Blood-brain barrier · Grey Matter

The blood-brain barrier is the sealed wall of the brain's capillaries, which lets in only what the brain needs (oxygen, glucose, selected amino acids) and keeps out most other molecules in the blood, so it protects neurons from fluctuations and toxins and also blocks most drugs.

Blood-brain barrier. The blood-brain barrier is the sealed wall of the brain's capillaries, which lets in only what the brain needs (oxygen, glucose, selected amino acids) and keeps out most other molecules in the blood, so it protects neurons from fluctuations and toxins and also blocks most drugs.

The barrier lies in the endothelial cells that line every brain capillary. Unlike capillaries elsewhere, these cells are joined by tight junctions, rows of proteins (claudin-5 above all) that close the gaps between them, and they make very few transport vesicles, so substances must pass through the cells themselves. Pericytes wrapped around the capillaries and the end-feet of astrocytes covering them induce and maintain these properties; together they form what is called the neurovascular unit.

Small fat-soluble molecules and gases diffuse through. Oxygen, carbon dioxide, alcohol, caffeine and many anaesthetics cross freely; charged and large molecules do not.

Nutrients use dedicated carriers. Glucose crosses on GLUT1, large neutral amino acids (including tryptophan and the L-DOPA used for Parkinson's disease) on LAT1, ketone bodies on monocarboxylate transporters.

It actively pumps out. Efflux transporters such as P-glycoprotein push many drugs back into the blood, which is why most small-molecule drugs and almost all antibodies reach the brain poorly.

It keeps some signals apart. Adrenaline and the gut's serotonin stay on the blood side, and the brain makes its own.

The barrier makes the brain a separate chemical country.

It keeps the neurons' surroundings steady and protected, at the price of making the brain hard to reach with medicine.

Questions: How can adrenaline strengthen memories if it does not cross the blood-brain barrier? Adrenaline released during an emotional or stressful event binds beta-adrenergic receptors on the sensory fibres of the vagus nerve. The vagus carries the signal to the nucleus of the solitary tract in the brainstem, which activates the locus coeruleus, and noradrenaline is then released in the amygdala and other regions involved in storing memories. In the work of McGaugh and colleagues, adrenaline given after training improves later memory in rats and humans, and blocking beta receptors in the amygdala or cutting the vagal route removes the effect. The body's alarm thus marks a moment as worth keeping without the hormone ever entering the brain. What does the blood-brain barrier let through, and which cells build it? The barrier itself is the endothelial cells of brain capillaries, sealed to one another by tight junctions built mainly of claudin-5; pericytes on the capillary wall and the end-feet of astrocytes that cover it induce and maintain those properties. Gases and small fat-soluble molecules (oxygen, carbon dioxide, alcohol, many anaesthetics) diffuse through the cells. Nutrients cross on dedicated carriers, glucose on GLUT1 and large neutral amino acids on LAT1, while efflux pumps such as P-glycoprotein push many drugs back into the blood. Charged molecules, proteins and most medicines are kept out, which protects the neurons' environment and makes the brain hard to treat. If most of the body's serotonin is made in the gut, why does it not reach the brain? About 90 % of the body's serotonin is made by enterochromaffin cells in the lining of the gut, where it regulates motility and is carried in the blood inside platelets. Serotonin is a charged molecule and does not cross the blood-brain barrier, so this peripheral pool and the brain's pool stay separate. The brain makes its own serotonin in the raphe nuclei from tryptophan, an amino acid that does cross the barrier on a transporter. The gut can still influence the brain through the vagus nerve, immune signals and the supply of tryptophan, which are indirect routes. Why do older antihistamines make people drowsy while newer ones do not? In the brain, histamine from the tuberomammillary nucleus of the hypothalamus helps sustain wakefulness, largely by exciting its targets through H1 receptors. First-generation H1 blockers such as diphenhydramine and doxylamine are fat-soluble and cross the blood-brain barrier, so besides calming an allergy they block that waking signal, which is why they are sold as sleep aids too. Second-generation drugs such as loratadine and fexofenadine are less fat-soluble and are pumped back out by the barrier's efflux transporters, so they block H1 receptors in the body and leave the brain's mostly untouched. The difference between the two generations is a difference in crossing the barrier.