Serotonin and Prefrontal Cortex Function: Neurons, Networks, and Circuits

Abstract

Higher-order executive tasks such as learning, working memory, and behavioral flexibility depend on the prefrontal cortex (PFC), the brain region most elaborated in primates. The prominent innervation by serotonin neurons and the dense expression of serotonergic receptors in the PFC suggest that serotonin is a major modulator of its function. The most abundant serotonin receptors in the PFC, 5-HT1A, 5-HT2A and 5-HT3A receptors, are selectively expressed in distinct populations of pyramidal neurons and inhibitory interneurons, and play a critical role in modulating cortical activity and neural oscillations (brain waves). Serotonergic signaling is altered in many psychiatric disorders such as schizophrenia and depression, where parallel changes in receptor expression and brain waves have been observed. Furthermore, many psychiatric drug treatments target serotonergic receptors in the PFC. Thus, understanding the role of serotonergic neurotransmission in PFC function is of major clinical importance. Here, we review recent findings concerning the powerful influences of serotonin on single neurons, neural networks, and cortical circuits in the PFC of the rat, where the effects of serotonin have been most thoroughly studied.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Miller EK, Cohen JD (2001) An integrative theory of prefrontal cortex function. Annu Rev Neurosci 24:167–202

    PubMed  CAS  Google Scholar 

  2. 2.

    Fuster J (2001) The prefrontal cortex—an update: time is of the essence. Neuron 30:319–333

    PubMed  CAS  Google Scholar 

  3. 3.

    Fuster JM (1997) The prefrontal cortex—anatomy, physiology and neuropsychology of the frontal lobe. Linpicott-Raven, Philadelphia-New York

    Google Scholar 

  4. 4.

    Pasupathy A, Miller EK (2005) Different time courses of learning-related activity in the prefrontal cortex and striatum. Nature 433:873–876

    PubMed  CAS  Google Scholar 

  5. 5.

    Antzoulatos EG, Miller EK (2011) Differences between neural activity in prefrontal cortex and striatum during learning of novel abstract categories. Neuron 71:243–249

    PubMed  CAS  Google Scholar 

  6. 6.

    Warden MR, Miller EK (2010) Task-dependent changes in short-term memory in the prefrontal cortex. J Neurosci 30:15801–15810

    PubMed  CAS  Google Scholar 

  7. 7.

    Freedman DJ et al (2001) Categorical representation of visual stimuli in the primate prefrontal cortex. Science 291:312–316

    PubMed  CAS  Google Scholar 

  8. 8.

    Chudasama Y et al (2003) Dissociable aspects of performance on the 5-choice serial reaction time task following lesions of the dorsal anterior cingulate, infralimbic and orbitofrontal cortex in the rat: differential effects on selectivity, impulsivity and compulsivity. Behav Brain Res 146:105–119

    PubMed  CAS  Google Scholar 

  9. 9.

    Dalley J, Everitt B, Robbins T (2011) Impulsivity, compulsivity, and top-down cognitive control. Neuron 69:680–694

    PubMed  CAS  Google Scholar 

  10. 10.

    Clarke HF et al (2004) Cognitive inflexibility after prefrontal serotonin depletion. Science 304:878–880

    PubMed  CAS  Google Scholar 

  11. 11.

    Gruber AJ et al (2010) More is less: a disinhibited prefrontal cortex impairs cognitive flexibility. J Neurosci 30:17102–17110

    PubMed  CAS  Google Scholar 

  12. 12.

    Rygula R et al (2010) Differential contributions of the primate ventrolateral prefrontal and orbitofrontal cortex to serial reversal learning. J Neurosci 30:14552–14559

    PubMed  CAS  Google Scholar 

  13. 13.

    Groenewegen HJ, Uylings HB (2000) The prefrontal cortex and the integration of sensory, limbic and autonomic information. Prog Brain Res 126:3–28

    PubMed  CAS  Google Scholar 

  14. 14.

    Hajos M et al (1998) An electrophysiological and neuroanatomical study of the medial prefrontal cortical projection to the midbrain raphe nuclei in the rat. Neuroscience 87:95–108

    PubMed  CAS  Google Scholar 

  15. 15.

    Peyron C et al (1998) Forebrain afferents to the rat dorsal raphe nucleus demonstrated by retrograde and anterograde tracing methods. Neuroscience 82:443–468

    PubMed  CAS  Google Scholar 

  16. 16.

    Sesack SR et al (1989) Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: an anterograde tract-tracing study with Phaseolus vulgaris leucoagglutinin. J Comp Neurol 290:213–242

    PubMed  CAS  Google Scholar 

  17. 17.

    Amargós-Bosch M et al (2004) Co-expression and in vivo interaction of serotonin1A and serotonin2A receptors in pyramidal neurons of prefrontal cortex. Cereb Cortex 14:281–299

    PubMed  Google Scholar 

  18. 18.

    Celada P et al (2001) Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: involvement of serotonin-1A, GABAA, and glutamate receptors. J Neurosci 21:9917–9929

    PubMed  CAS  Google Scholar 

  19. 19.

    Puig MV et al (2003) In vivo modulation of the activity of pyramidal neurons in the rat medial prefrontal cortex by 5-HT2A receptors: relationship to thalamocortical afferents. Cereb Cortex 13:870–882

    PubMed  Google Scholar 

  20. 20.

    Puig MV, Artigas F, Celada P (2005) Modulation of the activity of pyramidal neurons in rat prefrontal cortex by raphe stimulation in vivo: involvement of serotonin and GABA. Cereb Cortex 15:1–14

    PubMed  Google Scholar 

  21. 21.

