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Recent studies have highlighted the importance of understanding the architecture and function of microvasculature, and dysfunction of these microvessels may underlie neurodegenerative disease. Here, we utilize a high-precision ultrafast laser-induced photothrombosis (PLP) method to occlude single capillaries and then quantitatively study the effects on vasodynamics and surrounding neurons. Analysis of the microvascular architecture and hemodynamics after single-capillary occlusion reveals distinct changes upstream vs. downstream branches, which shows rapid regional flow redistribution and local downstream blood-brain barrier (BBB) leakage. Focal ischemia via capillary occlusions surrounding labeled target neurons induces dramatic and rapid lamina-specific changes in neuronal dendritic architecture. Further, we find that micro-occlusion at two different depths within the same vascular arbor results in distinct effects on flow profiles in layers 2/3 vs layer 4. The current results reveal laminar-scale regulation distinctions in microinfarct response and raise the possibility that relatively greater impacts on microvascular function contribute to cognitive decline in neurodegenerative disease. [Display omitted] • Single-capillary occlusion leads to rapid regional blood flow autoregulation • Focal capillary occlusions induce signs of neuronal degenerative change • Microvessel occlusions produce lamina-specific microvascular flow vasodynamics Zhu et al. utilize a precision photothrombosis technique to produce depth-targeted single capillary occlusions and reveal regional hemodynamic alternation, neurodegenerative change, and laminar-scale regulation distinctions induced by microvessel occlusion. This finding raises the possibility that microvascular dysfunction contributes to cognitive decline in neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Multiphoton microscopy has been a powerful tool in brain research, three-photon fluorescence microscopy is increasingly becoming an emerging technique for neurological research of the cortex in depth. Nonhuman primates play important roles in the study of brain science because of their neural and vascular similarity to humans. However, there are few research results of three-photon fluorescence microscopy on the brain of nonhuman primates due to the lack of optimized imaging systems and excellent fluorescent probes. Here we introduced a bright aggregation-induced emission (AIE) probe with excellent three-photon fluorescence efficiency as well as facile synthesis process and we validated its biocompatibility in the macaque monkey. We achieved a large-depth vascular imaging of approximately 1 mm in the cerebral cortex of macaque monkey with our lab-modified three-photon fluorescence microscopy system and the AIE probe. Functional measurement of blood velocity in deep cortex capillaries was also performed. Furthermore, the comparison of cortical deep vascular structure parameters across species was presented on the monkey and mouse cortex. This work is the first in vivo three-photon fluorescence microscopic imaging research on the macaque monkey cortex reaching the imaging depth of ∼1 mm with the bright AIE probe. The results demonstrate the potential of three-photon microscopy as primate-compatible method for imaging fine vascular networks and will advance our understanding of vascular function in normal and disease in humans. [ABSTRACT FROM AUTHOR]

Optical microscopy has enabled in vivo monitoring of brain structures and functions with high spatial resolution. However, the strong optical scattering in turbid brain tissue and skull impedes the observation of microvasculature and neuronal structures at a large depth. Herein, we proposed a strategy to overcome the influence induced by the high scattering effect of both skull and brain tissue via the combination of skull optical clearing (SOC) technique and three-photon fluorescence microscopy (3PM). The visible-NIR-II compatible skull optical clearing agents (VNSOCA) we applied reduced the skull scattering and water absorption in long wavelength by refractive index matching and H 2 O replacement to D 2 O respectively. 3PM with the excitation in the 1300-nm window reached 1.5 mm cerebrovascular imaging depth in cranial window assisted by a kind of bright aggregation-induced emission (AIE) nanoprobe we developed with a large three-photon absorption cross section. Combining the two advanced technologies together, we achieved so far the largest cerebrovascular imaging depth of 1.0 mm and neuronal imaging depth of> 700 µm through intact mouse skull. Dual-channel through-skull imaging of both brain vessels and neurons was also successfully realized, giving an opportunity of non-invasively monitoring the deep brain structures and functions at single-cell level simultaneously. [Display omitted] • Skull optical clearing and three-photon microscopy were combined to reduce scattering interference. • Aggregation-induced emission nanoprobes with extremely large three-photon absorption section benefit deep imaging. • Through-skull three-photon mouse cerebrovascular imaging achieved the largest 1.0 mm imaging depth. [ABSTRACT FROM AUTHOR]

Nanoparticle-assisted near-infrared (NIR) bioimaging and two-photon fluorescence microscopy (TPFM) are two important technologies in biophotonic research. In this work, we synthesize the dye named 2-(4-bromophenyl)-3-(4-(4-(diphenylamino)styryl)phenyl)fumaronitrile (TPABDFN), which had a large two-photon absorption cross-section and bright NIR emission. The dyes were then encapsulated with poly(styrene- co -maleic anhydride) (PSMA), forming fluorescent nanoparticles. The TPABDFN-PSMA nanoparticles possessed high chemical and optical stability, good biocompatibility, as well as large two-photon absorption cross-section (5.56 × 10 5 GM). Furthermore, we combined NIR bioimaging and TPFM together, and utilized TPABDFN-PSMA nanoparticles as fluorescent contrast agents for two-photon excited NIR microscopic imaging, with a 1040 nm-femtosecond laser. In vivo angiography of mice ear and brain was performed. Due to the deep penetration capability of both 1040 nm-excitation and NIR emission light, a very large in vivo microscopic imaging depth (∼1.2 mm) was achieved. NIR emissive and biocompatible TPABDFN-PSMA nanoparticles have great potential in disease diagnosis and clinical therapies, where deep-tissue imaging is required. [ABSTRACT FROM AUTHOR]

In this work, a series of new diketopyrrolopyrrole-based dyes have been synthesized by connecting tetraphenylethene to the diketopyrrolopyrrole core. All the four compounds exhibit good aggregation-induced emission property with nonemissive in the solution but strong red fluorescence in the aggregate or solid state. Also, these new dyes exhibit large two-photon absorption cross sections (σ), in which the σ data measured by the open aperture Z-scan technique are determined to be 150, 300, 1140 and 1016 GM for four dyes, respectively. In addition, compound with stilbene and four tetraphenylethene units ( DPP-TPE-3) was used as the luminogen and encapsulated into nanoparticles for cell imaging and two-photon excited fluorescence blood vessels imaging. The result indicates that it can be used as the effective fluorescence probe for bioimaging and has great potential for bioapplications. [ABSTRACT FROM AUTHOR]

Though commonly used, metal electrodes are incompatible with brain tissues, often leading to injury and failure to achieve long-term implantation. Here we report a subdural neural interface of hydrogel functioning as an ionic conductor, and elastomer as a dielectric. We demonstrate that it incurs a far less glial reaction and less cerebrovascular destruction than a metal electrode. Using a cat model, the hydrogel electrode was able to record electrical signals comparably in quality to a metal electrode. The hydrogel-elastomer neural interface also readily facilitated multimodal functions. Both the hydrogel and elastomer are transparent, enabling in vivo optical microscopy. For imaging, cerebral vessels and calcium signals were imaged using two-photon microscopy. The new electrode is compatible with magnetic resonance imaging and does not cause artifact images. Such a new multimodal neural interface could represent immediate opportunity for use in broad areas of application in neuroscience research and clinical neurology. [ABSTRACT FROM AUTHOR]