Cerebrospinal Fluid Flow Influences Neural Stem Cell Activity

Researchers have found that a physical mechanism in the brain, the flow of cerebrospinal fluid and the shear forces generated by that flow, influences the activity of neural stem cells via a distinctive set of biochemical signals. This will in turn influence the rate of neurogenesis, the creation of new neurons and their integration into existing neural networks. This process is important in learning, neurodegeneration, and the resilience of the brain when it comes to recovery from damage.

It is worth considering this recent discovery in the context of what is already known of reduced and impeded drainage of cerebrospinal fluid with age. The system of spaces through which cerebrospinal fluid circulates is not entirely closed off from the rest of the body, and normally drainage serves to remove metabolic wastes from the brain. It is thought that loss of drainage with age is an important contributing cause of the buildup of protein aggregates found in many neurodegenerative conditions, particularly the amyloid associated with Alzheimer's disease.

More generally, the production of cerebrospinal fluid declines with age, its fluid pressure falls, and the flow characteristics both change and diminish. It is well known that neurogenesis rates also fall with aging, at least in the well explored mouse brain, and setting aside the present controversy over the existence of adult human neurogenesis. That the fluid dynamics of cerebrospinal fluid ties into this aspect of aging is perhaps an important advance in understanding, given that we are likely to see an increased focus on this part of the brain's physiology from the Alzheimer's research community in the years ahead.

Flow of cerebrospinal fluid regulates neural stem cell division

Researchers have discovered that the flow of cerebrospinal fluid is a key signal for neural stem cell renewal. Neural stem cells in the brain can divide and mature into neurons and this process plays important roles in various regions of the brain - including olfactory sense and memory. These cells are located in what is known as the neurogenic stem cell niche one of which is located at the walls of the lateral ventricles, where they are in contact with circulating cerebrospinal fluid.

The cerebrospinal fluid fills the brain and its roles are still poorly understood. This work highlights the role of this fluid as a key signal - but this time not a chemical but a physical signal. The mechanism is controlled by the ENaC molecule. This abbreviation stands for epithelial sodium (Na) channel and describes a channel protein on the cell surface through which sodium ions stream into the cell's interior. "We were able to show in an experimental model that brain stem cells are no longer able to divide in the absence of ENaC. Conversely, a stronger ENaC function promotes cell proliferation."

Further tests showed that the function of ENaC is augmented by shear forces exerted on the cells by the cerebrospinal fluid. The physical stimulation causes the channel protein to open for longer time and allow sodium ions to flow into the cell, thus stimulating division. "The results came as a big surprise, since ENaC had previously only been known for its functions in the kidneys and lungs." Pharmacological ENaC blockers are already used clinically to relieve certain types of hypertension. Now it is known that they can also influence stem cells in the brain and thus brain function.

Epithelial Sodium Channel Regulates Adult Neural Stem Cell Proliferation in a Flow-Dependent Manner

One hallmark of adult neurogenesis is its adaptability to environmental influences. Here, we uncovered the epithelial sodium channel (ENaC) as a key regulator of adult neurogenesis as its deletion in neural stem cells (NSCs) and their progeny in the murine subependymal zone (SEZ) strongly impairs their proliferation and neurogenic output in the olfactory bulb.

Importantly, alteration of fluid flow promotes proliferation of SEZ cells in an ENaC-dependent manner, eliciting sodium and calcium signals that regulate proliferation via calcium-release-activated channels and phosphorylation of ERK. Flow-induced calcium signals are restricted to NSCs in contact with the ventricular fluid, thereby providing a highly specific mechanism to regulate NSC behavior at this special interface with the cerebrospinal fluid. Thus, ENaC plays a central role in regulating adult neurogenesis, and among multiple modes of ENaC function, flow-induced changes in sodium signals are critical for NSC biology.


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