    Puig MV, Ushimaru M, Kawaguchi Y (2008) Two distinct activity patterns of fast-spiking interneurons during neocortical UP states. Proc Natl Acad Sci 105:8428–8433

    PubMed  CAS  Google Scholar 

  22. 22.

    Mitchell BD, Macklis JD (2005) Large-scale maintenance of dual projections by callosal and frontal cortical projection neurons in adult mice. J Comp Neurol 482:17–32

    PubMed  Google Scholar 

  23. 23.

    Otsuka T, Kawaguchi Y (2011) Cell diversity and connection specificity between callosal projection neurons in the frontal cortex. J Neurosci 31:3862–3870

    PubMed  CAS  Google Scholar 

  24. 24.

    Wilson CJ (1987) Morphology and synaptic connections of crossed corticostriatal neuron in the rat. J Comp Neurol 263:567–580

    PubMed  CAS  Google Scholar 

  25. 25.

    Rumberger A et al (1998) Correlation of electrophysiology, morphology, and functions in corticotectal and corticopretectal projection neurons in rat visual cortex. Exp Brain Res 119:375–390

    PubMed  CAS  Google Scholar 

  26. 26.

    Kasper EM et al (1994) Pyramidal neurons in layer 5 of the rat visual cortex. I. Correlation among cell morphology, intrinsic electrophysiological properties, and axon targets. J Comp Neurol 339:459–474

    PubMed  CAS  Google Scholar 

  27. 27.

    Morishima M, Kawaguchi Y (2006) Recurrent connection patterns of corticostriatal pyramidal cells in frontal cortex. J Neurosci 26:4394–4405

    PubMed  CAS  Google Scholar 

  28. 28.

    Morishima M et al (2011) Highly differentiated projection-specific cortical subnetworks. J Neurosci 31:10380–10391

    PubMed  CAS  Google Scholar 

  29. 29.

    Brown SP, Hestrin S (2009) Intracortical circuits of pyramidal neurons reflect their long-range axonal targets. Nature 457:1133–1136

    PubMed  CAS  Google Scholar 

  30. 30.

    Hattox AM, Nelson SB (2007) Layer V neurons in mouse cortex projecting to different targets have distinct physiological properties. J Neurophysiol 98:3330–3340

    PubMed  Google Scholar 

  31. 31.

    Dembrow NC, Chitwood RA, Johnston D (2010) Projection-specific neuromodulation of medial prefrontal cortex neurons. J Neurosci 30:16922–16937

    PubMed  CAS  Google Scholar 

  32. 32.

    Gupta A, Wang Y, Markram H (2000) Organizing principles for a diversity of GABAergic interneurons and synapses in the neocortex. Science 287:273–278

    PubMed  CAS  Google Scholar 

  33. 33.

    Kawaguchi Y, Kubota Y (1997) GABAergic cell subtypes and their synaptic connections in rat frontal cortex. Cereb Cortex 7:476–486

    PubMed  CAS  Google Scholar 

  34. 34.

    Kawaguchi Y, Kubota Y (1998) Neurochemical features and synaptic connections of large physiologically-identified GABAergic cells in the rat frontal cortex. Neuroscience 85:677–701

    PubMed  CAS  Google Scholar 

  35. 35.

    Markram H et al (2004) Interneurons of the neocortical inhibitory system. Nat Rev Neurosci 5:793–807

    PubMed  CAS  Google Scholar 

  36. 36.

    Uematsu M et al (2008) Quantitative chemical composition of cortical GABAergic neurons revealed in transgenic venus-expressing rats. Cereb Cortex 18:315–330

    PubMed  Google Scholar 

  37. 37.

    Hoyer D et al (1994) International union of pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol Rev 46:157–203

    PubMed  CAS  Google Scholar 

  38. 38.

    Pompeiano M, Palacios JM, Mengod G (1992) Distribution and cellular localization of mRNA coding for 5-HT1A receptor in the rat brain: correlation with receptor binding. J Neurosci 12:440–453

    PubMed  CAS  Google Scholar 

  39. 39.

    Pompeiano M, Palacios JM, Mengod G (1994) Distribution of the serotonin 5-HT2 receptor family mRNAs: comparison between 5-HT2A and 5-HT2C receptors. Mol Brain Res 23:163–178

    PubMed  CAS  Google Scholar 

  40. 40.

    Weber E, Andrade R (2010) Htr2a gene and 5-HT2A receptor expression in the cerebral cortex studied using genetically modified mice. Front Neurosci 4:1–12

    Google Scholar 

  41. 41.

    de Almeida J, Mengod G (2007) Quantitative analysis of glutamatergic and GABAergic neurons expressing 5-HT2A receptors in human and monkey prefrontal cortex. J Neurochem 103:475–486

    PubMed  Google Scholar 

  42. 42.

    Kia HK et al (1996) Ultrastructural localization of 5-hydroxytryptamine(1A) receptors in the rat brain. J Neurosci Res 46:697–708

    PubMed  CAS  Google Scholar 

  43. 43.

    Lopez-Gimenez JF et al (1997) Selective visualization of rat brain 5-HT2A receptors by autoradiography with [3H]MDL 100,907. Naunyn Schmiedebergs Arch Pharmacol 356:446–454

    PubMed  CAS  Google Scholar 

  44. 44.

    Martín-Ruiz R et al (2001) Control of serotonergic function in medial prefrontal cortex by serotonin-2A receptors through a glutamate-dependent mechanism. J Neurosci 21:9856–9866

    PubMed  Google Scholar 

  45. 45.

