Abstract
Forebrain serotonin relevant for many psychological disorders arises in the hindbrain, primarily within the dorsal and median raphe nuclei (DR and MR). These nuclei are heterogeneous, containing several distinct groups of serotonin neurons. Here, new insight into the afferent and efferent connectivity of these areas is reviewed in correlation with their developmental origin. These data suggest that the caudal third of the DR, the area originally designated B6, may be misidentified as part of the DR as it shares many features of connectivity with the MR. By considering the rostral DR independently and affiliating the B6 to the MR, the diverse subgroups of serotonin neurons can be arranged with more coherence into two umbrella groups, each with distinctive domains of influence. Serotonin neurons within the rostral DR are uniquely interconnected with brain areas associated with emotion and motivation such as the amygdala, accumbens and ventral pallidum. In contrast serotonin neurons in the B6 and MR are characterized by their dominion over the septum and hippocampus. This distinction between the DR and B6/MR parallels their developmental origin and likely impacts their role in both behavior and psychopathology. Implications and further subdivisions within these areas are discussed.
Similar content being viewed by others
References
Aizawa H, Yanagihara S, Kobayashi M, Niisato K, Takekawa T, Harukuni R, McHugh TJ, Fukai T, Isomura Y, Okamoto H (2013) The synchronous activity of lateral habenular neurons is essential for regulating hippocampal theta oscillation. J Neurosci 33(20):8909–8921. doi:10.1523/JNEUROSCI.4369-12.2013
Alonso A, Merchan P, Sandoval JE, Sanchez-Arrones L, Garcia-Cazorla A, Artuch R, Ferran JL, Martinez-de-la-Torre M, Puelles L (2013) Development of the serotonergic cells in murine raphe nuclei and their relations with rhombomeric domains. Brain Struct Funct 218(5):1229–1277. doi:10.1007/s00429-012-0456-8
Amo R, Fredes F, Kinoshita M, Aoki R, Aizawa H, Agetsuma M, Aoki T, Shiraki T, Kakinuma H, Matsuda M, Yamazaki M, Takahoko M, Tsuboi T, Higashijima S, Miyasaka N, Koide T, Yabuki Y, Yoshihara Y, Fukai T, Okamoto H (2014) The habenulo-raphe serotonergic circuit encodes an aversive expectation value essential for adaptive active avoidance of danger. Neuron 84(5):1034–1048. doi:10.1016/j.neuron.2014.10.035
Arnone D, McIntosh AM, Ebmeier KP, Munafo MR, Anderson IM (2012) Magnetic resonance imaging studies in unipolar depression: systematic review and meta-regression analyses. Eur Neuropsychopharmacol 22(1):1–16. doi:10.1016/j.euroneuro.2011.05.003
Bach-Mizrachi H, Underwood MD, Tin A, Ellis SP, Mann JJ, Arango V (2008) Elevated expression of tryptophan hydroxylase-2 mRNA at the neuronal level in the dorsal and median raphe nuclei of depressed suicides. Mol psychiatry 13(5):507–513. doi:10.1038/sj.mp.4002143
Banasr M, Hery M, Printemps R, Daszuta A (2004) Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone. Neuropsychopharmacology 29(3):450–460. doi:10.1038/sj.npp.1300320
Bang SJ, Jensen P, Dymecki SM, Commons KG (2012) Projections and interconnections of genetically defined serotonin neurons in mice. Eur J Neurosci 35(1):85–96. doi:10.1111/j.1460-9568.2011.07936.x
