Eye Movements of the Murine P/Q Calcium Channel MutantRocker, and the Impact of Aging

2004 ◽  
Vol 91 (5) ◽  
pp. 2066-2078 ◽  
Author(s):  
John S. Stahl
Keyword(s):  
Eye Movements ◽  
Calcium Channel ◽  
Vestibular Stimulation ◽  
Downbeat Nystagmus ◽  
Ocular Motor ◽  
Gene Encoding ◽  
Optokinetic Responses ◽  
Cross Axis ◽  
Motor Abnormalities ◽  
The Impact

Mutations in the gene encoding the ion pore of the P/Q voltage-activated calcium channel (CACNA1A) are predicted to alter synaptic transmission and dendritic excitability within cerebellar granule and Purkinje cells. Determining the relationships between these alterations, neuronal activity, and behavior may yield insight into the relationship between neuronal intrinsic properties and signal processing within the ocular motor system. Toward this end, we compared ocular motor performance in the CACNA1A mutant rocker and C57BL/6 controls. Average vertical eye position was abnormally elevated in the mutants, a finding that may be analogous to downbeat nystagmus seen in human cerebellar disorders. Fast phases of vestibular nystagmus were slowed by approximately 18% of control values. The angular vestibuloocular reflex (VOR) in darkness and light (visual VOR, or VVOR), assessed at 0.1–1.6 Hz, exhibited subnormal gains at the highest stimulus frequencies and increased phase leads at the lowest stimulus frequencies. Horizontal optokinetic responses to constant velocity drum rotation of ±2.5–40°/s exhibited minimally reduced gains. Attempts to increase VOR gain by concomitant optokinetic and vestibular stimulation were confounded by the tendency of the mice to habituate to repetitive vestibular stimulation, but attempts to induce coupling of vertical eye movements to horizontal vestibular stimulation (cross-axis adaptation) generated rapid plastic changes in controls and little effect in mutants. With the notable exceptions of the vertical elevation and optokinetic gains, the ocular motor abnormalities were stable over a broad range of animal age, a result compatible with the abnormalities arising as direct consequences of the inborn alteration in calcium channel biophysics.

Eye Movements of the Murine P/Q Calcium Channel Mutant Tottering, and the Impact of Aging

2006 ◽  
Vol 95 (3) ◽  
pp. 1588-1607 ◽  
Author(s):  
John S. Stahl ◽  
Robert A. James ◽  
Brian S. Oommen ◽  
Freek E. Hoebeek ◽  
Chris I. De Zeeuw
Keyword(s):  
Eye Movements ◽  
Calcium Channel ◽  
Motor Behavior ◽  
Motor Deficits ◽  
Ocular Motor ◽  
Gene Encoding ◽  
Optokinetic Reflex ◽  
Behavioral Abnormalities ◽  
Cross Axis ◽  
The Impact

Mice carrying mutations of the gene encoding the ion pore of the P/Q calcium channel (Cacna1a) are an instance in which cerebellar dysfunction may be attributable to altered electrophysiology and thus provide an opportunity to study how neuronal intrinsic properties dictate signal processing in the ocular motor system. P/Q channel mutations can engender multiple effects at the single neuron, circuit, and behavioral levels; correlating physiological and behavioral abnormalities in multiple allelic strains will ultimately facilitate determining which alterations of physiology are responsible for specific behavioral aberrations. We used videooculography to quantify ocular motor behavior in tottering mutants aged 3 mo to 2 yr and compared their performance to data previously obtained in the allelic mutant rocker and C57BL/6 controls. Tottering mutants shared numerous abnormalities with rocker, including upward deviation of the eyes at rest, increased vestibuloocular reflex (VOR) phase lead at low stimulus frequencies, reduced VOR gain at high stimulus frequencies, reduced gain of the horizontal and vertical optokinetic reflex, reduced time constants of the neural integrator, and reduced plasticity of the VOR as assessed in a cross-axis training paradigm. Unlike rocker, young tottering mutants exhibited normal peak velocities of nystagmus fast phases, arguing against a role for neuromuscular transmission defects in the attenuation of compensatory eye movements. Tottering also differed by exhibiting directional asymmetries of the gains of optokinetic reflexes. The data suggest at least four pathophysiological mechanisms (two congenital and two acquired) are required to explain the ocular motor deficits in the two Cacna1a mutant strains.