    Pazos A, Palacios JM (1985) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain Res 346:205–230

    PubMed  CAS  Google Scholar 

  46. 46.

    Santana N et al (2004) Expression of serotonin1A and serotonin2A receptors in pyramidal and GABAergic neurons of the rat prefrontal cortex. Cereb Cortex 14:1100–1109

    PubMed  Google Scholar 

  47. 47.

    Willins DL, Deutch AY, Roth BL (1997) Serotonin 5-HT2A receptors are expressed on pyramidal cells and interneurons in the rat cortex. Synapse 27:79–82

    PubMed  CAS  Google Scholar 

  48. 48.

    Puig MV et al (2010) Serotonin modulates fast-spiking interneuron and synchronous activity in the rat prefrontal cortex through 5-HT1A and 5-HT2A receptors. J Neurosci 30:2211–2222

    PubMed  CAS  Google Scholar 

  49. 49.

    Azmitia EC et al (1996) Cellular localization of the 5-HT1A receptor in primate brain neurons and glial cells. Neuropsychopharmacology 14:35–46

    PubMed  CAS  Google Scholar 

  50. 50.

    Cruz DA et al (2004) Serotonin1A receptors at the axon initial segment of prefrontal pyramidal neurons in schizophrenia. Am J Psychiatry 161:739–742

    PubMed  Google Scholar 

  51. 51.

    Czyrak A et al (2003) Serotonin 5-HT1A receptors might control the output of cortical glutamatergic neurons in rat cingulate cortex. Brain Res 989:42–51

    PubMed  CAS  Google Scholar 

  52. 52.

    De Felipe J et al (2001) Pyramidal cell axons show a local specialization for GABA and 5-HT inputs in monkey and human cerebral cortex. J Comp Neurol 433:148–155

    Google Scholar 

  53. 53.

    Jakab RL, Goldman-Rakic PS (1998) 5-Hydroxytryptamine2A serotonin receptors in the primate cerebral cortex: possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites. Proc Natl Acad Sci 95:735–740

    PubMed  CAS  Google Scholar 

  54. 54.

    Marek GJ, Aghajanian GK (1999) 5-HT2A receptor or alpha1-adrenoceptor activation induces excitatory postsynaptic currents in layer V pyramidal cells of the medial prefrontal cortex. Eur J Pharmacol 367:197–206

    PubMed  CAS  Google Scholar 

  55. 55.

    Vucurovic K et al (2010) Serotonin 3A receptor subtype as an early and protracted marker of cortical interneuron subpopulations. Cereb Cortex 20:2333–2347

    PubMed  Google Scholar 

  56. 56.

    Jakab RL, Goldman-Rakic PS (2000) Segregation of serotonin 5-HT2A and 5-HT3 receptors in inhibitory circuits of the primate cerebral cortex. J Comp Neurol 417:337–348

    PubMed  CAS  Google Scholar 

  57. 57.

    Jansson A et al (2001) Relationships of 5-hydroxytryptamine immunoreactive terminal-like varicosities to 5-hydroxytryptamine-2A receptor-immunoreactive neuronal processes in the rat forebrain. J Chem Neuroanat 22:185–203

    PubMed  CAS  Google Scholar 

  58. 58.

    Morales M, Bloom FE (1997) The 5-HT3 receptor is present in different subpopulations of GABAergic neurons in the rat telencephalon. J Neurosci 17:3157–3167

    PubMed  CAS  Google Scholar 

  59. 59.

    Puig MV et al (2004) In vivo excitation of GABA interneurons in the medial prefrontal cortex through 5-HT3 receptors. Cereb Cortex 14:1365–1375

    PubMed  Google Scholar 

  60. 60.

    Zhou FM, Hablitz JJ (1999) Activation of serotonin receptors modulates synaptic transmission in rat cerebral cortex. J Neurophysiol 82:2989–2999

    PubMed  CAS  Google Scholar 

  61. 61.

    Ferezou I et al (2002) 5-HT3 receptors mediate serotonergic fast synaptic excitation of neocortical vasoactive intestinal peptide/cholecystokinin interneurons. J Neurosci 22:7389–7397

    PubMed  CAS  Google Scholar 

  62. 62.

    Morales M et al (1996) Cellular and subcellular immunolocalization of the type 3 serotonin receptor in the rat central nervous system. Mol Brain Res 36:251–260

    PubMed  CAS  Google Scholar 

  63. 63.

    Lee S et al (2010) The largest group of superficial neocortical GABAergic interneurons expresses ionotropic serotonin receptors. J Neurosci 30:16796–16808

    PubMed  CAS  Google Scholar 

  64. 64.

    Morales M et al (1996) The type 3 serotonin receptor is expressed in a subpopulation of GABAergic neurons in the rat neocortex and hippocampus. Brain Res 731:199–202

    PubMed  CAS  Google Scholar 

  65. 65.

    Troca-Marin J, Geijo-Barrientos E (2010) Inhibition by 5-HT of the synaptic responses evoked by callosal fibers on cortical neurons in the mouse. Eur J Physiol 460:1073–1085

    CAS  Google Scholar 

  66. 66.

    Crino PB et al (1990) Cellular localization of serotonin 1A, 1B and uptake sites in cingulate cortex of the rat. J Pharmacol Exp Ther 252:651–656

    PubMed  CAS  Google Scholar 

  67. 67.

