The rostral migratory stream (RMS) is a pathway found in the brain

Brain

The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

 of some animals along which neuronal precursors that originated in the subventricular zone

Subventricular zone

The subventricular zone is a paired brain structure situated throughout the lateral walls of the lateral ventricles. It has been associated with having four distinct layers of variable thickness and cell density, as well as cellular composition....

 (SVZ) of the brain migrate to reach the main olfactory bulb

Olfactory bulb

The olfactory bulb is a structure of the vertebrate forebrain involved in olfaction, the perception of odors.-Anatomy:In most vertebrates, the olfactory bulb is the most rostral part of the brain. In humans, however, the olfactory bulb is on the inferior side of the brain...

 (OB). This pathway has been studied in the rodent, rabbit, and both the squirrel and rheusus monkey. When the neurons reach the OB they differentiate into GABAergic interneurons as they are integrated into either the granule cell layer or periglomerular layer. The importance of the RMS lies in its ability to refine and even change an animal's sensitivity to smells, which explains its importance and larger size in the rodent brain as compared to the human brain, as our olfactory sense is not as developed.

Although it was originally believed that neurons could not regenerate in the adult brain, neurogenesis

Neurogenesis

Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...

 has been shown to occur in mammalian brains, including those of primates. However, neurogenesis is limited to the hippocampus

Hippocampus

The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...

 and SVZ, and the RMS is one mechanism neurons use to relocate from these areas.

The rostral migratory stream was named and discovered by J. Altman in 1969 using 3H-thymidine autoradiography in the rat brain. He was able to trace the migration of labeled cells from the SVZ into the main olfactory bulb. He also did some quantitative studies of the changing size of the rostral migratory stream in younger to older rats. There is still some ongoing debate about the extent of the RMS and adult SVZ neurogenesis of new neurons in humans.

Vascular cells

Vascular cells are known to play a prominent role in regulating proliferation of adult neural precursors. In the adult subgranular zone

Subgranular zone

The subgranular zone is a brain region in the hippocampus where adult neurogenesis occurs. It is one of the two major sites of adult neurogenesis in the brain, along with the subventricular zone .- Structure :...

 (SGZ), dense clusters of dividing cells were found to be anatomically close to the vasculature, especially capillaries. Contacts between adult SVZ neuronal precursors and blood vessels are unusually permeable and frequently devoid of astrocyte

Astrocyte

Astrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...

 and pericyte

Pericyte

A pericyte is a type of cell found in the central nervous system. These cells play an integral role in the maintenance of the blood brain barrier as well as several other homeostatic and hemostatic functions of the brain. Pericytes are also a key component of the neurovascular unit, which also...

 interferences, suggesting that blood-derived cues are gaining direct access to adult neural precursors and their progeny. The vasculature also provides the substrate for new neuron migration after injury in the adult striatum

Striatum

The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...

.

Astrocytes

Astrocytes form gap junctions and are closely associated with the vasculature and its basal lamina in the adult SVZ. They may serve as an interface to modulate influences of endothelial and circulation-derived factors as well as the availability of cytokines and growth factors in the basal lamina

Basal lamina

The basal lamina is a layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits. It is often confused with the basement membrane, and sometimes used inconsistently in the literature, see below....

. In addition, astrocytes derived from the neurogenic hippocampus and SVZ, but not from the non-neurogenic spinal cord

Spinal cord

The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...

, promote proliferation and neuronal fate commitment of multipotent adult neural stem cells in culture. Astrocytes express a number of secreted and membrane-attached factors both in vitro and in vivo that are known to regulate proliferation and fate specification of adult neural precursors as well as neuronal migration, maturation, and synapse

Synapse

In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...

 formation. In the adult SVZ, astrocytes express Robo

Roundabout (gene)

Roundabout is the gene for the Roundabout receptor. There is a family of Robo transmembrane receptors and they are the canonical receptors for the signaling molecule Slit, although there may be more Slit receptors besides Robo...

 receptors and regulate the rapid migration of SLIT1

SLIT1

Slit homolog 1 protein is a protein that in humans is encoded by the SLIT1 gene.-Further reading:...

-expressing neuroblasts through the RMS. Additionally, it has been proposed that the neuroblasts themselves play a role in modulating the astrocytes through Slit-Robo interactions. In the absence of Slit, astrocytic processes do not align correctly, or create the "tubes", instead running across the migrating neurons. Adult SVZ astrocytes also appear to release glutamate to regulate the survival of neuroblasts. Unique to the adult SVZ, ependymal cells lining the ventricular wall are in close association with neural precursors and their progeny, acting like a shield to protect the neurogenic niche.