Bland BH, Bland CE, MacIver MB (2015) Median raphe stimulation-induced motor inhibition concurrent with suppression of type 1 and type 2 hippocampal theta. Hippocampus. doi:10.1002/hipo.22521
Boldrini M, Underwood MD, Mann JJ, Arango V (2008) Serotonin-1A autoreceptor binding in the dorsal raphe nucleus of depressed suicides. J Psychiatr Res 42(6):433–442. doi:10.1016/j.jpsychires.2007.05.004
Brust RD, Corcoran AE, Richerson GB, Nattie E, Dymecki SM (2014) Functional and developmental identification of a molecular subtype of brain serotonergic neuron specialized to regulate breathing dynamics. Cell Rep 9(6):2152–2165. doi:10.1016/j.celrep.2014.11.027
Carboni E, Acquas E, Leone P, Perezzani L, Di Chiara G (1988) 5-HT3 receptor antagonists block morphine- and nicotine-induced place-preference conditioning. Eur J Pharmacol 151(1):159–160
Cheeta S, Irvine EE, Kenny PJ, File SE (2001) The dorsal raphe nucleus is a crucial structure mediating nicotine’s anxiolytic effects and the development of tolerance and withdrawal responses. Psychopharmacology 155(1):78–85
Cohen JY, Amoroso MW, Uchida N (2015) Serotonergic neurons signal reward and punishment on multiple timescales. eLife 4. doi:10.7554/eLife.06346
Commons KG (2008) Evidence for topographically organized endogenous 5-HT-1A receptor-dependent feedback inhibition of the ascending serotonin system. Eur J Neurosci 27(10):2611–2618
Commons KG (2015) Two major network domains in the dorsal raphe nucleus. J Comp Neurol. doi:10.1002/cne.23748
Crooks R, Jackson J, Bland BH (2012) Dissociable pathways facilitate theta and non-theta states in the median raphe–septohippocampal circuit. Hippocampus 22(7):1567–1576. doi:10.1002/hipo.20999
Dahlstrom A, Fuxe K (1964) Localization of monoamines in the lower brain stem. Experientia 20(7):398–399
Deakin JF, Graeff FG (1991) 5-HT and mechanisms of defence. J Psychopharmacol 5(4):305–315. doi:10.1177/026988119100500414
Diaz SL, Narboux-Neme N, Trowbridge S, Scotto-Lomassese S, Kleine Borgmann FB, Jessberger S, Giros B, Maroteaux L, Deneris E, Gaspar P (2013) Paradoxical increase in survival of newborn neurons in the dentate gyrus of mice with constitutive depletion of serotonin. Eur J Neurosci 38(5):2650–2658. doi:10.1111/ejn.12297
Encinas JM, Vaahtokari A, Enikolopov G (2006) Fluoxetine targets early progenitor cells in the adult brain. Proc Natl Acad Sci USA 103(21):8233–8238. doi:10.1073/pnas.0601992103
Fernandez SP, Cauli B, Cabezas C, Muzerelle A, Poncer JC, Gaspar P (2015) Multiscale single-cell analysis reveals unique phenotypes of raphe 5-HT neurons projecting to the forebrain. Brain Struct Funct. doi:10.1007/s00429-015-1142-4
Fornal CA, Metzler CW, Marrosu F, Ribiero-do-Valle LE, Jacobs BL (1996) A subgroup of dorsal raphe serotonergic neurons in the cat is strongly activated during oral-buccal movements. Brain Res 716(1–2):123–133. doi:10.1016/0006-8993(96)00006-6
Fox SR, Deneris ES (2012) Engrailed is required in maturing serotonin neurons to regulate the cytoarchitecture and survival of the dorsal raphe nucleus. J Neurosci 32(23):7832–7842. doi:10.1523/JNEUROSCI.5829-11.2012
Funato H, Sato M, Sinton CM, Gautron L, Williams SC, Skach A, Elmquist JK, Skoultchi AI, Yanagisawa M (2010) Loss of Goosecoid-like and DiGeorge syndrome critical region 14 in interpeduncular nucleus results in altered regulation of rapid eye movement sleep. Proc Natl Acad Sci USA 107(42):18155–18160. doi:10.1073/pnas.1012764107