    Maroteaux L et al (1992) Mouse 5HT1B serotonin receptor: cloning, functional expression, and localization in motor control centers. Proc Natl Acad Sci 89:3020–3024

    PubMed  CAS  Google Scholar 

  68. 68.

    Tanaka E, North RA (1993) Actions of 5-hydroxytryptamine on neurons of the rat cingulate cortex. J Neurophysiol 69:1749–1757

    PubMed  CAS  Google Scholar 

  69. 69.

    Compan V et al (1998) Differential effects of serotonin (5-HT) lesions and synthesis blockade on neuropeptide-Y immunoreactivity and 5-HT1A, 5-HT1B/1D and 5-HT2A/2C receptor binding sites in the rat cerebral cortex. Brain Res 795:264–276

    PubMed  CAS  Google Scholar 

  70. 70.

    Murakoshi T et al (2001) Multiple G-protein-coupled receptors mediate presynaptic inhibition at single excitatory synapses in the rat visual cortex. Neurosci Lett 309:117–120

    PubMed  CAS  Google Scholar 

  71. 71.

    Laurent A et al (2002) Activity-dependent presynaptic effect of serotonin 1B receptors on the somatosensory thalamocortical transmission in neonatal mice. J Neurosci 22:886–900

    PubMed  CAS  Google Scholar 

  72. 72.

    Torres-Escalante JL et al (2004) 5-HT1A, 5-HT2, and GABAB receptors interact to modulate neurotransmitter release probability in layer 2/3 somatosensory rat cortex as evaluated by the paired pulse protocol. J Neurosci Res 78:268–278

    PubMed  CAS  Google Scholar 

  73. 73.

    Kruglikov I, Rudy B (2008) Perisomatic GABA release and thalamocortical integration onto neocortical excitatory cells are regulated by neuromodulators. Neuron 58:911–924

    PubMed  CAS  Google Scholar 

  74. 74.

    Mathur BN et al (2011) Serotonin induces long-term depression at corticostriatal synapses. J Neurosci 31:7402–7411

    PubMed  CAS  Google Scholar 

  75. 75.

    Bianchi C et al (2007) Serotonin modulation of cell excitability and of [3H]GABA and [3H]d-aspartate efflux in primary cultures of rat cortical neurons. Neuropharmacology 52:995–1002

    PubMed  CAS  Google Scholar 

  76. 76.

    Boschert U et al (1994) The mouse 5-hydroxytryptamine(1B) receptor is localized predominantly on axon terminals. Neuroscience 58:167–182

    PubMed  CAS  Google Scholar 

  77. 77.

    Sari Y et al (1999) Cellular and subcellular localization of 5-hydroxytryptamine(1b) receptors in the rat central nervous system: immunocytochemical, autoradiographic and lesion studies. Neuroscience 88:899–915

    PubMed  CAS  Google Scholar 

  78. 78.

    Miner LA et al (2003) Ultrastructural localization of serotonin(2A) receptors in the middle layers of the rat prelimbic prefrontal cortex. Neuroscience 116:107–117

    PubMed  CAS  Google Scholar 

  79. 79.

    Seguela P, Watkins KC, Descarries L (1989) Ultrastructural relationships of axon terminals in the cerebral cortex of the adult rat. J Comp Neurol 289:129–142

    PubMed  CAS  Google Scholar 

  80. 80.

    Mulligan KA, Törk I (1988) Serotonergic innervation of the cat cerebral cortex. J Comp Neurol 270:86–110

    PubMed  CAS  Google Scholar 

  81. 81.

    DeFelipe J, Jones EG (1988) A light and electron microscopic study of serotonin-immunoreactive fibers and terminals in the monkey sensory-motor cortex. Exp Brain Res 71:171–182

    PubMed  CAS  Google Scholar 

  82. 82.

    DeFelipe J et al (1991) Synaptic relationships of serotonin-immunoreactive terminal baskets on GABA neurons in the cat auditory cortex. Cereb Cortex 1:117–133

    PubMed  CAS  Google Scholar 

  83. 83.

    Hornung JP, Celio MR (1992) The selective innervation by serotonergic axons of calbindin-containing interneurons in the neocortex and hippocampus of the marmoset. J Comp Neurol 320:457–467

    PubMed  CAS  Google Scholar 

  84. 84.

    Smiley JF, Goldman-Rakic PS (1996) Serotonergic axons in monkey prefrontal cerebral cortex synapse predominantly on interneurons as demonstrated by serial section electron microscopy. J Comp Neurol 367:431–443

    PubMed  CAS  Google Scholar 

  85. 85.

    Foehring RC et al (2002) Serotonergic modulation of supragranular neurons in rat sensorimotor cortex. J Neurosci 22:8238–8250

    PubMed  CAS  Google Scholar 

  86. 86.

    Andrade R, Malenka RC, Nicoll RA (1986) A G protein couples serotonin and GABAB receptors to the same channels in hippocampus. Science 234:1261–1265

    PubMed  CAS  Google Scholar 

  87. 87.

    Goodfellow NM et al (2009) Layer II/III of the prefrontal cortex: inhibition by the serotonin 5-HT1A receptor in development and stress. J Neurosci 29:10094–10103

    PubMed  CAS  Google Scholar 

  88. 88.

    Beique JC et al (2004) Serotonergic regulation of membrane potential in developing rat prefrontal cortex: coordinated expression of 5-hydroxytryptamine (5-HT)1A, 5-HT2A, and 5-HT7 receptors. J Neurosci 24:4807–4817

    PubMed  CAS  Google Scholar 

  89. 89.

