Circumventricular Organs (CVOs) & Blood-Brain Barrier

00:00 There are however a few places in the brain that are leakier of terms of the blood-brain barrier than others.

00:09 And these are areas that we term circumventricular organs. And this occur very close to ventricles such as the lateral ventricle, the 3rd ventricle, the 4th ventricle.

00:21 And these areas are such as the subfornical organ, the median eminence, the posterior pituitary, the pineal gland, the OVLT, and finally the area postrema.

00:38 These are all areas in which the blood-brain barrier is leakier. The ones that will focus on for fever, however, are likely the subfornical organ and the OVLT. Why? Because they are on close proximity to the hypothalamus.

00:56 You need to get the signal to the hypothalamus or otherwise, a fever will not occur.

01:00 So those other circumventricular organs would be less important for a fever transduction mechanism.

01:09 So how do you get the signal across the blood-brain barrier? For thinking about this, we probably need to discuss the blood-brain barrier to a greater degree.

01:19 So you have a good feel about what things can pass and what things cannot.

01:24 First thing to think about is there endothelial cells in the Blood - brain barrier and this form very tight junctions which repel most substances from crossing the blood-brain barrier.

01:38 Gases are one thing that can cross and this it does occur for things like oxygen, carbon dioxide.

01:45 There are some solutes that can transport across a blood-brain barrier, but they'll require a specific transport.

01:53 Finally, besides the endothelial layer, you also have an astrocyte layer. And that astrocyte layer forms tight junctions around that endothelial layer, and these are often times known as foot like projections.

02:09 And the next slide will demonstrate that better.

02:12 So these astrocytes provide both mechanical support, as well as regulate some passage of certain ions and nutrients.

02:21 In green here, they show these nice foot like projections that almost form kind of an armored plate around any individual capillary or endothelial cell.

02:32 The capillary itself though, is what will be transferring that prostaglandin signal to a certain portion of the brain.

02:41 The astrocyte foot like projections could be resisting that flow of information going from the capillary to the brain.

02:52 Now, I've talked a lot about prostaglandins. So we need to spend a minute or so and discuss what exactly is a prostaglandin,and what is this COX or cyclooxygenase enzyme that we've discussed in our previous slides.

03:08 The first things to think about, when you talk about this COX pathway is Arachidonic acid, which is the top portion of this particular slide.

03:17 Here, Arachidonic acid is a 20 carbon fat or fatty acid. COX or cyclooxygenase will breakdown that into another prostaglandin, PGH2, but it is the PGE2 that we're most concern about cause this is the fever resulting molecule.

03:41 So why do we have to think about that pathway? Well, antipyretic therapy such as aspirin or Tylenol block COX enzymes.

03:50 If you block the COX enzyme, you get less PGE2 formed.

03:55 What is it about PGE2 that is so important? PGE2 signals EP3 receptors on specific neurons that are located on the preoptic and to your hypothalamus.

04:09 So this is the signaling mechanism, by which a prostaglandin will stimulate a certain neuron and that neuron then will cause the fever response.

04:22 So this is PGE2 located on the slide. This will bind to an EP3 receptor, which is part of the G coupled protein receptor superfamily. And these are all the different kind of signaling molecules of the prostaglandin family.

04:41 You will target a very specific EP receptor and that's EP3. And let me show you what there are some EP3 receptors throughout the body and then will concentrate on the brain itself.

04:53 So this is an example of the various types of prostaglandin receptors. And the four primary types of receptors.

05:02 And those are EP1, 2, 3, and 4. They choose a slightly different second messenger-signaling pathway but EP3s are what we want to concentrate on.

05:14 You can see that as the bond here. You'll noticed that EP3 receptors are located throughout the body, whether it will be in the kidneys or some in the stomach. But we want to focus on as what occurs in the brain.

05:28 You can see the only type of receptor for prostaglandin E2 that is located either E1, 2, EP3 or EP4, only EP3 is expressed in the brain.