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Antioxidants prevent inflammation and preserve the optic projection and visual function in experimental neurotrauma.
Bernardo-Colón A, Vest V, Clark A, Cooper ML, Calkins DJ, Harrison FE, Rex TS
(2018) Cell Death Dis 9: 1097
MeSH Terms: Animals, Antioxidants, Ascorbic Acid, Axons, Diet, Ketogenic, Disease Models, Animal, Evoked Potentials, Visual, Inflammasomes, Inflammation, Interleukin-1alpha, Interleukin-1beta, Male, Mice, Mice, Inbred C57BL, Optic Nerve Injuries, Oxidative Stress, Reactive Oxygen Species, Retina, Superoxides, Vitamin E
Show Abstract · Added April 2, 2019
We investigated the role of oxidative stress and the inflammasome in trauma-induced axon degeneration and vision loss using a mouse model. The left eyes of male mice were exposed to over-pressure air waves. Wild-type C57Bl/6 mice were fed normal, high-vitamin-E (VitE), ketogenic or ketogenic-control diets. Mice lacking the ability to produce vitamin C (VitC) were maintained on a low-VitC diet. Visual evoked potentials (VEPs) and retinal superoxide levels were measured in vivo. Tissue was collected for biochemical and histological analysis. Injury increased retinal superoxide, decreased SOD2, and increased cleaved caspase-1, IL-1α, IL-1β, and IL-18 levels. Low-VitC exacerbated the changes and the high-VitE diet mitigated them, suggesting that oxidative stress led to the increase in IL-1α and activation of the inflammasome. The injury caused loss of nearly 50% of optic nerve axons at 2 weeks and astrocyte hypertrophy in mice on normal diet, both of which were prevented by the high-VitE diet. The VEP amplitude was decreased after injury in both control-diet and low-VitC mice, but not in the high-VitE-diet mice. The ketogenic diet also prevented the increase in superoxide levels and IL-1α, but had no effect on IL-1β. Despite this, the ketogenic diet preserved optic nerve axons, prevented astrocyte hypertrophy, and preserved the VEP amplitude. These data suggest that oxidative stress induces priming and activation of the inflammasome pathway after neurotrauma of the visual system. Further, blocking the activation of the inflammasome pathway may be an effective post-injury intervention.
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20 MeSH Terms
Virus-mediated EpoR76E gene therapy preserves vision in a glaucoma model by modulating neuroinflammation and decreasing oxidative stress.
Hines-Beard J, Bond WS, Backstrom JR, Rex TS
(2016) J Neuroinflammation 13: 39
MeSH Terms: Animals, Calcium-Binding Proteins, Cholera Toxin, Cytokines, Dependovirus, Disease Models, Animal, Erythropoietin, Evoked Potentials, Visual, Fluorescein Angiography, Gene Expression Regulation, Genetic Therapy, Glaucoma, Ki-67 Antigen, Mice, Mice, Inbred DBA, Microfilament Proteins, Microglia, Oxidative Stress, Photic Stimulation, Retina, Transduction, Genetic
Show Abstract · Added April 2, 2019
BACKGROUND - Glaucoma is a complex neurodegeneration and a leading cause of blindness worldwide. Current therapeutic strategies, which are all directed towards lowering the intraocular pressure (IOP), do not stop progression of the disease. We have demonstrated that recombinant adeno-associated virus (rAAV) gene delivery of a form of erythropoietin with attenuated erythropoietic activity (EpoR76E) can preserve retinal ganglion cells, their axons, and vision without decreasing IOP. The goal of this study was to determine if modulation of neuroinflammation or oxidative stress played a role in the neuroprotective activity of EPO.R76E.
METHODS - Five-month-old DBA/2J mice were treated with either rAAV.EpoR76E or a control vector and collected at 8 months of age. Neuroprotection was assessed by quantification of axon transport and visual evoked potentials. Microglia number and morphology and cytokine and chemokine levels were quantified. Message levels of oxidative stress-related proteins were assessed.
RESULTS - Axon transport and visual evoked potentials were preserved in rAAV.EpoR76E-treated mice. The number of microglia was decreased in retinas from 8-month-old rAAV.EpoR76E-treated mice, but proliferation was unaffected. The blood-retina barrier was also unaffected by treatment. Levels of some pro-inflammatory cytokines were decreased in retinas from rAAV.EpoR76E-treated mice including IL-1, IL-12, IL-13, IL-17, CCL4, and CCL5. TNFα messenger RNA (mRNA) was increased in retinas from 8-month-old mice compared to 3-month-old controls regardless of treatment. Expression of several antioxidant proteins was increased in retinas of rAAV.EpoR76E-treated 8-month-old mice.
