View source for Raphe nuclei

{{Short description|Moderate-size cluster of nuclei found in brain stem}}
{{Infobox brain
| Name = Raphe nuclei
| Latin = nuclei raphes
| Image = Gray694.png
| Caption = Section of the [[medulla oblongata]] at about the middle of the [[olive nucleus|olive]]. (Raphe nuclei not labeled, but 'raphe' labeled at left.)
| Image2 = Lower pons horizontal KB.svg
| Caption2 = Horizontal cross section of the brainstem at the lower pons. The raphe nucleus is labeled #18 in the middle.
| IsPartOf =
| Components =
| Artery =
| Vein =
| Acronym =
}}
The '''raphe nuclei''' ({{langx|el|ῥαφή}}, "seam")<ref name="Liddell & Scott">{{cite book | vauthors = Liddell HG, Scott R | date = 1940 | title = A Greek-English Lexicon | url = https://archive.org/details/b31364949_0003 | quote = revised and augmented throughout by Sir Henry Stuart Jones with the assistance of Roderick McKenzie | location = Oxford | publisher = Clarendon Press }}</ref> are a moderate-size cluster of [[nucleus (neuroanatomy)|nuclei]] found in the [[brain stem]]. They have [[5-HT1 receptor]]s which are coupled with [[Heterotrimeric G protein|Gi/Go-protein]]-inhibiting [[adenyl cyclase]]. They function as [[autoreceptor]]s in the brain and decrease the release of [[serotonin]]. The [[anxiolytic]] drug [[Buspirone]] acts as [[partial agonist]] against these receptors.<ref>{{cite book | first1 = George J. | last1 = Siegel | first2 = Bernard W. | last2 = Agranoff | first3 = Stephen K. | last3 = Fisher | first4 = R. Wayne | last4 = Albers | first5 = Michael D. | last5 = Uhler | name-list-style = vanc | title = Basic Neurochemistry | url = https://www.ncbi.nlm.nih.gov/books/NBK20385/ | edition = Sixth | year = 1999 | publisher = Lippincott Williams and Wilkins | isbn = 978-0-397-51820-3 | chapter = Understanding the neuroanatomical organization of serotonergic cells in brain provides insight into the functions of this neurotransmitter | chapter-url = https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=raphe+AND+serotonin+release+AND+bnchm%5Bbook%5D+AND+160428%5Buid%5D&rid=bnchm.section.946#949 | quote = In 1964, Dahlstrom and Fuxe (discussed in [2]), using the Falck-Hillarp technique of histofluorescence, observed that the majority of serotonergic soma are found in cell body groups, which previously had been designated as the raphe nuclei. }}</ref> [[Selective serotonin reuptake inhibitor]] (SSRI) [[antidepressant]]s are believed to act in these nuclei, as well as at their targets.<ref>{{cite journal | vauthors = Briley M, Moret C | title = Neurobiological mechanisms involved in antidepressant therapies | journal = Clinical Neuropharmacology | volume = 16 | issue = 5 | pages = 387–400 | date = October 1993 | pmid = 8221701 | doi = 10.1097/00002826-199310000-00002 }}</ref>

==Anatomy {{Anchor|Nucleus linearis}}==
The raphe nuclei are traditionally considered to be the medial portion of the [[reticular formation]], and
appear as a ridge of cells in the center and most medial portion of the [[brain stem]].

