Sight and insight – on the physiological role of nitric oxide in the visual system

[Abstract] Research in the fields of cellular communication and signal transduction in the brain has moved very rapidly in recent years. Nitric oxide (NO) is one of the latest discoveries in the arena of messenger molecules. Current evidence indicates that, in visual system, NO is produced in both postsynaptic and presynaptic structures and acts as a neurotransmitter, albeit of a rather unorthodox type. Under certain conditions it can switch roles to become either a neuronal ‘friend’ or ‘foe’. Nitric oxide is a gas that diffuses through all physiological barriers to act on neighbouring cells across an extensive volume on a specific time scale. It, therefore, has the opportunity to control the processing of vision from the lowest level of retinal transduction to the control of neuronal excitability in the visual cortex.Xunta de Galicia; XUGA13401B96Ministerio de Educación y Cultura; FIS97/040

Visual response augmentation in cat (and macaque) LGN: potentiation by corticofugally mediated gain control in the temporal domain

[Abstract] Visual responses of neurons are dependent on the context of a stimulus, not only in spatial terms but also temporally, although evidence for temporally separate visual influences is meagre, based mainly on studies in the higher cortex. Here we demonstrate temporally induced elevation of visual responsiveness in cells in the lateral geniculate nucleus (LGN) of cat and monkey following a period of high intensity (elevated contrast) stimulation. This augmentation is seen in 40–70% (monkey–cat) of cells tested and of all subtypes. Peaking at ∼ 3 min following the period of intense stimulation, it can last for 10–12 min and can be repeated and summed in time. Furthermore, it is dependent on corticofugal input, is seen even when high contrast stimuli of orthogonal orientation are used and therefore results from a/any prior increase in activity in the retino-geniculo-striate pathway. We suggest that this reflects a general mechanism for control of visual responsiveness; both a flexible and dynamic means of changing effectiveness of thalamic activity as visual input changes, but also a mechanism which is an emergent property of the thalamo-cortico-thalamic loop.Xunta de Galicia; XUGA13401B96Ministerio de Educación y Cultura; FIS-97/040

Magnetic field strength and reproducibility of neodymium magnets useful for transcranial static magnetic field stimulation of the human cortex

[Abstract] Objective. The application of transcranial static magnetic field stimulation (tSMS) in humans reduces the excitability of the motor cortex for a few minutes after the end of stimulation. However, when tSMS is applied in humans, the cortex is at least 2 cm away, so most of the strength of the magnetic field will not reach the target. The main objective of the study was to measure the strength and reproducibility of static magnetic fields produced by commercial neodymium magnets. Methods. We measured the strength and reproducibility of static magnetic fields produced by four different types of neodymium cylindrical magnets using a magnetic field-to-voltage transducer. Results. Magnetic field strength depended on magnet size. At distances 1.5 cm, the measurements made on the cylinder axis and 1.5 cm off the axis were comparable. The reproducibility of the results (i.e., the consistency of the field strength across magnets of the same size) was very high. Conclusions. These measurements offer a quantitative empirical reference for developing devices useful for tSMS protocols in both humans and animals.Ministerio de Educacion y Ciencia; BFU2009-0816

Modulatory effects mediated by metabotropic glutamate receptor 5 on lateral geniculate nucleus relay cells

[Abstract] Glutamate is thought to be the excitatory neurotransmitter in the lateral geniculate nucleus (LGN) of the cat, mediating visual transmission from the retina via ionotropic receptors of both d,l-α-amino-3-hydroxy-5-α-methyl-4-isoxazolepropionate and N-methyl-d-aspartate subtypes. Moreover, glutamate also exerts an important modulatory influence on LGN cells, where metabotropic glutamate receptors (mGluRs) seem to play a crucial role. Here we show in anesthetized adult cats that iontophoretic application of the specific mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) produced two, distinctly different, effects on LGN neurons. Visual responses to flashing spots and drifting gratings were attenuated (decreased by an average of 59%) in 13 of 23 of the cells but augmented (increased by an average of 60%) in 10 of 23 of the cells. Further, in each case when the specific mGluR5 agonist (R,S)-2-chloro-5-hydroxyphenylglycine was applied, the effects obtained were the opposite to those of MPEP. Data obtained in a second group of experiments to determine a possible interaction between mGluR5 blockade by MPEP and glutamate ionotropic receptors show that, in the majority of neurons (11 of 15, 73%), the MPEP-mediated effects seem to be independent of N-methyl-d-aspartate and d,l-α-amino-3-hydroxy-5-α-methyl-4-isoxazolepropionate receptor activity. Our results demonstrate a physiological role for mGluR5 in controlling retinal input and show, in vivo, a more intricate scenario than previously suggested, highlighting the complexity of metabotropic receptor interactions with excitatory and inhibitory elements in the thalamus.Ministerio de Ciencia y Tecnología; BFI2002-320

