The median raphe nucleus (MRN), also known as the superior central nucleus, is a nucleus in the brainstem composed of polygonal, fusiform, and piriform neurons, which exists rostral to the pontine raphe nucleus. The median raphe nucleus is one of several raphe nuclei that lies on the brainstem midline. It is one of two nuclei that are situated more superior to the others. The second of these nuclei is the dorsal raphe nucleus (DRN).[1] The MRN extends from the lower part of the dorsal raphe nucleus to an approximate position at the decussation of the superior cerebellar peduncle .[2]
| Median raphe nucleus | |
|---|---|
 This image shows the location of the raphe nuclei which includes the median raphe nucleus (seen in the bottom of the image near the brainstem) while also providing information about how it is used in the serotonin pathway which has various cognitive functions. | |
| Details | |
| Identifiers | |
| Latin | nucleus raphes medianus, nucleus centralis superior |
| NeuroNames | 562 |
| NeuroLex ID | birnlex_889 |
| TA98 | A14.1.05.603 |
| TA2 | 5956 |
| FMA | 72465 |
| Anatomical terms of neuroanatomy | |
The MRN projects extensively to the hippocampus, which is known to be essential for the formation of long-term memory. One study found that this raphe–hippocampus pathway plays a critical role in regulating hippocampal activity and likely associated memory consolidation processes. It has also been found to play a role in anxiety and depression, as one of the few parts of the brain that creates tryptophan hydroxylase.
Neurophysiology
editSerotonergic neurotransmission
editThe MRN is involved in the serotonin pathway.[3] Serotonin (5-HT) is the chief neurotransmitter of the median raphe nucleus.[4] According to one study, it represents the main source of serotonin (5-hydroxytryptamine (5-HT)) in the brain.[3] Stimulation of the MRN significantly increases the amount of 5-HT present in the brain.[5]
MRN is the main contributor of 5-HT to the dorsal hippocampus as well as anterior and posterior cortical areas.[5] Projections from the MRN extend to forebrain structures.[4] The serotonergic neurons of the MRN give rise to the majority of the ascending 5-HT projections to the forebrain limbic areas that control emotional behavior. Distinct projection areas of the MRN innervates the medial septum, cingulate and dorsal hippocampus.[1] A study found that around 8–12% of cells of the MRN were retrogradely double-labeled after paired injections in the medial septum CA1 region, medial septum CA3 region, medial septum dentate gyrus of the dorsal hippocampus, the lateral medial septum dentate gyrus, and the medial septum ventral hippocampus.[6] These cells of the MRN that send collateral projections to the medial septum and hippocampus may serve a unique role in modulation of desynchronization of hippocampus EEG.[6] Also, the MRN has significantly more single- and double-labeled cells after paired injections to the various medial septum and hippocampus regions than in DRN which demonstrate that MRN has more stronger projections to the medial septum and hippocampus than the DRN.[6] MRN fibers are course and large with spherical varicosities.[1] Neurotoxic 5-HT-releasing agents selectively destroy DRN projection fibers without affecting the dense coarse fibers from the MRN.[7] Most of the fibers that distribute to the medial septum terminate selectively within the medial septum-vertical limb of the diagonal band nucleus and lateral aspects of lateral septum. Most of the pronounced projections to hippocampal formation distribute to the stratum lacunosum-molecular of Ammon’s horn and granule cell layer and adjacent inner molecular layer of the dentate gyrus.[8]
GABAergic regulation
editThe MRN was also found to be involved in GABAergic inhibitory control of serotonergic neurotransmission: GABA antagonist injections into the rat MRN increased serotonin turnover.[9] Such relationship is also seen when the MRN is electrically stimulated and as a result behavioral inhibition is induced in rats.[clarification needed] These behaviors that are typically seen in rats during stressful situations involved crouching, teeth chattering, piloerection, and micturition. When the MRN is electrically stimulated, the behavioral response was not only suppressed but there was a counteraction with para-chlorophenylalanine (PCPA), a serotonin synthesis inhibitor. Such results demonstrate that the MRN is involved in behavioral inhibition as well.[10]
