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The role of neuromodulators in the cerebellum is not well understood. In particular, the behavioural significance of the cholinergic system in the cerebellum is unknown. To investigate the importance of cerebellar cholinergic signalling in behaviour, we infused acetylcholine receptor antagonists, scopolamine and mecamylamine, bilaterally into the rat cerebellum (centred on interpositus nucleus) and observed the motor effects through a battery of behavioural tests. These tests included unrewarded behaviour during open field exploration and a horizontal ladder walking task and reward-based beam walking and pellet reaching tasks. Infusion of a mix of the antagonists did not impair motor learning in the horizontal ladder walking or the reaching task but reduced spontaneous movement during open field exploration, impaired coordination during beam walking and ladder walking, led to fewer reaches in the pellet reaching task, slowed goal-directed reaching behaviour and reduced reward pellet consumption in a free access to food task. Infusion of the muscarinic antagonist scopolamine on its own resulted in deficits in motor performance and a reduction in the number of reward pellets consumed in the free access to food task. By contrast, infusion of the nicotinic antagonist mecamylamine on its own had no significant effect on any task, except beam walking traversal time, which was reduced. Together, these data suggest that acetylcholine in the cerebellar interpositus nucleus is important for the execution and coordination of voluntary movements mainly via muscarinic receptor signalling, especially in relation to reward-related behaviour., (© 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The caudal fastigial nuclei (cFN) are the output nuclei by which the medio-posterior cerebellum influences the production of saccades toward a visual target. On the basis of the organization of their efferences to the premotor burst neurons and the bilateral control of saccades, the hypothesis was proposed that the same unbalanced activity accounts for the dysmetria of all saccades during cFN unilateral inactivation, regardless of whether the saccade is horizontal, oblique, or vertical. We further tested this hypothesis by studying, in two head-restrained macaques, the effects of unilaterally inactivating the caudal fastigial nucleus on saccades toward a target moving vertically with a constant, increasing or decreasing speed. After local muscimol injection, vertical saccades were deviated horizontally toward the injected side with a magnitude that increased with saccade size. The ipsipulsion indeed depended on the tested target speed but not its instantaneous value because it did not increase (decrease) when the target accelerated (decelerated). By subtracting the effect on contralesional horizontal saccades from the effect on ipsilesional ones, we found that the net bilateral effect on horizontal saccades was strongly correlated with the effect on vertical saccades. We explain how this correlation corroborates the bilateral hypothesis and provide arguments against the suggestion that the instantaneous saccade velocity would somehow be "encoded" by the discharge of Purkinje cells in the oculomotor vermis. NEW & NOTEWORTHY Besides causing dysmetric horizontal saccades, unilateral inactivation of caudal fastigial nucleus causes an ipsipulsion of vertical saccades. This study is the first to quantitatively describe this ipsipulsion during saccades toward a moving target. By subtracting the effects on contralesional (hypometric) and ipsilesional (hypermetric) horizontal saccades, we find that this net bilateral effect is strongly correlated with the ipsipulsion of vertical saccades, corroborating the suggestion that a common disorder affects all saccades.

The perineuronal net (PNN) is a specialized type of extracellular matrix found in the central nervous system. The PNN forms on fast spiking neurons during postnatal development but the ontogeny of PNN development has yet to be elucidated. By studying the development and prevalence of the PNN in the juvenile and adult rat brain, we may be able to understand the PNN's role in development and learning and memory. We show that the PNN is fully developed in the deep cerebellar nuclei (DCN) of rats by P18. By using enzymatic digestion of the PNN with chondroitinase ABC (ChABC), we are able to study how digestion of the PNN affects cerebellar-dependent eyeblink conditioning in vivo and perform electrophysiological recordings from DCN neurons in vitro. In vivo degradation of the PNN resulted in significant differences in eyeblink conditioning amplitude and area. Female animals in the vehicle group demonstrated higher levels of conditioning as well as significantly higher post-probe conditioned responses compared to males in that group, differences not present in the ChABC group. In vitro, we found that DCN neurons with a disrupted PNN following exposure to ChABC had altered membrane properties, fewer rebound spikes, and decreased intrinsic excitability. Together, this study further elucidates the role of the PNN in cerebellar learning in the DCN and is the first to demonstrate PNN degradation may erase sex differences in delay conditioning., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The cerebellum is crucial for various associative sensorimotor behaviors. Delay eyeblink conditioning (DEC) depends on the simplex lobule-interposed nucleus (IN) pathway, yet it is unclear how other cerebellar modules cooperate during this task. Here, we demonstrate the contribution of the vermis-fastigial nucleus (FN) pathway in controlling DEC. We found that task-related modulations in vermal Purkinje cells and FN neurons predict conditioned responses (CRs). Coactivation of the FN and the IN allows for the generation of proper motor commands for CRs, but only FN output fine-tunes unconditioned responses. The vermis-FN pathway launches its signal via the contralateral ventral medullary reticular nucleus, which converges with the command from the simplex-IN pathway onto facial motor neurons. We propose that the IN pathway specifically drives CRs, whereas the FN pathway modulates the amplitudes of eyelid closure during DEC. Thus, associative sensorimotor task optimization requires synergistic modulation of different olivocerebellar modules each provide unique contributions.

Patients with essential tremor, vocal tremor, torticollis, myoclonus-dystonia and posthypoxic myoclonus often benefit in a surprisingly rapid and robust manner from ingestion of a modest amount of alcohol (ethanol). Despite considerable investigation, the mechanism of ethanol's ability to produce this effect remains a mystery. In this paper, we review the pharmacology of ethanol and its analogue GHB (or sodium oxybate), summarize the published literature of alcohol-responsive hyperkinetic movement disorders, and demonstrate videos of patients we have treated over the last fifteen years with either an ethanol challenge or with chronic sodium oxybate therapy. We then propose a novel explanation for this phenomenon-namely, that ingestion of modest doses of ethanol (or sodium oxybate) normalizes the aberrant motor networks underling these disorders. We propose that alcohol and its analogues improve clinical symptoms and their physiologic correlate by restoring the normal firing pattern of the major outflow pathways of the cerebellum (the Purkinje cells and deep cerebellar nuclei), We present evidence to support this hypothesis in animal models and in affected patients, and suggest future investigations to test this model., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2020 The Author(s).)

Objectives: The aim of this study was to determine potential metabolism and histological modifications due to gadolinium retention within deep cerebellar nuclei (DCN) after linear gadolinium-based contrast agent injection (gadodiamide) in rats at 1 year after the last injection., Materials and Methods: Twenty female rats received 20 doses of gadodiamide (0.6 mmol of gadolinium per kilogram each) over 5 weeks. They were followed at 1 week (M0), 6 weeks (M1), and 54 to 55 weeks (M13) postinjections to evaluate hypersignal on unenhanced T1-weighted magnetic resonance imaging and metabolic alterations by H magnetic resonance spectroscopy (H-MRS). At 1 year postinjections, brains were sampled to determine the localization of gadolinium within cerebellum by laser ablation inductively coupled mass spectroscopy and to evaluate morphological changes by semiquantitative immunofluorescence analysis., Results: There is a significant increase of the ratio DCN/brainstem for the gadodiamide group at M0 (+7.2% vs control group = 0.989 ± 0.01), M1 (+7.6% vs control group = 1.002 ± 0.018), and it lasted up to M13 (+4.7% vs control group = 0.9862 ± 0.008). No variation among metabolic markers (cellular homeostasis [creatine, choline, taurine], excitatory neurotransmitter [glutamate], and metabolites specific to a cellular compartment [N-acetyl aspartate for neurons and myo-inositol for glial cells]) were detected by H-MRS between gadodiamide and saline groups at M0, M1, and M13. At M13, laser ablation inductively coupled mass spectroscopy demonstrated that long-term gadolinium retention occurred preferentially in DCN. No histological abnormalities (including analysis of astrocytes, neurons, and microglial cells) were found in the rostral part of DCN., Conclusions: Repeated administration of gadodiamide lead to a retention of gadolinium preferentially within DCN at 1 year postinjections. This retention did not lead to any detectable changes of the measured metabolic biomarkers nor histological alterations.