In order from [[Caudal (anatomical term)|caudal]] to [[Anatomical terms of location#Directional terms|rostral]], the raphe nuclei are known as the ''[[nucleus raphe obscurus]]'', the ''[[nucleus raphe pallidus]]'', the ''[[nucleus raphe magnus]]'', the ''[[pontine raphe nucleus|nucleus raphe pontis]]'', the ''[[median raphe nucleus]]'', ''[[dorsal raphe nucleus]]'', ''caudal linear nucleus''.<ref name="Törk">{{cite journal | vauthors = Törk I | title = Anatomy of the serotonergic system | journal = Annals of the New York Academy of Sciences | volume = 600 | issue = 1 | pages = 9–34; discussion 34–5 | date = 1990 | pmid = 2252340 | doi = 10.1111/j.1749-6632.1990.tb16870.x | bibcode = 1990NYASA.600....9T }}</ref> In the first systematic examination of the raphe nuclei, Taber ''et al.''. (1960)<ref name="Taber '60a">{{cite journal | vauthors = Taber E, Brodal A, Walberg F | title = The raphe nuclei of the brain stem in the cat. I. Normal topography and cytoarchitecture and general discussion | journal = The Journal of Comparative Neurology | volume = 114 | issue = 2 | pages = 161–87 | date = April 1960 | pmid = 13836517 | doi = 10.1002/cne.901140205 }}</ref> originally proposed the existence of two linear nuclei (nucleus linearis intermedius and nucleus linearis rostralis). This study was published before techniques enabling the visualization of serotonin or the enzymes participating in its synthesis had been developed, as first demonstrated by Dahlström and Fuxe in 1964.<ref name=D&F>{{cite journal | vauthors = Dahlstroem A, Fuxe K | journal = Acta Physiologica Scandinavica. Supplementum | volume = 232 | issue = Suppl | pages = SUPPL 232:1–55 | date = 1964 | pmid = 14229500 | title = Evidence for the Existence of Monoamine-Containing Neurons in the Central Nervous System. I. Demonstration of Monoamines in the Cell Bodies of Brain Stem Neurons }}</ref> Later, it was revealed that of these two nuclei, only the former (nucleus linearis intermedius, now known as the caudal linear nucleus), proved to contain serotonin-producing neurons,<ref>{{cite journal | vauthors = Halliday GM, Törk I | title = Serotonin-like immunoreactive cells and fibres in the rat ventromedial mesencephalic tegmentum | journal = Brain Research Bulletin | volume = 22 | issue = 4 | pages = 725–35 | date = April 1989 | pmid = 2736398 | doi = 10.1016/0361-9230(89)90092-0 }}</ref> though both of them contain dopaminergic neurons.<ref name="Ikemoto">{{cite journal | vauthors = Ikemoto S | title = Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex | journal = Brain Research Reviews | volume = 56 | issue = 1 | pages = 27–78 | date = November 2007 | pmid = 17574681 | pmc = 2134972 | doi = 10.1016/j.brainresrev.2007.05.004 }}</ref>

In some works (e.g.<ref name=Nieuwenhuys>{{cite book|last1=Nieuwenhuys|first1=Rudolf|last2=Voogd|first2=Jan|last3=van Huijzen|first3=Chris | name-list-style = vanc |title=The human central nervous system|url=https://archive.org/details/humancentralnerv00nieu_478|url-access=limited|date=2008|publisher=Springer|location=Berlin|pages=[https://archive.org/details/humancentralnerv00nieu_478/page/n889 890], 893|edition=4}}</ref>), researchers have grouped the nuclei lineares into one nucleus, the '''''nucleus linearis'''''<!--Phrase redirects to anchor and is bolded per MOS:BOLD-->, shrinking the number of raphe to seven, e.g.,
[[NeuroNames]] makes the following ordering:<ref>{{BrainInfo|ancil|190}}</ref>
* Raphe nuclei of [[medulla oblongata]]
** [[Nucleus raphe obscurus]]
** [[Nucleus raphe magnus]]
** [[Nucleus raphe pallidus]]
* Raphe nuclei of the [[pons|pontine]] reticular formation
** [[Pontine raphe nucleus|Nucleus raphe pontis]]
** [[Inferior central nucleus|Nucleus centralis inferior]]
* Raphe nuclei of the [[midbrain]] reticular formation
** [[Superior central nucleus|Nucleus centralis superior]] (''median raphe nucleus'')
** [[Dorsal raphe nucleus|Nucleus raphe dorsalis]]