CONCLUSIONS - Treatment with rAAV.EpoR76E preserves vision in the DBA/2J model of glaucoma at least in part by decreasing infiltration of peripheral immune cells, modulating microglial reactivity, and decreasing oxidative stress.
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MeSH Terms
Neural control of visual search by frontal eye field: chronometry of neural events and race model processes.
Nelson MJ, Murthy A, Schall JD
(2016) J Neurophysiol 115: 1954-69
MeSH Terms: Animals, Evoked Potentials, Visual, Frontal Lobe, Macaca mulatta, Macaca radiata, Neurons, Reaction Time, Saccades, Visual Fields
Show Abstract · Added May 9, 2017
We investigated the chronometry of neural processes in frontal eye fields of macaques performing double-step saccade visual search in which a conspicuous target changes location in the array on a random fraction of trials. Durations of computational processes producing a saccade to original and final target locations (GO1 and GO2, respectively) are derived from response times (RT) on different types of trials. In these data, GO2 tended to be faster than GO1, demonstrating that inhibition of the initial saccade did not delay production of the compensated saccade. Here, we measured the dynamics of visual, visuomovement, and movement neuron activity in relation to these processes by examining trials when neurons instantiated either process. First, we verified that saccades were initiated when the discharge rate of movement neurons reached a threshold that was invariant across RT and trial type. Second, the time when visual and visuomovement neurons selected the target and when movement neuron activity began to accumulate were not significantly different across trial type. Third, the interval from the beginning of accumulation to threshold of movement-related activity was significantly shorter when instantiating the GO2 relative to the GO1 process. Differences observed between monkeys are discussed. Fourth, random variation of RT was accounted for to some extent by random variation in both the onset and duration of selective activity of each neuron type but mostly by variation of movement neuron accumulation duration. These findings offer new insights into the sources of control of target selection and saccade production in dynamic environments.
Copyright © 2016 the American Physiological Society.
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Neural mechanisms of coarse-to-fine discrimination in the visual cortex.
Purushothaman G, Chen X, Yampolsky D, Casagrande VA
(2014) J Neurophysiol 112: 2822-33
MeSH Terms: Animals, Discrimination, Psychological, Evoked Potentials, Visual, Galago, Neurons, Reaction Time, Visual Cortex
Show Abstract · Added February 12, 2015
Vision is a dynamic process that refines the spatial scale of analysis over time, as evidenced by a progressive improvement in the ability to detect and discriminate finer details. To understand coarse-to-fine discrimination, we studied the dynamics of spatial frequency (SF) response using reverse correlation in the primary visual cortex (V1) of the primate. In a majority of V1 cells studied, preferred SF either increased monotonically with time (group 1) or changed nonmonotonically, with an initial increase followed by a decrease (group 2). Monotonic shift in preferred SF occurred with or without an early suppression at low SFs. Late suppression at high SFs always accompanied nonmonotonic SF dynamics. Bayesian analysis showed that SF discrimination performance and best discriminable SF frequencies changed with time in different ways in the two groups of neurons. In group 1 neurons, SF discrimination performance peaked on both left and right flanks of the SF tuning curve at about the same time. In group 2 neurons, peak discrimination occurred on the right flank (high SFs) later than on the left flank (low SFs). Group 2 neurons were also better discriminators of high SFs. We examined the relationship between the time at which SF discrimination performance peaked on either flank of the SF tuning curve and the corresponding best discriminable SFs in both neuronal groups. This analysis showed that the population best discriminable SF increased with time in V1. These results suggest neural mechanisms for coarse-to-fine discrimination behavior and that this process originates in V1 or earlier.
Copyright © 2014 the American Physiological Society.
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7 MeSH Terms
Beta oscillation dynamics in extrastriate cortex after removal of primary visual cortex.
Schmiedt JT, Maier A, Fries P, Saunders RC, Leopold DA, Schmid MC
(2014) J Neurosci 34: 11857-64
MeSH Terms: Animals, Biological Clocks, Electroencephalography, Evoked Potentials, Visual, Female, Macaca mulatta, Photic Stimulation, Visual Cortex, Visual Pathways
Show Abstract · Added January 20, 2015
The local field potential (LFP) in visual cortex is typically characterized by the following spectral pattern: before the onset of a visual stimulus, low-frequency oscillations (beta, 12-20 Hz) dominate, whereas during the presentation of a stimulus these oscillations diminish and are replaced by fluctuations at higher frequencies (gamma, >30 Hz). The origin of beta oscillations in vivo remains unclear, as is the basis of their suppression during visual stimulation. Here we investigate the contribution of ascending input from primary visual cortex (V1) to beta oscillation dynamics in extrastriate visual area V4 of behaving monkeys. We recorded LFP activity in V4 before and after resecting a portion of V1. After the surgery, the visually induced gamma LFP activity in the lesion projection zone of V4 was markedly reduced, consistent with previously reported spiking responses (Schmid et al., 2013). In the beta LFP range, the lesion had minimal effect on the normal pattern of spontaneous oscillations. However, the lesion led to a surprising and permanent reversal of the normal beta suppression during visual stimulation, with visual stimuli eliciting beta magnitude increases up to 50%, particularly in response to moving stimuli. This reversed beta activity pattern was specific to stimulus locations affected by the V1 lesion. Our results shed light on the mechanisms of beta activity in extrastriate visual cortex: The preserved spontaneous oscillations point to a generation mechanism independent of the geniculostriate pathway, whereas the positive beta responses support the contribution of visual information to V4 via direct thalamo-extrastriate projections.
