Neuroanatomy, Nucleus of Raphe (2023)

Neuroanatomy, Nucleus of Raphe (1)Neuroanatomy, Nucleus of Raphe

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The raphe nuclei are located in the midline of the brainstem along the midbrain, pons, and medulla oblongata. These nuclei contain mainly serotonergic neurons, which release serotonin (5-hydroxytryptamine) with autocrine and paracrine effects, as well as synaptic connections. Serotonin generation comes from L-tryptophan through a two-step process catalyzed by tryptophan hydroxylase and L-aromatic amino acid decarboxylase. Upon release, serotonin binds postsynaptically to a 5-HT receptor, whose subtypes exert different physiological effects. Presynaptic 5-HT autoreceptors modulate the subsequent release of serotonin. The serotonin reuptake transporter (SERT) is responsible for presynaptic reuptake. Serotonin is primarily metabolized by monoamine oxidase.[1]

The most rostral nuclei located in the midbrain and rostral pons (caudal linear nucleus, dorsal raphe, and median raphe) have projections that extend to structures in the forebrain. These projections modulate behavioral and emotional functioning, including regulation of mood, memory, and the sleep-wake cycle. The caudal nuclei of the caudal pons and medulla oblongata (greater raphe, darker raphe, and paler raphe) project primarily to spinal cord structures; this occurs through projections parallel to the ventral, intermediate, and dorsal columns. They modulate nociception and movement.[2]

A decrease in serotonergic input to the limbic system has been the longstanding and leading model for the pathogenesis of major depression. Decreased serotonin synthesis, low-affinity binding to postsynaptic receptors, increased responsiveness of presynaptic autoreceptors, and rapid serotonin degradation have links to clinical depression. These differences in physiology are generally due to genetic polymorphisms, which explains the increased susceptibility in patients with a family history of depression. Although the pathogenesis of depression is multifactorial in most patients, enhancement of serotonergic transmission with selective serotonin reuptake inhibitors (SSRIs) has been the first-line treatment for depression.[3]

structure and function

The raphe nuclei are divided into rostral and caudal groups. The rostral group contains most of the serotonergic neurons in the brain. Within this group is the caudal linear nucleus, which contains serotonergic, catecholaminergic, and substance P-producing neurons. The dorsal raphe nucleus is located between the oculomotor nucleus and the median pons, and extends from the midline to the gray matter. periaqueductal. The median raphe extends from the caudal border of the superior cerebellar peduncles to the motor nucleus of V. Inputs to the dorsal and median raphe come from the limbic system. Glutamatergic innervation comes from the hypothalamic nuclei, ventral tegmental area, and cingulate cortex, while GABAergic innervation is also provided by the hypothalamus. Efferents from the rostral group project by two pathways, one to the lateral cortex via the internal capsule and the other to the hypothalamus, amygdala, hippocampus, and medial cortex via the medial forebrain tract. Cortical innervation is concentrated mainly in layer IV.[2]

The caudal group contains the raphe magnus, which is in the midline of the pons at the level of the nucleus of VII. Neurons of the raphe magnum produce serotonin, thyrotropin-releasing hormone, and substance P. The dark raphe is located in the midline of the dorsal cord and primarily expresses substance P. Finally, the pale raphe is found between the pyramids. These nuclei receive catecholaminergic innervation from the periaqueductal gray, amygdala, and hypothalamic nuclei. The caudal group projects to the dorsal, intermediate, and ventral horns of the spinal cord via two parallel pathways.[2]

Serotonergic pathways originating from the raphe nuclei are involved in a variety of physiological and behavioral functions. Corticolimbic projections from the rostral group to the amygdala, hippocampus, thalamus, and basal ganglia modulate emotion, mood, stress response, and cognition. Additional functions include regulation of appetite, sleep cycles, movement, sexual function, and movement.[4]Likewise, the nuclear entrance of the raphe strongly modifies the perception of pain. Descending projections modulate the response to painful stimuli in the dorsal horn of the spinal cord. Similarly, serotonergic input to pain-sensitive regions of the thalamus and cells of the arcuate nucleus of the hypothalamus produce an analgesic effect.[5]