==Nomenclature==
The Latin names commonly used for most of these nuclei are grammatically and orthographically incorrect. Latin grammar would require to use the [[genitive case]] ''raphes'' ('of the seam') instead of the [[nominative case]] ''raphe'' ('seam') in these Latin expressions. The main authority in anatomical names, [[Terminologia Anatomica]] uses for example ''nucleus raphes magnus''<ref name="FCAT">{{cite book | author = Federative Committee on Anatomical Terminology (FCAT) | date = 1998 | title = Terminologia Anatomica | location = Stuttgart | publisher = Thieme }}</ref> instead of the grammatically incorrect ''nucleus raphe magnus''. The spelling ''raphe/raphes'' however can also be contested as numerous sources<ref name="Hyrtl1880">Hyrtl, J. (1880). ''Onomatologia Anatomica. Geschichte und Kritik der anatomischen Sprache der Gegenwart.'' Wien: Wilhelm Braumüller. K.K. Hof- und Universitätsbuchhändler.</ref><ref name="Foster1891">{{cite book | vauthors = Foster FD | date = 1891–1893 | title = An illustrated medical dictionary. Being a dictionary of the technical terms used by writers on medicine and the collateral sciences, in the Latin, English, French, and German languages. | location = New York | publisher = D. Appleton and Company }}</ref><ref name="Triepel1910b">{{cite book | vauthors = Triepel H | date = 1910 | title = Die anatomischen Namen. Ihre Ableitung und Aussprache. Mit einem Anhang: Biographische Notizen. (Dritte Auflage) | location = Wiesbaden | publisher = Verlag J.F. Bergmann }}</ref> indicate that ''raphe'' is an incorrect Latin rendering of the Ancient Greek word ῥαφή as the initial letter rho with [[rough breathing]] (''spiritus asper'') is normally rendered as ''rh'' in Latin.<ref name="Hyrtl1880"/> The edition of the [[Nomina Anatomica]] that was ratified in [[Jena]] in 1935 used ''rhaphe'' instead of ''raphe''.<ref name="Kopsch">{{cite book | vauthors = Kopsch F | date = 1941 | title = Die Nomina anatomica des Jahres 1895 (B.N.A.) nach der Buchstabenreihe geordnet und gegenübergestellt den Nomina anatomica des Jahres 1935 (I.N.A.) (3. Auflage). | location = Leipzig | publisher = Georg Thieme Verlag }}</ref><ref name="Stieve1949">{{cite book | vauthors = Stieve H | date = 1949 | title = Nomina Anatomica. Zusammengestellt von der im Jahre 1923 gewählten Nomenklatur-Kommission, unter Berücksichtigung der Vorschläge der Mitglieder der Anatomischen Gesellschaft, der Anatomical Society of Great Britain and Ireland, sowie der American Association of Anatomists, überprüft und durch Beschluß der Anatomischen Gesellschaft auf der Tagung in Jena 1935 endgültig angenommen. (Vierte Auflage) | location = Jena | publisher = Verlag Gustav Fischer }}</ref>

==Projections==
These nuclei interact with almost every pertinent portion of the brain, but only a few of them have specifically independent interaction. These select nuclei are discussed as follows.

Overall, the caudal raphe nuclei, including the nucleus raphe magnus, nucleus raphe pallidus and nucleus raphe obscurus, all project towards the spinal cord and brain stem. The more-rostral nuclei, including the nucleus raphe pontis, nucleus centralis superior (also called median raphe nucleus, mRN) and nucleus raphe dorsalis (dRN) project towards the brain areas of higher function <ref>{{cite web | author = BilZ0r  |author2 = Erowid  | year = 2005 | url = http://www.erowid.org/psychoactives/pharmacology/images/pharmacology_article2-4-med.png | title = Figure 4. Diagram of the human brain showing the divergent serotonergic projections of the raphe nuclei to both cortical and subcortical locations throughout the brain. | format = PNG | work = The Neuropharmacology of Hallucinogens: a technical overview | publisher = Erowid Pharmacology Vaults | access-date = 18 April 2006 }}</ref>

The numerous projections from the mRN and dRN to key brain structures make serotonergic system fundamental in regulating brain homeostasis. However, studies also show feedback loops from numerous areas of the brain controlling the serotonergic neurons located in the [[nucleus raphe dorsalis]], including the orbital cortex, [[cingulate cortex]], medial [[preoptic area]], lateral [[preoptic area]], and several areas of the [[hypothalamus]]. The connection between these areas, particularly between the [[nucleus raphe dorsalis]] and the orbital cortices, is thought to have influences on [[Depression (mood)|depression]] and [[obsessive compulsive disorder]] prognosis.<ref>{{cite journal | vauthors = Peyron C, Petit JM, Rampon C, Jouvet M, Luppi PH | title = Forebrain afferents to the rat dorsal raphe nucleus demonstrated by retrograde and anterograde tracing methods | journal = Neuroscience | volume = 82 | issue = 2 | pages = 443–68 | date = January 1998 | pmid = 9466453 | doi = 10.1016/s0306-4522(97)00268-6 }}</ref>
[[File:Dopamine_and_serotonin_pathways.png|thumb|right|Dopamine and serotonin pathways in the brain]]