GABA and glycine are inhibitory neurotransmitters. However, the mechanisms underlying the formation of GABAergic and glycinergic synapses remain unclear. The influence of GABAergic input deprivation on inhibitory terminal formation was investigated using Purkinje cell (PC)-specific vesicular GABA transporter (VGAT) knockout (L7-VGAT) mice, in which GABA release from PCs diminishes in an age-dependent manner. We compared the late development of GABAergic and glycinergic terminals in the cerebellar nucleus (CN) between control and L7-VGAT mice. In the control CN, the density of glutamate decarboxylase (GAD)-positive dots remained unchanged between postnatal 2 months (P2M) and 13 months (P13M), whereas glycine transporter 2 (GlyT2)-positive dots increased in density during this time frame. No difference in the density of GlyT2-positive dots was observed between control and L7-VGAT mice at P2M, but the density was significantly higher in the L7-VGAT fastigial nuclei (FN) than the control FN at P13M. When VGAT was absent from PC terminals, GlyT2-positive dots included GAD and VGAT and formed synapses. These results indicated that GABAergic terminals were formed by P2M, glycinergic terminals were actively formed after P2M, and more glycinergic terminals were formed in the L7-VGAT FN than in the control FN, suggesting that the increased glycinergic terminals may derive from interneurons within the FN and may also release GABA. These results suggest that the deprivation of GABAergic inputs from PCs may accelerate the formation of co-releasing terminals derived from interneurons and that the inhibitory terminal numbers and types may be regulated by the quantity of functional GABAergic inputs., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Metronidazole (MNZ) is prescribed for the treatment of infection caused by anaerobic bacteria and protozoa. Metronidazole-induced encephalopathy (MIE) has been known to be a side-effect, although its onset ratio is unclear. However, to the best of our knowledge, MIE associated with hyperbaric oxygen therapy (HBO) has not been previously reported. Here, we present the case of a 68-year-old man with mandibular osteomyelitis who received metronidazole for 49 days and received five times HBO therapy. He visited our hospital for evaluation and treatment of peripheral neuropathy, speech disturbance, nausea, and disturbance of gait after 47 days of initiating metronidazole treatment. Brain magnetic resonance imaging revealed hyperintense lesions in the cerebellar dentate nuclei, which was consistent with MIE. The patient's ataxic symptoms improved in 15 days after the discontinuation of MNZ. This is the first report demonstrating case of MIE could be related with HBO, as far as we had searched., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Axon regeneration after cerebral ischemia in mammals is inadequate to restore function, illustrating the need to design better strategies for improving outcomes. Improvement of axon regeneration has been achieved through fastigial nucleus electrostimulation (FNS) in animal researches. However, the mechanisms underlying this neuroprotection remain poorly understood. Increasing the levels of the second messenger cyclic AMP (cAMP) enhances axon regeneration, making it an excellent candidate molecule that has therapeutic potential. In the present study, we examined the expression of cAMP signaling in ischemic brain tissues following focal cerebral ischemia. Adult rats were subjected to ischemia induced by middle cerebral artery occlusion (MCAO). A dipolar electrode was placed into the cerebellum to stimulate the cerebellar fastigial nucleus for 1 h after ischemia. Neurological deficits and the expressions of cAMP, PKA (protein kinase A) and ROCK (Rho-kinase) were determined. Axonal regeneration was measured by upregulation of growth-associated protein 43 (GAP43). The data indicated that FNS significantly enhanced axonal regeneration and motor function recovery after cerebral ischemia. FNS also significantly increased cAMP and PKA levels after ischemic brain injury. All the beneficial effects of FNS were blocked by Rp-cAMP, an antagonist of PKA. Our research suggested that the axonal regeneration conferred by FNS was likely achieved via the regulation of cAMP/PKA pathway., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Research has implicated the deep cerebellar nuclei in autism. This study questioned whether fastigial nuclei abnormalities account for some of the irregular social behaviors seen in autism. Bilateral cannulation surgery was performed on 13 rats. An ABABAB reversal design was implemented. All animals received a microinfusion of saline during the baseline (A) phases. The experimental animal was placed in an open field with an unfamiliar confederate animal, and social interactions between the two animals were measured for 10 min. Seven animals received microinfusions of bupivacaine during the treatment phases (B), which temporarily inactivated the fastigial nuclei. Six control animals received saline again, and social interaction was retested. This sequence was executed 3 times over 6 days to achieve an ABABAB reversal design. Because the cerebellum is involved in motor behavior, the animals' locomotion was analyzed to ensure results were not because of locomotor deficits. A gait analysis and distance traveled in the open field were used to measure locomotion. No differences were found in locomotor behavior. Results of the social interaction analyses indicate animals with inactivated fastigial nuclei engage in less intense social interactions and engage in more behaviors to prevent social interaction. Knowledge that the fastigial nuclei mediate social interaction can further the understanding of pathology in the autistic brain and lead to breakthrough treatments. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Conditioning-specific reflex modification (CRM) of the rabbit eyeblink response is an associative phenomenon characterized by increases in the frequency, size, and peak latency of the reflexive unconditioned eyeblink response (UR) when the periorbital shock unconditioned stimulus (US) is presented alone following conditioning, particularly to lower intensity USs that produced minimal responding prior to conditioning. Previous work has shown that CRM shares many commonalities with the conditioned eyeblink response (CR) including a similar response topography, suggesting the two may share similar neural substrates. The following study examined the hypothesis that the interpositus nucleus (IP) of the cerebellum, an essential part of the neural circuitry of eyeblink conditioning, is also required for the acquisition of CRM. Tests for CRM occurred following delay conditioning under muscimol inactivation of the IP and also after additional conditioning without IP inactivation. Results showed that IP inactivation blocked acquisition of CRs and the timing aspect of CRM but did not prevent increases in UR amplitude and area. Following the cessation of inactivation, CRs and CRM latency changes developed similarly to controls with intact IP functioning, but with some indication that CRs may have been facilitated in muscimol rabbits. In conclusion, CRM timing and CRs both likely require the development of plasticity in the IP, but other associative UR changes may involve non-cerebellar structures interacting with the eyeblink conditioning circuitry, a strong candidate being the amygdala, which is also likely involved in the facilitation of conditioning. Other candidates worth consideration include the cerebellar cortex, prefrontal and motor cortices., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The caudal fastigial nuclei (cFN) are the output nuclei by which the medio-posterior cerebellum influences the production of saccadic and pursuit eye movements. We investigated the consequences of unilateral inactivation on the pursuit eye movement made immediately after an interceptive saccade toward a centrifugal target. We describe here the effects when the target moved along the horizontal meridian with a 10 or 20°/s speed. After muscimol injection, the monkeys were unable to track the present location of the moving target. During contralesional tracking, the velocity of postsaccadic pursuit was reduced. This slowing was associated with a hypometria of interceptive saccades such that gaze direction always lagged behind the moving target. No correlation was found between the sizes of saccade undershoot and the decreases in pursuit speed. During ipsilesional tracking, the effects on postsaccadic pursuit were variable across the injection sessions, whereas the interceptive saccades were consistently hypermetric. Here also, the ipsilesional pursuit disorder was not correlated with the saccade hypermetria either. The lack of correlation between the sizes of saccade dysmetria and changes of postsaccadic pursuit speed suggests that cFN activity exerts independent influences on the neural processes generating the saccadic and slow eye movements. It also suggests that the cFN is one locus where the synergy between the two motor categories develops in the context of tracking a moving visual target. We explain how the different fastigial output channels can account for these oculomotor tracking disorders. NEW & NOTEWORTHY Inactivation of the caudal fastigial nucleus impairs the ability to track a moving target. The accuracy of interceptive saccades and the velocity of postsaccadic pursuit movements are both altered, but these changes are not correlated. This absence of correlation is not compatible with an impaired common command feeding the circuits producing saccadic and pursuit eye movements. However, it suggests an involvement of caudal fastigial nuclei in their synergy to accurately track a moving target.

