The Molecular Mechanisms of Neural Flow Coupling: A New Concept

Abstract

The phenomenon known as neural flow coupling (NFC) occurs at the capillary level where there are no known pressure controlling structures. Recent developments in advanced magnetic resonance imaging technologies have made possible in vivo direct investigations of water physiology that have shed new insight on the water dynamics of the cortical pericapillary space and their complex functionality in relation to NFC. Neural activities initiate a chain of events that ultimately affect NFC. First, neural activities generate extracellular acidification. Extracellular acidosis in turn produces inhibition of aquaporin-4 (AQP-4) located at the end feet of pericapillary astrocytes, the water channel which regulates water influx into the pericapillary space and, hence, interstitial flow. Reduction of pericapillary water pressure results in a negative balance between pericapillary and intraluminal capillary pressure, allowing for capillary caliber expansion. Proton permeability through the tight junctions of the blood brain barrier is significantly high owing to the Grotthuss proton "tunneling" mechanism and, therefore, carbonic anhydrase (CA) type IV (CA-IV) anchored to the luminal surface of brain capillaries functions as scavenger of extracellular protons. CA-IV inhibition by acetazolamide or carbon dioxide results in the accumulation of extracellular protons, causing AQP-4 inhibition and a secondary increase in rCBF.

Keywords: aquaporin 4; interstitial flow; neural activation; neuro flow coupling; protons.

Figure 1

Virchow Robin space and interstitial flow. The ventricles and subarachnoid space represent the cerebrospinal fluid (CSF) space in the brain. The Virchow Robin space is a continuous canal surrounding penetrating vessels. Interstitial flow runs within the Virchow Robin space and drains into the subarachnoid space. Contrary to the classical concept of CSF flow, water CSF within the subarachnoid space is now believed to be dependent on interstitial flow in the Virchow Robin space. Although not as yet mainstream, the Virchow Robin space likely surrounds the medullary veins and subependymal veins as well. As shown in Figure 3, water influx from the systemic circulation into CSF is strongly dependent on interstitial flow in the Virchow Robin space through aquaporin‐4 (AQP‐4).

Figure 2

Vessel diameter is determined by tension of smooth muscle in artery, arteriole, venule, and vein (Brain Vessels). Capillaries are devoid of muscle and in capillaries with tight endothelium such as brain capillaries, capillary caliber is determined by the pressure balance between luminal and outer fluid pressures (Brain Capillary). For capillaries with leaky endothelium (Common Capillary), pressure balance is quickly equalized without capillary caliber changes.

Figure 3

Pericapillary water dynamics. Water permeability of brain capillaries is restricted due to the tight endothelium, presence of tight junctions and active suppression of AQP‐1. By contrast, significant water flow is present in the Virchow Robin space (interstitial flow) and is supported by active water inflow through AQP‐4. Although it has not been clearly confirmed (?), interstitial flow may similarly be present along the medullary and subependymal veins.

Figure 4

Neural activation. Neural activation produces extracellular acidification accompanied by increase in rCBF and astrocyte swelling. Proton inhibition of AQP‐4 results in a reduction of water flow from astrocytes into the pericapillary Virchow Robin space, astrocyte swelling and capillary expansion due to reduction of pericapillary fluid pressure.

Figure 5

CA‐IV system. Complex of CA‐IV anchored to luminal surface of cerebral capillary, human NBC1 sodium bicarbonate cotransporter and intracellular CA‐II. Their proximity maximizes the transmembrane HCO₃ ⁻ gradient local to NBC1 and thereby activates the transport rate. Because of the high proton permeability through tight junctions, capillary CA‐IV with NBC1 and CA‐II effectively function as scavenger of extracellular protons generated by neural activation. CA inhibition by acetazolamide or excess of CO₂ in capillary blood results in accumulation of extracellular protons.