Wednesday, June 11, 2008

Raphe neurons

The raphe neurons project axons to widespread areas of cortex. Numerous studies have shown that the raphe inhibits distant structures.

The raphe nuclei are part of the reticular formation of the mesencephalon. There are two major clusters of 5-HT-synthesizing neurons, shown in blue in the Figure below. There is also a group of 5-HT-containing neurons located on the ventral medulla (white asterisk).

The two main groups of raphe neurons are referred to as the rostral and caudal groups. The rostral group of 5-HT neurons, localized in the pons and mesencephalon, contains the nucleus centralis superior and dorsal raphe nucleus (DRN), which supply most of the 5-HT to the forebrain. The rostral group ascends in the medial forebrain bundle to widespread areas of the diencephalon and telencephalon. Some of the targets of DRN axons include the medial prefrontal cortex, sensorimotor and associative parietal cortex, non-specific intrathalamic nuclei and midline nuclei of thalamus, striatum, and the mesencephalic reticular formation. The rostral-projecting DRN contains the largest aggregate of 5-HT-containing cells in the nervous system, and it has been the subject of a disproportionately large amount of research relative to the other raphe nuclei.

The caudal or inferior group of 5-HT-synthesizing neurons, localized in the medulla, contains nuclei which supply most of the 5-HT to the spinal cord. The axons of caudal 5-HT nuclei form a bulbospinal tract that descends in the lateral and ventral funiculi of spinal cord, and terminates in the substantia gelatinosa of spinal cord, a region involved in pain perception. Medullary 5-HT-containing neurons in the brain stem also project to the sympathetic outflow in the spinal cord, targeting the sympathetic intermediolateral cell column. Serotonin is involved in mediating inhibition of sympathetic activity, because lesions of 5-HT containing axons in the cervical spinal cord can abolish the inhibition of sympathetic discharge produced by raphe stimulation.

Afferents to the raphe neurons come from spinal cord, cerebellum, cortex, caudate nucleus, hypothalamus, and habenular nuclei. Raphe cells also receive afferent input from fluid-borne substances in the blood and cerebrospinal fluid. Raphe cell bodies and dendrites tend to cluster near blood vessels, branching off the vertebral and basilar arteries. Dendrites are the most commonly found profiles in the raphe nucleus.

The DRN is composed of dopaminergic and GABAergic neurons, not only serotonergic neurons. In some areas of the rat DRN, GABA and 5-HT coexist in the same neuron. The DRN displays immunoreactivity for GABA, tyrosine hydroxylase, substance P, calbindin, parvalbumin, and calretinin.

Why are the raphe neurons so great?

With far-reaching axons that can have a million or more synaptic contacts, and dendrites that sense body temperature, glucose, pH, and CO2 and O2 levels in nearby blood and CSF, the raphe neurons can exert a powerful effect on widespread regions of the body. How do the raphe neurons accomplish this wide array of tasks? Serotonin-containing neurons have a historical role as some of the largest, most central neurons in the organism. These neurons are very active in DNA and protein synthesis, and build larger cell bodies and innervate larger postsynaptic target areas compared to most neurons. 

Some of the largest neurons in the snail and leech are 5-HT-containing giant neurons. The nuclei of the largest neurons of mature Aplysia contains 0.2 ug DNA, more than 200,000 times the haploid amount. What distinguishes neuronal giants from other cells is that their dendrites provide a large receptive area for synaptic input and their axons allow communication with target organs over great distances, consequently these neuronal giants are required to synthesize more DNA and RNA than other cells to maintain the structural integrity of their extensive processes. Neuronal giants require a large turnover of protein for enzymatic and structural function. Most, if not all, of this intense DNA and protein synthesis occurs in the cell body where large quantities of ribosomes surround the nucleus. It is thought that some neuronal giants are able to synthesize more DNA and RNA through polyploidy and polyteny.

Although they do not have exceptionally large cell bodies, raphe neurons may be able to sustain high levels of DNA synthesis through polyploidy. In a study of adult rabbit 5-HT neurons, approximately 10% of raphe magnus neurons had two nucleoli, as shown in the figure below. Cresyl violet staining revealed enlarged nuclei and minimal cytoplasm in raphe magnus cell bodies. The function of this high DNA content is unknown, but it might be related to endoreplication, which means replication of specific parts of the genome.

The diagram below shows two large 5-HT-containing neurons in snail. This bilateral pair of serotonergic giant cells in Helix pomatia sends large axons to the esophagus and buccal ganglia and feeding musculature of the oral region. Giant neurons of the snail are involved in secretory processes and are more metabolically active than other neurons.

The largest cells in the leech Hirudoo medicinalis nervous system are the colossal cells of Retzius, shown below. These cells survive well in culture and have been studied extensively. Retzius cells synthesize and contain 5-HT, and have an exceptionally large size and DNA content. Much of the secretion of 5-HT from Retzius cells is from the somatic release of neurotransmitter from the huge cell body, a process that involves dense core vesicles.

It is known that Retzius cells contain a high amount of 5-HT because the cell bodies of dehydrated Retzius cells fluoresce strongly when exposed to formaldehyde vapor. Like raphe neurons, Retzius cells have gap junctions that electrically couple to other Retzius cells.


Jacobs B. L. and C. A. Fornal (1999). Activity of serotonergic neurons in behaving animals. Neuropsychopharmacology 21, 9S-15S. 

Gillette R. (1991). On the Significance of Neuronal Giantism in Gastropods. Biological Bulletin 180, 234-240. doi:10.2307/1542393