(Video) Raphe Nuclei | Serotonin System Anatomy

Blood and lymphatic supply

As the raphe nuclei pass along the medial brainstem, the blood supply is derived primarily from penetrating branches of the basilar artery in the midbrain and pons region, and branches of the anterior spinal artery in the medulla. spinal[6]

surgical considerations

Brain stem surgery remains challenging but may be a useful treatment strategy for lesions such as brain stem gliomas. Auxiliary in the surgical approach is the intraoperative monitoring of auditory, motor, and somatosensory evoked potentials, as well as cranial nerve mapping. These features help determine the safest entry area for surgery. For tegmental pons lesions near the raphe nuclei, an infratentorial supracerebellar approach provides good access with minimal disturbance to surrounding structures such as the raphe nuclei.[7]

In recent studies, electrical stimulation of the raphe magna increased myelination and reduced symptoms in a multiple sclerosis mouse model. In the future, surgeons may implant deep brain stimulators into the raphe nuclei to treat conditions such as multiple sclerosis.[8]

clinical significance

Research shows that abnormalities in the dorsal raphe nucleus have implications for major depressive disorder (MDD) and suicidality. MDD ranks as the leading cause of disability in developed countries, according to the World Health Organization. Genetic polymorphisms affecting tryptophan availability, serotonin-degrading tryptophan hydroxylase 2 monoamine oxidase activity, 5-HT1 autoreceptors, and serotonin transporters confer risk of depression, particularly when symptoms appear early in life . In posterior depression, loss of dorsal raphe volume, as well as decreased connectivity with the posterior cingulate cortex, are more strongly implicated.[3]These changes can develop through a variety of means, including age-related degeneration and heart attack.

Based on this understanding, SSRIs are considered the first-line treatment for MDD. The mechanism of action of this drug is to increase synaptic serotonin concentration by binding to and inhibiting the presynaptic serotonin reuptake transporter and decreasing the responsiveness of 5-HT autoreceptors. The idea is that this increased concentration of serotonin, specifically at limbic synapses, results in a more positive evaluation of emotional information. Over time, this change gradually results in a clinical antidepressant effect as conscious cognitive processing changes and prior emotional associations are modified. This clinical effect typically occurs for 4 to 6 weeks.[9]Other classes of antidepressants also increase serotonin transmission. Monoamine oxidase inhibitors slow the breakdown of serotonin. Tricyclic antidepressants (TCAs) decrease the responsiveness of alpha-2 and 5-HT1A adrenergic receptors, resulting in increased serotonin transmission.

The fact that other treatment modalities for depression target the transmission of dopamine, norepinephrine, and catecholamines implies that the serotonergic system is one of multiple components in the pathogenesis of depression. For example, in patients who respond well to selective norepinephrine reuptake inhibitors, catecholamine rather than serotonin depletion is more closely related to symptomatology. Furthermore, some patients experience an improvement in symptoms when SSRI therapy is supplemented with a second agent, such as a dopamine agonist, highlighting a multifactorial etiology. Current research is exploring new targets to alleviate MDD symptoms, and to do so more quickly.[10]Furthermore, research on the microbiota-gut-brain axis holds promise for future treatment modalities. While the raphe nuclei synthesize most of the serotonin in the central nervous system, most of the serotonin throughout the body is synthesized in the gastrointestinal tract. Research linking abnormal gut microbiota to depressive symptoms highlights environmental factors in the pathogenesis of MDD. Studies showing that depressive symptoms are reversible with normal microbiota transplantation hold promise for future therapeutic measures.[11]

Alterations in serotonin pathways are also implicated in chronic pain syndromes, given the well-known pain modulation process at the level of the dorsal horn of the spinal cord by descending projections of the raphe nuclei. For this reason, SSRIs and TCAs may be considered to treat fibromyalgia, chronic pelvic pain, diabetic neuropathy, and headache syndromes.[12]

other problems

Serotonin syndrome is a medical emergency that can be precipitated by the interaction or overdose of serotonergic drugs, causing hyperactivity of the 5HT-1A and 5HT-2A receptors. Patients present with altered mental status, tremors, hyperreflexia, muscle rigidity, fever, tachycardia, and hypertension as a result of excessive central and peripheral nervous system serotonergic activation. Treatment is supportive and, most importantly, discontinuation of all serotonergic drugs, and the prognosis is favorable.[13]Neuroleptic malignant syndrome also shares some of the symptoms of serotonin syndrome-like hyperthermia, altered mental status, and autonomic instability. But neuroleptic malignant syndrome demonstrates bradyflexia, lead pipe rigidity, and extrapyramidal features. Therefore, it is imperative to identify these emergencies early to prevent mortality.