Gaspar P, Lillesaar C (2012) Probing the diversity of serotonin neurons. Philos Trans R Soc Lond B Biol Sci 367(1601):2382–2394. doi:10.1098/rstb.2011.0378
Goutagny R, Loureiro M, Jackson J, Chaumont J, Williams S, Isope P, Kelche C, Cassel JC, Lecourtier L (2013) Interactions between the lateral habenula and the hippocampus: implication for spatial memory processes. Neuropsychopharmacology 38(12):2418–2426. doi:10.1038/npp.2013.142
Grahn RE, Will MJ, Hammack SE, Maswood S, McQueen MB, Watkins LR, Maier SF (1999) Activation of serotonin-immunoreactive cells in the dorsal raphe nucleus in rats exposed to an uncontrollable stressor. Brain Res 826(1):35–43
Hale MW, Lowry CA (2011) Functional topography of midbrain and pontine serotonergic systems: implications for synaptic regulation of serotonergic circuits. Psychopharmacology 213(2–3):243–264. doi:10.1007/s00213-010-2089-z
Hammack SE, Richey KJ, Schmid MJ, LoPresti ML, Watkins LR, Maier SF (2002) The role of corticotropin-releasing hormone in the dorsal raphe nucleus in mediating the behavioral consequences of uncontrollable stress. J Neurosci 22(3):1020–1026
Hammack SE, Schmid MJ, LoPresti ML, Der-Avakian A, Pellymounter MA, Foster AC, Watkins LR, Maier SF (2003) Corticotropin releasing hormone type 2 receptors in the dorsal raphe nucleus mediate the behavioral consequences of uncontrollable stress. J Neurosci 23(3):1019–1025
Hayashi K, Nakao K, Nakamura K (2015) Appetitive and aversive information coding in the primate dorsal raphe nucleus. J Neurosci 35(15):6195–6208. doi:10.1523/JNEUROSCI.2860-14.2015
Imai H, Steindler DA, Kitai ST (1986) The organization of divergent axonal projections from the midbrain raphe nuclei in the rat. J Comp Neurol 243(3):363–380
Jacobs BL, Azmitia EC (1992) Structure and function of the brain serotonin system. Physiol Rev 72(1):165–229
Jacobs BL, Fornal CA (1999) Activity of serotonergic neurons in behaving animals. Neuropsychopharmacology 21(2 Suppl):9S–15S. doi:10.1016/S0893-133X(99)00012-3
Jensen P, Farago AF, Awatramani RB, Scott MM, Deneris ES, Dymecki SM (2008) Redefining the serotonergic system by genetic lineage. Nat Neurosci 11(4):417–419. doi:10.1038/nn2050
Kinney GG, Kocsis B, Vertes RP (1994) Injections of excitatory amino acid antagonists into the median raphe nucleus produce hippocampal theta rhythm in the urethane-anesthetized rat. Brain Res 654(1):96–104
Kirby LG, Lucki I (1997) Interaction between the forced swimming test and fluoxetine treatment on extracellular 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the rat. J Pharmacol Exp Ther 282(2):967–976
Kirk IJ, Mackay JC (2003) The role of theta-range oscillations in synchronising and integrating activity in distributed mnemonic networks. Cortex 39(4–5):993–1008
Kocsis B, Vertes RP (1992) Dorsal raphe neurons: synchronous discharge with the theta rhythm of the hippocampus in the freely behaving rat. J Neurophysiol 68(4):1463–1467
Kocsis B, Vertes RP (1996) Midbrain raphe cell firing and hippocampal theta rhythm in urethane-anaesthetized rats. Neuroreport 7(18):2867–2872
Lechin F, van der Dijs B, Hernandez-Adrian G (2006) Dorsal raphe vs. median raphe serotonergic antagonism. Anatomical, physiological, behavioral, neuroendocrinological, neuropharmacological and clinical evidences: relevance for neuropharmacological therapy. Prog Neuropsychopharmacol Biol Psychiatry 30(4):565–585. doi:10.1016/j.pnpbp.2005.11.025