scholarly journals Qualitative and quantitative assessment of magnetic vestibular stimulation in humans

2020 ◽  
Vol 30 (6) ◽  
pp. 353-361
Author(s):  
Rebecca S. Dewey ◽  
Rachel Gomez ◽  
Chris Degg ◽  
David M. Baguley ◽  
Paul M. Glover
Keyword(s):  
Magnetic Field ◽  
Objective Measure ◽  
Quantitative Measure ◽  
Vestibular Stimulation ◽  
Initial Study ◽  
Clinical Test ◽  
Healthy Control ◽  
Student’S T ◽  
The Impact ◽  
The Magnetic Field

The sensation of phantom motion or exhibition of bodily sway is often reported in the proximity of an MR scanner. It is proposed that the magnetic field stimulates the vestibular system. There are a number of possible mechanisms responsible, and the relative contributions of susceptibility on the otolithic receptors and the Lorentz force on the cupulae have not yet been explored. This exploratory study aims to investigate the impact of being in the proximity of a 7.0 T MR scanner. The modified clinical test of sensory interaction on balance (mCTSIB) was used to qualitatively ascertain whether or not healthy control subjects who passed the mCTSIB in normal conditions 1) experienced subjective sensations of dizziness, vertigo or of leaning or shifting in gravity when in the magnetic field and 2) exhibited visibly increased bodily sway whilst in the magnetic field compared to outside the magnetic field. Condition IV of the mCTSIB was video recorded outside and inside the magnetic field, providing a semi-quantitative measure of sway. For condition IV of the mCTSIB (visual and proprioceptive cues compromised), all seven locations/orientations around the scanner yielded significantly more sway than at baseline (p < 0.01 FDR). A Student’s t-test comparing the RMS velocity of a motion marker on the upper arm during mCTSIB condition IV showed a significant increase in the amount of motion exhibited in the field (T = 2.59; d.f. = 9; p = 0.029) compared to outside the field. This initial study using qualitative measures of sway demonstrates that there is evidence for MR-naïve individuals exhibiting greater sway while performing the mCTSIB in the magnetic field compared to outside the field. Directional polarity of sway was not significant. Future studies of vestibular stimulation by magnetic fields would benefit from the development of a sensitive, objective measure of balance function, which can be performed inside a magnetic field.

scholarly journals The Role of Mitochondria in Carcinogenesis

2021 ◽  
Vol 22 (10) ◽  
pp. 5100
Author(s):  
Paulina Kozakiewicz ◽  
Ludmiła Grzybowska-Szatkowska ◽  
Marzanna Ciesielka ◽  
Jolanta Rzymowska
Keyword(s):  
Prostate Cancer ◽  
Mitochondrial Dna ◽  
Nuclear Dna ◽  
Dna Polymorphisms ◽  
Gene Encoding ◽  
Dna Mutations ◽  
Nadh Ubiquinone Oxidoreductase ◽  
Gene Coi ◽  
The Impact

The mitochondria are essential for normal cell functioning. Changes in mitochondrial DNA (mtDNA) may affect the occurrence of some chronic diseases and cancer. This process is complex and not entirely understood. The assignment to a particular mitochondrial haplogroup may be a factor that either contributes to cancer development or reduces its likelihood. Mutations in mtDNA occurring via an increase in reactive oxygen species may favour the occurrence of further changes both in mitochondrial and nuclear DNA. Mitochondrial DNA mutations in postmitotic cells are not inherited, but may play a role both in initiation and progression of cancer. One of the first discovered polymorphisms associated with cancer was in the gene NADH-ubiquinone oxidoreductase chain 3 (mt-ND3) and it was typical of haplogroup N. In prostate cancer, these mutations and polymorphisms involve a gene encoding subunit I of respiratory complex IV cytochrome c oxidase subunit 1 gene (COI). At present, a growing number of studies also address the impact of mtDNA polymorphisms on prognosis in cancer patients. Some of the mitochondrial DNA polymorphisms occur in both chronic disease and cancer, for instance polymorphism G5913A characteristic of prostate cancer and hypertension.

scholarly journals The Impact of Neonatal Morbidities on Smooth Pursuit Eye Movements in Very Preterm Infants