Background: Olive oil is a food additive and used in many biological studies as a solvent for other chemicals, including drugs., Aim: The present study aimed to investigate the effects of olive oil on rats' cerebellum structure and motor function., Materials and Methods: Male rats were randomly divided into two groups orally receiving distilled water and olive oil (1 ml/kg/day). At the end of week 4, motor function was assessed in the rotarod test. The cerebellum was removed for stereo-logical assessment. Data were analyzed using a two-way repeated measures ANOVA for rotarod test and Kruskal-Wallis and Mann-Whitney U test for quantitative histological parameters., Results: Performance of the olive oil-treated rats in fixed and accelerating speed rotarod was better and their riding time (endurance) was greater compared to the control group (p<0.05). However, no significant difference was found between the two groups regarding the total volume of the cerebellar hemisphere, its cortex, and deep cerebellar nuclei. The total number of the Purkinje, Bergman, and Golgi of the granular layer as well as neurons of the deep cerebellar nuclei was 26 - 36% higher in the olive oil-treated rats than in the distilled water treated group (p<0.03)., Conclusion: The study findings suggest that olive oil has neuroprotective effects on the cerebellum and induces better performance of the rats in the rotarod.

The caudal fastigial nuclei (cFN) are the output nuclei by which the medio-posterior cerebellum influences the production of visual saccades. We investigated in two head-restrained monkeys their contribution to the generation of interceptive saccades toward a target moving centrifugally by analyzing the consequences of a unilateral inactivation (10 injection sessions). We describe here the effects on saccades made toward a centrifugal target that moved along the horizontal meridian with a constant (10, 20, or 40°/s), increasing (from 0 to 40°/s over 600 ms), or decreasing (from 40 to 0°/s over 600 ms) speed. After muscimol injection, the monkeys were unable to foveate the current location of the moving target. The horizontal amplitude of interceptive saccades was reduced during contralesional target motions and hypermetric during ipsilesional ones. For both contralesional and ipsilesional saccades, the magnitude of dysmetria increased with target speed. However, the use of accelerating and decelerating targets revealed that the dependence of dysmetria upon target velocity was not due to the current velocity but to the required amplitude of saccade. We discuss these results in the framework of two hypotheses, the so-called "dual drive" and "bilateral" hypotheses. NEW & NOTEWORTHY Unilateral inactivation of the caudal fastigial nucleus impairs the accuracy of saccades toward a moving target. Like saccades toward a static target, interceptive saccades are hypometric when directed toward the contralesional side and hypermetric when they are ipsilesional. The dysmetria depends on target velocity, but the use of accelerating or decelerating targets reveals that velocity is not the crucial parameter. We extend the bilateral fastigial control of saccades and fixation to the production of interceptive saccades.

Background and Purpose: In view of the recent observations that gadolinium deposits in brain tissue after intravenous injection, our aim of this study was to compare signal changes in the globus pallidus and dentate nucleus on unenhanced T1-weighted MR images in patients receiving serial doses of gadobutrol, a macrocyclic gadolinium-based contrast agent, with those seen in patients receiving linear gadolinium-based contrast agents., Materials and Methods: This was a retrospective analysis of on-site patients with brain tumors. Fifty-nine patients received only gadobutrol, and 60 patients received only linear gadolinium-based contrast agents. Linear gadolinium-based contrast agents included gadoversetamide, gadobenate dimeglumine, and gadodiamide. T1 signal intensity in the globus pallidus, dentate nucleus, and pons was measured on the precontrast portions of patients' first and seventh brain MRIs. Ratios of signal intensity comparing the globus pallidus with the pons (globus pallidus/pons) and dentate nucleus with the pons (dentate nucleus/pons) were calculated. Changes in the above signal intensity ratios were compared within the gadobutrol and linear agent groups, as well as between groups., Results: The dentate nucleus/pons signal ratio increased in the linear gadolinium-based contrast agent group ( t = 4.215, P < .001), while no significant increase was seen in the gadobutrol group ( t = -1.422, P = .08). The globus pallidus/pons ratios followed similarly, with an increase in the linear gadolinium-based contrast agent group ( t = 2.931, P < .0001) and no significant change in those receiving gadobutrol ( t = 0.684, P = .25)., Conclusions: Successive doses of gadobutrol do not result in T1 shortening compared with changes seen in linear gadolinium-based contrast agents., (© 2018 by American Journal of Neuroradiology.)

Background and Purpose: Previous studies have evaluated various gadolinium based contrast agents and their association with gadolinium retention, however, there is a discrepancy in the literature concerning the linear agent gadobenate dimeglumine. Our aim was to determine whether an association exists between the administration of gadobenate dimeglumine and the development of intrinsic T1-weighted signal in the dentate nucleus and globus pallidus., Materials and Methods: In this single-center, retrospective study, the signal intensity of the globus pallidus, dentate nucleus, thalamus, and middle cerebellar peduncle was measured on unenhanced T1-weighted images in 29 adult patients who had undergone multiple contrast MRIs using exclusively gadobenate dimeglumine (mean, 10.1 ± 3.23 doses; range, 6-18 doses). Two neuroradiologists, blinded to the number of prior gadolinium-based contrast agent administrations, separately placed ROIs within the globi pallidi, thalami, dentate nuclei, and middle cerebellar peduncles on the last MR imaging examinations. The correlations between the globus pallidus:thalamus and the dentate nucleus:middle cerebellar peduncle signal intensity ratios with the number of gadolinium-based contrast agent administrations and cumulative dose were tested with either 1-tailed Pearson or Spearman correlations. A priori, P < .05 was considered statistically significant., Results: Both the globus pallidus:thalamus and dentate nucleus:middle cerebellar peduncle ratios showed significant correlation with the number of gadolinium-based contrast agent administrations ( r = 0.39, P = .017, and r = 0.58, P = .001, respectively). Additionally, the globus pallidus:thalamus and dentate nucleus:middle cerebellar peduncle ratios showed significant correlation with the cumulative dose of gadobenate dimeglumine ( r = 0.48, P = .004, and r = 0.43, P = .009, respectively). Dentate nucleus hyperintensity was qualitatively present on the last MR imaging in 79.3%-86.2% of patients and in all patients who had received >10 doses., Conclusions: At high cumulative doses (commonly experienced by patients, for example, with neoplastic disease), gadobenate dimeglumine is associated with an increase in the globus pallidus:thalamus and dentate nucleus:middle cerebellar peduncles signal intensity ratios., (© 2018 by American Journal of Neuroradiology.)

Objective: There has been controversy as to whether gadobutrol, one of the widely used macrocyclic gadolinium-based contrast agents, can lead to gadolinium retention after serial injections. Our aim was to validate whether serial administrations of gadobutrol can cause signal increase in the dentate nucleus (DN) and globus pallidus (GP) on unenhanced T1-weighted magnetic resonance (MR) images due to gadolinium retention., Materials and Methods: A total of 189 patients who had undergone at least 2 contrast-enhanced MR scans using only gadobutrol between August 2009 and August 2016 were retrospectively included. The DN-to-pons and GP-to-thalamus signal intensity (SI) ratio differences on unenhanced T1-weighted MR images were calculated by subtracting the SI ratios at the first MR images from those at the last MR images. One-sample t tests were used to evaluate whether the SI ratio differences differed from 0. Linear regression and Pearson correlations were performed to assess correlations between SI ratio differences and various confounding variables, including the number of MR scans, mean time interval between MR scans, age, sex, history of radiation therapy or chemotherapy, and renal and liver functions., Results: Patients underwent a mean of 5.9 ± 6.3 contrast-enhanced MR scans with a mean interval of 42.8 ± 49.5 weeks between the scans. Sixty-three patients underwent 6 or more MR scans, whereas 126 patients underwent fewer than 6 MR scans. Neither the DN-to-pons SI nor the GP-to-thalamus SI ratio differences differed significantly from 0, with mean values of -0.012 ± 0.115 (P = 0.148) and 0.012 ± 0.111 (P = 0.126), respectively., Conclusions: Serial administrations of gadobutrol did not result in signal increases in the DN or GP on unenhanced T1-weighted MR images due to gadolinium retention.

Introduction: Treatment with lithium can cause several neurological side effects, even at therapeutic levels., Case Report: We report the case of a 49-year-old woman, with bipolar disorder and depression, undergoing treatment with lithium, antidepressants and antipsychotics, who was admitted to hospital due to a clinical picture of visual hallucinations with an elevated lithaemia of 2.1 mEq/L (therapeutic range: 0.6-1.2 mEq/L). The patient developed a severe encephalopathy that required the use of assisted ventilation in the intensive care unit. Initial magnetic resonance imaging showed a reversible bilateral symmetrical hyperintensity in the dentate nuclei in T2 and T2-FLAIR sequences. Over the following months she gradually developed a pancerebellar syndrome with evidence of a marked loss of bilateral volume in the cerebellum, above all at the expense of the vermis, which was accompanied by a permanent and disabling cerebellar syndrome., Conclusions: Although treatment with lithium can cause a variety of neurological side effects, they are usually reversible. However, they occasionally give rise to permanent and disabling sequelae, as in the case of the patient reported here, with a marked and progressive cerebellar atrophy, accompanied by permanent sequelae in the form of a disabling cerebellar syndrome. The cerebellar neurotoxicity of lithium must be taken into account in the broad differential diagnosis of cerebellar ataxia in adults.