Li H, Scholl JL, Tu W, Hassell JE, Watt MJ, Forster GL, Renner KJ (2014) Serotonergic responses to stress are enhanced in the central amygdala and inhibited in the ventral hippocampus during amphetamine withdrawal. Eur J Neurosci 40(11):3684–3692. doi:10.1111/ejn.12735
Liu Z, Zhou J, Li Y, Hu F, Lu Y, Ma M, Feng Q, Zhang JE, Wang D, Zeng J, Bao J, Kim JY, Chen ZF, El Mestikawy S, Luo M (2014) Dorsal raphe neurons signal reward through 5-HT and glutamate. Neuron 81(6):1360–1374. doi:10.1016/j.neuron.2014.02.010
Malberg JE, Duman RS (2003) Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology 28(9):1562–1571. doi:10.1038/sj.npp.1300234
Maru E, Takahashi LK, Iwahara S (1979) Effects of median raphe nucleus lesions on hippocampal EEG in the freely moving rat. Brain Res 163(2):223–234
Matsumoto M, Hikosaka O (2009) Representation of negative motivational value in the primate lateral habenula. Nat Neurosci 12(1):77–84. doi:10.1038/nn.2233
McDevitt RA, Hiroi R, Mackenzie SM, Robin NC, Cohn A, Kim JJ, Neumaier JF (2011) Serotonin 1B autoreceptors originating in the caudal dorsal raphe nucleus reduce expression of fear and depression-like behavior. Biol Psychiatry 69(8):780–787. doi:10.1016/j.biopsych.2010.12.029
McDevitt RA, Tiran-Cappello A, Shen H, Balderas I, Britt JP, Marino RA, Chung SL, Richie CT, Harvey BK, Bonci A (2014) Serotonergic versus nonserotonergic dorsal raphe projection neurons: differential participation in reward circuitry. Cell Rep 8(6):1857–1869. doi:10.1016/j.celrep.2014.08.037
Meyer-Bernstein EL, Morin LP (1999) Electrical stimulation of the median or dorsal raphe nuclei reduces light-induced FOS protein in the suprachiasmatic nucleus and causes circadian activity rhythm phase shifts. Neuroscience 92(1):267–279
Mikkelsen JD, Hay-Schmidt A, Larsen PJ (1997) Central innervation of the rat ependyma and subcommissural organ with special reference to ascending serotoninergic projections from the raphe nuclei. J Comp Neurol 384(4):556–568
Miyazaki K, Miyazaki KW, Doya K (2012) The role of serotonin in the regulation of patience and impulsivity. Mol Neurobiol 45(2):213–224. doi:10.1007/s12035-012-8232-6
Miyazaki KW, Miyazaki K, Tanaka KF, Yamanaka A, Takahashi A, Tabuchi S, Doya K (2014) Optogenetic activation of dorsal raphe serotonin neurons enhances patience for future rewards. Curr Biol 24(17):2033–2040. doi:10.1016/j.cub.2014.07.041
Molliver ME (1987) Serotonergic neuronal systems: what their anatomic organization tells us about function. J Clin Psychopharmacol 7(6 Suppl):3S–23S
Morin LP (1999) Serotonin and the regulation of mammalian circadian rhythmicity. Ann Med 31(1):12–33
Muzerelle A, Scotto-Lomassese S, Bernard JF, Soiza-Reilly M, Gaspar P (2014) Conditional anterograde tracing reveals distinct targeting of individual serotonin cell groups (B5-B9) to the forebrain and brainstem. Brain Struct Funct. doi:10.1007/s00429-014-0924-4
Neckers LM, Schwartz JP, Wyatt RJ, Speciale SG (1979) Substance P afferents from the habenula innervate the dorsal raphe nucleus. Exp Brain Res 37(3):619–623
Ogawa SK, Cohen JY, Hwang D, Uchida N, Watabe-Uchida M (2014) Organization of monosynaptic inputs to the serotonin and dopamine neuromodulatory systems. Cell Rep 8(4):1105–1118. doi:10.1016/j.celrep.2014.06.042