    Araneda R, Andrade R (1991) 5-Hydroxytryptamine2 and 5-hydroxytryptamine1A receptors mediate opposing responses on membrane excitability in rat association cortex. Neuroscience 40:399–412

    PubMed  CAS  Google Scholar 

  90. 90.

    Villalobos C et al (2005) Serotonergic regulation of calcium-activated potassium currents in rodent prefrontal cortex. Eur J Neurosci 22:1120–1126

    PubMed  Google Scholar 

  91. 91.

    Zhang ZW, Arsenault D (2005) Gain modulation by serotonin in pyramidal neurones of the rat prefrontal cortex. J Physiol 566:379–394

    PubMed  CAS  Google Scholar 

  92. 92.

    Spain WJ (1994) Serotonin has different effects on two classes of Betz cells from the cat. J Neurophysiol 72:1925–1937

    PubMed  CAS  Google Scholar 

  93. 93.

    Haj-Dahmane S, Andrade R (1996) Muscarinic activation of a voltage-dependent cation nonselective current in rat association cortex. J Neurosci 16:3848–3861

    PubMed  CAS  Google Scholar 

  94. 94.

    Gulledge AT et al (2009) M1 receptors mediate cholinergic modulation of excitability in neocortical pyramidal neurons. J Neurosci 29:9888–9902

    PubMed  CAS  Google Scholar 

  95. 95.

    Greene CC, Schwindt PC, Crill WE (1994) Properties and ionic mechanisms of a metabotropic glutamate receptor-mediated slow after depolarization in neocortical neurons. J Neurophysiol 72:693–704

    PubMed  CAS  Google Scholar 

  96. 96.

    Libri V et al (1997) Metabotropic glutamate receptor subtypes mediating slow inward tail current (IADP) induction and inhibition of synaptic transmission in olfactory cortical neurones. Br J Pharmacol 120:1083–1095

    PubMed  CAS  Google Scholar 

  97. 97.

    McCormick DA, Williamson A (1989) Convergence and divergence of neurotransmitter action in human cerebral cortex. Proc Natl Acad Sci 86:8098–8102

    PubMed  CAS  Google Scholar 

  98. 98.

    Haj-Dahmane S, Andrade R (1998) Ionic mchanism of the slow afterdepolarization induced by muscarinic receptor activation in rat prefrontal cortex. J Neurophysiol 80:1197–1210

    PubMed  CAS  Google Scholar 

  99. 99.

    Fowler MA et al (2007) Corticolimbic expression of TRPC4 and TRPC5 channels in the rodent brain. PLoS One 2:e573

    PubMed  Google Scholar 

  100. 100.

    Yan HD, Villalobos C, Andrade R (2009) TRPC channels mediate a muscarinic receptor-induced after depolarization in cerebral cortex. J Neurosci 29:10038–10046

    PubMed  CAS  Google Scholar 

  101. 101.

    Zhong P, Yan Z (2011) Differential regulation of the excitability of prefrontal cortical fast-spiking interneurons and pyramidal neurons by serotonin and fluoxetine. PLoS One 6:e16970

    PubMed  CAS  Google Scholar 

  102. 102.

    Beique JC et al (2007) Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex. Proc Natl Acad Sci 104:9870–9875

    PubMed  Google Scholar 

  103. 103.

    Lambe EK, Goldman-Rakic PS, Aghajanian GK (2000) Serotonin induces EPSCs preferentially in layer V pyramidal neurons of the frontal cortex in the rat. Cereb Cortex 10:974–980

    PubMed  CAS  Google Scholar 

  104. 104.

    Davies MF et al (1987) Two distinct effects of 5-hydroxytryptamine on single cortical neurons. Brain Res 423:347–352

    PubMed  CAS  Google Scholar 

  105. 105.

    Aghajanian GK, Marek GJ (1997) Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells. Neuropharmacology 36:589–599

    PubMed  CAS  Google Scholar 

  106. 106.

    Xiang Z, Prince DA (2003) Heterogeneous actions of serotonin on interneurons in rat visual cortex. J Neurophysiol 89:1278–1287

    PubMed  CAS  Google Scholar 

  107. 107.

    Gulledge AT et al (2007) Heterogeneity of phasic cholinergic signaling in neocortical neurons. J Neurophysiol 97:2215–2229

    PubMed  CAS  Google Scholar 

  108. 108.

    Leslie MJ, Bennett-Clarke CA, Rhoades RW (1992) Serotonin 1B receptors form a transient vibrissa-related pattern in the primary somatosensory cortex of the developing rat. Brain Res Dev 69:143–148

    CAS  Google Scholar 

  109. 109.

    Bennett-Clarke CA et al (1993) Serotonin 1B receptors in the developing somatosensory and visual cortices are located on thalamocortical axons. Proc Natl Acad Sci 90:153–157

    PubMed  CAS  Google Scholar 

  110. 110.

    Salichon N et al (2001) Excessive activation of serotonin (5-HT) 1B receptors disrupts the formation of sensory maps in monoamine oxidase A and 5-HT transporter knock-out mice. J Neurosci 21:884–896

    PubMed  CAS  Google Scholar 

  111. 111.

    Oleskevich S, Lacalle JC (1992) Reduction of GABAb inhibitory postsynaptic potentials by serotonin via pre- and postsynaptic mechanisms in CA3 pyramidal cells of rat hippocampus in vitro. Synapse 12:173–188

    PubMed  CAS  Google Scholar 

  112. 112.