Effects of static magnetic fields on the visual cortex: reversible visual deficits and reduction of neuronal activity

[Abstract] Noninvasive brain stimulation techniques have been successfully used to modulate brain activity, have become a highly useful tool in basic and clinical research and, recently, have attracted increased attention due to their putative use as a method for neuro-enhancement. In this scenario, transcranial static magnetic stimulation (SMS) of moderate strength might represent an affordable, simple, and complementary method to other procedures, such as Transcranial Magnetic Stimulation or direct current stimulation, but its mechanisms and effects are not thoroughly understood. In this study, we show that static magnetic fields applied to visual cortex of awake primates cause reversible deficits in a visual detection task. Complementary experiments in anesthetized cats show that the visual deficits are a consequence of a strong reduction in neural activity. These results demonstrate that SMS is able to effectively modulate neuronal activity and could be considered to be a tool to be used for different purposes ranging from experimental studies to clinical applications.Ministerio de Ciencia e Innovación; BFU2013-45343-P

Synergistic effects of applying static magnetic fields and diazepam to improve EEG abnormalities in the pilocarpine epilepsy rat model

[Abstract] The lithium-pilocarpine rat model is a well-known model of temporal epilepsy. Recently we found that transcranial static magnetic stimulation (tSMS) delay and reduce the signs of EEG in this model. We aim to test the effect of combining the therapeutic action of tSMS and diazepam, a drug used to treat status epilepticus. We induce epilepsy in 12 Sprague-Dawley rats. Animals were classified as "magnet" when a magnetic neodymium cylinder was placed over the skull or "control" when a stainless-steel replica was used. Diazepam was injected 60-min after the second doses of pilocarpine injection. We found a reduction in the number of spikes/minute for magnet condition compared with sham condition, reaching significance at 60 min after diazepam injection. The Root-Mean-Square shown a significant reduction in magnet animals compared with those receiving diazepam (Tukey's-test 30 and 60 min after diazepam injection, p < 0.01; 40 and 50 min after diazepam injection, p < 0.05). Furthermore, the power spectrum analysis shown a reduction in delta, theta, alpha and beta bands, on the diazepam + magnet animals compared to the diazepam + sham group. Analysis of high-frequency oscillations revealed an increased in the ripples due to pilocarpine being reduced by diazepam. Our results demonstrate that application of tSMS previously to diazepam potentiates the effect of the drug by reducing the electroencephalographic pattern associated with epileptiform discharges. We suggest a new synergistic cooperation between pharmacology and neuromodulation as a future treatment for epilepsy.Instituto de Salud Carlos III; PI21/00151Xunta de Galicia; ED431C 2022/0

Suppression of V1 feedback produces a shift in the topographic representation of receptive fields of LGN cells by unmasking latent retinal drives

[Abstract] In awake monkeys, we used repetitive transcranial magnetic stimulation (rTMS) to focally inactivate visual cortex while measuring the responsiveness of parvocellular lateral geniculate nucleus (LGN) neurons. Effects were noted in 64/75 neurons, and could be divided into 2 main groups: (1) for 39 neurons, visual responsiveness decreased and visual latency increased without apparent shift in receptive field (RF) position and (2) a second group (n = 25, 33% of the recorded cells) whose excitability was not compromised, but whose RF position shifted an average of 4.5°. This change is related to the retinotopic correspondence observed between the recorded thalamic area and the affected cortical zone. The effect of inactivation for this group of neurons was compatible with silencing the original retinal drive and unmasking a second latent retinal drive onto the studied neuron. These results indicate novel and remarkable dynamics in thalamocortical circuitry that force us to reassess constraints on retinogeniculate transmission

