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Raphe nuclei
Raphe nuclei
from Wikipedia
Raphe nuclei
Section of the medulla oblongata at about the middle of the olive. (Raphe nuclei not labeled, but 'raphe' labeled at left.)
Horizontal cross section of the brainstem at the lower pons. The raphe nucleus is labeled #18 in the middle.
Details
Identifiers
Latinnuclei raphes
MeSHD011903
NeuroLex IDnlx_anat_20090205
TA98A14.1.04.257
A14.1.04.318
A14.1.05.402
A14.1.05.601
A14.1.06.401
TA26035, 5955
FMA84017
Anatomical terms of neuroanatomy

The raphe nuclei (Greek: ῥαφή, "seam")[1] are a moderate-size cluster of nuclei found in the brain stem. They have 5-HT1 receptors which are coupled with Gi/Go-protein-inhibiting adenyl cyclase. They function as autoreceptors in the brain and decrease the release of serotonin. The anxiolytic drug Buspirone acts as partial agonist against these receptors.[2] Selective serotonin reuptake inhibitor (SSRI) antidepressants are believed to act in these nuclei, as well as at their targets.[3]

Anatomy

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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 to rostral, the raphe nuclei are known as the nucleus raphe obscurus, the nucleus raphe pallidus, the nucleus raphe magnus, the nucleus raphe pontis, the median raphe nucleus, dorsal raphe nucleus, caudal linear nucleus.[4] In the first systematic examination of the raphe nuclei, Taber et al.. (1960)[5] 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.[6] 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,[7] though both of them contain dopaminergic neurons.[8]

In some works (e.g.[9]), researchers have grouped the nuclei lineares into one nucleus, the nucleus linearis, shrinking the number of raphe to seven, e.g., NeuroNames makes the following ordering:[10]

Nomenclature

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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[11] instead of the grammatically incorrect nucleus raphe magnus. The spelling raphe/raphes however can also be contested as numerous sources[12][13][14] 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.[12] The edition of the Nomina Anatomica that was ratified in Jena in 1935 used rhaphe instead of raphe.[15][16]

Projections

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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 [17]

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 and obsessive compulsive disorder prognosis.[18]

Dopamine and serotonin pathways in the brain

Function

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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.[19]

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.[20]

Thermoregulation

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A large increase in sympathetic nerve activity was observed when an excitatory amino acid was injected into the 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.[21]

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.[22]

The raphe nuclei and the effects of ghrelin

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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.[23]

See also

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References

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Further reading

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Revisions and contributorsEdit on WikipediaRead on Wikipedia
from Grokipedia
The raphe nuclei are a group of midline nuclei in the , extending from the through the to the , composed primarily of serotonergic neurons that synthesize and release serotonin (5-hydroxytryptamine, or 5-HT) to modulate various physiological and behavioral processes. These nuclei serve as the principal source of the central serotonin system, with neurons deriving serotonin from the L-tryptophan via the enzyme , and serotonin acting through a family of G-protein-coupled receptors (5-HT1 to 5-HT7) as well as ligand-gated ion channels (5-HT3). Serotonin reuptake is regulated by the (SERT), while its degradation occurs via enzymes, ensuring precise control of synaptic and extrasynaptic signaling. Structurally, the raphe nuclei are divided into rostral and caudal clusters, each with distinct anatomical organization and projection patterns. The rostral group includes the (primarily in the and upper ), median raphe nucleus (in the ), and caudal linear nucleus (in the ), containing a mix of serotonergic, catecholaminergic, and substance P-producing neurons that project diffusely to regions such as the cortex, hippocampus, , and . In contrast, the caudal group—comprising the raphe magnus, raphe obscurus, and raphe pallidus nuclei (located in the lower and medulla)—features serotonergic neurons that extend descending projections to nuclei and all levels of the , including the dorsal, intermediate, and ventral horns. These projections enable both classical synaptic transmission and broader paracrine or volume transmission effects. Functionally, the raphe nuclei play critical roles in regulating mood, , sleep-wake cycles, pain perception, , and autonomic functions through their serotonergic outputs. Rostral nuclei, particularly the dorsal raphe, are key modulators of emotional processing, anxiety, reward-seeking behavior, and , with projections influencing limbic and cortical circuits to promote adaptive responses to environmental stressors. Caudal nuclei contribute to descending inhibitory pathways for via the raphe magnus and to visceral and somatic motor regulation through spinal projections, helping maintain in sensory and motor systems. Dysfunctions in these nuclei are implicated in neuropsychiatric disorders, including (where reduced serotonergic tone is observed) and syndromes, as well as conditions like from excessive 5-HT activity; treatments such as selective serotonin reuptake inhibitors (SSRIs) target SERT to enhance signaling, though therapeutic effects typically emerge after 4-6 weeks.