Objective: The aim of this study was to evaluate whether an association exists between T1-signal increase in the dentate nucleus (DN) on unenhanced magnetic resonance imaging and previous administration of gadoxetic acid and gadodiamide., Materials and Methods: This retrospective study was approved by the institutional review board; the requirement for informed patient consent was waived. A total of 132 patients (male-female ratio, 86:46; mean age, 68.8 ± 11.6 years) who underwent imaging between December 2000 and April 2016 were divided into 4 groups: patients with 5 or more administrations of gadoxetic acid ("gadoxetic acid ≥5 administrations" group), only 1 administration of gadoxetic acid ("gadoxetic acid 1 administration" group), no gadolinium-based contrast agent (GBCA) administration or chronic liver disease (CLD; "no GBCA administration and no CLD" group), and 5 or more administrations of gadodiamide ("gadodiamide ≥5 administrations" group). Unenhanced T1-weighted images were quantitatively analyzed by 2 radiologists. Intergroup comparison of DN-to-pons signal intensity ratios was performed by the Dunn test, with the no GBCA administration and no CLD group as control. Interobserver agreement was assessed by intraclass correlation coefficients., Results: The DN-to-pons ratio of the "gadodiamide ≥5 administrations" group was significantly higher (P < 0.0001) and those of the "gadoxetic acid ≥5 administrations" and "gadoxetic acid 1 administration" groups did not differ significantly (P = 0.3912 and 1.0000, respectively) compared with the DN-to-pons ratio of the "no GBCA administration and no CLD" group. The interobserver intraclass correlation coefficient for measurement of DN-to-pons ratio was excellent (0.835; 95% confidence interval, 0.767-0.883)., Conclusions: Hyperintensity in the DN on unenhanced T1-weighted images is associated with previous administration of gadodiamide but not gadoxetic acid. Although the number of administrations for the 2 GBCA groups was identical, the administered dose of gadoxetic acid was only a quarter the amount of gadolinium as those with gadodiamide. This difference might influence the results of this study.

Background: Saccade pulse amplitude adaptation is mediated by the dorsal cerebellar vermis and fastigial nucleus. Long-term depression at the parallel fibre-Purkinjie cell synapses has been suggested to provide a cellular mechanism for the corresponding learning process. The mechanisms and sites of this plasticity, however, are still debated., Objective: To test the role of cerebellar plasticity phenomena on adaptive saccade control., Methods: We evaluated the effect of continuous theta burst stimulation (cTBS) over the posterior vermis on saccade amplitude adaptation and spontaneous recovery of the initial response. To further identify the substrate of synaptic plasticity responsible for the observed adaptation impairment, subjects were pre-treated with memantine, an N-methyl-d-aspartate receptor (NMDAR) antagonist., Results: Amplitude adaptation was altered by cTBS, suggesting that cTBS interferes with cerebellar plasticity involved in saccade adaptation. Amplitude adaptation and spontaneous recovery were not affected by cTBS when recordings were preceded by memantine administration., Conclusion: The effects of cTBS are NMDAR-dependent and are likely to involve long-term potentiation or long-term depression at specific synaptic connections of the granular and molecular layer, which could effectively take part in cerebellar motor learning., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Diolistic labeling is increasingly utilized in neuroscience as an efficient, reproducible method for visualization of neuronal morphology. The use of lipophilic carbocyanine dyes, combined with particle-mediated biolistic delivery allows for non-toxic fluorescent labeling of multiple neurons in both living and fixed tissue. Since first described, this labeling method has been modified to fit a variety of research goals and laboratory settings., New Method: Diolistic labeling has traditionally relied on commercially available devices for the propulsion of coated micro-particles into tissue sections. Recently, laboratory built biolistic devices have been developed which allow for increased availability and customization. Here, we discuss a custom biolistic device and provide a detailed protocol for its use., Results: Using custom diolistic labeling we have characterized alterations in neuronal morphology of the lateral/dentate nucleus of the rat cerebellum. Comparisons were made in developing rat pups exposed to abnormally high levels of 5-methyloxytryptamine (5-MT) pre-and postnatally. Using quantitative software; dendritic morphology, architecture, and synaptic connections, were analyzed., Comparison With Existing Method(s): The rapid nature of custom diolistics coupled with passive diffusion of dyes and compatibility with confocal microscopy, provides an unparalleled opportunity to examine features of neuronal cells at high spatial resolution in a three-dimensional tissue environment., Conclusions: While decreasing the associated costs, the laboratory-built device also overcomes many of the obstacles associated with traditional morphological labeling, to allow for reliable and reproducible neuronal labeling. The versatility of this method allows for its adaptation to a variety of laboratory settings and neuroscience related research goals., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Gadolinium is toxic and to avoid its deposition in tissues, it must be chemically bonded with nonmetal ions to facilitate its excretion by the kidneys. High signal intensity in the dentate nucleus (DN) and globus pallidus (GP) on unenhanced T1-weighted MR images has been both morphologically and pathologically linked to gadolinium-based contrast agent (GBCA) retention in the brain. The purpose of this study was to determine whether repeated administrations of GBCA would affect the uptake of 18 F-FDG in the DN and GP on PET/CT. Methods: Three hundred seventy-six patients who underwent both contrast-enhanced MR (CE MR) of the brain and PET/CT from January 2004 to October 2015 were identified. Patients with a history of brain irradiation or hepatic or renal disease were excluded. The SUV max was measured in the DN and GP on the PET/CT scan in patients who had 3-6 successive CE MR brain studies. The SUV max of the corresponding areas in the control group of patients who had not undergone previous CE MR and who had a normal, unenhanced MR finding of the brain was also measured. A Wilcoxon 2-sample test was used for statistical analysis. Results: Fifteen of 376 (4%) patients (mean age ± SD, 54 ± 18 y; 10 men and 5 women) were included in the subject group, and 15 patients (mean age ± SD, 36 ± 9 y; 11 men and 4 women) were included in the control group. The median DN SUV max was significantly lower in the subject group than in the control group (5.4 vs. 6.4, respectively; P = 0.021). Similarly, the median GP SUV max was significantly lower in the subject group than in the control group (8.8 vs. 12.1, respectively; P = 0.003). Conclusion: The median SUV max in the DN and GP was 16% and 27% lower, respectively, in patients who received GBCAs than in those who had not received GBCAs, possibly related to gadolinium deposition in these areas., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose To determine the effect of more than 20 serial injections of macrocyclic gadolinium-based contrast agents (GBCAs) on the signal intensity (SI) of the dentate nucleus (DN) on unenhanced T1-weighted magnetic resonance (MR) images. Materials and Methods In this retrospective, institutional review board-approved study, 33 patients who underwent at least 20 consecutive MR imaging examinations (plus an additional MR imaging for reference) with the exclusive use of macrocyclic GBCAs gadoterate meglumine and gadobutrol were analyzed. SI ratio differences were calculated for DN-to-pons and DN-to-middle cerebellar peduncle (MCP) ratios by subtracting the SI ratio at the first MR imaging examination from the SI ratio at the last MR imaging examination. One-sample t tests were used to examine if the SI ratio differences differed from 0, and Bayes factors were calculated to quantify the strength of evidence for each test. Results Patients underwent a mean of 23.03 ± (standard deviation) 4.20 GBCA administrations (mean accumulated dose, 491.21 mL ± 87.04 of a 0.5 M GBCA solution) with an average of 12.09 weeks ± 2.16 between every administration. Both ratio differences did not differ significantly from 0 (DN-to-pons ratio: -0.0032 ± 0.0154, P = .248; DN-to-MCP ratio: -0.0011 ± 0.0093, P = .521), and one-sided Bayes factors provided substantial to strong evidence against an SI ratio increase (Bayes factor for DN-to-pons ratio = 0.09 and that for DN-to-MCP ratio = 0.12). Conclusion The study indicates that 20 or more serial injections of macrocyclic GBCAs administered with on average 3 months between each injection are not associated with an SI increase in the DN. © RSNA, 2016.