Copyright © 2014 the authors 0270-6474/14/3411857-08$15.00/0.
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9 MeSH Terms
Microcircuitry of agranular frontal cortex: testing the generality of the canonical cortical microcircuit.
Godlove DC, Maier A, Woodman GF, Schall JD
(2014) J Neurosci 34: 5355-69
MeSH Terms: Action Potentials, Animals, Brain Mapping, Evoked Potentials, Visual, Female, Frontal Lobe, Interneurons, Macaca mulatta, Macaca radiata, Male, Pyramidal Cells, Reaction Time, Synaptic Potentials, Visual Cortex
Show Abstract · Added February 12, 2015
We investigated whether a frontal area that lacks granular layer IV, supplementary eye field, exhibits features of laminar circuitry similar to those observed in primary sensory areas. We report, for the first time, visually evoked local field potentials (LFPs) and spiking activity recorded simultaneously across all layers of agranular frontal cortex using linear electrode arrays. We calculated current source density from the LFPs and compared the laminar organization of evolving sinks to those reported in sensory areas. Simultaneous, transient synaptic current sinks appeared first in layers III and V followed by more prolonged current sinks in layers I/II and VI. We also found no variation of single- or multi-unit visual response latency across layers, and putative pyramidal neurons and interneurons displayed similar response latencies. Many units exhibited pronounced discharge suppression that was strongest in superficial relative to deep layers. Maximum discharge suppression also occurred later in superficial than in deep layers. These results are discussed in the context of the canonical cortical microcircuit model originally formulated to describe early sensory cortex. The data indicate that agranular cortex resembles sensory areas in certain respects, but the cortical microcircuit is modified in nontrivial ways.
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14 MeSH Terms
Multisensory response modulation in the superficial layers of the superior colliculus.
Ghose D, Maier A, Nidiffer A, Wallace MT
(2014) J Neurosci 34: 4332-44
MeSH Terms: Animals, Auditory Perception, Cats, Evoked Potentials, Auditory, Evoked Potentials, Visual, Male, Nerve Net, Neurons, Superior Colliculi, Visual Pathways, Visual Perception
Show Abstract · Added January 20, 2015
The mammalian superior colliculus (SC) is made up of seven distinct layers. Based on overall differences in neuronal morphology, afferent and efferent projection patterns, physiological properties, and presumptive behavioral role, the upper three layers have been classically grouped together as the superficial layers and the remaining four layers collectively make up the deep layers. Although the superficial layers receive their primary inputs from the retina and primary visual cortex, the deep layers receive inputs from extrastriate visual cortical areas and from auditory, somatosensory, and motor-related structures. In contrast, there is no evidence of monosynaptic nonvisual inputs to the superficial layers. However, more recent studies have revealed anatomical connections between the superficial and deep layers, thus providing the substrate for possible communication between these two functional divisions of the SC. In this study, we provide physiological evidence for auditory influences on visual responses in the superficial layers of the SC. Using extracellular recordings of local field potentials (LFPs) and multiunit activity, we demonstrate multisensory effects in the superficial layers of the cat SC such that subthreshold auditory activity (as seen in the LFP) modulates visual responses (reflected in spiking activity) when the two stimuli are presented together. These results have important implications for our understanding of the functional organization of the SC and for the neural basis of multisensory integration in general.
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Infrared neural stimulation of primary visual cortex in non-human primates.