2011 ◽  
Vol 70 ◽  
pp. 352-352 ◽  
Author(s):  
K Strand Brodd ◽  
K Rosander ◽  
H Grönqvist ◽  
G Holmström ◽  
B Strömberg ◽  
...  
Keyword(s):  
Eye Movements ◽  
Preterm Infants ◽  
Smooth Pursuit ◽  
Smooth Pursuit Eye Movements ◽  
Very Preterm Infants ◽  
Very Preterm ◽  
Pursuit Eye Movements ◽  
The Impact

scholarly journals Neural Basis of Visually Guided Head Movements Studied With fMRI

2003 ◽  
Vol 89 (5) ◽  
pp. 2516-2527 ◽  
Author(s):  
Laurent Petit ◽  
Michael S. Beauchamp
Keyword(s):  
Eye Movements ◽  
Head Movement ◽  
Brain Activity ◽  
Posterior Part ◽  
Vestibular Stimulation ◽  
Head Movements ◽  
Oculomotor Control ◽  
Imaging Studies ◽  
Neural Basis ◽  
Temporoparietal Junction

We used event-related fMRI to measure brain activity while subjects performed saccadic eye, head, and gaze movements to visually presented targets. Two distinct patterns of response were observed. One set of areas was equally active during eye, head, and gaze movements and consisted of the superior and inferior subdivisions of the frontal eye fields, the supplementary eye field, the intraparietal sulcus, the precuneus, area MT in the lateral occipital sulcus and subcortically in basal ganglia, thalamus, and the superior colliculus. These areas have been previously observed in functional imaging studies of human eye movements, suggesting that a common set of brain areas subserves both oculomotor and head movement control in humans, consistent with data from single-unit recording and microstimulation studies in nonhuman primates that have described overlapping eye- and head-movement representations in oculomotor control areas. A second set of areas was active during head and gaze movements but not during eye movements. This set of areas included the posterior part of the planum temporale and the cortex at the temporoparietal junction, known as the parieto-insular vestibular cortex (PIVC). Activity in PIVC has been observed during imaging studies of invasive vestibular stimulation, and we confirm its role in processing the vestibular cues accompanying natural head movements. Our findings demonstrate that fMRI can be used to study the neural basis of head movements and show that areas that control eye movements also control head movements. In addition, we provide the first evidence for brain activity associated with vestibular input produced by natural head movements as opposed to invasive caloric or galvanic vestibular stimulation.

Extracting a needle from a haystack: reanalysis of whole genome data reveals a readily translatable finding

2009 ◽  
Vol 39 (8) ◽  
pp. 1231-1235 ◽  
Author(s):  
R. Keers ◽  
A. E. Farmer ◽  
K. J. Aitchison
Keyword(s):  
Bipolar Disorder ◽  
Calcium Channel ◽  
Unmet Need ◽  
Whole Genome ◽  
Nucleotide Polymorphisms ◽  
Gene Encoding ◽  
Genome Data ◽  
Early Results ◽  
Genome Association ◽  
Genome Study

There is significant unmet need for more effective treatments for bipolar disorder. The drug discovery process is becoming prohibitively expensive. Hence, biomarker clues to assist or shortcut this process are now widely sought. Using the publicly available data from the whole genome association study conducted by the Wellcome Trust Case Control Consortium, we sought to identify groups of genetic markers (single nucleotide polymorphisms) in which each marker was independently associated with bipolar disorder, with a less stringent threshold than that set by the original investigators (p⩽1×10−4). We identified a group of markers occurring within the CACNA1C gene (encoding the alpha subunit of the calcium channel Cav1.2). We then ascertained that this locus had been previously associated with the disorder in both a smaller and a whole genome study, and that a number of drugs blocking this channel (including verapamil and diltiazem) had been trialled in the treatment of bipolar disorder. The dihydropyridine-based blockers such as nimodipine that bind specifically to Cav1.2 and are more penetrant to the central nervous system have shown some promising early results; however, further trials are indicated. In addition, migraine is commonly seen in affective disorder, and calcium channel antagonists are successfully used in the treatment of migraine. One such agent, flunarizine, is structurally related to other first-generation derivatives of antihistamines such as antipsychotics. This implies that flunarizine could be useful in the treatment of bipolar disorder, and, furthermore, that other currently licensed drugs should be investigated for antagonism of Cav1.2.

scholarly journals Subplasmalemmal hydrogen peroxide triggers calcium influx in gonadotropes

