Researchers from Westlake University and the Westlake Institute for Advanced Study, along with other institutes in China, recently conducted a study to deepen our understanding of neurovascular coupling (NVC), the intricate relationship between neuronal activity and cerebral blood flow. Published in Nature Neuroscience, their findings reveal a synaptic-like transmission mechanism that drives NVC, occurring at neural-arteriolar smooth muscle cell junctions (NsMJs).Â
The study aimed to elucidate how active neural information is conveyed to arterioles in the brain, a process critical for the regulation of cerebral blood flow. By utilizing two-photon focal optogenetics in the mouse cerebral cortex, the researchers demonstrated that single glutamatergic axons dilate their innervating arterioles through synaptic-like transmission at NsMJs.Â
The research employed advanced techniques such as correlative light electron microscopy (CLEM), RNA-sequencing, immunogold EM, calcium imaging, and single-axon optogenetics. These methodologies enabled the scientists to examine in detail how neurons contribute to cerebral blood flow.Â
The team identified different types of NsMJ structures and neurotransmitter receptors expressed by smooth muscle cells of arterioles. They discovered functional NMDA receptors in the smooth muscle cells, which modulate the excitatory neurotransmitter glutamate involved in synaptic plasticity and cognitive functions.Â
The study uncovered that presynaptic parental-daughter boutons make dual innervations on postsynaptic dendrites and on arteriolar smooth muscle cells, which express various neuromediator receptors, including a low level of the glutamate NMDA receptor subunit 1 (Grin1).Â
By disrupting NsMJ transmission through smooth muscle cell-specific knockout of GluN1, the researchers observed diminished functional hyperemia caused by optogenetic and whisker stimulation. Notably, the absence of the GluN1 subunit in smooth muscle cells reduced brain atrophy following cerebral ischemia by preventing Ca2+ overload during arteriolar constriction induced by ischemia-induced spreading depolarization.Â
In essence, the genetic manipulation of NMDA receptors in smooth muscle cells resulted in reduced vasoconstriction and facilitated recovery after an ischemic stroke. The study concludes that NsMJ transmission is a crucial driver of NVC, providing new insights into stroke research.Â
The significance of this research extends to potential applications in studying ischemic strokes and developing treatments. By understanding the role of transmission between neural axons and smooth muscle cells, researchers could explore novel approaches to prevent the spread of damage caused by ischemic strokes and enhance the recovery of affected individuals.Â
In summary, the study sheds light on the intricate mechanisms of neurovascular coupling and introduces a promising avenue for stroke research. The findings may pave the way for future investigations into the role of the identified transmission mechanism in ischemic strokes and contribute to the development of innovative treatments to mitigate the impact of these devastating events on patients’ lives.Â
Journal Reference Â
Dongdong Zhang et al, Synaptic-like transmission between neural axons and arteriolar smooth muscle cells drives cerebral neurovascular coupling, Nature Neuroscience (2024). DOI: 10.1038/s41593-023-01515-0,