== Function ==
The raphe nuclei have a vast impact upon the central nervous system.
Many of the neurons in the nuclei (but not the majority) are serotonergic; i.e., contain [[serotonin]], a type of [[monoamine]] neurotransmitter and are modulated through fibrous pathways in the midbrain.<ref>{{cite journal | vauthors = Azmitia EC, Segal M | title = An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat | journal = The Journal of Comparative Neurology | volume = 179 | issue = 3 | pages = 641–67 | date = June 1978 | pmid = 565370 | doi = 10.1002/cne.901790311 }}</ref>

Projections from the raphe nuclei also terminate in the dorsal horn of spinal gray matter where they regulate the release of [[enkephalins]], which inhibit pain sensation.

The raphe nuclei provide feedback to the [[suprachiasmatic nuclei]] (SCN), thus contributing in circadian rhythms in animals. The SCN transmits to the raphe nuclei via the [[dorsomedial hypothalamic nucleus]] altering serotonin levels for sleep/wake states. The raphe nuclei will then transmit feedback to the SCN about the animal's vigilance and levels of alertness. This reciprocal feedback between the two structures provides an adaptable yet stable basis of circadian rhythms.<ref>{{cite book | veditors = Monti JM | others = Samüel Deurveilher and Kazue Semba | title = Serotonin and Sleep: Molecular, Functional and Clinical Aspects | url = https://archive.org/details/serotoninsleepmo00jmmo | url-access = limited | pages = [https://archive.org/details/serotoninsleepmo00jmmo/page/n123 103]–131 | year = 2008 | publisher = Birkhäuser Basel | isbn = 978-3-7643-8560-6 | chapter = Reciprocal connections between the suprachiasmatic nucleus and the midbrain raphe nuclei: A putative role in the circadian control of behavioral states | doi = 10.1007/978-3-7643-8561-3_4 }}</ref>

=== Thermoregulation ===

A large increase in sympathetic nerve activity was observed when an excitatory amino acid was injected into the [[Nucleus raphe pallidus|raphe pallidus]], resulting in both brown adipose tissue (BAT) temperature and heart rate increasing. This suggests that activation of the raphe nucleus results in an increase in sympathetic activity to the BAT.<ref name="pmid14596844">{{cite journal | vauthors = Madden CJ, Morrison SF | title = Excitatory amino acid receptor activation in the raphe pallidus area mediates prostaglandin-evoked thermogenesis | journal = Neuroscience | volume = 122 | issue = 1 | pages = 5–15 | date = 2003 | pmid = 14596844 | doi = 10.1016/s0306-4522(03)00527-x }}</ref>

The raphe pallidus wasn't switched off using 8-OH-DPAT, which in turn reduced body temperature due to a reduced response to cold. This suggests the importance of the raphe nucleus in responding appropriately to the cold.<ref>{{cite journal | vauthors = Nakamura K, Morrison SF | title = Central efferent pathways mediating skin cooling-evoked sympathetic thermogenesis in brown adipose tissue | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 292 | issue = 1 | pages = R127-36 | date = January 2007 | pmid = 16931649 | pmc = 2441894 | doi = 10.1152/ajpregu.00427.2006 }}</ref>

=== Sleep and arousal regulation ===
According to Michel Jouve from Lyon, there is a contradiction in study findings regarding the relationship between serotonin and sleep: initially, serotonin was believed to act as a neuromodulator of sleep, as destruction of serotonergic neurons in the raphe nuclei or inhibition of serotonin synthesis induced severe insomnia. However, studies showed that the electrical activity of serotonergic cell bodies and serotonin release increases during wakefulness and decreases during sleep, which appears at first glance to contradict the idea of serotonin contributing to sleep.<ref name=":0">{{Cite journal |last=Jouvet |first=M |date=August 1999 |title=Sleep and Serotonin An Unfinished Story |url=https://www.nature.com/doifinder/10.1016/S0893-133X(99)00009-3 |journal=Neuropsychopharmacology |language=en |volume=21 |issue=2 |pages=24S–27S |doi=10.1016/S0893-133X(99)00009-3}}</ref> For the same author, serotonin release during wakefulness can trigger a cascade of genomic events in some sleep-promoting neurons in the preoptic area, allowing it under certain conditions to also contribute to increased sleep propensity and regulation of slow-wave sleep,<ref name=":0" /> Cespigluou, from the same laboratory, explains that serotonin (5-HT) participates in sleep in two distinct ways. First, when released during wakefulness via axonal nerve endings, it influences the synthesis of sleep-promoting substances in specific brain regions. Second, when released during sleep within the dorsal raphe nucleus by dendrites of serotonergic neurons, it contributes to silencing serotonergic cell bodies through an auto-inhibitory process.<ref>{{Cite journal |last=Cespuglio |first=Raymond |date=September 2018 |title=Serotonin: its place today in sleep preparation, triggering or maintenance |url=https://linkinghub.elsevier.com/retrieve/pii/S1389945718302284 |journal=Sleep Medicine |language=en |volume=49 |pages=31–39 |doi=10.1016/j.sleep.2018.05.034}}</ref>