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Neuroanatomy, Nucleus of Raphe (2)
The hindbrain or rhombencephalon; Transverse section of the medulla oblongata around the middle of the olive, Pyramid, Raphe, Vagus nerve, Arcate fibers, Ligule, Vagus nuclei
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(Video) 2-Minute Neuroscience: The Thalamus


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(Video) 2-Minute Neuroscience: Periaqeuductal Gray (PAG)

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What is the nucleus raphe in Neuroanatomy? ›

The raphe nuclei are positioned midline in the brainstem throughout the midbrain, pons, and medulla. These nuclei contain primarily serotonergic neurons, which release serotonin (5-hydroxytryptamine) with autocrine and paracrine effects, as well as synaptic connections.

What is the function of the Raphae nucleus? ›

The dorsal raphe nucleus (DRN) is a heterogeneous brainstem nucleus located in the midbrain and pons. Via widespread projections, which target a multitude of brain areas, its neurons utilize many transmitters to control various physiological functions, including learning, memory and affect.

Is the raphe nuclei associated with anxiety? ›

Using these vectors, we demonstrate that acute activation of serotonergic neurons in the dorsal raphe nucleus increases active coping with inescapable stress in rats and mice in a time-locked manner, and that acute inhibition of these neurons increases anxiety-like behaviors specifically in rats.

Where are raphe nuclei located in the brain? ›

The raphe nuclei are distributed near the midline of the brainstem along its entire rostro-caudal extension. The serotonergic neurons are their main neuronal components, although a proportion of them lie in subdivisions of the lateral reticular formation.

What are the components of raphe nuclei? ›

It consists of the: raphe magnus nucleus, raphe obscurus nucleus, and raphe pallidus nucleus. The raphe pallidus nucleus is the smallest of the raphe nuclei. The projections from the raphe nuclei are pervasive, carrying serotonin throughout the central nervous system.

What is raphe in anatomy? ›

Anatomically, a raphe is derived from the Greek word for a seam. It describes the intersection or seam in a tissue or organ between two separate parts, particularly when they were embryologically separate from each other.

What does activating the raphe nucleus induce? ›

Based on results from genetic, neuropharmacological and electrophysiological studies, serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) apparently function predominantly to promote wakefulness and inhibit REM sleep.

What neurotransmitters are in the dorsal raphe nucleus? ›

The dorsal raphe nucleus has been known to project to the lateral hypothalamus, along with the locus coeruleus and the tuberomammillary nucleus. The neurotransmitters of these three aforementioned nuclei, which project to the lateral hypothalamus, are serotonin, norepinephrine and histamine respectively.

Does raphe nuclei produce dopamine? ›

Anatomical and physiological evidence also revealed that the dorsal raphé nucleus (DRN), a major source of serotonin, and the dopamine system receive common inputs from brain regions associated with appetitive and aversive information processing.

What part of the brain signals anxiety? ›

The amygdala, located deep inside the brain, is part of the emotional brain. According to this theory, we only feel anxiety when signals from the emotional brain overpower the cognitive brain, and into our consciousness.

Is the dorsal raphe nucleus associated with depression? ›

The dorsal raphe nucleus (DRN) has been repeatedly implicated as having a significant relationship with depression, along with its serotoninergic innervation. However, functional connectivity of the DRN in depression is not well understood.

Which area of the brain is most often associated with anxiety __? ›

The amygdala is responsible for the expression of fear and aggression as well as species-specific defensive behavior, and it plays a role in the formation and retrieval of emotional and fear-related memories. (Fig. 2 depicts the amygdala's involvement in fear circuitry).

What is another name for the raphe nuclei? ›

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.

Is dopamine an excitatory or inhibitory? ›

Dopamine. Dopamine (DA) is a neurotransmitter secreted by the neurons of the substantia nigra. It is considered a special type of neurotransmitter because its effects are both excitatory and inhibitory.