Purpose: Recent studies reported an increase in the dentate nucleus (DN)-to-pons signal intensity (SI) ratio (DN-pons SI ratio) on unenhanced T1-weighted images in patients who received consecutive serial injections of linear gadolinium-based contrast agents (GBCAs). In contrast, most studies found no increase in the DN-pons SI ratio when patients were treated with consecutive serial injections of macrocyclic GBCAs. However, the potential difference between macrocyclic and linear GBCAs has never been assessed in individuals who received subsequent applications of both contrast agents. In this retrospective study, we assessed the evolution of the DN-pons SI ratio change in patients that were treated with a comparable number of serial consecutive injections of the linear GBCA gadopentetate dimeglumine and subsequent serial injections of the macrocyclic GBCAs gadobutrol and gadoterate meglumine., Materials and Methods: Data of 36 patients was analyzed. All patients underwent at least 5 consecutive administrations of the linear GBCA gadopentetate dimeglumine followed by an equal number of consecutive administrations of the macrocyclic GBCA gadobutrol. In 12 of the 36 patients, 5 or more final consecutive injections of the macrocyclic GBCA gadoterate meglumine were analyzed additionally. The difference of DN-pons SI ratios on unenhanced T1-weighted images was calculated by subtracting the ratio at the first examination from the ratio at the last examination in each of the 3 periods., Results: The mean DN-pons SI ratio difference in the gadopentetate dimeglumine period was significantly greater than 0 (mean ± SD, 0.0448 ± 0.0345; P < 0.001), whereas the mean DN-pons SI ratio difference in the subsequent gadobutrol and gadoterate meglumine period was significantly smaller than 0 (gadobutrol: -0.0178 ± 0.0459, P = 0.026; gadoterate meglumine: -0.0250 ± 0.0284, P = 0.011)., Conclusions: In this observational study, the application of the linear GBCA gadopentetate dimeglumine was associated with a DN-pons SI ratio increase, whereas subsequent applications of the macrocyclic GBCAs gadobutrol or gadoterate meglumine in the same patients were not. Rather, the current data tentatively suggest a decrease in preexisting hyperintensities over time when linear GBCAs are changed to macrocyclic GBCAs, potentially indicating a washout effect or precipitation of gadolinium. Future patient studies need to include control groups to replicate the present results, and additional animal studies should be conducted to clarify the underlying mechanism of the proposed SI decrease.

It is well known that the cerebellar fastigial nucleus (FN) is involved in cardiovascular modulation, and has direct evidence of cholinergic activity; however, whether and how acetylcholine (ACh) in the FN modulates blood pressure has not been investigated. In this study, we analyzed mean arterial pressure, maximal change in mean arterial pressure, and the reaction time of blood pressure changes after microinjection of cholinergic reagents into the FN in anesthetized rats. The results showed that ACh evoked a concentration-dependent (10, 30 and 100mM) effect on blood pressure down-regulation. The muscarinic ACh (mACh) receptor antagonist atropine, but not the nicotinic ACh (nACh) receptor antagonist mecamylamine, blocked the ACh-mediated depressor response. The mACh receptor agonist oxotremorine M, rather than nACh receptor agonist nicotine, mimicked the ACh-mediated blood pressure decrease in a dose-dependent manner (10, 30 and 100mM). These results indicate that cholinergic input in the cerebellar FN exerts a depressor effect on systemic blood pressure regulation, and such effects are substantially contributed by mACh rather than nACh receptors, although the precise mechanism concerning the role of mACh receptor in FN-mediated blood pressure modulation remains to be elucidated., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social cognition, disordered communication, restricted interests and repetitive behaviors. Furthermore, abnormalities in basic motor control, skilled motor gestures, and motor learning, are common in ASD. These characteristics have been attributed to a possible defect in the pre- and postnatal development of specific neural networks including the dentate-thalamo-cortical pathway, which is involved in motor learning, automaticity of movements, and higher cognitive functions. The current study utilized custom diolistic labeling and unbiased stereology to characterize morphological alterations in neurons of the dentate nucleus of the cerebellum in developing rat pups exposed to abnormally high levels of the serotonergic agonist 5-methyloxytryptamine (5-MT) pre-and postnatally. Occurring in as many as 30% of autistic subjects, developmental hyperserotonemia (DHS) is the most consistent neurochemical finding reported in autism and has been implicated in the pathophysiology of ASD. This exposure produced dramatic changes in dendritic architecture and synaptic features. We observed changes in the dendritic branching morphology which did not lead to significant differences (p>0.5) in total dendritic length. Instead, DHS groups presented with dendritic trees that display changes in arborescence, that appear to be short reaching with elaborately branched segments, presenting with significantly fewer (p>0.001) dendritic spines and a decrease in numeric density when compared to age-matched controls. These negative changes may be implicated in the neuropathological and functional/behavioral changes observed in ASD, such as delays in motor learning, difficulties in automaticity of movements, and deficits in higher cognitive functions., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

The activity of the deep cerebellar nuclei (DCN) neurons conveys the bulk of the output of the cerebellum. To generate these motor signals, DCN neurons integrate synaptic inputs with their own spontaneous activity. We have previously reported that N-type voltage-gated Ca(2+) channels modulate the spontaneous activity of the majority of juvenile DCN neurons in vitro. Specifically, pharmacologically blocking N-type Ca(2+) channels increases their firing rate causing DCN cells to burst. Adult DCN neurons however, behaved differently. To further investigate this change, we have studied here the effect of cadmium on the firing rate of DCN neurons in acute cerebellar slices obtained from adult (>2 months old) or juvenile (12-21 days old) rats and mice. Strikingly, and in contrast to juvenile DCN cells, cadmium did not affect the pacemaking of adult DCN cells. The activity of Purkinje cells (PCs) however was transformed into high-frequency bursting, regardless the age. Further, we questioned whether these findings could be due to an artifact associated with the added difficulty of preparing adult DCN slices. Hence we proceeded to examine the spontaneous activity of DCN neurons in anesthetized juvenile and adult rats and mice in vivo. When cadmium was injected into the DCN in vivo no significant change in firing rate was observed, conversely to most juvenile DCN neurons which showed high-frequency bursts after cadmium injection. In these same animals, PCs pacemaking showed no developmental difference. Thus our results demonstrate a remarkable age-dependent functional modification in the regulation of DCN neurons pacemaking., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

Objective: The objective of this study was to evaluate signal changes in the dentate nucleus on unenhanced T1-weighted MR images after multiple administrations of gadopentetate dimeglumine versus gadobutrol., Materials and Methods: Two study groups were identified, each of which included 25 consecutive patients. Each group received six or more administrations of either gadobutrol only or gadopentetate dimeglumine only, without having had exposure to any other gadolinium-based contrast agent (GBCA). The mean signal intensity (SI) in the dentate nucleus on unenhanced T1-weighted MR images was measured, with the use of the pons and the cerebellar peduncle as references to calculate the DNP SI ratio (i.e., the ratio of the SI in the dentate nucleus to the SI in the pons) and the DCP SI ratio (i.e., the ratio of the SI in the dentate nucleus to the SI in the cerebellar peduncle)., Results: After six administrations of gadopentetate dimeglumine, the SI in the dentate nucleus on unenhanced T1-weighted MR images increased from a DCP SI ratio of 0.997 before administration to 1.034 after the last of six administrations (p = 0.0007) and then to 1.063 after all administrations (p = 0.0004). No statistically significant increase was noted in association with administration of gadobutrol, for which the DCP SI ratio was 0.995 before administration, 1.009 after the last of six administrations (p = 0.1172), and 0.992 after all administrations (p = 0.7592). The change in the DCP SI ratio after administration of gadopentetate dimeglumine correlated with the number of administrations the patient received (p < 0.0001)., Conclusion: Unenhanced T1 signal hyperintensity was observed in the dentate nucleus after multiple administrations of gadopentetate dimeglumine, a linear ionic agent, but not after multiple administrations of gadobutrol, a macrocyclic GBCA.