Oh SW, Harris JA, Ng L, Winslow B, Cain N, Mihalas S, Wang Q, Lau C, Kuan L, Henry AM, Mortrud MT, Ouellette B, Nguyen TN, Sorensen SA, Slaughterbeck CR, Wakeman W, Li Y, Feng D, Ho A, Nicholas E, Hirokawa KE, Bohn P, Joines KM, Peng H, Hawrylycz MJ, Phillips JW, Hohmann JG, Wohnoutka P, Gerfen CR, Koch C, Bernard A, Dang C, Jones AR, Zeng H (2014) A mesoscale connectome of the mouse brain. Nature 508(7495):207–214. doi:10.1038/nature13186
Okaty BW, Freret ME, Rood BD, Brust RD, Hennessy ML, deBairos D, Kim JC, Cook MN, Dymecki SM (2015) Multi-scale molecular deconstruction of the serotonin neuron system. Neuron 88(4):774–791. doi:10.1016/j.neuron.2015.10.007
Pan WX, McNaughton N (2004) The supramammillary area: its organization, functions and relationship to the hippocampus. Prog Neurobiol 74(3):127–166. doi:10.1016/j.pneurobio.2004.09.003
Paxinos G, Franklin K (2004) The mouse brain in stereotaxic coordinates. Compact Second Edition edn, Elsevier
Paxinos G, Watson C (1998) The Rat Brain in Stereotaxic Coordinates, 4th edn. Academic Press, San Diego
Pollak Dorocic I, Furth D, Xuan Y, Johansson Y, Pozzi L, Silberberg G, Carlen M, Meletis K (2014) A whole-brain atlas of inputs to serotonergic neurons of the dorsal and median raphe nuclei. Neuron 83(3):663–678. doi:10.1016/j.neuron.2014.07.002
Quina LA, Tempest L, Ng L, Harris JA, Ferguson S, Jhou TC, Turner EE (2015) Efferent pathways of the mouse lateral habenula. J Comp Neurol 523(1):32–60. doi:10.1002/cne.23662
Rasmussen K, Kallman MJ, Helton DR (1997) Serotonin-1A antagonists attenuate the effects of nicotine withdrawal on the auditory startle response. Synapse 27(2):145–152. doi:10.1002/(SICI)1098-2396(199710)27:2<145:AID-SYN5>3.0.CO;2-E
Rive MM, van Rooijen G, Veltman DJ, Phillips ML, Schene AH, Ruhe HG (2013) Neural correlates of dysfunctional emotion regulation in major depressive disorder. A systematic review of neuroimaging studies. Neurosci Biobehav Rev 37(10 Pt 2):2529–2553. doi:10.1016/j.neubiorev.2013.07.018
Rygula R, Clarke HF, Cardinal RN, Cockcroft GJ, Xia J, Dalley JW, Robbins TW, Roberts AC (2014) Role of central serotonin in anticipation of rewarding and punishing outcomes: effects of selective amygdala or orbitofrontal 5-HT depletion. Cereb Cortex. doi:10.1093/cercor/bhu102
Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301(5634):805–809. doi:10.1126/science.1083328
Sego C, Goncalves L, Lima L, Furigo IC, Donato J Jr, Metzger M (2014) Lateral habenula and the rostromedial tegmental nucleus innervate neurochemically distinct subdivisions of the dorsal raphe nucleus in the rat. J Comp Neurol 522(7):1454–1484. doi:10.1002/cne.23533
Sheline YI, Barch DM, Donnelly JM, Ollinger JM, Snyder AZ, Mintun MA (2001) Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study. Biol Psychiatry 50(9):651–658
Soubrie P (1986) Reconciling the role of central serotonin neurons in human and animal behavior. Behav Brain Res 9(2):319–364
Sperling R, Commons KG (2011) Shifting topographic activation and 5-HT1A receptor-mediated inhibition of dorsal raphe serotonin neurons produced by nicotine exposure and withdrawal. Eur J Neurosci 33(10):1866–1875. doi:10.1111/j.1460-9568.2011.07677.x
Sporns O (2011) Networks of the Brain. The MIT Press, Cambridge
