Raphe Nuclei (Dorsal and Median)

Anatomy

• The upper (rostral) cluster of serotonergic nuclei lined up along the brainstem midline (raphe: seam); the lower cluster (raphe magnus, obscurus, pallidus) lies in the medulla and projects to the spinal cord.
• Dorsal raphe (DR): in the midbrain and upper pons, ventral to the aqueduct and PAG; the source of most serotonergic fibers in the forebrain.
• Median raphe (MnR, superior central nucleus): in the midline of the upper pons, ventral to the DR; projects especially to the hippocampus and septum.
• Some neurons are not serotonergic: GABA, glutamate and dopamine neurons are also present.

Functions

• Regulation of mood and of emotional reactivity to negative stimuli.
• Impulse control: being able to wait for a delayed reward and to stop behavior in the face of punishment.
• Sleep–wake: most active when awake, reduced in NREM sleep and silent in REM sleep; contributes to appetite and circadian rhythm.
• Coping with stress: uncontrollable stress overactivates the DR; perceived controllability brakes this via the mPFC (the learned helplessness model; Maier and Seligman, 2016).
• MnR: regulation of hippocampal rhythm and contextual memory.

Connections and chemistry

• DR → prefrontal cortex, striatum, amygdala, thalamus, hypothalamus
• MnR → hippocampus and septum
• mPFC → DR (controllability; braking stress)
• Lateral habenula → DR and VTA (inhibition)
• Serotonin: 5-HT1A (autoreceptor), 5-HT2A, 5-HT2C, 5-HT3 receptors; SERT (the SSRI target)

Development

Developmental course through childhood and adolescence.

• Serotonergic neurons form in the early weeks of embryonic life; serotonin also acts as a trophic signal that influences neuronal migration and circuit formation.
• In mice, blocking the serotonin transporter early in life increases anxiety-like behavior in adulthood (Ansorge et al., 2004); the long-term effects of SSRI exposure in human pregnancy are debated.
• A different developmental course of brain serotonin synthesis capacity has been found in children with ASD (Chugani et al., 1999).

Clinical

• Depression, anxiety and OCD: the target of SSRIs is the serotonin transporter. Sertraline, fluoxetine and fluvoxamine are FDA-approved for pediatric OCD; fluoxetine and escitalopram for adolescent depression.
• Antidepressants carry a boxed warning on the risk of suicidal thoughts and behavior under age 25; close monitoring is needed in the first weeks of treatment.
• Serotonin syndrome: agitation, hyperthermia and clonus with combinations of serotonergic drugs.
• Findings of low serotonergic function have been reported in impulsive aggression and self-harm.
• ASD: some children have elevated blood serotonin (hyperserotonemia).

Treatment

This region from the perspective of medication, psychotherapy and neuromodulation. Letter badges are evidence levels.

• Adolescent depression (TADS; ages 12–17, 439 patients, 12 weeks): response 71% with fluoxetine + CBT, 61% with fluoxetine alone, 43% with CBT alone and 35% with placebo. The largest reduction in suicidal thinking was with combined treatment (TADS, 2004). By week 36 all three active arms reached 81–86%. A
• Childhood anxiety (CAMS; ages 7–17, 488 patients): much improved with sertraline + CBT 80.7%, CBT 59.7%, sertraline 54.9%, placebo 23.7%; combined treatment was superior to both (Walkup et al., 2008). A
• Starting an SSRI: begin with a low dose and monitor closely in the first weeks for suicidal thoughts and activation (restlessness, insomnia); continue treatment for at least 6–12 months. A
• To prevent serotonin syndrome, combinations of serotonergic drugs (e.g. an SSRI with tramadol, linezolid or triptans) are reviewed. B

Assessment

Neuropsychological tasks and measures that probe this region's function.

• Emotional processing and negative bias tasks (emotional face recognition, dot-probe)
• Delay discounting and waiting tasks: impulsivity
• Acute tryptophan depletion paradigm (research)
• Imaging of the serotonin transporter (SERT) and 5-HT1A receptor with PET (research)

Lesions and damage

Clinical findings expected with damage or dysfunction.

• Isolated raphe lesions are rare in humans; in animals, serotonin depletion leads to impulsivity, aggression and sleep disturbance.
• In animal studies, high-dose MDMA (ecstasy) damages serotonergic axons.

In the model

How this structure is defined in the 3D model, and the data source.

Harvard AAN v2.0 dorsal raphe (DR) and median raphe (MnR) labels; two separate parts in the same color. The caudal raphe nuclei of the medulla (magnus, obscurus, pallidus) are not in the atlas.

References

Full citations for the card; links go to the paper (DOI) or a PubMed search.

1. Treatment for Adolescents With Depression Study (TADS) Team. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression. JAMA 2004;292(7):807–820. Search PubMed
2. Walkup JT et al. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N Engl J Med 2008;359(26):2753–2766. Search PubMed