Objectives: It is not known whether current use of the medication primidone affects brain γ-aminobutyric acid (GABA) concentrations. This is an important potential confound in studies of the pathophysiology of essential tremor (ET), one of the most common neurological diseases. We compared GABA concentrations in the dentate nucleus in 6 ET patients taking primidone versus 26 ET patients not taking primidone., Methods: (1)H magnetic resonance spectroscopy was performed using a 3.0-T Siemens Tim Trio scanner. The MEGA-PRESS J-editing sequence was used for GABA detection in 2 cerebellar volumes of interest (left and right) that included the dentate nucleus., Results: The right dentate GABA concentration was similar in the 2 groups (2.21 ± 0.46 [on primidone] vs 1.93 ± 0.39 [not on primidone], P = 0.15), as was the left dentate GABA concentration (1.61 ± 0.35 [on primidone] vs 1.67 ± 0.34 [not on primidone], P = 0.72). The daily primidone dose was not associated with either right or left dentate GABA concentrations (P = 0.89 and 0.76, respectively)., Conclusions: We did not find a difference in dentate GABA concentrations between 6 ET patients taking daily primidone and 26 ET patients not taking primidone. Furthermore, there was no association between daily primidone dose and dentate GABA concentration. These data suggest that it is not necessary to exclude ET patients on primidone from magnetic resonance spectroscopy studies of dentate GABA concentration, and if assessment of these concentrations was to be developed as a biomarker for ET, primidone usage would not confound interpretation of the results.

Objectives: The aim of this study was to compare changes in signal intensity (SI) ratios of the dentate nucleus (DN) to pons and cerebrospinal fluid (CSF) on unenhanced T1-weighted magnetic resonance imaging (MRI) scans between the first and last MRI using the linear gadolinium-based contrast agent gadobenate dimeglumine., Materials and Methods: The study was approved by the ethical committee of the University of Heidelberg (S-324/2014), and written informed consent was waived due to the retrospective character of the study. Fifty patients who underwent at least 5 consecutive MRI examinations (plus an additional last MRI for reference) with the exclusive use of gadobenate dimeglumine were analyzed retrospectively. The difference of DN-to-pons and DN-to-CSF mean SI ratios was calculated on unenhanced T1-weighted images between the first and last examination. Results were compared with previously published data on gadopentetate dimeglumine and gadoterate meglumine., Results: Signal intensity ratio differences for DN-to-pons and DN-to-CSF were significantly greater than 0 (pons: 0.0399 ± 0.0307, P < 0.001; CSF: 0.1439 ± 0.1524, P < 0.001). No control variable consistently predicted the SI ratio difference for the DN-to-pons and the DN-to-CSF ratio. Compared with previously published data, the difference in SI increase between gadopentetate dimeglumine and gadobenate dimeglumine was not significant for the DN-to-pons ratio (P = 0.906). In contrast, the DN-to-CSF ratio difference was significantly lower (P < 0.001) for gadobenate dimeglumine. Dentate nucleus-to-pons (P < 0.001) and DN-to-CSF (P = 0.017) ratio differences were both significantly higher for gadobenate dimeglumine than for gadoterate meglumine., Conclusions: The present study found an increase in SI in the DN after serial injections of gadobenate dimeglumine. Further studies are needed to clarify the potential of different linear gadolinium-based contrast agents to cause SI increase in the DN.

Objectives: To prospectively compare in healthy rats the effect of multiple injections of macrocyclic (gadoterate meglumine) and linear (gadodiamide) gadolinium-based contrast agents (GBCAs) on T1-weighted signal intensity in the deep cerebellar nuclei (DCN), including the dentate nucleus., Materials and Methods: Healthy rats (n = 7/group) received 20 intravenous injections of 0.6 mmol of gadolinium (Gd) per kilogram (4 injections per week during 5 weeks) of gadodiamide, gadoterate meglumine, or hyperosmolar saline (control group). Brain T1-weighted magnetic resonance imaging was performed before and once a week during the 5 weeks of injections and during 5 additional weeks (treatment-free period). Gadolinium concentrations were measured with inductively coupled plasma mass spectrometry in plasma and brain. Blinded qualitative and quantitative evaluations of the T1 signal intensity in DCN were performed, as well as a statistical analysis on quantitative data., Results: A significant and persistent T1 signal hyperintensity in DCN was observed only in gadodiamide-treated rats. The DCN-to-cerebellar cortex signal ratio was significantly increased from the 12th injection of gadodiamide (1.070 ± 0.024) compared to the gadoterate meglumine group (1.000 ± 0.033; P < 0.001) and control group (1.019 ± 0.022; P < 0.001) and did not significantly decrease during the treatment-free period. Total Gd concentrations in the gadodiamide group were significantly higher in the cerebellum (3.66 ± 0.91 nmol/g) compared with the gadoterate meglumine (0.26 ± 0.12 nmol/g; P < 0.05) and control (0.06 ± 0.10 nmol/g; P < 0.05) groups., Conclusions: Repeated administrations of the linear GBCA gadodiamide to healthy rats are associated with progressive and persistent T1 signal hyperintensity in the DCN, with Gd deposition in the cerebellum in contrast with the macrocyclic GBCA gadoterate meglumine for which no effect was observed.

Stress exerts profound inhibitory effects on reproductive function by suppression of the pulsatile release of GnRH and therefore LH. Besides the corticotrophin-releasing factor (CRF), this effect also might be mediated via GABAergic signaling within the arcuate nucleus (ARC) since its inhibitory effects on LH pulses and increased activity during stress. In the present study, we investigated the role of endogenous GABAergic signaling within the ARC in stress-induced suppression of LH pulses. Ovariectomised oestradiol-replaced rats were implanted with bilateral and unilateral cannulae targeting toward the ARC and lateral cerebral ventricle respectively. Blood samples (25 μl) were taken via chronically implanted cardiac catheters every 5 min for 6 h for measurement of LH pulses. Intra-ARC infusion of GABAA receptor antagonist, bicuculline (0.2 pmol in 200 nl artificial cerebrospinal fluid (aCSF) each side, three times at 20-min intervals) markedly attenuated the inhibitory effect of lipopolysaccharide (LPS; 25 μg/kg i.v.) but not restraint (1 h) stress on pulsatile LH secretion. In contrast, restraint but not LPS stress-induced suppression of LH pulse frequency was reversed by intra-ARC administration of GABABR antagonist, CGP-35348 (1.5 nmol in 200 nl aCSF each side, three times at 20-min intervals). Moreover, intra-ARC application of either bicuculline or CGP-35348 attenuated the inhibitory effect of CRF (1 nmol in 4 μl aCSF, i.c.v.) on the LH pulses. These data indicate a pivotal and differential role of endogenous GABAA and GABAB signaling mechanisms in the ARC with respect to mediating immunological and psychological stress-induced suppression of the GnRH pulse generator respectively., (© 2015 Society for Endocrinology.)

The dentate nucleus of the cerebellum may appear as hyperintense on unenhanced T1 magnetic resonance images (MRIs) of the brain. Recently, T1 signal hyperintensity has received attention owing to data on the association of this finding with the history of multiple injections of gadolinium-based contrast agents, specifically gadodiamide, in patients with multiple sclerosis and brain metastases. We conducted a retrospective study on patients with a meningioma who had routinely undergone follow-up enhanced MRI scans with gadodiamide. Across a time interval of 18 months (from January 2013 to July 2014), we identified 102 consecutive patients eligible for this study. A significant increase in T1 hyperintensity of the dentate nuclei of the cerebellum on nonenhanced scans was observed between the first and the last MRI in the group of patients with a history of at least 6 enhanced MRI scans (P < 0.01), whereas no differences were observed in the group with 1 to 5 enhanced MRI scans (P = 0.74). Further research is necessary to shed light on the mechanism of the T1 hyperintensity as well as on the histological and microstructural appearance of the dentate nucleus after multiple intravenous injections of gadodiamide. The finding raises the question of substantial dechelation of this agent in patients with normal renal function.