The lemniscal–cuneate recurrent excitation is suppressed by strychnine and enhanced by GABAA antagonists in the anaesthetized cat

[Abstract] In the somatosensory system, cuneolemniscal (CL) cells fire high frequency doublets of spikes facilitating the transmission of sensory information to diencephalic target cells. We studied how lemniscal feedback affects ascending transmission of cutaneous neurons of the middle cuneate nucleus. Electrical stimulation of the contralateral medial lemniscus and of the skin at sites evoking responses with minimal threshold induced recurrent activation of CL cells at a latency of 1–3.5 ms. The lemniscal feedback activation was suppressed by increasing the stimulating intensity at the same sites, suggesting recurrent-mediated lateral inhibition. The glycine antagonist strychnine blocked the recurrent excitatory responses while GABAA antagonists uncovered those obscured by stronger stimulation. CL cells sharing a common receptive field (RF) potentiate one another by recurrent activation and disinhibition, the disinhibition being produced by serial interactions between glycinergic and GABAergic interneurons. Conversely, CL cells with different RFs inhibit each other through recurrent GABA-mediated inhibition. The lemniscal feedback would thus enhance the surround antagonism of a centre response by increasing the spatial resolution and the transmission of weak signals.Consejo Interinstitucional de Ciencia y Tecnología; PM99-002

Completing the corticofugal loop: a visual role for the corticogeniculate Type 1 metabotropic glutamate receptor

[Abstract] The way in which the brain deals with sensory information relies not only on feedforward processing of signals from the periph- ery but also on feedback inputs. This is the case of the massive projection back from layer 6 in the visual cortex to the thalamus, for which, despite being the greatest single source of synaptic contacts, the functional role still remains unclear. In the cat lateral geniculate nucleus, part of this cortical feedback is mediated by type 1 metabotropic glutamate receptors (mGluR1s), which are exclusively located on distal segments of the relay-cell dendrites. Here we show that in adult cats the cortex uses a synaptic drive mediated by these receptors (mGluR1) specifically to enhance the excitatory center of the thalamic receptive field. Moreover the effect is maximum in response to those stimuli that effectively drive cortical cells, and importantly, it does not affect the spatiotemporal structure of the thalamic receptive field. Therefore, cortex, by closing this corticofugal “loop,” is able to increase the gain of its thalamic input within a focal spatial window, selecting key features of the incoming signal.Comision Interministerial de Ciencia y Tecnologia (España); PB1998-017

Endocannabinoid CB1 receptors modulate visual output from the thalamus

[Abstract] Rationale Endocannabinoids have emerged as a modulatory brain system affecting different types of synapses, broadly distributed throughout the CNS, which explain the diverse psychophysical effects observed following activation of the endocannabinoid system. Objectives and methods The present study aimed to characterize the effect of CB1-mediated activity in the visual thalamus. In vivo single-unit extracellular recordings were performed in anaesthetized adult pigmented rats, measuring visual and spontaneous activity, combined with application of CB1 receptor agonists (anandamide, 2-AG, and O2545) and one antagonist, AM251. Results CB1 receptors activation revealed two cellular populations, with excitatory effects on ∼28% of cells and inhibitory in ∼72%, actions which were blocked by the antagonist AM251. The agonist action significantly altered both spontaneous and visual activity, shifting the signal-tonoise ratio (S/N), with accompanying changes in the variability within the visual response. Increased responses by agonist application were accompanied by a decrease in S/N and an increase in variability, while those cells inhibited by the agonist showed an increase in S/N and a decrease in variability. There was no obvious correlation between the two effects and any other response property suggesting a more general role in modulating all information passing from LGN to cortex. Conclusions Our data support a role for CB1 at the level of the thalamus acting as a dynamic modulator of visual information being sent to the cortex, apparently maintaining the salience of the signal within upper and lower boundaries. This may account for some of the behavioral effects of cannabis.Ministerio de Ciencia e Innovación; BFU2009-08169Xunta de Galicia; 2007/000140-