Other glial cells

Ependymal cells actively regulate neuronal fate specification of adult neural precursors through release of Noggin. Beating of the cilia of ependymal cells appears to set up concentration gradients of guidance molecules, such as cytokines TNF-α and IGF-1, to direct migration of neuroblasts. Microglia

Microglia

Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...

 also actively regulate adult neurogenesis. Under basal conditions, apoptotic corpses of newly generated neurons are rapidly phagocytosed from the niche by unactivated microglia in the adult SGZ. Under inflammatory conditions, reactivated microglia

Microglia

Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...

 can have both beneficial and detrimental effects on different aspects of adult neurogenesis, depending on the balance between secreted molecules with pro- and anti-inflammatory action. In one study, the activation of microglia and recruitment of T cells were suggested to be required for enriched environment-induced SGZ neurogenesis.

Migration mechanics

Cells in the RMS are believed to move by "chain migration". These neuroblasts are connected by membrane specializations and move along each other towards the olfactory bulb through glial tubes. The pathway and mechanisms behind this movement are detailed below.

Ventriculo-olfactory neurogenic system (VONS)

The olfactory system is made up in part of the rostral migratory stream which stretches from the subventricular zone in the wall of the lateral ventricle, through the basal forebrain, to the olfactory bulb (OB). The VONS is name given to this pathway, and it consists of the subventricular zone, the RMS, the olfactory tract and the olfactory bulb. Developing neurons leaving the subventricular zone and enter the rostral migratory stream and travel caudally and ventrally along the undersurface of the caudate nucleus; this is referred to as the descending limb. Upon reaching the ventral side of the caudate nucleus the neurons follow the rostal limb and travel ventrally and rostrally, entering the anterior olfactory cortex (AOC). The AOC gives rise to the olfactory tract which ends in the olfactory bulb.

Glial framework

Developing neurons travel toward the olfactory bulb along the RMS via glial tubes, which mark the division between the differentiated nervous tissue and the tissue with embryonic characteristics. Uniquely, the cells travel tangential to the brain surface, parallel to the pial surfaces rather than radially like most developing neurons. Neurons that migrate tangentially are typically believed to migrate independently of radial glia

Radial glia

Radial glial cells are a pivotal cell type in the developing central nervous system involved in key developmental processes, from patterning and neuronal migration to their recently discovered role as precursors during neurogenesis. They arise early in development from neuroepithelial cells...

 but in the RMS researchers believe this is not the case. Adult rat glial tubes have been observed via light and electron microscopy and described as a meshwork of astrocytic bodies and processes . They have been determined to be astrocytes based on the typical expression of GFAP (glial fibrillary acidic protein) and more specifically as protoplasmic astrocytes based on their morphology. Furthermore, these glial cells were found to positive for vimentin

Vimentin

Vimentin is a type III intermediate filament protein that is expressed in mesenchymal cells. IF proteins are found in all metazoan cells as well as bacteria. IF, along with tubulin-based microtubules and actin-based microfilaments, comprise the cytoskeleton...

 expression, a protein commonly found in embryonic or immature glial cells. The developing neurons are identified by their expression of the cell surface molecule PSA-NCAM, which has been identified as a typical embryonic form of NCAM, and β-tubulin, a protein often found in postmitotic neuroblasts proving the cells of RMS are committed to developing into neurons and will do so upon entry into the olfactory bulb. The neurons form both clusters and chains along the lumen

Lumen

Lumen can mean:* Lumen , the SI unit of luminous flux* Lumen , the cavity or channel within a tubular structure* Thylakoid lumen, the inner membrane space of the chloroplast* Phenobarbital...

 of these glial tubes.
Once the developing neurons reach the core of the olfactory bulb, they detach from the RMS, which is initiated by Reelin

Reelin

Reelin is a large secreted extracellular matrix protein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this important role in early development, reelin continues to work in the adult brain. It modulates the...

 and tenascin

Tenascin

Tenascins are extracellular matrix glycoproteins. They are abundant in the extracellular matrix of developing vertebrate embryos and they reappear around healing wounds and in the stroma of some tumors.-Types:...

 and move radially toward glomeruli, this migration is dependent on tenascin-R

Tenascin-R

Tenascin-R is a protein that in humans is encoded by the TNR gene.- Function :Tenascin-R is an extracellular matrix protein expressed primarily in the central nervous system. It is a member of the tenascin gene family, which includes at least 3 genes in mammals: TNC , TNX , and TNR...

, and differentiate into subtypes of interneurons. These neurons have been studied in vivo via electrophysiology

Electrophysiology

Electrophysiology is the study of the electrical properties of biological cells and tissues. It involves measurements of voltage change or electric current on a wide variety of scales from single ion channel proteins to whole organs like the heart...

 and confocal imaging.

Cell signaling

The nature of the molecular cues involved in the correct targeting of the migrating precursors remains a question. The secretion of a chemoattractant factor by the OB appears as a possibility. Nevertheless, tissue derived from this structure had no directive influence on the migration. On the other hand, a septum

Septum

In anatomy, a septum is a wall, dividing a cavity or structure into smaller ones.-In human anatomy:...