Stein DJ, Hollander E, Liebowitz MR (1993) Neurobiology of impulsivity and the impulse control disorders. J Neuropsychiatry Clin Neurosci 5(1):9–17
Valentino RJ, Lucki I, Van Bockstaele E (2009) Corticotropin-releasing factor in the dorsal raphe nucleus: linking stress coping and addiction. Brain Res 1314:29–37. doi:10.1016/j.brainres.2009.09.100
Valjakka A, Vartiainen J, Tuomisto L, Tuomisto JT, Olkkonen H, Airaksinen MM (1998) The fasciculus retroflexus controls the integrity of REM sleep by supporting the generation of hippocampal theta rhythm and rapid eye movements in rats. Brain Res Bull 47(2):171–184
Vertes RP (1981) An analysis of ascending brain stem systems involved in hippocampal synchronization and desynchronization. J Neurophysiol 46(5):1140–1159
Vertes RP (1991) A PHA-L analysis of ascending projections of the dorsal raphe nucleus in the rat. J Comp Neurol 313(4):643–668
Vertes RP, Kocsis B (1997) Brainstem-diencephalo-septohippocampal systems controlling the theta rhythm of the hippocampus. Neuroscience 81(4):893–926
Vertes R, Linley S (2008) Efferent and afferent connections of the dorsal and median raphe nuclei in the rat. In: Monti J, Pandi-Perumal S, Jacobs B, Nutt D (eds) Serotonin and sleep: molecular, functional and clinical aspects. Birkhauser Verlag, Switzerland
Vertes RP, Hoover WB, Viana Di Prisco G (2004) Theta rhythm of the hippocampus: subcortical control and functional significance. Behav Cogn Neurosci Rev 3(3):173–200. doi:10.1177/1534582304273594
Weissbourd B, Ren J, DeLoach KE, Guenthner CJ, Miyamichi K, Luo L (2014) Presynaptic partners of dorsal raphe serotonergic and GABAergic neurons. Neuron 83(3):645–662. doi:10.1016/j.neuron.2014.06.024
Wirtshafter D (2001) The control of ingestive behavior by the median raphe nucleus. Appetite 36(1):99–105. doi:10.1006/appe.2000.0373
Wu HH, Levitt P (2013) Prenatal expression of MET receptor tyrosine kinase in the fetal mouse dorsal raphe nuclei and the visceral motor/sensory brainstem. Dev Neurosci 35(1):1–16. doi:10.1159/000346367
Yamakawa GR, Antle MC (2010) Phenotype and function of raphe projections to the suprachiasmatic nucleus. Eur J Neurosci 31(11):1974–1983. doi:10.1111/j.1460-9568.2010.07228.x
Acknowledgments
Thanks to Dr. Patricia Gaspar for generous permission to use a modified figure from Muzerelle et al. as well as for comments on the manuscript. Additional thoughtful comments were provided by Drs. Daniel Ehlinger, Jessica Babb (Boston Children’s Hospital/Harvard Medical School), Dr. Bernat Kocsis (Beth Israel Deaconess/Harvard Medical School), Dr. Ben Okaty, Dr. Susan Dymecki (Harvard Medical School) and the reviewers; although all omissions, over-simplifications and errors remain my own. Funding provided by the National Institutes of Health Grants DA021801 and HD036379, the Brain and Behavior Foundation NARSAD Independent Investigator Award, and the Sara Page Mayo Foundation for Pediatric Pain Research.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Dr. Commons has no conflict of interest.
Rights and permissions
About this article
Cite this article
Commons, K.G. Ascending serotonin neuron diversity under two umbrellas. Brain Struct Funct 221, 3347–3360 (2016). https://doi.org/10.1007/s00429-015-1176-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00429-015-1176-7