Our previous work has shown that cerebellar interposed nucleus (IN) modulates immune function. Herein, we reveal mechanism underlying the immunomodulation. Treatment of bilateral cerebellar IN of rats with 3-mercaptopropionic acid (3-MP), a glutamic acid decarboxylase antagonist that reduces γ-aminobutyric acid (GABA) synthesis, enhanced cellular and humoral immune responses to bovine serum albumin, whereas injection of vigabatrin, a GABA-transaminase inhibitor that inhibits GABA degradation, in bilateral cerebellar IN attenuated the immune responses. The 3-MP or vigabatrin administrations in the cerebellar IN decreased or increased hypothalamic GABA content and lymphoid tissues' norepinephrine content, respectively, but did not alter adrenocortical or thyroid hormone levels in serum. In addition, a direct GABAergic projection from cerebellar IN to hypothalamus was found. These findings suggest that GABAergic neurons in cerebellar IN regulate immune system via hypothalamic and sympathetic pathways., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: Disrupting thalamocortical activity patterns has proven to be a promising approach to stop generalized spike-and-wave discharges (GSWDs) characteristic of absence seizures. Here, we investigated to what extent modulation of neuronal firing in cerebellar nuclei (CN), which are anatomically in an advantageous position to disrupt cortical oscillations through their innervation of a wide variety of thalamic nuclei, is effective in controlling absence seizures., Methods: Two unrelated mouse models of generalized absence seizures were used: the natural mutant tottering, which is characterized by a missense mutation in Cacna1a, and inbred C3H/HeOuJ. While simultaneously recording single CN neuron activity and electrocorticogram in awake animals, we investigated to what extent pharmacologically increased or decreased CN neuron activity could modulate GSWD occurrence as well as short-lasting, on-demand CN stimulation could disrupt epileptic seizures., Results: We found that a subset of CN neurons show phase-locked oscillatory firing during GSWDs and that manipulating this activity modulates GSWD occurrence. Inhibiting CN neuron action potential firing by local application of the γ-aminobutyric acid type A (GABA-A) agonist muscimol increased GSWD occurrence up to 37-fold, whereas increasing the frequency and regularity of CN neuron firing with the use of GABA-A antagonist gabazine decimated its occurrence. A single short-lasting (30-300 milliseconds) optogenetic stimulation of CN neuron activity abruptly stopped GSWDs, even when applied unilaterally. Using a closed-loop system, GSWDs were detected and stopped within 500 milliseconds., Interpretation: CN neurons are potent modulators of pathological oscillations in thalamocortical network activity during absence seizures, and their potential therapeutic benefit for controlling other types of generalized epilepsies should be evaluated., (© 2015 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Objective: To investigate the effect of neurogenic neuroprotection conferred by cerebellar fastigial nucleus stimulation (FNS) and the role of PPARγ-mediated inflammation in a rat model of cerebral ischemia reperfusion., Methods: After a continuous 1 hour fastigial nucleus electric stimulation, the male Sprague Dawley (SD) rats were given middle cerebral artery occlusion (MCAO) for 1, 3, 6, 9, 12 and 15 hours undergoing reperfusion with intravenous recombinant tissue plasminogen activator (rt-PA), while the control group received without FNS. After 72 h of reperfusion, the neurological deficits, infarct volume and brain edema were evaluated. The brain tissue in ischemic penumbra was determined the myeloperoxidase (MPO) activity by a spectrophotometer and expression of PPARγ was measured by Rt-PCR and Western blotting., Results: Our findings showed that FNS group had significantly reduced infarct volume and brain edema, and improved neurological deficits compared with the control group, especially in 6 h and 9 h reperfusion subgroups (p<0.05). The expression levels of PPARγ increased gradually and the peak may be before and after 9 h reperfusion, the 3 h, 6 h, 9 h, 12 h and 15 h reperfusion subgroups were higher than each control group (p<0.05). The MPO activity of 6 h, 12 h and 15 h reperfusion subgroups were higher than each control group (p<0.05)., Conclusions: The neuroprotective effects of FNS have been shown to prolong the therapeutic window in cerebral ischemia/reperfusion, which might be related to the PPARγ mediated-inflammation in penumbral region.

Autism spectrum disorders (ASD) is diagnosed in males at a much higher rate than females. For this reason, the majority of autism research has used male subjects exclusively. However; more recent studies using genetic sex as a factor find that the development of the male and female brain is differentially affected by ASD. That is, the natural sex-specific differences that exist between male and female brains lead to sexually dimorphic expressions of autism. Here we investigate the putative sexual dimorphism that exists in the deep cerebellar nuclei of male and female rats exposed to valproic acid (VPA) on embryological day 12.5. We find natural sex-specific differences in adult nucleus area, length, and estimated cell populations. Therefore VPA exposure during embryology creates some sex-specific deficits such as higher cell counts in the VPA males and lower cell counts in the VPA females. At the same time, some effects of VPA exposure occur regardless of sex. That is, smaller nucleus area and length lead to truncated nuclei in both VPA males and females. These deficits are more pronounced in the VPA males suggesting that genetic sex could play a role in teratogenic susceptibility to VPA. Taken together our results suggests that VPA exposure induces sexually dimorphic aberrations in morphological development along a mediolateral gradient at a discrete region of the hindbrain approximate to rhombomere (R) 1 and 2. Sex-specific disruption of the local and long-range projections emanating from this locus of susceptibility could offer a parsimonious explanation for the brain-wide neuroanatomical variance reported in males and females with ASD., (Published by Elsevier Ltd.)

In the mammalian cerebellum, deep cerebellar nuclear (DCN) cells convey all information from cortical Purkinje cells (PCs) to premotor nuclei and other brain regions. However, how DCN cells integrate inhibitory input from PCs with excitatory inputs from other sources has been difficult to assess, in part due to the large spatial separation between cortical PCs and their target cells in the nuclei. To circumvent this problem we have used a Cre-mediated genetic approach to generate mice in which channelrhodopsin-2 (ChR2), fused with a fluorescent reporter, is selectively expressed by GABAergic neurons, including PCs. In recordings from brain slice preparations from this model, mammalian PCs can be robustly depolarized and discharged by brief photostimulation. In recordings of postsynaptic DCN cells, photostimulation of PC axons induces a strong inhibition that resembles these cells' responses to focal electrical stimulation, but without a requirement for the glutamate receptor blockers typically applied in such experiments. In this optogenetic model, laser pulses as brief as 1 ms can reliably induce an inhibition that shuts down the spontaneous spiking of a DCN cell for ∼50 ms. If bursts of such brief light pulses are delivered, a fixed pattern of bistable bursting emerges. If these pulses are delivered continuously to a spontaneously bistable cell, the immediate response to such photostimulation is inhibitory in the cell's depolarized state and excitatory when the membrane has repolarized; a less regular burst pattern then persists after stimulation has been terminated. These results indicate that the spiking activity of DCN cells can be bidirectionally modulated by the optically activated synaptic inhibition of cortical PCs., (Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.)

The cerebellum is necessary and sufficient for the acquisition and execution of adaptively timed conditioned motor responses following repeated paired presentations of a conditioned stimulus and an unconditioned stimulus. The underlying plasticity depends on the convergence of conditioned and unconditioned stimuli signals relayed to the cerebellum by the pontine nucleus and the inferior olive (IO), respectively. Adaptive timing of conditioned responses relies on the correctly predicted onset of the unconditioned stimulus, usually a noxious somatosensory stimulus. We addressed two questions: First, does the IO relay information regarding the duration of somatosensory stimuli to the cerebellum? Multiple-unit recordings from the IO of anesthetized rats that received periorbital airpuffs of various durations revealed that sustained somatosensory stimuli are invariably transformed into phasic IO outputs. The phasic response was followed by a post-peak depression in IO activity as compared to baseline, providing the cerebellum with a highly synchronous signal, time-locked to the stimulus' onset. Second, we sought to examine the involvement of olivocerebellar interactions in this signal transformation. Cerebello-olivary inhibition was interrupted using temporary pharmacological inactivation of cerebellar output nuclei, resulting in more sustained (i.e., less synchronous) IO responses to sustained somatosensory stimuli, in which the post-peak depression was substituted with elevated activity as compared to baseline. We discuss the possible roles of olivocerebellar negative-feedback loops and baseline cerebello-olivary inhibition levels in shaping the temporal dynamics of the IO's response to somatosensory stimuli and the consequences of this shaping for cerebellar plasticity and its ability to adapt to varying contexts.