According to Monti from Uruguay, who based his conclusions on electrophysiological, neurochemical, genetic, and neuropharmacological approaches, serotonin (5-HT) originating from the dorsal raphe nucleus primarily promotes wakefulness and inhibits rapid eye movement (REM) sleep, the stage during which dreaming occurs.<ref>{{Cite journal |last=Monti |first=Jaime M. |date=August 2018 |title=Serotonin control of sleep-wake behavior |url=https://linkinghub.elsevier.com/retrieve/pii/S1087079210001334 |journal=Sleep Medicine Reviews |language=en |volume=15 |issue=4 |pages=269–281 |doi=10.1016/j.smrv.2010.11.003}}</ref> For Barbara Estone Jones, Serotonergic raphe neurons promote a seemingly quiet or satiated waking state, which though exclusive of REMS, can actually be conducive to SWS<ref>{{Cite journal |last=Jones |first=Barbara E |date=2003 |title=Arousal systems |url=https://imrpress.com/journal/FBL/8/6/10.2741/1074 |journal=Frontiers in Bioscience |language=en |volume=8 |issue=6 |pages=s438–451 |doi=10.2741/1074}}</ref>

===The raphe nuclei and the effects of ghrelin===
More recent studies of the Raphe Nuclei done with rats involve the effects of [[ghrelin]] on the [[dorsal raphe nucleus]]. When administered, larger doses of ghrelin act centrally on the raphe nucleus, [[hippocampus]], and [[amygdala]] which causes dramatic increases in food intake, memory retention, and increases in anxiety. The effects of ghrelin are seen on the raphe nucleus as soon as an hour after injection, suggesting rapid changes in the structure of the nucleus. Changes also occur after 24 hours suggesting delayed modifications as well.<ref>{{cite journal | vauthors = Carlini VP, Varas MM, Cragnolini AB, Schiöth HB, Scimonelli TN, de Barioglio SR | title = Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin | journal = Biochemical and Biophysical Research Communications | volume = 313 | issue = 3 | pages = 635–41 | date = January 2004 | pmid = 14697239 | doi = 10.1016/j.bbrc.2003.11.150 }}</ref>

== See also ==
* [[Locus ceruleus]]
* [[Substantia nigra]]
* [[Pedunculopontine nucleus]]
* [[List of regions in the human brain]]

== References ==
{{Reflist|2}}

== Further reading ==
{{refbegin}}
* {{cite web | last = Currie | first = David | name-list-style = vanc | year = 2005 | url = http://faculty.etsu.edu/currie/ras.htm | title = A Lecture, Higher Brain Function: Activation of the Brain and Levels of Consciousness | publisher = [[East Tennessee State University]] | access-date = 18 April 2006 }}
* {{cite journal | vauthors = Sari Y | title = Serotonin1B receptors: from protein to physiological function and behavior | journal = Neuroscience and Biobehavioral Reviews | volume = 28 | issue = 6 | pages = 565–82 | date = October 2004 | pmid = 15527863 | doi = 10.1016/j.neubiorev.2004.08.008 }}
* {{cite journal | vauthors = McKittrick CR, Blanchard DC, Blanchard RJ, McEwen BS, Sakai RR | title = Serotonin receptor binding in a colony model of chronic social stress | journal = Biological Psychiatry | volume = 37 | issue = 6 | pages = 383–93 | date = March 1995 | pmid = 7772647 | doi = 10.1016/0006-3223(94)00152-S | doi-access = free }}
{{refend}}

{{Medulla}}
{{Pons}}
{{Mesencephalon}}
{{Neurotransmitter systems}}
{{Authority control}}

[[Category:Brainstem nuclei]]
[[Category:Serotonin]]