What do raphe nuclei of reticular formation produce? ›

The reticular formation is divided into three columns: raphe nuclei (median), gigantocellular reticular nuclei (medial zone), and parvocellular reticular nuclei (lateral zone). The raphe nuclei are the place of synthesis of the neurotransmitter serotonin, which plays an important role in mood regulation.

What neurotransmitter is in median raphe? ›

Because a dense population of neurons in the median raphe nucleus primarily contain serotonin, a prominent neurotransmitter in the median raphe nucleus is serotonin (5-HT).

Is the raphe nucleus in the medulla? ›

The raphe magnus nucleus (RMg) is located in the caudal pons and the most rostral portion of the medulla (Figure 11.3).

What is the importance of raphe? ›

The dorsal raphe nucleus (DRN) is an important nucleus in pain modulation. It has abundant 5-HT neurons and many other neurotransmitter and/or neuromodulator containing neurons. Its vast fiber connections to other parts of the central nervous system provide a morphological basis for its pain modulating function.

Where can a raphe be found? ›

The raphe neurons are located in the central tegmentum of the midbrain and the upper pons. They are serotonergic neurons projecting to wide areas of the cerebral cortex and the striatum.

What muscle contains a raphe? ›

The pharyngeal raphe is a raphe that serves as the origin and insertion for several of the pharyngeal constrictors (thyropharyngeal part of the inferior pharyngeal constrictor muscle, middle pharyngeal constrictor muscle, superior pharyngeal constrictor muscle).

What is the function of the dorsal raphe nucleus in sleep? ›

In the endogenous sleep-wake regulating pathways, the DRN promotes wakefulness via excitatory projections to the cerebral cortex and other wakefulness-promoting nuclei, and via inhibitory projections to sleep-promoting nuclei [1–3, 7].

What neurotransmitter is in the Raphe Magnus nucleus? ›

SEROTONIN. Serotonin has long been suggested to be a major neurotransmitter in descending controls. Serotonin is contained in a high proportion of nucleus raphe magnus cells, and in terminals of descending fibers in the dorsal horn.

Where is serotonin produced in the brain? ›

In the central nervous system (CNS), serotonin is almost exclusively produced in neurons originating in the raphe nuclei located in the midline of the brainstem. These serotonin-producing neurons form the largest and most complex efferent system in the human brain.

Is dopamine a hormone or chemical? ›

Dopamine is a chemical released in the brain that makes you feel good. Having the right amount of dopamine is important both for your body and your brain.

Is serotonin an excitatory or inhibitory? ›

Serotonin is an inhibitory neurotransmitter. Serotonin helps regulate mood, sleep patterns, sexuality, anxiety, appetite and pain.

What receptors stimulate dopamine? ›

Dopamine functions by acting on DAergic receptors, which are classified as D1-like receptors (D1 and D5) and D2-like receptors (D2, D2, and D4).

What nerve cells produce dopamine? ›

Abstract. Dopaminergic neurons of the midbrain are the main source of dopamine (DA) in the mammalian central nervous system.

In what nucleus is dopamine released during experiencing something pleasurable? ›

Dopamine is known as a pleasure molecule that is released in the nucleus accumbens area of the brain when we do pleasurable things — like eat food, have sex, or even take prescription opioids (drugs).

What part of the brain calms you down? ›

The prefrontal cortex is the part of the brain that evolved most recently, and it can be exquisitely sensitive to even temporary everyday anxieties and worries. When things are going well, the prefrontal cortex acts as a control center that keeps our baser emotions and impulses in check.

What neurotransmitters are imbalanced in anxiety? ›

The “Chemical Imbalance” Theory

The neurotransmitters serotonin, dopamine, norepinephrine, and gamma-aminobutyric acid (GABA) are specifically believed to be linked to mood and anxiety disorders. 1 These neurotransmitters are in charge of regulating various bodily and mental functions.

Where is the fear center of the brain? ›

The fear response starts in a region of the brain called the amygdala. This almond-shaped set of nuclei in the temporal lobe of the brain is dedicated to detecting the emotional salience of the stimuli – how much something stands out to us.

