Preserved blood-brain barrier and neurovascular coupling in female 5xFAD model of Alzheimer's disease.

Introduction: Dysfunction of the cerebral vasculature is considered one of the key components of Alzheimer's disease (AD), but the mechanisms affecting individual brain vessels are poorly understood.

Methods: Here, using two-photon microscopy in superficial cortical layers and imaging across brain regions, we characterized blood-brain barrier (BBB) function and neurovascular coupling (NVC) at the level of individual brain vessels in adult female 5xFAD mice, an aggressive amyloid- (A) model of AD.

Results: We report a lack of abnormal increase in adsorptive-mediated transcytosis of albumin and preserved paracellular barrier for fibrinogen and small molecules despite an extensive load of A.

Impaired dynamics of precapillary sphincters and pericytes at first-order capillaries predict reduced neurovascular function in the aging mouse brain.

The microvascular inflow tract, comprising the penetrating arterioles, precapillary sphincters and first-order capillaries, is the bottleneck for brain blood flow and energy supply. Exactly how aging alters the structure and function of the microvascular inflow tract remains unclear. By in vivo four-dimensional two-photon imaging, we reveal an age-dependent decrease in vaso-responsivity accompanied by a decrease in vessel density close to the arterioles and loss of vascular mural cell processes, although the number of mural cell somas and their alpha smooth muscle actin density were preserved.

MEMS micro-coils for magnetic neurostimulation.

Micro-coil magnetic stimulation of brain tissue presents new challenges for MEMS micro-coil probe fabrication. The main challenges are threefold; (i) low coil resistance for high power efficiency, (ii) low leak current from the probe into the in vitro experimental set-up, (iii) adaptive MEMS process technology because of the dynamic research area, which requires agile design changes. Taking on these challenges, we present a MEMS fabrication process that has three main features; (i) multilayer resist lift-off process to pattern up to 1800-nm-thick metal films, and special care is taken to obtain high conductivity thin-films by physical vapor deposition, and (ii) all micro-coil Al wires are encapsulated in at least 200 nm of ALD alumina and 6-μm-thick parylene C such the leak resistance is high (>210 GΩ), (iii) combining a multi-step DRIE process and maskless photolithography for adaptive design and device fabrication.

Precapillary sphincters and pericytes at first-order capillaries as key regulators for brain capillary perfusion.

Rises in local neural activity trigger local increases of cerebral blood flow, which is essential to match local energy demands. However, the specific location of microvascular flow control is incompletely understood. Here, we used two-photon microscopy to observe brain microvasculature in vivo.

ATP induces contraction of cultured brain capillary pericytes via activation of P2Y-type purinergic receptors.

Brain capillary pericytes have been suggested to play a role in the regulation of cerebral blood flow under physiological and pathophysiological conditions. ATP has been shown to cause constriction of capillaries under ischemic conditions and suggested to be involved in the "no-reflow" phenomenon. To investigate the effects of extracellular ATP on pericyte cell contraction, we studied purinergic receptor activation of cultured bovine brain capillary pericytes.

Precapillary sphincters maintain perfusion in the cerebral cortex.

Active nerve cells release vasodilators that increase their energy supply by dilating local blood vessels, a mechanism termed neurovascular coupling and the basis of BOLD functional neuroimaging signals. Here, we reveal a mechanism for cerebral blood flow control, a precapillary sphincter at the transition between the penetrating arteriole and first order capillary, linking blood flow in capillaries to the arteriolar inflow. The sphincters are encircled by contractile mural cells, which are capable of bidirectional control of the length and width of the enclosed vessel segment.

Sensory Stimulation-Induced Astrocytic Calcium Signaling in Electrically Silent Ischemic Penumbra.

Middle cerebral artery occlusion (MCAO) induces ischemia characterized by a densely ischemic focus, and a less densely ischemic penumbral zone in which neurons and astrocytes display age-dependent dynamic variations in spontaneous Ca activities. However, it is unknown whether penumbral nerve cells respond to sensory stimulation early after stroke onset, which is critical for understanding stimulation-induced stroke therapy. In this study, we investigated the ischemic penumbra's capacity to respond to somatosensory input.

In Vivo Three-Dimensional Two-Photon Microscopy to Study Conducted Vascular Responses by Local ATP Ejection Using a Glass Micro-Pipette.

Maintenance of normal brain function requires a sufficient and efficient supply of oxygen and nutrition by a complex network of vessels. However, the regulation of cerebral blood flow (CBF) is incompletely understood, especially at the capillary level. Two-photon microscopy is a powerful tool widely used to study CBF and its regulation.

Spontaneous astrocytic Ca activity abounds in electrically suppressed ischemic penumbra of aged mice.

Experimental focal cortical ischemic lesions consist of an ischemic core and a potentially salvageable peri-ischemic region, the ischemic penumbra. The activity of neurons and astrocytes is assumed to be suppressed in the penumbra because the electrical function is interrupted, but this is incompletely elucidated. Most experimental stroke studies used young adult animals, whereas stroke is prevalent in the elderly population.

para-Aminothiophenol Radical Reaction-Functionalized Gold Nanoprobe for One-to-All Detection of Five Reactive Oxygen Species In Vivo.

Five major reactive oxygen species (ROS) are generated in diseases including HO, OH, O, ROO, and O. Simultaneous detection of the five ROS with a single probe is crucial for a comprehensive understanding of the development and progression of many diseases, such as cancer and inflammatory diseases. However, currently reported detection systems are limited by targeting one ROS with one probe.

Stimulation-induced increases in cerebral blood flow and local capillary vasoconstriction depend on conducted vascular responses.

