Implantation and Extraction of Penetrating Electrode Arrays in Minipig Retinas.

Purpose: This work was motivated by the goals of demonstrating methods to fabricate and implant large numbers of penetrating arrays into the retina and the feasibility of extraction.

Methods: Arrays of inactive, three-dimensional (3D) SU-8 structures were microfabricated onto 13-µm polyimide substrates. Standard vitreoretinal surgical techniques were used with an approach for subretinal implantation of arrays in 12 mini-pigs.

Rapid Changes in Synaptic Strength After Mild Traumatic Brain Injury.

Traumatic brain injury (TBI) affects millions of Americans annually, but effective treatments remain inadequate due to our poor understanding of how injury impacts neural function. Data are particularly limited for mild, closed-skull TBI, which forms the majority of human cases, and for acute injury phases, when trauma effects and compensatory responses appear highly dynamic. Here we use a mouse model of mild TBI to characterize injury-induced synaptic dysfunction, and examine its progression over the hours to days after trauma.

Mild Blast Injury Produces Acute Changes in Basal Intracellular Calcium Levels and Activity Patterns in Mouse Hippocampal Neurons.

Mild traumatic brain injury (mTBI) represents a serious public health concern. Although much is understood about long-term changes in cell signaling and anatomical pathologies associated with mTBI, little is known about acute changes in neuronal function. Using large scale Ca imaging in vivo, we characterized the intracellular Ca dynamics in thousands of individual hippocampal neurons using a repetitive mild blast injury model in which blasts were directed onto the cranium of unanesthetized mice on two consecutive days.

Region-specific alterations in astrocyte and microglia morphology following exposure to blasts in the mouse hippocampus.

Traumatic brain injury (TBI) is a serious public health concern, especially injuries from repetitive insults. The main objective of this study was to immunocytochemically examine morphological alterations in astrocytes and microglia in the hippocampus 48h following a single blast versus multiple blasts in adult C57BL/6 mice. The effects of ketamine and xylazine (KX), two common anesthetic agents used in TBI research, were also evaluated due to the confounding effect of anesthetics on injury outcome.

Visual system pathology in humans and animal models of blast injury.

Injury from blast exposure is becoming a more prevalent cause of death and disability worldwide. The devastating neurological impairments that result from blasts are significant and lifelong. Progress in the development of effective therapies to treat injury has been slowed by its heterogeneous pathology and the dearth of information regarding the cellular mechanisms involved.

Evidence for a functional adrenomedullin signaling pathway in the mouse retina.

Purpose: Adrenomedullin (ADM) is a small, secreted peptide often associated with vasodilation. However, ADM can also function as a neurotransmitter/neuromodulator, and studies suggest ADM is upregulated in the eye in several ocular diseases. However, no studies to date have described an ADM signaling pathway in the retina.

Characterization of nitric oxide signaling pathways in the mouse retina.

Nitric oxide (NO) is a gaseous neuromodulator with physiological functions in every retinal cell type. NO is synthesized by several nitric oxide synthases (NOS) and often functions through its second messenger, cyclic guanosine monophosphate (cGMP), and protein kinase G (PKG). This study combined NO imaging, immunocytochemistry, biochemistry, and molecular biology to localize NO and its downstream signaling pathways in the mouse retina.

Inhibition of the adrenomedullin/nitric oxide signaling pathway in early diabetic retinopathy.

The nitric oxide (NO) signaling pathway is integrally involved in visual processing and changes in the NO pathway are measurable in eyes of diabetic patients. The small peptide adrenomedullin (ADM) can activate a signaling pathway to increase the enzyme activity of neuronal nitric oxide synthase (nNOS). ADM levels are elevated in eyes of diabetic patients and therefore, ADM may play a role in the pathology of diabetic retinopathy.

Transduction of the inner mouse retina using AAVrh8 and AAVrh10 via intravitreal injection.

Adeno-associated virus (AAV) is a proven, safe and effective vector for gene delivery in the retina. There are over 100 serotypes of AAV, and AAV2 through AAV9 have been evaluated in the retina. Each AAV serotype has different cell tropism and transduction efficiency.

Increased neuronal nitric oxide synthase activity in retinal neurons in early diabetic retinopathy.

Purpose: There are increased levels of nitric oxide (NO) in diabetic retinas. The purpose of this study was to determine the extent that neuronal nitric oxide synthase (nNOS) contributes to the increased levels of retinal NO in early diabetic retinopathy by examining the expression and activity of nNOS in retinal neurons after 5 weeks of diabetes.

Methods: Changes in NO levels were measured using NO imaging of retinal neurons in mice with streptozotocin-induced diabetes for five weeks.

Functional localization of the nitric oxide/cGMP pathway in the salamander retina.

Nitric oxide (NO) is a gaseous neuromodulator that has physiological functions in every cell type in the retina. Evidence indicates that NO often plays a role in the processing of visual information in the retina through the second messenger cyclic guanosine monophosphate (cGMP). Despite numerous structural and functional studies of this signaling pathway in the retina, none have examined many of the elements of this pathway within a single study in a single species.

Identification of alternate transcripts of neuronal nitric oxide synthase in the mouse retina.

Nitric oxide (NO) is a major signaling molecule in the retina and CNS, with physiological roles in every cell type in the retina. Previous work shows that neuronal nitric oxide synthase (nNOS) is an important source of NO in the vertebrate retina. There are distinct, active alternative transcripts of nNOS observed in many tissues, including testes and brain, that may differ in both localization and enzyme kinetics.

Interactions of the gaseous neuromodulators nitric oxide, carbon monoxide, and hydrogen sulfide in the salamander retina.