Which part of the brain is linked to depression _________________? ›

According to an fMRI study, decreased brain activity in the hippocampus was reported82 in depressive patients. Reduced gray matter volume and reduced functional activity in the hippocampus would lead to negative emotion and the inability of cognitive processing in depressive patients.

What neurotransmitter connections are there with depression? ›

The monoamine-deficiency theory posits that the underlying pathophysiological basis of depression is a depletion of the neurotransmitters serotonin, norepinephrine or dopamine in the central nervous system. Serotonin is the most extensively studied neurotransmitter in depression.

What in the brain causes severe anxiety? ›

Anxiety happens when a part of the brain, the amygdala, senses trouble. When it senses threat, real or imagined, it surges the body with hormones (including cortisol, the stress hormone) and adrenaline to make the body strong, fast and powerful.

What are two brain regions associated with anxiety disorders? ›

  • Amygdala. ...
  • Medial prefrontal cortex. ...
  • Hippocampus. ...
  • Insular cortex. ...
  • Summary.

Which neurotransmitter has been most often implicated in anxiety disorders? ›

The role of the inhibitory neurotransmitter GABA has long been regarded as central to the regulation of anxiety and this neurotransmitter system is the target of benzodiazepines and related drugs used to treat anxiety disorders.

What breaks down dopamine? ›

Degradation. Dopamine is broken down into inactive metabolites by a set of enzymes—monoamine oxidase (MAO), catechol-O-methyl transferase (COMT), and aldehyde dehydrogenase (ALDH), acting in sequence. Both isoforms of monoamine oxidase, MAO-A and MAO-B, effectively metabolize dopamine.

Which activity releases the most dopamine? ›

Sex, shopping, smelling cookies baking in the oven — all these things can trigger dopamine release, or a "dopamine rush."

What enzyme destroys the neurotransmitter? ›

Acetylcholinesterase (AChE) is a cholinergic enzyme primarily found at postsynaptic neuromuscular junctions, especially in muscles and nerves. It immediately breaks down or hydrolyzes acetylcholine (ACh), a naturally occurring neurotransmitter, into acetic acid and choline.

Is the raphe nucleus in the brainstem? ›

The raphe nuclei are distributed near the midline of the brainstem along its entire rostro-caudal extension. The serotonergic neurons are their main neuronal components, although a proportion of them lie in subdivisions of the lateral reticular formation.

What does the RAS do in the brain? ›

The Reticular Activating System (RAS) is a bundle of nerves that sits in your brainstem. And its job is to regulate behavioural arousal, consciousness and motivation.

What is the raphe nucleus of the medulla? ›

The medullary raphé nuclei are involved in controlling cardiovascular, respiratory, and thermoregulatory functions, as well as mediating stress-induced tachycardia and hyperthermia.

What are the raphe nuclei of the reticular formation? ›

The reticular formation is divided into three columns: raphe nuclei (median), gigantocellular reticular nuclei (medial zone), and parvocellular reticular nuclei (lateral zone). The raphe nuclei are the place of synthesis of the neurotransmitter serotonin, which plays an important role in mood regulation.

Where are the dorsal and median raphe nuclei? ›

The MRN is located between the posterior end of the superior cerebellar peduncles and the V. Afferents of the motor nucleus. It is one of two nuclei, the other being the dorsal raphe nucleus (DnR), in the midbrain-pons.

Does the raphe nucleus promote sleep? ›

Based on results from genetic, neuropharmacological and electrophysiological studies, serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) apparently function predominantly to promote wakefulness and inhibit REM sleep.

What is the nucleus of Raphe Magnus? ›

The nucleus raphe magnus (NRM) is a serotonergic nucleus located in the rostral ventromedial medulla of the brainstem. Axons of the NRM project to the spinal cord (Bowker et al., 1982), terminating primarily in the dorsal horn (Jones and Light, 1990).


1. 2-Minute Neuroscience: Midbrain
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2. Neurology | Midbrain Anatomy & Function
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3. Brainstem (Midbrain, Pons, and Medulla) Mnemonics (Memorable Neurology Lecture 7)
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4. Basal Ganglia 3D Tour
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5. Sleep/Wake Cycles
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6. The Serotonergic Raphe Promote Sleep in Zebrafish and Mice
(Cell Press)


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