Big break! Changing the steady state of blood flow in the brain can induce anxiety.

We have to rely on cerebral blood flow (CBF) to provide energy substrate for the brain and remove metabolites because of its vigorous metabolism, complex physiological functions, high oxygen consumption and no energy reserves.since the 19th century, it has been widely accepted that carbon dioxide (CO2) / H + is one of the most powerful factors to increase cerebral blood flow perfusion. This effect of CO2 on cerebral blood vessels is called cerebrovascular reactivity.diseases such as hypertension and diabetes can weaken this reaction and make cerebrovascular reactivity a useful diagnostic indicator of early vascular pathology, but the specific molecular mechanism of cerebrovascular reactivity is not clear.on January 4, 2020, Markus schwanninger research team from the Institute of clinical pharmacology and toxicology of Lubeck University published an article in the famous international journal PNAs, revealing that the H + receptor gpr4 on the cerebral endothelial cells regulates the cerebral vascular reactivity, which causes anxiety like behavior after this reactivity disorder.previous studies have shown that ATP is an important mediator of CO2 / H + neuronal response, which regulates the diameter of cerebral arterioles by acting on purinergic P2Y receptors in brain endothelial cells and smooth muscle cells.therefore, the researchers believe that cerebrovascular reactivity is mediated by P2Y receptors, but unfortunately, they did not observe any impairment of cerebrovascular reactivity in mice with P2Y receptors on specific brain endothelial cells.the researchers did not suffer from this negative result. They focused on the orphan G protein coupled receptor (GPR), a family of proteins that can be activated at very low concentrations of H +, in which gpr4 and gpr68 are expressed in blood vessels.they constructed gpr4 and gpr68 knockout mice respectively, which was a risky thing, but this risk also brought huge benefits. After gpr4 knockout, blood flow in cerebral cortex decreased, that is, cerebrovascular reactivity was impaired.further in situ hybridization showed that gpr4 was mainly expressed in endothelial cells, which indicated that CO2 / H + promoted cortical blood flow through gpr4 on endothelial cells.studies have shown that gpr4 can activate G α s, camp and G α Q / 11 mediated signaling pathway (g α Q / 11 is fully known as G protein α subunit Q / 11 subtype of vascular smooth muscle cells).however, the cAMP level did not increase in the process of increasing the cerebral cortex CO2, on the contrary, its level was decreased, which indicated that camp did not participate in the process, it is likely that G α Q / 11 participated in the process.in normal mice, the increase of CO2 concentration and cortical blood flow was accompanied by the increase of vascular diameter.the researchers found that after g α Q / 11 was specifically knocked out on endothelial cells, cortical blood flow was reduced in different concentrations (10%, 20%) of CO2, and the reduction was greater than that of gpr4.in addition, transient respiratory inhibition (3 seconds) promoted cortical vascular reactivity in normal mice, but did not affect g α Q / 11 specific knockout mice.what is more surprising is that the G α Q / 11 knockout mice do not participate in the response of CO2 to cortical blood flow, which further indicates that G α Q / 11 signal on cerebral endothelial cells regulates the response of CO2 to cortical blood flow, and this regulation is specific.amygdala is a key brain region regulating fear memory and anxiety.does increasing blood flow in this brain region affect related behavioral changes? The researchers exposed normal mice and G α Q / 11 specific knockout mice to 10% CO2. Using fear memory behavior, they found that normal mice experienced increased stiffness after exposure to CO2. Surprisingly, G α Q / 11 specific knockout mice promoted more rigid behavior. in addition, open field test and elevated test further found that G α Q / 11 specific knockout mice showed obvious anxiety like behavior after CO2 exposure, but did not appear in normal mice. in vitro experiments showed that the vascular diameter of amygdala increased after CO2 stimulation. these results suggest that impaired vascular reactivity may induce anxiety like behavior in mice. it is worth noting that CO2 exposure does not promote blood flow in all brain regions. the posterior trapezoid nucleus (RTN) is an accident. The neurons in this region are mainly glutamatergic interneurons, which can selectively innervate the ventral respiratory nerve group. after exposure to CO2, the blood vessels in this brain region of normal mice even contracted. What is more surprising is that G α Q / 11 specific knockout mice did not damage the cortical blood vessels as before, and the vascular diameter did not change. in order to further understand the opposite effect of blood vessels in brainstem and subcortical regions (non brainstem areas) on CO2, the researchers conducted a histochemical analysis of the vascular tissues in these two brain regions, and found that there were significant differences in the mRNA expression of NOS 3 (eNOS) and its related genes. further experiments showed that no released by endothelial cells in brainstem area was significantly lower than that in subcortical area after CO2 exposure, while pgf1 α and PGE2 derivatives of prostacyclin were more different between the two brain regions. this suggests that vasodilative prostacyclin may be the decisive factor for the opposite effect of these two brain regions on CO2. in conclusion, we found that gpr4 on endothelial cells regulates CO2 dependent cerebrovascular reactivity by activating g α Q / 11 signal, and there are different brain regions in the brain that respond to CO2 differently. damage to brain reactivity can cause anxiety like behavior. references; Jan wenzela, cathrin E. hansena, Carla Betton，Impaired endothelium-mediated cerebrovascular reactivity promotes anxiety and respiration disorders in mice ; The cover picture and article picture are all from the network history related literature: Science sub Journal: TGF β signal or the key to pathological changes caused by vascular barrier damage in aging process nature: all you want to know about the brain "goalkeeper" blood-brain barrier! 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