Anatomy and Nomenclature

Location and Structure

The raphe nuclei constitute a cluster of primarily serotonergic nuclei situated along the midline of the within the medial , extending continuously from the rostrally to the . This positioning reflects their name, derived from ῥαφή (rhaphḗ), meaning "seam," which alludes to their alignment along the brainstem's central seam. The nuclei were first systematically identified and classified into nine groups (B1–B9) by Dahlström and Fuxe in 1964 through fluorescence histochemical mapping of monoamine-containing neurons. Anatomically, the raphe nuclei are subdivided into rostral and caudal groups based on their rostrocaudal distribution. The rostral group encompasses the caudal linear nucleus, (in the and rostral , adjacent to the ), and median raphe nucleus (spanning the from the superior cerebellar peduncles to the trigeminal motor nucleus, including the pontine raphe nucleus or PnR). In contrast, the caudal group includes the raphe magnus nucleus (in the caudal at the level of the facial nucleus), raphe obscurus nucleus (in the dorsal medulla), and raphe pallidus nucleus (ventral to the obscurus, between the medullary pyramids). These groups exhibit a paramedian , with neurons originating from a thin strip of progenitor cells and showing some lateral migration in certain regions. Histologically, the raphe nuclei feature loosely clustered serotonergic neurons that lack sharply defined borders, blending diffusely into surrounding tissue and intermingled with non-serotonergic cell types. Neuron density varies, with more stratified arrangements in periventricular and superficial zones, while intermediate zones display sparser distribution. For gross visualization, Nissl staining highlights the overall neuronal architecture, whereas against 2 (TPH2) specifically delineates serotonergic cells due to its role as the biosynthetic enzyme for serotonin.

Subdivisions and Naming Conventions

The raphe nuclei are subdivided into rostral and caudal groups based on their anatomical positions along the midline. The rostral group includes the caudal linear nucleus, (DRN or DR; B6 and B7), and median raphe nucleus (MRN or MnR; B8, incorporating the pontine raphe nucleus or PnR at B5), located primarily in the and . The caudal group comprises the nucleus raphe magnus (NRM or RMg; B3), nucleus raphe obscurus (NRO or ROb; B2), and nucleus raphe pallidus (NRP or RPa; B1), extending into the . These subdivisions align with the serotonergic cell group classification proposed by Dahlström and Fuxe in 1964, who identified nine clusters (B1–B9) of monoaminergic neurons in the rat brainstem using histofluorescence techniques. Specifically, B5 corresponds to the PnR (part of MRN); B6 and B7 to parts of the DRN (caudal and principal portions, respectively); B8 to the MRN and caudal linear nucleus; B1 to the RPa; B2 to the ROb; B3 to the RMg; B4 to the supragenual nucleus; and B9 to the supralemniscal nucleus. This B-group system remains the foundational nomenclature for mapping serotonergic populations across species. The term "raphe" derives from ῥαφή (rhaphḗ), meaning "seam" or "stitch," reflecting the midline arrangement of these nuclei, and was adopted into Latin in the early during mapping efforts. Historical nomenclature evolved from initial cytoarchitectonic descriptions in the 1950s, such as those by Olszewski and Baxter (1954), to standardized terms in modern brain atlases like Paxinos and Watson (1986, updated editions), which provide detailed delineations for brains. A minor grammatical debate persists in usage: while Latin genitive "raphes" (of the seam) might be expected for compound names, the nominative singular "raphe" predominates in neuroanatomical . Nomenclature shows consistency between and humans, with equivalent structures like the DRN and RMg identified in both via histological and methods; however, human raphe nuclei exhibit slightly more diffuse boundaries due to larger size. In , Paxinos and Watson atlases assign stereotaxic coordinates (e.g., DRN at approximately -4.8 mm from in sagittal planes), while human variants rely on MRI-based atlases like the Big Brain or MNI space, where the DRN aligns near the at coordinates around x=0, y=-24 mm, z=-18 mm. Species-specific variations include a more compact pontine raphe in compared to , influencing precise delineation in cross-species studies.

Neurochemistry

Serotonin Synthesis and Release

The serotonin (5-HT) biosynthetic pathway in raphe nuclei neurons begins with the uptake of the L-tryptophan (L-Trp), which serves as the primary precursor. The rate-limiting step involves the enzyme tryptophan hydroxylase 2 (TPH2), which converts L-Trp to 5-hydroxytryptophan (5-HTP) in the presence of molecular oxygen, iron, and as a cofactor. This is followed by of 5-HTP to 5-HT, catalyzed by (AADC), also known as DOPA decarboxylase. The overall reaction can be summarized as: L-TrpTPH25-HTPAADC5-HT\text{L-Trp} \xrightarrow{\text{TPH2}} \text{5-HTP} \xrightarrow{\text{AADC}} \text{5-HT}
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