Synaptosomal-associated protein of 25kDa (SNAP25), vesicle-associated membrane protein 1 (VAMP1) and 2 (VAMP2) are components of soluble N-ethylmaleimide-sensitive fusion attachment protein receptors (SNARE) complex which is involved in synaptic vesicle exocytosis, a fundamental step in neurotransmitter release. SNARE expression in cerebellum correlates with specific neurotransmitter pathways underlying synaptic diversification and defined synaptic properties. In this study we firstly characterized the distribution of SNAP25, VAMP1 and VAMP2 in the nerve terminals of a defined cerebellar region, the deep cerebellar nuclei (DCN), of adult and newborn rats. Then, given the pivotal role of estradiol (E2) in the synaptic organization of the cerebellar circuitry in early postnatal life, we examined whether administration of E2 in the newborn DCN affected synaptic density and changed the distribution of the presynaptic proteins SNAP25, VAMP1 and VAMP2, together with post synaptic density protein 95 (PSD95). Results showed that: (1) distribution of SNAP25, VAMP1 and VAMP2 in adult DCN differs significantly from that found in newborn DCN; (2) administration of E2 in the newborn DCN affected synaptic density and also changed the distribution of the pre- and postsynaptic proteins. The differential distribution of SNAP25, VAMP1 and VAMP2 in nerve terminals of adult and newborn rats may correlate with specific stages of neuronal phenotypic differentiation. The effects of E2 on SNAP25, VAMP1, VAMP2, PDS95 and synaptic density suggest that pre- and postsynaptic proteins are under estrogenic control during development and that synaptic maturation can also be related with the activity of this steroid., (Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.)

Phenytoin is a commonly prescribed anticonvulsant drug; however, there is evidence that long-term administration is related to cerebellar ataxia, cerebellar atrophy, loss of Purkinje cells, and hyperplasia of Bergman glia cells. The aim of the present study was to detect and describe any possible alterations of the Purkinje cells, and neurons of the dentate nucleus, as those can be seen with the use of silver impregnation techniques, such as Golgi and Nauta method. The study was performed on a 7-year-old boy who was under phenytoin treatment for more than 3.5 years and had clinical manifestations of cerebellar ataxia. Golgi silver impregnation technique revealed substantial loss of dendritic spines and tertiary dendritic branches, both on the Purkinje cells and the neurons of the dentate nucleus, whereas the Nauta method demonstrated swollen and degenerated axons of Purkinje cells.

The therapeutic potential of scFv-h3D6 has recently been shown in the 3xTg-AD mice. A clear effect on amyloid β (Aβ) oligomers and certain apolipoproteins in the brain was found, but no effect was seen in the cerebellum. Here, cellular vulnerability of the 3xTg-AD cerebellum is described for the first time, together with its protection by scFv-h3D6. Neuron depletion in the DCN was regionally variable and followed a mediolateral axis of involvement that was greatest in the fastigial nucleus, lesser in the interpositus and negligible in the dentate nucleus. A sole and low intraperitoneal dose of scFv-h3D6 protected 3xTg-AD DCN neurons from death. Further studies might provide interesting information about both the potential of scFv-h3D6 as a therapeutic agent and the role of the cerebellum in AD.

Dimethyl sulfoxide (DMSO) is an amphipathic molecule widely used to solubilize water-insoluble compounds. In many studies it was reported that DMSO is capable of affecting several biological processes, thus resulting in a potential cause for the misinterpretation of experimental data. Recent papers showed that DMSO modified the brain bioelectric activity in animal models of epilepsy. In an in vivo model of temporal lobe epilepsy in the rat, we examined the effects of different doses (10%, 50% and 100%) of DMSO on the maximal dentate activation (MDA). The results show that DMSO induced a dose-dependent significant reduction of the electrically induced paroxysmal activity., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

The caudal part of the cerebellar fastigial nucleus (CFN) influences the horizontal component of saccades. Previous reports show that activity in the CFN contralateral to saccade direction aids saccade acceleration and that activity in the ipsilateral CFN aids saccade deceleration. Here we refine this description by characterizing how blocking CFN activity changes the distance that the eye rotates during each of 4 phases of saccades, the increasing and decreasing saccade acceleration (phases 1 and 2) and deceleration (3 and 4). We found that unilateral CFN inactivation increases total eye rotation to ∼1.8× normal. This resulted from rotation increases in all four phases of ipsiversive saccades. Rotation during phases 1 and 2 increases slightly, more during phase 3, and most during phase 4, to ∼4.4× normal. Thus, the ipsilateral CFN normally reduces eye rotation throughout a saccade but reduces it the most near saccade end. After unilateral CFN inactivation, rotation during contraversive saccades was ∼0.8× normal. This resulted from decreased rotation during phases 1-3, to ∼0.7× normal, and then normal rotation during phase 4. Thus the CFN contraversive to saccade direction normally increases eye rotation during acceleration and the first phase of deceleration. These data indicate that the influences of the CFNs on saccades overlap extensively and that there is a smooth shift from predominance of the contralateral CFN early in a saccade to the ipsilateral CFN later. The pathway from the CFN to contralateral IBNs and then to the abducens nucleus can account for these effects., (Published by Elsevier B.V.)

Aim: To investigate the effects of microinjection of the GABA(A) receptor agonist muscimol into cerebellar fastigial nucleus (FN) on stress-induced gastric mucosal damage and the underlying mechanism in rats., Methods: Stress-induced gastric mucosal damage was induced in adult male SD rats by restraining and immersing them in cold water for 3 h. GABA(A) receptor agonist or antagonist was microinjected into the lateral FN. The decussation of superior cerebellar peduncle (DSCP) was electrically destroyed and the lateral hypothalamic area (LHA) was chemically ablated by microinjection of kainic acid. The pathological changes in the gastric mucosa were evaluated using TUNEL staining, immunohistochemistry staining and Western blotting., Results: Microinjection of muscimol (1.25, 2.5, and 5.0 μg) into FN significantly exacerbated the stress-induced gastric mucosal damage in a dose-dependent manner, whereas microinjection of GABA(A) receptor antagonist bicuculline attenuated the damage. The intensifying effect of muscimol on gastric mucosal damage was abolished by electrical lesion of DSCP or chemical ablation of LHA performed 3 d before microinjection of muscimol. Microinjection of muscimol markedly increased the discharge frequency of the greater splanchnic nerve, significantly increased the gastric acid volume and acidity, and further reduced the gastric mucosal blood flow. In the gastric mucosa, further reduced proliferation cells, enhanced apoptosis, and decreased anti-oxidant levels were observed following microinjection of muscimol., Conclusion: Cerebellar FN participates in the regulation of stress-induced gastric mucosal damage, and cerebello-hypothalamic circuits contribute to the process.

Our previous work has shown that the cerebellar fastigial nucleus (FN) is involved in modulation of lymphocyte function. Herein, we investigated effect of FN γ-aminobutyric acid (GABA)-ergic projections to the hypothalamus on lymphocytes to understand pathways and mechanisms underlying cerebellar immunomodulation. By injection of Texas red dextran amine (TRDA), an anterograde tracer, into FN, we found that the TRDA-labeled fibers from the FN traveled through the superior cerebellar peduncle (SCP), crossed in decussation of SCP (XSCP), entered the hypothalamus, and primarily terminated in the lateral hypothalamic area (LHA). Further, by injecting Fluoro-Ruby (FR), a retrograde tracer, in LHA, we observed that the FR-stained fibers retrogradely passed through XSCP and reached FN. Among these FR-positive neurons in the FN, there were GABA-immunoreactive cells. We then microinjected vigabatrin, which is an inhibitor of GABA-transaminase (GABA-T) that degrades GABA, bilaterally into FN. The vigabatrin treatment increased both number of GABA-immunoreactive neurons in FN-LHA projections and GABA content in the hypothalamus. Simultaneously, vigabatrin significantly reduced concanavalin A (Con A)-induced lymphocyte proliferation, anti-sheep red blood cell (SRBC) IgM antibody level, and natural killer (NK) cell number and cytotoxicity. In support of these findings, we inhibited GABA synthesis by using 3-mercaptopropionic acid (3-MP), which antagonizes glutamic acid decarboxylase (GAD). We found that the inhibition of GABA synthesis caused changes that were opposite to those when GABA was increased with vigabatrin. These findings show that the cerebellar FN has a direct GABAergic projection to the hypothalamus and that this projection actively participates in modulation of lymphocytes., (Copyright © 2012 Elsevier Inc. All rights reserved.)