Regulation of dopaminergic neurotransmission
editProjections stemming from the MRN modulate dopaminergic activity within the forebrain.[11] Additionally MnR projections are part of a behavioral disinhibition/inhibition system that produces phenotypes resembling behavioral variations manifested during manic and depressive phases of bipolar disorder.[11]
Mood disorders
editThe MRN is one of the few brain regions producing tryptophan hydroxylase, a rate-limiting enzyme of serotonin biosynthesis. Increased levels of tryptophan hydroxylase 2 mRNA (and, consequently, tryptophan hydroxylase) have been noted in suicidal depressed individuals as compared to non-psychiatric controls.[12]
Animal models indicate that inactivation of serotonergic neurons of the median raphe nucleus induces anxiolysis, suggesting involvement of the MRN in anxiety.[4]
Hallucinogens
editInhibition of the MRN in cats by lysergic acid diethylamide (LSD) and psilocin, two serotonin agonist hallucinogens, leads to dose dependent behavioral changes, indicating the MRN may be an important site of action for humans hallucinations.[13]
Memory
editThe MRN projects extensively to the hippocampus, which is known to be essential for the formation of long-term memory. One study found that this raphe–hippocampus pathway plays a critical role in regulation of hippocampal activity and likely associated memory consolidation processes.[14] It has been shown that the MRN is a contributor of serotonergic agents, especially 5-HT to the hippocampus. These findings, together with the demonstration that serotonergic agents block long-term potentiation (LTP) and 5-HT antagonists enhance LTP and/or memory makes it clear that the MRN is involved in formation of long term memory in the hippocampus.[6]
Hippocampal theta waves
editThe MRN was found to play a vital role in hippocampal desynchronization; it exerts an inhibitory effect on the mechanism for hippocampal theta wave generation.[15] Also, median raphe nucleus suppresses theta bursts of the medial septal area neurons. Numerous studies reveal that lesions in the MRN continuously caused ongoing theta activity, and when the MRN was injected with pharmacological agents, the neurons displayed inhibited activity or reduced excitatory to drive them to produce theta at short latencies and for long durations. Therefore, MRN is a functional antagonist of the reticular formation which plays a critical role in hippocampal theta generation.[6]
References
edit- ^ a b c Beck, Sheryl G.; Pan, Yu-Zhen; Akanwa, Adaure C.; Kirby, Lynn G. (February 2004). "Median and dorsal raphe neurons are not electrophysiologically identical". Journal of Neurophysiology. 91 (2): 994–1005. doi:10.1152/jn.00744.2003. ISSN 0022-3077. PMC 2830647. PMID 14573555.
- ^ Beliveau, V; Svarer, C; Frokjaer, VG; Knudsen, GM; Greve, DN; Fisher, PM (1 August 2015). "Functional connectivity of the dorsal and median raphe nuclei at rest". NeuroImage. 116: 187–95. doi:10.1016/j.neuroimage.2015.04.065. PMC 4468016. PMID 25963733.
- ^ a b Van De Kar, L. D.; Lorens, S. A. (1979-02-16). "Differential serotonergic innervation of individual hypothalamic nuclei and other forebrain regions by the dorsal and median midbrain raphe nuclei". Brain Research. 162 (1): 45–54. doi:10.1016/0006-8993(79)90754-6. ISSN 0006-8993. PMID 761086.
- ^ a b c Andrade, Telma GCS; Zangrossi, Hélio; Graeff, Frederico G (2013-12-01). "The median raphe nucleus in anxiety revisited". Journal of Psychopharmacology. 27 (12): 1107–1115. doi:10.1177/0269881113499208. ISSN 0269-8811. PMID 23999409.
- ^ a b McQuade, R.; Sharp, T. (1997). "Functional Mapping of Dorsal and Median Raphe 5-Hydroxytryptamine Pathways in Forebrain of the Rat Using Microdialysis". Journal of Neurochemistry. 69 (2): 791–796. doi:10.1046/j.1471-4159.1997.69020791.x. ISSN 1471-4159. PMID 9231740.
