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Nature Neuroscience: New breakthrough in neurovascular coupling theory!

   |  March 21, 2024

Blood supply powers neural computations in the brain. Fluctuations in computational activity produce commensurate alterations in the regional cerebral blood flow (CBF) within seconds, termed neurovascular coupling (NVC). Impaired NVC function can lead to cerebral microcirculation ischemia and hypoxia, affect local nerve signal conduction, cause and aggravate cerebral small vessel disease, and may even lead to cognitive dysfunction and dementia.

The 130-year-old metabolic hypothesis explaining NVC has become increasingly controversial, with cell-type-specific and neurotransmitter-mediated mechanisms recently emerging as the primary mechanism of CBF regulation. However, the molecular and cellular pathways underpinning this neural messenger delivery specificity remain largely unknown. In addition, how active neural information is conveyed to the targeted arterioles in the brain remains poorly understood.

 Contact between aSMCs and axons through gaps in astrocytic endfeet

On January 2, 2024, Jiemin Jia’s team from Westlake University published a research paper titled Synaptic-like transmission between neural axons and arteriolar smooth muscle cells drives cerebral neurovascular coupling in the journal of Nature Neuroscience, demonstrating that single glutamatergic axons dilate their innervating arterioles via synaptic-like transmission between neural-arteriolar smooth muscle cells (aSMCs). These findings reveal a “novel bridge” for direct communication between neurons and cerebral blood vessels, providing new understandings to the rapid and precise regulation of cerebral circulation.

In this study, the research team used serial block face scanning electron microscopy (SBF-SEM) and three-dimensional (3D) reconstruction of volumetric correlative light electron microscopy (EM) to comprehensively analyze the ultrastructure of penetrating arterioles (approximately 480 μm depth) and cells in their surrounding tissues in mouse barrel cortex. Results showcased “gaps” between astrocytic endfeet and penetrating arterioles. Peripheral pre-synaptic daughter boutons pass through these gaps, insert into the basement membrane surrounding aSMCs, and form “neural–arteriolar smooth muscle cell junctions (NsMJs)” with aSMCs, establishing a “new bridge” for neurovascular communication that has not been shown previously.

 Contact between aSMCs and axons through gaps in astrocytic endfeet
Fig. 1 Contact between aSMCs and axons through gaps in astrocytic endfeet

To confirm the role of NsMJs in conveying information, the research team first examined whether aSMCs have receptors to receive neurotransmitter signals. Results demonstrated that aSMCs in the brain express a variety of neurotransmitter receptors, including NMDAR, glutamate neurotransmitter receptors that allow the influx of calcium ions.

The authors then activated the presynaptic membrane of NsMJs to confirm the binding of neuron-secreted neurotransmitters and their receptors on aSMCs that regulates vasodilation and vasoconstriction. The team pioneered the optogenetic activation technique of intracranial single axons and dendrites, simultaneously tracking diameter changes of the targeted arteries. Results demonstrated that specific activation of a single presynaptic glutamatergic axon induced arterial relaxation, increasing the diameter by nearly 15%. Furthermore, through the classic whisker stimulation experiment, the researchers observed that disrupting Glu-NsMJ transmission significantly inhibited NVC (the laser speckle contrast imaging system of RWD was applied in these experiments). These findings revealed that NsMJs modulate cerebral vasoconstriction and vasodilation.

 Disruption of Glu-NsMJ transmission significantly inhibited NVC (the laser speckle contrast imaging system of RWD was applied in these experiments to monitor blood flow changes)
Fig. 2 Disruption of Glu-NsMJ transmission significantly inhibited NVC (the laser speckle contrast imaging system of RWD was applied in these experiments to monitor blood flow changes)

The aforementioned results confirm a new pathway for neurons to directly regulate CBF. So how does this regulatory mechanism translate into cerebrovascular diseases? To answer this question, the team explored further in a mouse middle cerebral arterial occlusion (MCAO) model where acute ischemic stroke produced excessive glutamate release and generated spreading depolarization of aSMCs, leading to subsequent arteriolar constrictions and secondary ischemia. By specifically knocking out the GluN1 subunit of the NMDAR on aSMCs, arterial toxicity and subsequent brain atrophy were alleviated, thus the improvement of motor function recovery and the reduction in mortality.

Knocking out GluN1 in aSMCs promotes functional recovery after ischemic stroke
Fig. 3 Knocking out GluN1 in aSMCs promotes functional recovery after ischemic stroke

In summary, this study confirms the “synaptic-like (NsMJs)” structure between neurons and blood vessels in the brain, which can regulate vasodilation and vasoconstriction under physiological and pathological conditions, providing a “new bridge” for direct neurovascular communications. These results offer a new perspective for in-depth understanding of the cerebral blood supply mechanism that may spark new ideas for stroke treatment. 

Research highlights in methodology

This study reveals a new pathway by which neurons regulate CBF. The research team applied a number of techniques in their experiments such as animal surgical modeling, serial block face scanning electron microscopy (SBF-SEM), three-dimensional (3D) reconstruction of volumetric correlative light electron microscope, calcium imaging, electrophysiological recording, two-photon optogenetics, animal microcirculatory blood flow imaging analysis, immunohistochemistry, and animal behavior detection.

RWD has been deeply involved in the field of life science research for 21 years and has been committed to providing customers with reliable solutions and services. In this study, the researchers used the laser speckle contrast imaging (LSCI) system (RFLSI III, RWD Life Sciences), ensuring the smooth implementation. In addition, RWD also provides complete solutions for experiment techniques, including animal surgical modeling, calcium imaging, electrophysiological recording, immunohistochemistry, and animal behavior detection involved in this study.

Up to now, RWD has offered solutions and services in more than 100 countries and regions. Our customers include 2,300+ hospitals, 1,000+ research institutes, and 6,000+ universities around the world, helping global researchers publish 14,500+ SCI-cited articles and being widely recognized by the industry.

Zhang, D., Ruan, J., Peng, S. et al. Synaptic-like transmission between neural axons and arteriolar smooth muscle cells drives cerebral neurovascular coupling. Nat Neurosci 27, 232–248 (2024).

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