were followed by an induction protocol where membrane hyperpolarizing pulses, mimicking IPSPs evoked by flocculus inputs, were paired with single vestibular nerve stimuli. A robust LTD developed at vestibular synapses when the afferent EPSPs coincided with membrane hyperpolarisation, while EPSPs occurring before or after the simulated IPSPs induced no lasting change. Furthermore, the iSTDP rule also successfully predicted the effects of a complex protocol using EPSP trains designed to mimic classical conditioning. Conclusions: These results, in strong support of theoretical predictions, suggest that the cerebellum alters the strength of vestibular synapses on MVN neurons through hetero-synaptic, anti-Hebbian iSTDP. Since the iSTDP rule does not depend on post-synaptic firing, it suggests a possible mechanism for VOR adaptation without compromising gaze-holding and VOR performance in vivo

Interactions between Stress and Vestibular Compensation - A Review

Elevated levels of stress and anxiety often accompany vestibular dysfunction, while conversely complaints of dizziness and loss of balance are common in patients with panic and other anxiety disorders. The interactions between stress and vestibular function, and plasticity have been investigated both in animal models and in clinical studies. Evidence from animal studies indicates that vestibular symptoms are effective in activating the stress axis, and that the acute stress response is important in promoting compensatory synaptic and neuronal plasticity in the vestibular system and cerebellum. The role of stress in human vestibular disorders is complex, and definitive evidence is lacking. This article reviews the evidence from animal and clinical studies with a focus on the effects of stress on the central vestibular pathways and their role in the pathogenesis and management of human vestibular disorders

N-Acetyl-L-Leucine Accelerates Vestibular Compensation after Unilateral Labyrinthectomy by Action in the Cerebellum and Thalamus

An acute unilateral vestibular lesion leads to a vestibular tone imbalance with nystagmus, head roll tilt and postural imbalance. These deficits gradually decrease over days to weeks due to central vestibular compensation (VC). This study investigated the effects of i.v. N-acetyl-DL-leucine, N-acetyl-L-leucine and N-acetyl-D-leucine on VC using behavioural testing and serial [18F]-Fluoro-desoxyglucose ([18F]-FDG)-mu PET in a rat model of unilateral chemical labyrinthectomy (UL). Vestibular behavioural testing included measurements of nystagmus, head roll tilt and postural imbalance as well as sequential whole-brain [18F]FDG-mu PET was done before and on days 1, 3, 7 and 15 after UL. A significant reduction of postural imbalance scores was identified on day 7 in the N-acetyl-DL-leucine (p < 0.03) and the N-acetyl-L-leucine groups (p < 0.01),compared to the sham treatment group, but not in the N-acetyl-D-leucine group (comparison for applied dose of 24 mg i.v. per rat, equivalent to 60 mg/kg body weight, in each group). The course of postural compensation in the DL-and L-group was accelerated by about 6 days relative to controls. The effect of N-acetyl-L-leucine on postural compensation depended on the dose: in contrast to 60 mg/kg, doses of 15 mg/kg and 3.75 mg/kg had no significant effect. N-acetyl-L-leucine did not change the compensation of nystagmus or head roll tilt at any dose. Measurements of the regional cerebral glucose metabolism (rCGM) by means of mu PET revealed that only N-acetyl-L-leucine but not N-acetyl-D-leucine caused a significant increase of rCGM in the vestibulocerebellum and a decrease in the posterolateral thalamus and subthalamic region on days 3 and 7. A similar pattern was found when comparing the effect of N-acetyl-L-leucine on rCGM in an UL-group and a sham UL-group without vestibular damage. In conclusion, N-acetyl-L-leucine improves compensation of postural symptoms after UL in a dose-dependent and specific manner, most likely by activating the vestibulocerebellum and deactivating the posterolateral thalamus

Loss of β-III Spectrin Leads to Purkinje Cell Dysfunction Recapitulating the Behavior and Neuropathology of Spinocerebellar Ataxia Type 5 in Humans

Mutations in SPTBN2, the gene encoding β-III spectrin, cause spinocerebellar ataxia type 5 in humans (SCA5), a neurodegenerative disorder resulting in loss of motor coordination. How these mutations give rise to progressive ataxia and what the precise role β-III spectrin plays in normal cerebellar physiology are unknown. We developed a mouse lacking full length β-III spectrin and found that homozygous mice reproduced features of SCA5 including gait abnormalities, tremor, deteriorating motor coordination, Purkinje cell loss and cerebellar atrophy (molecular layer thinning). In vivo analysis reveals an age-related reduction in simple spike firing rate in surviving β-III(−/−) Purkinje cells while in vitro studies show these neurons to have reduced spontaneous firing, smaller sodium currents and dysregulation of glutamatergic neurotransmission. Our data suggest an early loss of EAAT4- (protein interactor of β-III spectrin) and subsequent loss of GLAST-mediated uptake may play a role in neuronal pathology. These findings implicate a loss of β-III spectrin function in SCA5 pathogenesis and indicate there are at least two physiological effects of β-III spectrin loss that underpin a progressive loss of inhibitory cerebellar output, namely an intrinsic Purkinje cell membrane defect due to reduced sodium currents and alterations in glutamate signaling