Functional neuroimaging, such as fMRI, is based on coupling neuronal activity and accompanying changes in cerebral blood flow (CBF) and metabolism. However, the relationship between CBF and events at the level of the penetrating arterioles and capillaries is not well established. Recent findings suggest an active role of capillaries in CBF control, and pericytes on capillaries may be major regulators of CBF and initiators of functional imaging signals.

Effect of electrical forepaw stimulation on capillary transit-time heterogeneity (CTH).

Functional hyperemia reduces oxygen extraction efficacy unless counteracted by a reduction of capillary transit-time heterogeneity of blood. We adapted a bolus tracking approach to capillary transit-time heterogeneity estimation for two-photon microscopy and then quantified changes in plasma mean transit time and capillary transit-time heterogeneity during forepaw stimulation in anesthetized mice (C57BL/6NTac). In addition, we analyzed transit time coefficient of variance = capillary transit-time heterogeneity/mean transit time, which we expect to remain constant in passive, compliant microvascular networks.

Differential responses to high-frequency electrical stimulation in ON and OFF retinal ganglion cells.

Objective: The field of retinal prosthetics for artificial vision has advanced considerably in recent years, however clinical outcomes remain inconsistent. The performance of retinal prostheses is likely limited by the inability of electrical stimuli to preferentially activate different types of retinal ganglion cell (RGC).

Approach: Here we examine the response of rabbit RGCs to high-frequency stimulation, using biphasic pulses applied at 2000 pulses per second.

The role of the microcirculation in delayed cerebral ischemia and chronic degenerative changes after subarachnoid hemorrhage.

The mortality after aneurysmal subarachnoid hemorrhage (SAH) is 50%, and most survivors suffer severe functional and cognitive deficits. Half of SAH patients deteriorate 5 to 14 days after the initial bleeding, so-called delayed cerebral ischemia (DCI). Although often attributed to vasospasms, DCI may develop in the absence of angiographic vasospasms, and therapeutic reversal of angiographic vasospasms fails to improve patient outcome.

The response of retinal neurons to high-frequency stimulation.

Objective: High-rate pulse trains have proven to be effective in cochlear prosthetics and, more recently, have been shown to elicit a wide range of interesting response properties in axons of the peripheral nervous system. Surprisingly, the effectiveness of such trains for use in retinal prostheses has not been explored.

Approach: Using cell-attached patch clamp methods, we measured the in vitro response of two rabbit retinal ganglion cell types, OFF-brisk transient (OFF-BT) and ON-OFF directionally selective (DS), to trains of biphasic pulses delivered at 2000 pulses per second (PPS).

The role of the cerebral capillaries in acute ischemic stroke: the extended penumbra model.

The pathophysiology of cerebral ischemia is traditionally understood in relation to reductions in cerebral blood flow (CBF). However, a recent reanalysis of the flow-diffusion equation shows that increased capillary transit time heterogeneity (CTTH) can reduce the oxygen extraction efficacy in brain tissue for a given CBF. Changes in capillary morphology are typical of conditions predisposing to stroke and of experimental ischemia.

High frequency electric stimulation of retinal neurons elicits physiological signaling patterns.

The effectiveness of retinal prosthetics will depend on their ability to elicit patterns of neural activity that can be recognized by the visual cortex. While conventional short-duration pulses activate retinal neurons effectively, many nearby neurons are thought to respond similarly to a given pulse train--a situation that is non-physiological. Use of pulse trains delivered at rates > 1000 pulses per second (PPS) in cochlear prosthetics help to avoid phase-locked responses but have not been evaluated in the retina; here, we explored the response to trains of 2000 PPS.

Response variability to high rates of electric stimulation in retinal ganglion cells.

To improve the quality of prosthetic vision, it is important to understand how retinal neurons respond to electric stimulation. Previous studies present conflicting reports as to the maximum rate at which retinal ganglion cells can "follow" pulse trains, i.e.

Spatiotemporal properties of multipeaked electrically evoked potentials elicited by penetrative optic nerve stimulation in rabbits.

Purpose: To investigate the spatiotemporal properties of the cortical responses elicited by intraorbital optic nerve (ON) stimulation with penetrating electrodes as means of designing optimal stimulation strategies for an ON visual prosthesis.

Methods: The ON of rabbits was exposed by orbital surgery for electrical stimulation. Craniotomy was performed to expose the visual cortex contralateral to the operated eye.

Low-hemorrhage-risk surgical approach to expose the optic nerve in rabbits without bony removal and rectus resection.

Objective: A low-hemorrhage-risk surgical approach to expose the optic nerve (ON) in rabbits through the orbital process of the frontal bone without removal of the bony orbit and resection of the rectus muscle was explored and assessed in this study. This approach will be used to investigate a new visual prosthesis that requires intraorbital ON stimulation with penetrating electrodes. Animals Chinese Albino rabbits (n = 10).

Response properties of electrically evoked potential elicited by multi-channel penetrative optic nerve stimulation in rabbits.

Visual prosthesis is a potential way to restore partial vision for the patients with degenerative retinal diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD). Optic nerve stimulation with penetrating microelectrode array has been suggested as a possible method for visual prosthesis. The purpose of this study was to investigate the feasibility and basic response properties of cortical responses elicited by optic nerve stimulation with penetrating electrodes in rabbits.

Recognition of pixelized Chinese characters using simulated prosthetic vision.

The rehabilitation of the reading ability of the blind with a limited number of stimulating electrodes is regarded as one of the major functions of the envisioned visual prosthesis. This article systematically studied how many pixels of individual Chinese characters should be needed for correct and economic recognition by blind Chinese subjects. In this study, 40 normal-sighted subjects were tested on a self-developed platform HanziConvertor (Institute for Laser Medicine & Bio-photonics, Shanghai Jiaotong University, China) with digital imaging processing capacities to convert images of printed text into various pixelized patterns made up of discrete dots, and present them orderly on a computer screen.