Form and Function of the Vertebrate and Invertebrate Blood-Brain Barriers

Abstract

The need to protect neural tissue from toxins or other substances is as old as neural tissue itself. Early recognition of this need has led to more than a century of investigation of the blood-brain barrier (BBB). Many aspects of this important neuroprotective barrier have now been well established, including its cellular architecture and barrier and transport functions. Unsurprisingly, most research has had a human orientation, using mammalian and other animal models to develop translational research findings. However, cell layers forming a barrier between vascular spaces and neural tissues are found broadly throughout the invertebrates as well as in all vertebrates. Unfortunately, previous scenarios for the evolution of the BBB typically adopt a classic, now discredited 'scala naturae' approach, which inaccurately describes a putative evolutionary progression of the mammalian BBB from simple invertebrates to mammals. In fact, BBB-like structures have evolved independently numerous times, complicating simplistic views of the evolution of the BBB as a linear process. Here, we review BBBs in their various forms in both invertebrates and vertebrates, with an emphasis on the function, evolution, and conditional relevance of popular animal models such as the fruit fly and the zebrafish to mammalian BBB research.

Keywords: blood-brain barrier; evolution; morphology; nervous system; neurovascular unit.

Figure 1

Evolution of blood-brain barriers in Bilateria. Parsimony-based reconstruction of ancestral states shows BBB at the vascular endothelium as apomorphy of vertebrates; glial BBBs have evolved multiple times independently. Boxes show simplified depictions of the BBB; localization of the BBB is indicated by black occlusions between cells. Box color refers to character state in the cladogram. Phylogeny simplified after [27,28,29,30]; most invertebrate taxa without a BBB have been left out for sake of simplification. Ancestral state reconstruction was performed using Mesquite 3.61 [31] silhouette images courtesy of phylopic.org.

Figure 2

Schematic representation of the blood-brain barrier in mammals in the context of the neurovascular unit. Cross-section of a mammalian BBB with associated components of the neurovascular unit (NVU). Mammals have an endothelial barrier with tight junctions (black bar) between the endothelial cells. The function of the BBB depends upon the synergistic interaction of the many cellular components that make up the NVU. Astrocytes, pericytes, neurons, microglia, and perivascular macrophages can modulate the permeability of the BBB via direct contact and/or via release of paracrine factors such as cytokines. Image adapted from [36,37].

Figure 3

Schematic representation of the blood-brain barrier in fish. Cross section of a fish neurovascular unit; black bars indicate the site of the BBB. (A): NVU of lamprey and hagfish. Hagfish/lamprey have an endothelial barrier with tight junctions between endothelial cells. Glial cells form a continuous layer around endothelial cells. Basal lamina is present; no pericytes are present. (B): NVU of chimaeras. Chimaeras have an endothelial barrier, basal lamina, and a discontinuous glial layer. Pericytes are not present. (C): NVU of elasmobranchs—sharks and skates. Glial cells form the BBB and are joined by tight junction proteins. Endothelial cells are not joined by tight junctions and form a leaky layer. Pericytes are present between glial cells and endothelial cells. Basal lamina is present. (D): NVU of sturgeons. Sturgeons have a glial BBB, but glial cells are not joined by tight junctions. Endothelial cells are joined by tight junctions but form a leaky layer. Pericytes are not present; basal lamina is present. (E): NVU of teleosts. Teleosts have an endothelial BBB, and endothelial cells are joined by tight junctions. Glial cells are radial glia and are discontinuous. Pericytes are present and are between endothelial cells and glial cells. Basal lamina is present. (F): NVU of lungfish. Lungfish have an endothelial BBB, and endothelial cells are joined by tight junctions. Glial cells are present and are discontinuous. Perivascular cells are present, but it is unclear whether these cells are pericytes. Basal lamina is present.

Figure 4

Schematic representation of the blood-brain barrier in arthropods. Cross section of an arthropod brain. Avascular supply of the brain (left) as found, e.g., in insects: The brain is surrounded by lacunae filled with hemolymph which bathes and thus supplies the brain. Vascular supply of the brain (right) as found, e.g., in decapod crustaceans and some arachnids (such as spiders and scorpions): arteries enter the brain and at their open endings release hemolymph into fine lacunae. A BBB exists between the nervous tissue and both the fine intracerebral lacunae as well as the lacunae surrounding the brain.

Figure 5

Schematic representation of the blood-brain barrier in cephalopods. Cross section of vessels in the brain; black bars indicate the site of the BBB. In arteries, the vascular endothelium is continuous; the diffusion barrier is located at the layer of pericytes. In capillaries and veins, the vascular endothelium is discontinuous; the diffusion barrier is located at the level of the perivascular glial epithelium. The vascular endothelium in capillaries is highly discontinuous; in the finest capillaries, the pericyte layer is discontinuous as well.