Cayce JM, Friedman RM, Chen G, Jansen ED, Mahadevan-Jansen A, Roe AW
(2014) Neuroimage 84: 181-90
MeSH Terms: Action Potentials, Animals, Brain Mapping, Evoked Potentials, Visual, Feasibility Studies, Humans, Infrared Rays, Macaca, Neurons, Photic Stimulation, Visual Cortex
Show Abstract · Added March 31, 2014
Infrared neural stimulation (INS) is an alternative neurostimulation modality that uses pulsed infrared light to evoke spatially precise neural activity that does not require direct contact with neural tissue. With these advantages INS has the potential to increase our understanding of specific neural pathways and impact current diagnostic and therapeutic clinical applications. In order to develop this technique, we investigate the feasibility of INS (λ=1.875μm, fiber diameter=100-400μm) to activate and modulate neural activity in primary visual cortex (V1) of Macaque monkeys. Infrared neural stimulation was found to evoke localized neural responses as evidenced by both electrophysiology and intrinsic signal optical imaging (OIS). Single unit recordings acquired during INS indicated statistically significant increases in neuron firing rates that demonstrate INS evoked excitatory neural activity. Consistent with this, INS stimulation led to focal intensity-dependent reflectance changes recorded with OIS. We also asked whether INS is capable of stimulating functionally specific domains in visual cortex and of modulating visually evoked activity in visual cortex. We found that application of INS via 100μm or 200μm fiber optics produced enhancement of visually evoked OIS response confined to the eye column where INS was applied and relative suppression of the other eye column. Stimulating the cortex with a 400μm fiber, exceeding the ocular dominance width, led to relative suppression, consistent with involvement of inhibitory surrounds. This study is the first to demonstrate that INS can be used to either enhance or diminish visual cortical response and that this can be done in a functional domain specific manner. INS thus holds great potential for use as a safe, non-contact, focally specific brain stimulation technology in primate brains.
© 2013.
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11 MeSH Terms
On the origin of event-related potentials indexing covert attentional selection during visual search: timing of selection by macaque frontal eye field and event-related potentials during pop-out search.
Purcell BA, Schall JD, Woodman GF
(2013) J Neurophysiol 109: 557-69
MeSH Terms: Animals, Appetitive Behavior, Attention, Brain Waves, Cerebral Cortex, Evoked Potentials, Visual, Feedback, Psychological, Macaca radiata, Male, Task Performance and Analysis, Visual Fields
Show Abstract · Added February 12, 2015
Event-related potentials (ERPs) have provided crucial data concerning the time course of psychological processes, but the neural mechanisms producing ERP components remain poorly understood. This study continues a program of research in which we investigated the neural basis of attention-related ERP components by simultaneously recording intracranially and extracranially from macaque monkeys. Here, we compare the timing of attentional selection by the macaque homologue of the human N2pc component (m-N2pc) with the timing of selection in the frontal eye field (FEF), an attentional-control structure believed to influence posterior visual areas thought to generate the N2pc. We recorded FEF single-unit spiking and local field potentials (LFPs) simultaneously with the m-N2pc in monkeys performing an efficient pop-out search task. We assessed how the timing of attentional selection depends on task demands by direct comparison with a previous study of inefficient search in the same monkeys (e.g., finding a T among Ls). Target selection by FEF spikes, LFPs, and the m-N2pc was earlier during efficient pop-out search rather than during inefficient search. The timing and magnitude of selection in all three signals varied with set size during inefficient but not efficient search. During pop-out search, attentional selection was evident in FEF spiking and LFP before the m-N2pc, following the same sequence observed during inefficient search. These observations are consistent with the hypothesis that feedback from FEF modulates neural activity in posterior regions that appear to generate the m-N2pc even when competition for attention among items in a visual scene is minimal.
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11 MeSH Terms
Impact of response duration on multisensory integration.
Ghose D, Barnett ZP, Wallace MT
(2012) J Neurophysiol 108: 2534-44
MeSH Terms: Acoustic Stimulation, Animals, Cats, Evoked Potentials, Auditory, Evoked Potentials, Visual, Neurons, Afferent, Photic Stimulation, Superior Colliculi, Time
Show Abstract · Added March 19, 2014
Multisensory neurons in the superior colliculus (SC) have been shown to have large receptive fields that are heterogeneous in nature. These neurons have the capacity to integrate their different sensory inputs, a process that has been shown to depend on the physical characteristics of the stimuli that are combined (i.e., spatial and temporal relationship and relative effectiveness). Recent work has highlighted the interdependence of these factors in driving multisensory integration, adding a layer of complexity to our understanding of multisensory processes. In the present study our goal was to add to this understanding by characterizing how stimulus location impacts the temporal dynamics of multisensory responses in cat SC neurons. The results illustrate that locations within the spatial receptive fields (SRFs) of these neurons can be divided into those showing short-duration responses and long-duration response profiles. Most importantly, discharge duration appears to be a good determinant of multisensory integration, such that short-duration responses are typically associated with a high magnitude of multisensory integration (i.e., superadditive responses) while long-duration responses are typically associated with low integrative capacity. These results further reinforce the complexity of the integrative features of SC neurons and show that the large SRFs of these neurons are characterized by vastly differing temporal dynamics, dynamics that strongly shape the integrative capacity of these neurons.
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9 MeSH Terms