    Johnson SW, Mercuri NB, North RA (1992) 5-Hydroxytryptamine1B receptors block the GABAB synaptic potential in rat dopamine neurons. J Neurosci 12:2000–2006

    PubMed  CAS  Google Scholar 

  113. 113.

    Kishimoto K, Koyama S, Akaike N (2001) Synergistic mu-opioid and 5-HT1A presynaptic inhibition of GABA release in rat periaqueductal gray neurons. Neuropharmacology 41:529–538

    PubMed  CAS  Google Scholar 

  114. 114.

    Yan QS, Yan SE (2001) Serotonin-1B receptor-mediated inhibition of [3H]GABA release from rat ventral tegmental area slices. J Neurochem 79:914–922

    PubMed  CAS  Google Scholar 

  115. 115.

    Koyama S et al (2002) Role of presynaptic 5-HT1A and 5-HT3 receptors in modulation of synaptic GABA transmission in dissociated rat basolateral amygdala neurons. Life Sci 72:375–387

    PubMed  CAS  Google Scholar 

  116. 116.

    Katsurabayashi S et al (2003) A distinct distribution of functional presynaptic 5-HT receptor subtypes on GABAergic nerve terminals projecting to single hippocampal CA1 pyramidal neurons. Neuropharmacology 44:1022–1030

    PubMed  CAS  Google Scholar 

  117. 117.

    Mlinar B, Falsini C, Corradetti R (2003) Pharmacological characterization of 5-HT1B receptor-mediated inhibition of local excitatory synaptic transmission in the CA1 region of rat hippocampus. Br J Pharmacol 138:71–80

    PubMed  CAS  Google Scholar 

  118. 118.

    Matsuoka T, Hasuo H, Akasu T (2004) 5-Hydroxytryptamine 1B receptors mediate presynaptic inhibition of monosynaptic IPSC in the rat dorsolateral septal nucleus. Neurosci Res 48:229–238

    PubMed  CAS  Google Scholar 

  119. 119.

    Hashimoto K, Kita H (2008) Serotonin activates presynaptic and postsynaptic receptors in rat globus pallidus. J Neurophysiol 99:1723–1732

    PubMed  CAS  Google Scholar 

  120. 120.

    Gartside SE et al (2000) Neurochemical and electrophysiological studies on the functional significance of burst firing in serotonergic neurons. Neuroscience 98:295–300

    PubMed  CAS  Google Scholar 

  121. 121.

    McQuade R, Sharp T (1995) Release of cerebral 5-hydroxytryptamine evoked by electrical stimulation of the dorsal and median raphe nuclei: effect of a neurotoxic amphetamine. Neuroscience 68:1079–1088

    PubMed  CAS  Google Scholar 

  122. 122.

    Puig MV, Celada P, Artigas F (2004) Serotonergic control of prefrontal cortex. Rev Neurol 39:539–547

    PubMed  CAS  Google Scholar 

  123. 123.

    Hajós M et al (2003) In vivo inhibition of neuronal activity in the rat ventromedial prefrontal cortex by midbrain-raphe nuclei: role of 5-HT1A receptors. Neuropharmacology 45:72–81

    PubMed  Google Scholar 

  124. 124.

    Li YQ et al (2001) Morphological features and electrophysiological properties of serotonergic and non-serotonergic projection neurons in the dorsal raphe nucleus. An intracellular recording and labeling study in rat brain slices. Brain Res 900:110–118

    PubMed  CAS  Google Scholar 

  125. 125.

    Wang S et al (2009) In vivo effects of activation and blockade of 5-HT2A/2C receptors in the firing activity of pyramidal neurons of medial prefrontal cortex in a rodent model of Parkinson's disease. Exp Neurol 219:239–248

    PubMed  CAS  Google Scholar 

  126. 126.

    Celada P et al (2008) The hallucinogen DOI reduces low-frequency oscillations in rat prefrontal cortex: reversal by antipsychotic drugs. Biol Psychiatry 64:392–400

    PubMed  CAS  Google Scholar 

  127. 127.

    Ji D, Wilson MA (2007) Coordinated memory replay in the visual cortex and hippocampus during sleep. Nat Neurosci 10:100–107

    PubMed  CAS  Google Scholar 

  128. 128.

    Marshall L et al (2006) Boosting slow oscillations during sleep potentiates memory. Nature 444:610–613

    PubMed  CAS  Google Scholar 

  129. 129.

    Landsness EC et al (2009) Sleep-dependent improvement in visuomotor learning: a causal role for slow waves. Sleep 32:1273–1284

    PubMed  Google Scholar 

  130. 130.

    Louie K, Wilson MA (2001) Temporally structured replay of awake hippocampal ensemble activity during rapid eye movement sleep. Neuron 29:145–156

    PubMed  CAS  Google Scholar 

  131. 131.

    Stickgold R (2005) Sleep-dependent memory consolidation. Nature 437:1272–1278

    PubMed  CAS  Google Scholar 

  132. 132.

    Fries P et al (2001) Modulation of oscillatory neuronal synchronization by selective visual attention. Science 291:1560–1563

    PubMed  CAS  Google Scholar 

  133. 133.

    Fries P (2009) Neuronal gamma-band synchronization as a fundamental process in cortical computation. Annu Rev Neurosci 32:209–224

    PubMed  CAS  Google Scholar 

  134. 134.

    Buschman TJ, Miller EK (2007) Top–down versus bottom–up control of attention in the prefrontal and posterior parietal cortices. Science 315:1860–1862

    PubMed  CAS  Google Scholar 

  135. 135.