Noisy galvanic vestibular stimulation promotes GABA release in the substantia nigra and improves locomotion in hemiparkinsonian rats

Dopamine related disorders usually respond to dopaminergic drugs, but not all symptoms are equally responsive. In Parkinson’s disease (PD) in particular, axial symptoms resulting in impaired gait and postural control are difficult to treat. Stochastic vestibular stimulation (SVS) has been put forward as a method to improve CNS function in dopamine related disorders, but the mechanisms of action are not well understood. This thesis aimed to investigate the effects of SVS on neuronal brain activity and to evaluate the possible enhancing effect of SVS on motor control in PD and on cognitive functions and motor learning in Attention deficit hyperactivity disorder (ADHD). Behavioural tests were conducted in the 6-OHDA rat model of PD using the accelerating Rotarod and the Montoya skilled reach test to evaluate the effect of SVS on motor control. The effect of SVS on brain activity was assessed using in vivo microdialysis and immunohistochemistry. We evaluated the effect of SVS on postural control and Parkinsonism in patients with PD and the effect of SVS on cognitive function in people with ADHD. The behavioural animal studies indicate that SVS may have an enhancing effect on locomotion, but not skilled forepaw function. SVS increased GABA transmission in the ipsilesional substantia nigra (SN) and may have a rebalancing effect on dysfunctional brain activity. SVS increased c-Fos activity more than levodopa and saline in the vestibular nucleus of all animals. c-Fos expression was also higher in this region in the 6-OHDA lesioned than in shamlesioned animals, supporting the theory that SVS may have larger effects in the dopamine depleted brain. SVS increased c-Fos expression in the habenula nucleus substantially more than levodopa did. Furthermore, SVS and levodopa had similar effects on many brain regions, including the striatum, where saline had no effect. The clinical studies revealed improvement of postural control in PD during SVS. There was a trend towards reduced Parkinsonism during SVS when off levodopa. No substantial effects were found on cognitive performance in ADHD. In PD, SVS may improve motor control by inhibiting the overactive SN, possibly through a non-dopaminergic modulatory pathway involving increased neurotransmission in the habenula nucleus. SVS could be trialled in larger studies to evaluate long-term effects on treatment resistant axial symptoms associated with PD

Lesion-induced plasticity in rat vestibular nucleus neurones dependent on glucocorticoid receptor activation

We have recently shown that neurones in the rostral region of the medial vestibular nucleus (MVN) develop a sustained increase in their intrinsic excitability within 4 h of a lesion of the vestibular receptors of the ipsilateral inner ear. This increased excitability may be important in the rapid recovery of resting activity in these neurones during ‘vestibular compensation’, the behavioural recovery that follows unilateral vestibular deafferentation. In this study we investigated the role of the acute stress that normally accompanies the symptoms of unilateral labyrinthectomy (UL), and in particular the role of glucocorticoid receptors (GRs), in the development of the increase in excitability in the rostral MVN cells after UL in the rat.The compensatory increase in intrinsic excitability (CIE) of MVN neurones failed to occur in animals that were labyrinthectomized under urethane anaesthesia and kept at a stable level of anaesthesia for either 4 or 6 h after UL, so that they did not experience the stress normally associated with the vestibular deafferentation syndrome. In these animals, ‘mimicking’ the stress response by administration of the synthetic GR agonist dexamethasone at the time of UL, restored and somewhat potentiated CIE in the MVN cells. Administration of dexamethasone in itself had no effect on the intrinsic excitability of MVN cells in sham-operated animals.In animals that awoke after labyrinthectomy, and which therefore experienced the full range of oculomotor and postural symptoms of UL, there was a high level of Fos-like immunoreactivity in the paraventricular nucleus of the hypothalamus over 1·5-3 h post-UL, indicating a strong activation of the stress axis.The GR antagonist RU38486 administered at the time of UL abolished CIE in the rostral MVN cells, and significantly delayed behavioural recovery as indicated by the persistence of circular walking. The mineralocorticoid receptor (MR) antagonist spironolactone administered at the time of UL had no effect.Vestibular compensation thus involves a novel form of ‘metaplasticity’ in the adult brain, in which the increase in intrinsic excitability of rostral MVN cells and the initial behavioural recovery are dependent both on the vestibular deafferentation and on the activation of glucocorticoid receptors, during the acute behavioural stress response that follows UL. These findings help elucidate the beneficial effects of neuroactive steroids on vestibular plasticity in various species including man, while the lack of such an effect in the guinea-pig may be due to the significant differences in the physiology of the stress axis in that species