-derived secreted factor showed a repulsive effect on the SVZ cells. More recently, it has been shown that the secreted molecule SLIT shows such a repelling effect on SVZ-derived precursors. Furthermore, integrins have been demonstrated to have a regulatory influence on precursor cell chain-migration and regulation of their divisions.
The highly polysialylated form of the neural cell adhesion molecule (NCAM) appears as another candidate. Mice lacking NCAM show a dramatically size-reduced OB and an accumulation of migrating precursors along the RMS. It is possible that lack of NCAM results in agitation of neuron–glia interactions, and modifications in these interactions might in turn be responsible for the inhibition of migration in the RMS. It has been demonstrated that a cross talk exists between neurons and glial cells and data in favor of an active role of PSA–NCAM in this process has been presented. The lack of PSA–NCAM on the surface of migrating precursors might alter the proliferative properties of this glial cell population, a scenario that appears reminiscent of astrogliosis

Astrogliosis

Astrocytosis is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons, typically because of hypoglycemia or oxygen deprivation .It usually takes place in prion infections...

 occurring in neurodegenerative diseases even before any signs of neuronal damage.

Existence in humans

The presence of an analogous RMS in humans has been difficult to identify, possibly because the olfactory bulb is significantly less developed in humans than in rodents and thus harder to study, and much of the previous scientific work has been called into question concerning the RMS in humans. In the developing fetal brain and in young postnatal infants, chains of immature neurons typical of the RMS were observed. However, there was little evidence for the existence of a migrating chain along the SVZ or olfactory peduncle to the bulb in the adult human brain, even though there was a distinct population of adult neuronal stem cells in the SVZ. These researchers studied subjects from 0 to 84 years of age by analyzing brain sections that had been removed during surgery or during autopsies. They discovered that cells that expressed DCX and PSA-NCAM,are present in the brain sections taken from infants, but have disappeared by 18 months. Yet further studies indicated the presence of a small population of migrating immature neurons, which originate solely from the SVZ. These neuroblasts appear singly or in pairs without forming chains, in contrast to the elongated chains of neuroblasts observed in the rodent RMS. This suggests that the RMS is drastically reduced beyond infancy and especially into adulthood, but is not absent. However, a direct correlation between stem cell quiescence and age has been difficult to determine due to a high level of variability between individuals. Thus an RMS analogous structure in the adult human brain remains highly controversial.

Age related decline

The extent of age-related RMS decline in humans has been the subject of significant debate. The decline of neurogenesis in the and migration from the hippocampus in humans has already been well documented. Furthermore, age-related declines in the activities of SVZ stem cells, which migrate to the OB via the RMS, are in place by middle-age in rodents. In elderly mice, studies showed that the population of actively dividing SVZ cells and the rate of interneuron replacement in the OB are both drastically reduced, indicating an age related decline in neuronal proliferation and migration through the RMS. This decline was shown to be due to neuronal stem cell quiescence in the SVZ even by middle age, and not destruction, much like in the hippocampus.

Pharmaceuticals

Another topic in current RMS research pertains to pharmaceuticals. Scientists are still trying to tackle the difficult task of administering drugs into the brain and getting them past the selective blood-brain barrier

Blood-brain barrier

The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...

. In an April 2011 study, scientists Scranton, Fletcher, Sprague, Jimenez, and Digicayliogly from the University of Texas San Antonio conducted a study testing the role of the RMS in “intranasal delivery of drugs into the CNS”. In this study, the experimenters disrupted the RMS in mice, which obstructed “the uptake of intranasally administered radioligands into the CNS.” Fluorescent tracers were also used to track the medicine throughout the brain. It was found that the medicine spread to all regions of the brain including the olfactory bulb. The study concluded that the RMS was extremely prevalent and necessary in the central nervous system in order to deliver drugs intranasally. The study also noted that this research on the RMS is not sufficient, but instead needs to be expanded. Some of the limits and capabilities of the RMS are still unknown, as well as some of the hazards of it. If drugs are to be administered into the CNS through the RMS, all of the details of the RMS must be known in order to ensure safe delivery of the drugs to the brain.

α6β1 integrin

A 2003 study was conducted in Canada by J.G. Emsley and T. Hagg testing a specific integrin

Integrin

Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....

, alpha-six-beta-one, and the role it plays RMS. The study researched the principle that chemoattractive molecules may play an important role in neuroblast migration in the RMS. The study of this one particular integrin was conducted in mice. By using antibodies to bind to α6β1 integrin subunits, found on the neuroblasts, the researchers observed that the migration was disrupted. Furthermore, they investigated the mechanism through which α6β1 integrin functions and determined it was via the chemoattractant laminin. This was completed by injecting laminin

Laminin

Laminins are major proteins in the basal lamina , a protein network foundation for most cells and organs...

and observing that doing so drew “neuroblasts away from their normal course of migration”. The researchers concluded with the idea that this research could prove useful for therapeutics purposes in that neuroblasts could potentially be drawn to locations of injury or disease.

External links

• Chain migration in the SVZ-RMS - figure from an article.
• See Joseph Altman's original research