The three gaseous neuromodulators nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) are endogenously produced in vertebrate retinas. The NO/cyclic guanosine monophosphate (cGMP) and CO/cGMP pathways have been previously shown to interact synergistically in the turtle retina to increase cGMP levels. In this study, we examined H2S as a modulator of cGMP-like immunoreactivity (-LI) and its interactions with the NO/CO/cGMP signaling pathways in the tiger salamander retina.

Role of acetylcholine in nitric oxide production in the salamander retina.

Although acetylcholine is one of the most widely studied neurotransmitters in the retina, many questions remain about its downstream signaling mechanisms. In this study we initially characterized the cholinergic neurotransmitter system in the salamander retina by localizing a variety of cholinergic markers. We then examined the link between both muscarinic and nicotinic receptor activation and nitric oxide production by using immunocytochemistry for cyclic guanosine monophosphate (cGMP) as an indicator.

Comparative localization of cystathionine beta-synthase and cystathionine gamma-lyase in retina: differences between amphibians and mammals.

Hydrogen sulfide (H(2)S) is a gaseous neuromodulator that can be synthesized by the transsulfuration enzymes cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CGL). In this study we examined H(2)S as a potential neuromodulator in vertebrate retina. CBS-like immunoreactivity (LI) was found in somas in the inner nuclear layer and as punctate staining in the inner and outer plexiform layers in the salamander retina.

Cellular and subcellular localization of PDE10A, a striatum-enriched phosphodiesterase.

PDE10A is a recently identified phosphodiesterase that is highly expressed by the GABAergic medium spiny projection neurons of the mammalian striatum. Inhibition of PDE10A results in striatal activation and behavioral suppression, suggesting that PDE10A inhibitors represent a novel class of antipsychotic agents. In the present studies we further elucidate the localization of this enzyme in striatum of rat and cynomolgus monkey.

Gycine and GABA interact to regulate the nitric oxide/cGMP signaling pathway in the turtle retina.

Nitric oxide (NO) is a free radical that is important in retinal signal transduction and cyclic guanosine monophosphate (cGMP) is a critical downstream messenger of NO. The NO/cGMP signaling pathway has been shown to modulate neurotransmitter release and gap junction coupling in horizontal cells and amacrine cells, and increase the gain of the light response in photoreceptors. However, many of the mechanisms controlling the production of NO and cGMP remain unclear.

Imaging of nitric oxide in the retina.

Nitric oxide (NO) is the most widespread signaling molecule found in the retina in that it can be made by every retinal cell type. NO is able to influence a wide variety of synaptic mechanisms ranging from increasing or decreasing neurotransmitter release to the modulation of gap junction conductivity. Although biochemical methods can analyze overall levels of NO, such methods cannot indicate the specific cell types involved.

Nitric oxide stimulates gamma-aminobutyric acid release and inhibits glycine release in retina.

Nitric oxide (NO) modulates the uptake and/or release of neurotransmitters through a variety of cellular mechanisms. However, the pharmacological and biochemical processes underlying these neurochemical effects of NO often remain unclear. In our study, we used immunocytochemical methods to study the effects of NO, cyclic guanosine monophosphate (cGMP), and peroxynitrite on the uptake and release of gamma-aminobutyric acid (GABA) and glycine in the turtle retina.

GABA(A) and GABA(C) receptor antagonists increase retinal cyclic GMP levels through nitric oxide synthase.

The nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signal transduction pathway plays a role in every retinal cell type. Previous studies have shown that excitatory glutamatergic synaptic pathways can increase cGMP-like immunoreactivity (cGMP-LI) in retina through stimulation of NO production, but little is known about the role of synaptic inhibition in the modulation of cGMP-LI. Gamma-amino-n-butyric acid (GABA) plays critical roles in modulating excitatory synaptic pathways in the retina.

Inhibitors of nitric oxide synthase block carbon monoxide-induced increases in cGMP in retina.

Previous studies indicate that the gaseous messengers carbon monoxide (CO) and nitric oxide (NO) can interact to cause robust increases in intracellular cGMP levels in the retina. The purpose of the present study was to investigate the biochemical basis of the interactions between NO and CO for these increases. Turtle retinas were incubated in vitro with CO to stimulate cGMP production in the presence or absence of the nitric oxide synthase inhibitors N-omega-nitro-L-arginine methyl ester and S-methyl-thiocitrulline.

Activation of the cGMP/nitric oxide signal transduction system by nicotine in the retina.

Acetylcholine is one of the primary excitatory neurotransmitters/neuromodulators in the retina, but little is known about the downstream signaling pathways it can activate. The present study immunocytochemically examines the potential sources of acetylcholine and the location of the nicotinic cholinergic receptors in the turtle retina. It also examines how activation of these receptors can influence the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signal-transduction pathways.

Subcellular localization of neuronal nitric oxide synthase in turtle retina: electron immunocytochemistry.

Recent studies imaging nitric oxide (NO) production in the retina have indicated a much wider distribution of NO production than would be suggested by previous light-microscopic localizations of neuronal nitric oxide synthase (nNOS). To help resolve this discrepancy, the present study analyzed the ultrastructural localization of nNOS-like immunoreactivity (-LI) in all layers of the retina. In the ellipsoids of rod photoreceptors and the accessory elements of double cones, nNOS-LI was associated with some atypical mitochondria.

Direct imaging of NMDA-stimulated nitric oxide production in the retina.

In the retina, nitric oxide (NO) functions in network coupling, light adaptation, neurotransmitter receptor function, and synaptic release. Neuronal nitric oxide synthase (nNOS) is present in the retina of every vertebrate species investigated. However, although nNOS can be found in every retinal cell type, little is known about the production of NO in specific cells or about the diffusion of NO within the retina.