The median raphe nucleus (MRN), also known as the superior central nucleus, is a

nucleus Nucleus (: nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucleu ...

in the

brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is conti ...

composed of polygonal, fusiform, and piriform neurons, which exists rostral to the

pontine raphe nucleus The pontine raphe nucleus is one of the raphe nuclei. It is located in the pontine tegmentum The pontine tegmentum, or dorsal pons, is the dorsal part of the pons located within the brainstem. The ventral part or ventral pons is known as the b ...

. The median raphe nucleus is one of several

raphe nuclei The raphe nuclei (, "seam") 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 ...

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 The dorsal raphe nucleus is one of the raphe nuclei. It is situated in the brainstem at the midline. It has rostral and caudal subdivisions: * The rostral aspect of the ''dorsal'' raphe is further divided into interfascicular, ventral, ventrolater ...

(DRN). The MRN extends from the lower part of the dorsal raphe nucleus to an approximate position at the decussation of the superior cerebellar peduncle . The MRN projects extensively to the

hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...

, which is known to be essential for the formation of

long-term memory Long-term memory (LTM) is the stage of the Atkinson–Shiffrin memory model in which informative knowledge is held indefinitely. It is defined in contrast to sensory memory, the initial stage, and short-term or working memory, the second stage ...

. One study found that this raphe–hippocampus pathway plays a critical role in regulating hippocampal activity and likely associated

memory consolidation Memory consolidation is a category of processes that stabilize a memory trace after its initial acquisition. A memory trace is a change in the nervous system caused by memorizing something. Consolidation is distinguished into two specific processe ...

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 Tryptophan hydroxylase (TPH) is an enzyme () involved in the synthesis of the monoamine neurotransmitter serotonin. Tyrosine hydroxylase, phenylalanine hydroxylase, and tryptophan hydroxylase together constitute the family of biopterin-depen ...

Neurophysiology

Serotonergic neurotransmission

The MRN is involved in the

serotonin pathway A serotonin pathway identifies aggregate projections from neurons which synthesize and communicate the monoamine neurotransmitter serotonin. These pathways are relevant to different psychiatric and neurological disorders. Pathways Function Gi ...

Serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

(5-HT) is the chief neurotransmitter of the median raphe nucleus. According to one study, it represents the main source of serotonin (5-hydroxytryptamine (5-HT)) in the brain''.'' Stimulation of the MRN significantly increases the amount of 5-HT present in the brain. MRN is the main contributor of 5-HT to the dorsal hippocampus as well as anterior and posterior cortical areas. Projections from the MRN extend to forebrain structures. 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. 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 The dentate gyrus (DG) is one of the subfields of the hippocampus, in the hippocampal formation. The hippocampal formation is located in the temporal lobe of the brain, and includes the hippocampus (including CA1 to CA4) subfields, and other su ...

of the dorsal hippocampus, the lateral medial septum dentate gyrus, and the medial septum ventral hippocampus. 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. 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. MRN fibers are course and large with spherical varicosities. Neurotoxic 5-HT-releasing agents selectively destroy DRN projection fibers without affecting the dense coarse fibers from the MRN. 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.

GABAergic regulation

The MRN was also found to be involved in GABAergic inhibitory control of serotonergic neurotransmission: GABA antagonist injections into the rat MRN increased serotonin turnover. Such relationship is also seen when the MRN is electrically stimulated and as a result behavioral inhibition is induced in rats. 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 Fenclonine, also known as ''para''-chlorophenylalanine (PCPA), acts as a selective and irreversible inhibitor of tryptophan hydroxylase, which is a rate-limiting enzyme in the biosynthesis of serotonin. It has been used experimentally to treat c ...

(PCPA), a serotonin synthesis inhibitor. Such results demonstrate that the MRN is involved in behavioral inhibition as well.

Regulation of dopaminergic neurotransmission

Projections stemming from the MRN modulate dopaminergic activity within the forebrain. 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.

Mood disorders

The MRN is one of the few brain regions producing

, 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. Animal models indicate that inactivation of serotonergic neurons of the median raphe nucleus induces anxiolysis, suggesting involvement of the MRN in anxiety.

Hallucinogens

Inhibition of the MRN in cats by

lysergic acid diethylamide Lysergic acid diethylamide, commonly known as LSD (from German ; often referred to as acid or lucy), is a Semisynthesis, semisynthetic, Hallucinogen, hallucinogenic compound derived from ergot, known for its powerful psychological effects and ...

(LSD) and

psilocin Psilocin, also known as 4-hydroxy-''N'',''N''-dimethyltryptamine (4-HO-DMT), is a substituted tryptamine alkaloid and a serotonergic psychedelic. It is present in most psychedelic mushrooms together with its phosphorylated counterpart psilocy ...

, two

serotonin agonist A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin (5-hydroxytryptamine; 5-HT), a neurotransmitter and hormone and the endogenous ligand of t ...

hallucinogens Hallucinogens, also known as psychedelics, entheogens, or historically as psychotomimetics, are a large and diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mo ...

, leads to dose dependent behavioral changes, indicating the MRN may be an important site of action for humans hallucinations.

Memory

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 regulation of hippocampal activity and likely associated memory consolidation processes. 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.

Hippocampal theta waves

The MRN was found to play a vital role in hippocampal desynchronization; it exerts an inhibitory effect on the mechanism for hippocampal

theta wave Theta waves generate the theta rhythm, a neural oscillation in the brain that underlies various aspects of cognition and behavior, including learning, memory, and spatial navigation in many animals. It can be recorded using various electrophys ...

generation. 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.

References

{{DEFAULTSORT:Median Raphe Nucleus Pons