    Engel AK, Fries P, Singer W (2001) Dynamic predictions: oscillations and synchrony in top–down processing. Nat Rev Neurosci 2:704–716

    PubMed  CAS  Google Scholar 

  136. 136.

    Bollimunta A et al (2011) Neuronal mechanisms and attentional modulation of corticothalamic alpha oscillations. J Neurosci 31:4935–4943

    PubMed  CAS  Google Scholar 

  137. 137.

    Siegel M, Warden MR, Miller EK (2009) Phase-dependent neuronal coding of objects in short-term memory. Proc Natl Acad Sci 106:21341–21346

    PubMed  CAS  Google Scholar 

  138. 138.

    Jensen O et al (2002) Oscillations in the alpha band (9–2 Hz) increase with memory load during retention in a short-term memory task. Cereb Cortex 12:877–882

    PubMed  Google Scholar 

  139. 139.

    Benchenane K, Tiesinga PH, Battaglia FP (2011) Oscillations in the prefrontal cortex: a gateway to memory and attention. Curr Opin Neurobiol 21:475–485

    PubMed  CAS  Google Scholar 

  140. 140.

    Contreras D, Steriade M (1995) Cellular basis of EEG slow rhythms: a study of dynamic corticothalamic relationships. J Neurosci 15:604–622

    PubMed  CAS  Google Scholar 

  141. 141.

    Mukovski M et al (2007) Detection of active and silent states in neocortical neurons from the field potential signal during slow-wave sleep. Cereb Cortex 17:400–414

    PubMed  Google Scholar 

  142. 142.

    Steriade M, Nuñez A, Amzica F (1993) A novel slow (< 1 Hz) oscillation of neocortical neurons in vivo: depolarizing and hyperpolarizing components. J Neurosci 13:3252–3265

    PubMed  CAS  Google Scholar 

  143. 143.

    Dringenberg HC, Vanderwolf CH (1997) Neocortical activation: modulation by multiple pathways acting on central cholinergic and serotonergic systems. Exp Brain Res 116:160–174

    PubMed  CAS  Google Scholar 

  144. 144.

    Portas CM, Bjorvatn B, Ursin R (2000) Serotonin and the sleep/wake cycle: special emphasis on microdialysis studies. Prog Neurobiol 60:13–35

    PubMed  CAS  Google Scholar 

  145. 145.

    Steriade M (2006) Grouping of brain rhythms in corticothalamic systems. Neuroscience 137:1087–1106

    PubMed  CAS  Google Scholar 

  146. 146.

    Ward LM (2003) Synchronous neural oscillations and cognitive processes. Trends Cogn Sci 7:553–559

    PubMed  Google Scholar 

  147. 147.

    Howard MW et al (2003) Gamma oscillations correlate with working memory load in humans. Cereb Cortex 13:1369–1374

    PubMed  Google Scholar 

  148. 148.

    Singer W (1999) Neuronal synchrony: a versatile code for the definition of relations? Neuron 24:49–65

    PubMed  CAS  Google Scholar 

  149. 149.

    Cardin JA et al (2009) Driving fast-spiking cells induces gamma rhythm and controls sensory responses. Nature 459:663–667

    PubMed  CAS  Google Scholar 

  150. 150.

    Sohal VS et al (2009) Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 459:698–702

    PubMed  CAS  Google Scholar 

  151. 151.

    Bartos M, Vida I, Jonas P (2007) Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks. Nat Rev Neurosci 8:45–56

    PubMed  CAS  Google Scholar 

  152. 152.

    Whittington MA, Traub RD (2003) Interneuron diversity series: inhibitory interneurons and network oscillations in vitro. Trends Neurosci 26:676–682

    PubMed  CAS  Google Scholar 

  153. 153.

    Oren I, Hajos N, Paulsen O (2010) Identification of the current generator underlying cholinergically induced gamma frequency field potential oscillations in the hippocampal CA3 region. J Physiol 588:785–797

    PubMed  CAS  Google Scholar 

  154. 154.

    Gulyás AI et al (2010) Parvalbumin-containing fast-spiking basket cells generate the field potential oscillations induced by cholinergic receptor activation in the hippocampus. J Neurosci 30:15134–15145

    PubMed  Google Scholar 

  155. 155.

    Monosov IE, Trageser JC, Thompson KG (2008) Measurements of simultaneously recorded spiking activity and local field potentials suggest that spatial selection emerges in the frontal eye field. Neuron 57:614–625

    PubMed  CAS  Google Scholar 

  156. 156.

    Nielsen KJ, Logothetis NK, Rainer G (2006) Dissociation between local field potentials and spiking activity in macaque inferior temporal cortex reveals diagnosticity-based encoding of complex objects. J Neurosci 26:9639–9645

    PubMed  CAS  Google Scholar 

  157. 157.

    Kreuter JD et al (2004) Cocaine-induced Fos expression in rat striatum is blocked by chloral hydrate or urethane. Neuroscience 127:233–242

    PubMed  CAS  Google Scholar 

  158. 158.

    Lu J, Greco MA (2006) Sleep circuitry and the hypnotic mechanism of GABA-A drugs. J Clin Sleep Med 2:S19–S26

    PubMed  Google Scholar 

  159. 159.

    Monti JM (2011) Serotonin control of sleep–wake behavior. Sleep Med Rev 15:269–281

    PubMed  Google Scholar 

  160. 160.

    Monti JM, Jantos H (2008) The roles of dopamine and serotonin, and of their receptors, in regulating sleep and waking. Prog Brain Res 172:625–646

    PubMed  CAS  Google Scholar 

  161. 161.