2018 ◽  
Vol 293 (41) ◽  
pp. 16028-16042 ◽  
Author(s):  
An K. Dang ◽  
Nathan L. Chaplin ◽  
Dilyara A. Murtazina ◽  
Ulrich Boehm ◽  
Colin M. Clay ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Calcium Channels ◽  
Nadph Oxidase ◽  
Calcium Channel ◽  
Anterior Pituitary ◽  
Calcium Influx ◽  
Ros Generation ◽  
Primary Mouse ◽  
The Impact ◽  
Stimulation Of

Gonadotropin-releasing hormone (GnRH) stimulation of its eponymous receptor on the surface of endocrine anterior pituitary gonadotrope cells (gonadotropes) initiates multiple signaling cascades that culminate in the secretion of luteinizing and follicle-stimulating hormones, which have critical roles in fertility and reproduction. Enhanced luteinizing hormone biosynthesis, a necessary event for ovulation, requires a signaling pathway characterized by calcium influx through L-type calcium channels and subsequent activation of the mitogen-activated protein kinase extracellular signal-regulated kinase (ERK). We previously reported that highly localized subplasmalemmal calcium microdomains produced by L-type calcium channels (calcium sparklets) play an essential part in GnRH-dependent ERK activation. Similar to calcium, reactive oxygen species (ROS) are ubiquitous intracellular signaling molecules whose subcellular localization determines their specificity. To investigate the potential influence of oxidant signaling in gonadotropes, here we examined the impact of ROS generation on L-type calcium channel function. Total internal reflection fluorescence (TIRF) microscopy revealed that GnRH induces spatially restricted sites of ROS generation in gonadotrope-derived αT3-1 cells. Furthermore, GnRH-dependent stimulation of L-type calcium channels required intracellular hydrogen peroxide signaling in these cells and in primary mouse gonadotropes. NADPH oxidase and mitochondrial ROS generation were each necessary for GnRH-mediated stimulation of L-type calcium channels. Congruently, GnRH increased oxidation within subplasmalemmal mitochondria, and L-type calcium channel activity correlated strongly with the presence of adjacent mitochondria. Collectively, our results provide compelling evidence that NADPH oxidase activity and mitochondria-derived hydrogen peroxide signaling play a fundamental role in GnRH-dependent stimulation of L-type calcium channels in anterior pituitary gonadotropes.

scholarly journals The vestibular-related frontal cortex and its role in smooth-pursuit eye movements and vestibular-pursuit interactions

2006 ◽  
Vol 16 (1-2) ◽  
pp. 1-22 ◽  
Author(s):  
Junko Fukushima ◽  
Teppei Akao ◽  
Sergei Kurkin ◽  
Chris R.S. Kaneko ◽  
Kikuro Fukushima
Keyword(s):  
Eye Movements ◽  
Frontal Cortex ◽  
Smooth Pursuit ◽  
Vestibular Stimulation ◽  
Target Motion ◽  
Head Movements ◽  
Image Motion ◽  
Target Velocity ◽  
Eye Velocity ◽  
Pursuit Neurons

In order to see clearly when a target is moving slowly, primates with high acuity foveae use smooth-pursuit and vergence eye movements. The former rotates both eyes in the same direction to track target motion in frontal planes, while the latter rotates left and right eyes in opposite directions to track target motion in depth. Together, these two systems pursue targets precisely and maintain their images on the foveae of both eyes. During head movements, both systems must interact with the vestibular system to minimize slip of the retinal images. The primate frontal cortex contains two pursuit-related areas; the caudal part of the frontal eye fields (FEF) and supplementary eye fields (SEF). Evoked potential studies have demonstrated vestibular projections to both areas and pursuit neurons in both areas respond to vestibular stimulation. The majority of FEF pursuit neurons code parameters of pursuit such as pursuit and vergence eye velocity, gaze velocity, and retinal image motion for target velocity in frontal and depth planes. Moreover, vestibular inputs contribute to the predictive pursuit responses of FEF neurons. In contrast, the majority of SEF pursuit neurons do not code pursuit metrics and many SEF neurons are reported to be active in more complex tasks. These results suggest that FEF- and SEF-pursuit neurons are involved in different aspects of vestibular-pursuit interactions and that eye velocity coding of SEF pursuit neurons is specialized for the task condition.

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