Neurovascular coupling (NVC), the interaction between neural activity and vascular response, ensures normal brain function by maintaining brain homeostasis. We previously reported altered cerebrovascular responses during functional hyperemia in chronically stressed animals. However, the underlying neuronal-level changes associated with those hemodynamic changes remained unclear. Here, using in vivo and ex vivo experiments, we investigate the neuronal origins of altered NVC dynamics under chronic stress conditions in adult male mice. Stimulus-evoked hemodynamic and neural responses, especially beta and gamma-band local field potential activity, were significantly lower in chronically stressed animals, and the NVC relationship, itself, had changed. Further, using acute brain slices, we discovered that the underlying cause of this change was dysfunction of neuronal nitric oxide synthase (nNOS)-mediated vascular responses. Using FISH to check the mRNA expression of several GABAergic subtypes, we confirmed that only nNOS mRNA was significantly decreased in chronically stressed mice. Ultimately, chronic stress impairs NVC by diminishing nNOS-mediated vasodilation responses to local neural activity. Overall, these findings provide useful information in understanding NVC dynamics in the healthy brain. More importantly, this study reveals that impaired nNOS-mediated NVC function may be a contributory factor in the progression of stress-related diseases.
Abnormal formation of solid thrombus inside a blood vessel
can
cause thrombotic morbidity and mortality. This necessitates early
stage diagnosis, which requires quantitative assessment with a small
volume, for effective therapy with low risk to unwanted development
of various diseases. We propose a micro-ultrasonic diagnosis using
an all-optical ultrasound-based spectral sensing (AOUSS) technique
for sensitive and quantitative characterization of early stage and
whole blood coagulation. The AOUSS technique detects and analyzes
minute viscoelastic variations of blood at a micro-ultrasonic spot
(<100 μm) defined by laser-generated focused ultrasound (LGFU).
This utilizes (1) a uniquely designed optical transducer configuration
for frequency-spectral matching and wideband operation (6 dB widths:
7–32 MHz and d.c. ∼ 46 MHz, respectively) and (2) an
empirical mode decomposition (EMD)-based signal process particularly
adapted to nonstationary LGFU signals backscattered from the spot.
An EMD-derived spectral analysis enables one to assess viscoelastic
variations during the initiation of fibrin formation, which occurs
at a very early stage of blood coagulation (1 min) with high sensitivity
(frequency transition per storage modulus increment = 8.81 MHz/MPa).
Our results exhibit strong agreement with those obtained by conventional
rheometry (Pearson’s R > 0.95), which are
also confirmed by optical microscopy. The micro-ultrasonic and high-sensitivity
detection of AOUSS poses a potential clinical significance, serving
as a screening modality to diagnose early stage clot formation (e.g.,
as an indicator for hypercoagulation of blood) and stages of blood-to-clot
transition to check a potential risk for development into thrombotic
diseases.
A transient cytosolic delivery system for accurate Cas9 ribonucleoprotein is a key factor for target specificity of the CRIPSR/Cas9 toolkit. Owing to the large size of the Cas9 protein and a long negative strand RNA, the development of the delivery system is still a major challenge. Here, a size‐controlled lipopeptide‐based nanosome system is reported, derived from the blood‐brain barrier‐permeable dNP2 peptide which is capable of delivering a hyperaccurate Cas9 ribonucleoprotein complex (HypaRNP) into human cells for gene editing. Each nanosome is capable of encapsulating and delivering ≈2 HypaRNP molecules into the cytoplasm, followed by nuclear localization at 4 h post‐treatment without significant cytotoxicity. The HypaRNP thus efficiently enacts endogenous eGFP silencing and editing in human embryonic kidney cells (up to 27.6%) and glioblastoma (up to 19.7% frequency of modification). The lipopeptide‐based nanosome system shows superior delivery efficiency, high controllability, and simplicity, thus providing biocompatibility and versatile platform approach for CRISPR‐mediated transient gene editing applications.
The role of parvalbumin (PV) interneurons in vascular control is poorly understood. Here, we investigated the hemodynamic responses elicited by optogenetic stimulation of PV interneurons using electrophysiology, functional magnetic resonance imaging (fMRI), wide-field optical imaging (OIS), and pharmacological applications. As a control, forepaw stimulation was used. Stimulation of PV interneurons in the somatosensory cortex evoked a biphasic fMRI response in the photostimulation site and negative fMRI signals in projection regions. Activation of PV neurons engaged two separable neurovascular mechanisms in the stimulation site. First, an early vasoconstrictive response caused by the PV-driven inhibition is sensitive to the brain state affected by anesthesia or wakefulness. Second, a later ultraslow vasodilation lasting a minute is closely dependent on the sum of interneuron multiunit activities, but is not due to increased metabolism, neural or vascular rebound, or increased glial activity. The ultraslow response is mediated by neuropeptide substance P (SP) released from PV neurons under anesthesia, but disappears during wakefulness, suggesting that SP signaling is important for vascular regulation during sleep. Our findings provide a comprehensive perspective about the role of PV neurons in controlling the vascular response.
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