    Williams GV, Rao SG, Goldman-Rakic PS (2002) The physiological role of 5-HT2A receptors in working memory. J Neurosci 22:2843–2854

    PubMed  CAS  Google Scholar 

  162. 162.

    Liy-Salmeron G, Meneses A (2008) Effects of 5-HT drugs in prefrontal cortex during memory formation and the ketamine amnesia-model. Hippocampus 18:965–974

    PubMed  CAS  Google Scholar 

  163. 163.

    Carter OL et al (2005) Using psilocybin to investigate the relationship between attention, working memory, and the serotonin 1A and 2A receptors. J Cog Neurosci 17:1497–1508

    Google Scholar 

  164. 164.

    Scholes KE et al (2006) Acute serotonin and dopamine depletion improves attentional control: findings from the Stroop task. Neuropsychopharmacology 32:1600–1610

    PubMed  Google Scholar 

  165. 165.

    Clarke HF et al (2005) Prefrontal serotonin depletion affects reversal learning but not attentional set shifting. J Neurosci 25:532–538

    PubMed  CAS  Google Scholar 

  166. 166.

    Dalley JW et al (2002) Deficits in impulse control associated with tonically-elevated serotonergic function in rat prefrontal cortex. Neuropsychopharmacology 26:716–728

    PubMed  CAS  Google Scholar 

  167. 167.

    Winstanley CA et al (2004) 5-HT2A and 5-HT2C receptor antagonists have opposing effects on a measure of impulsivity: interactions with global 5-HT depletion. Psychopharmacology 176:376–385

    PubMed  CAS  Google Scholar 

  168. 168.

    Harrison AA, Everitt BJ, Robbins TW (1997) Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance: interactions with dopaminergic mechanisms. Psychopharmacology 133:329–342

    PubMed  CAS  Google Scholar 

  169. 169.

    Wingen M, Kuypers KPC, Ramaekers JG (2007) Selective verbal and spatial memory impairment after 5-HT1A and 5-HT2A receptor blockade in healthy volunteers pre-treated with an SSRI. J Psychopharmacol 21:477–485

    PubMed  CAS  Google Scholar 

  170. 170.

    Fernández-Pérez S, Pache DM, Sewell RDE (2005) Co-administration of fluoxetine and WAY100635 improves short-term memory function. Eur J Pharmacol 522:78–83

    PubMed  Google Scholar 

  171. 171.

    Carli M et al (2004) The serotonin 5-HT2A receptors antagonist M100907 prevents impairment in attentional performance by NMDA receptor blockade in the rat prefrontal cortex. Neuropsychopharmacology 29:1637–1647

    Google Scholar 

  172. 172.

    Carli M et al (2006) Dissociable contribution of 5-HT1A and 5-HT2A receptors in the medial prefrontal cortex to different aspects of executive control such as impulsivity and compulsive perseveration in rats. Neuropsychopharmacology 31:757–767

    PubMed  CAS  Google Scholar 

  173. 173.

    Boulougouris V, Tsaltas E (2008) Serotonergic and dopaminergic modulation of attentional processes. Prog Brain Res 172:517–542

    PubMed  CAS  Google Scholar 

  174. 174.

    Boulougouris V, Glennon JC, Robbins TW (2007) Dissociable effects of selective 5-HT2A and 5-HT2C receptor antagonists on serial spatial reversal learning in rats. Neuropsychopharmacology 33:2007–2019

    PubMed  Google Scholar 

  175. 175.

    Winstanley CA et al (2003) Intra-prefrontal 8-OH-DPAT and M100907 improve visuospatial attention and decrease impulsivity on the five-choice serial reaction time task in rats. Psychopharmacology 167:304–314

    PubMed  CAS  Google Scholar 

  176. 176.

    Talpos JC, Wilkinson LS, Robbins TW (2006) A comparison of multiple 5-HT receptors in two tasks measuring impulsivity. J Psychopharmacol 20:47–58

    PubMed  CAS  Google Scholar 

  177. 177.

    Puig MV (2011) Serotonergic modulation of the prefrontal cortex: from neurons to brain waves. In Psychiatric Disorders—Worldwide Advances (Ed. T. Uehara, InTech), URL: http://www.intechopen.com/articles/show/title/serotonergic-modulation-of-the-prefrontal-cortex-from-neurons-to-brain-waves

Download references

Acknowledgments

We are grateful to Francesc Artigas, Miquel Bosch, Pau Celada, and Yasuo Kawaguchi for their guidance and support. We also thank Daniel Avesar for contributing the data for Fig. 2. This work has been supported by a number of grants and fellowships from the Spanish, Japanese and U.S. governments. These include a fellowship from the Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS; M.V.P), a fellowship from the Japan Society for the Promotion of Science (JSPS, M.V.P.), a NARSAD Young Investigator Award from the Brain and Behavior Research Foundation (A.T.G.) and PHS grant R01 MH83806 (A.T.G.).

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Affiliations

Authors

Corresponding author

Correspondence to M. Victoria Puig.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Puig, M.V., Gulledge, A.T. Serotonin and Prefrontal Cortex Function: Neurons, Networks, and Circuits. Mol Neurobiol 44, 449–464 (2011). https://doi.org/10.1007/s12035-011-8214-0

Download citation

Keywords

  • Prefrontal cortex
  • Serotonin receptors
  • Neural oscillations
  • Pyramidal neuron
  • Fast-spiking interneuron
  • Electrophysiology