- ^ a b c d e McKenna, James Timothy; Vertes, Robert P (April 2001). "Collateral projections from the median raphe nucleus to the medial septum and hippocampus". Brain Research Bulletin. 54 (6): 619–630. doi:10.1016/s0361-9230(01)00465-8. ISSN 0361-9230. PMID 11403988.
- ^ Mamounas, L. A.; Mullen, C. A.; O'Hearn, E.; Molliver, M. E. (1991-12-15). "Dual serotoninergic projections to forebrain in the rat: morphologically distinct 5-HT axon terminals exhibit differential vulnerability to neurotoxic amphetamine derivatives". The Journal of Comparative Neurology. 314 (3): 558–586. doi:10.1002/cne.903140312. ISSN 0021-9967. PMID 1814975.
- ^ Vertes, Robert P.; Fortin, William J.; Crane, Alison M. (1999). "Projections of the median raphe nucleus in the rat". Journal of Comparative Neurology. 407 (4): 555–582. doi:10.1002/(sici)1096-9861(19990517)407:4<555::aid-cne7>3.0.co;2-e. ISSN 1096-9861. PMID 10235645.
- ^ Forchetti, Concetta M.; Meek, James L. (1981-02-09). "Evidence for a tonic GABAergic control of serotonin neurons in the median raphe nucleus". Brain Research. 206 (1): 208–212. doi:10.1016/0006-8993(81)90118-9. ISSN 0006-8993. PMID 7470888.
- ^ Graeff, F. G.; Silveira Filho, N. G. (1978-10-01). "Behavioral inhibition induced by electrical stimulation of the median raphe nucleus of the rat". Physiology & Behavior. 21 (4): 477–484. doi:10.1016/0031-9384(78)90116-6. ISSN 0031-9384. PMID 154108.
- ^ a b Pezzato, Fernanda A.; Can, Adem; Hoshino, Katsumasa; Horta, José de Anchieta C.; Mijares, Miriam G.; Gould, Todd D. (2015-04-01). "Effect of lithium on behavioral disinhibition induced by electrolytic lesion of the median raphe nucleus". Psychopharmacology. 232 (8): 1441–1450. doi:10.1007/s00213-014-3775-z. ISSN 1432-2072. PMC 4388762. PMID 25345734.
- ^ Bach-Mizrachi, Helene; Underwood, Mark D.; Kassir, Suham A.; Bakalian, Mihran J.; Sibille, Etienne; Tamir, Hadassah; Mann, J. John; Arango, Victoria (April 2006). "Neuronal Tryptophan Hydroxylase mRNA Expression in the Human Dorsal and Median Raphe Nuclei: Major Depression and Suicide". Neuropsychopharmacology. 31 (4): 814–824. doi:10.1038/sj.npp.1300897. ISSN 1740-634X. PMID 16192985.
- ^ Trulson, M.E., Preussler DW and Trulson V.M. Differential effects of hallucinogenic drugs on the activity of serotonin-containing neurons in the nucleus centralis superior and nucleus raphe pallidus in free-moving cats. American Society for Pharmacology and Experimental Therapeutics Volume 228, Issue 1, pp. 94-102, 1 January 1984
- ^ 4. Wang, D.V., Yau, H., Broker, C.J., Tsou, J., Bonci, A. & Ikemoto, S. Mesopontine median raphe regulates hippocampal ripple oscillation and memory consolidation. Nature Neuroscience 18, 728-735, 2015
- ^ Maru, Eiichi; Takahashi, Lorey K.; Iwahara, Shinkuro (1979-03-16). "Effects of median raphe nucleus lesions on hippocampal EEG in the freely moving rat". Brain Research. 163 (2): 223–234. doi:10.1016/0006-8993(79)90351-2. ISSN 0006-8993. PMID 218681.