Raphe Nuclei

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Fig. 1. Schematic drawing depicting the location of the serotonergic cell body groups in a sagittal section of the rat central nervous system and their major projections. OT, olfactory tuberculum; Sept, septum; C. Put, nucleus caudate-putamen; G. Pal, globus pallidus; T, thalamus; H, habenula; S. Nigra, substantia nigra.[1] [1]

Basic Information

During the mid-nineteen century it was observed that the serum that was left after the clotting of the blood could constrict vascular smooth muscle so as to increase the vascular tone. It was later discovered that blood platelets were a source of this substance. Rapport and his collaborators[1] later isolated this compound and named it serotonin(5-hydrocytryptamine). Since the structure of 5-HT is hydrophilic and this would imply that I would not be able to pass through the blood-brain barrier and thus the presence of 5-HT in the blood suggested that it was produced in the brain. In 1964, Dahlstrom and Fuxe using the method of histoflurescence found that the majority of serotonergic soma was found in the midline of the brainstem. This locus had been designated as the raphe nuclei[1]. One fact that must be kept in mind is that not all the neurons in the raphe nuclei are serotonergic.

Anatomy

Dahlstrom and Fuxe described nine groups of serotonin-containing cell bodies, designated B1 to B9. Fig 1 shows the nine nuclei and the regions of the brain that they innervate. The B1 to B4 are located in the midpons to caudal medulla. The largest group of serotonergic cells is B7 . It is continuous with the B6 group of cells and they together form the dorsal raphe nucleus. B8 is termed as median raphe nucleus(the nucleus central superior). Group B9 is located in the ventrolateral tegmentum of the pons of the midbrain. The dorsal and the median raphe nuclei give rise to distinct projections in the forebrain region. Within the raphe, neurons are organized into groups that send axons to specific areas of the brain. The organized innervations of fore brain structures by raphe neurons implies that the function of the neurons are dependent on their origin and terminal projections.

Some researchers use a different method of nomenclature for the Raphe nuclei. NeuroNames (provide link--Pkatz 20:51, 1 September 2008 (EDT)) has a classification of the raphe nuclei into seven parts:

  • Raphe nuclei of medulla:-
    • Nucleus raphe obscures
    • Nucleus raphe magnus
    • Nucleus pallidus.
  • Raphe nuclei of the pontine reticular formation
    • Pontine raphe nucleus
    • Inferior central nucleus
  • Raphe nuclei of the Midbrain reticular formation
    • Superior central nucleus
    • Dorsal Raphe nucleus

Specification of the Neurons

As mentioned earlier the total number of the serotonergic neurons is really small. In Rats the number of neurons is around 20,000. The neurons are generated in the early stages of embryonic development. It has been commonly observed that a day after the generation of the neurons they can start the production of 5-HT[3]. The raphe neurons also start profuse axon tracts and project into many parts of the brain and the spinal cord. Based on the labeled 5-HT uptake experiments and immunohistochemical techniques difference in the raphe nuclei neurons have been observed.

The axons of the neurons from the median raphe nucleus, type M, have coarse large spherical varicosities, while the ones from the dorsal raphe, type D, have very fine and small pleomorphic varicosities.

This model for possible interaction between serotonergic and GABAergic neuron in the raphe nuclei. Image Taken from :- The Pharmacology of the Neurochemical Transmission in the Midbrain Raphe Nuclei of the Rat, Curr Neuropharmacol. 2006 October; 4(4): 313–339.
This is a simplified diagram of the D- and the M- type of raphe neurons. [2]

The serotonergic neurons of the raphe nuclei exhibit spontaneous discharge activity of 1-5 spikes per second. [5] The activity of this neurons is controlled by three different events that take place in the nuclei. The events initially start of with the slow firing activity of 5-HT neurons, the autoinhibitory action of 5-HT and also by the signals provided by non-5-HT receptors. Both axon and dendrite act as the site for the 5-HT release [6]. The non-5-HT neurons in the raphe nuclei are GABA-containing interneurons. These neurons establish local inhibitory connections with the 5-HT neurons. It has been observed that GABA inhibits serotonergic system as it reduces the turn-over rate of 5-HT in the raphe nuclei. [6]

Molecular profile

  • Neurotransmitter: Serotonin is a combination of the hydroxyl group in the 5 position of the indole nucleus and a primary amine nitrogen.[1] 5-HT is released from the serotonergic varicosities into the extra neuronal space and not at defined synaptic sites. The diffusion area of 5-HT is >20µm of the active receptor.[2]
doi:10.1038/nrn125. The original table shows a lot more information then what is displayed here
  • Receptor: Most 5-HT receptors in the Raphe neurons are G-proteins. When the ligand binds to this receptor it will activate and intracellular second messenger cascade. Seven classes of Receptor are know in case of mice. The information of the receptor is given in the table.


Behavior

Serotonin plays an important role in the modulation of mood swings, anger, anxiety, aggression, body temperature, sleep, appetite, metabolism and sexuality. Serotonin is one of the major players in stimulating vomiting. Researcher have found that mutation in the 5-HT2A receptor was common in patients with major depression and suicidal tendencies. Studies on human patients groups have also shown that lower levels of serotonin leads to the shift of the behavior pattern to aggressiveness. Gross and et al, have found that Serotonin 1A receptor acts during the development of a mice and leads to normal anxiety like behavior in adult mice. The knock – out of this receptor in these mice have shown higher levels of anxiety in the mice. Groups of Researchers have also found that mice with defective serotonin receptors or 5-HT levels show deviations from the normal pattern of behavior in case of a maze experiment.

Midbrain serotonergic neurons are closely associated with large arteries. Shown are confocal images of transverse midbrain slices after injecting arteries with fluorescent albumin (red) and performing immunohistochemistry for TPH (green). Source: Severson C I, et al. (2003)

Serotonin has also been linked with SIDS ( sudden infant death syndrome). Lesurtel M. el al have shown that low levels of serotonin in mice brainstems that control heartbeat and breathing maybe one of the reasons for SIDS. Lately it has also been found that the serotonergic neurons in raphe have central respiratory chemoreceptos. It has also been proposed that the mid brain raphe neurons can sense the carbon dioxide. It is also believed that the raphe can induce anxiety, arousal or cerebrovascular modification so as to maintain the pH homeostasis.

References

  1. Basic neurochemistry 3rd edition,edited by George J. Siegel ... [et al.] (need complete reference --Pkatz 21:10, 1 September 2008 (EDT)
  2. en.wikipedia.org (need more specific reference --Pkatz 21:10, 1 September 2008 (EDT))
  3. Dos Santos L, et al. Serotonergic neurons in the median raphe nucleus regulate inhibitory avoidance but not escape behavior in the rat elevated T-maze test of anxiety.Psychopharmacology (Berl). 2005 Jun;179(4):733-41. Epub 2004 Dec 24.
  4. Gaspar P, et al. The developmental role of serotonin: news from mouse molecular genetics. Nature Reviews Neuroscience 4, 1002-1012 (December 2003) | doi:10.1038/nrn1256
  5. Gross C,et al. Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult.Nature 416, 396-400 (28 March 2002) | doi:10.1038/416396a
  6. The Pharmacology of the Neurochemical Transmission in the Midbrain Raphe Nuclei of the Rat, Curr Neuropharmacol. 2006 October; 4(4): 313–339
  7. Severson C A et al. Midbrain serotonergic neurons are central pH chemoreceptors. Nature Neuroscience 6, 1139 - 1140 (2003)| doi:10.1038/nn1130