Hippocampus and serotonin

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  • http://www.nimh.nih.gov/health/publications/the-numbers-count-mental-disorders-in-america/index.shtml#MajorDepressiveDiagnostic and Statistical Manual of Mental Disorders. (DSM)
  • Hippocampus and serotonin

    1. 1. The Hippocampus and Serotonin Receptors:
    2. 2. A table of contents • • • • Characteristics of the Raphe Nuclei Function of the Raphe Nuclei Malfunction of the hippocampus in depression Serotonin Receptors (5-HTRs) and Signal Transduction • 5-HT innervations in the hippocampus • Signal Transduction of the pyramidal cells • Summary 1
    3. 3. A table of contents • • • • Characteristics of the Raphe Nuclei Function of the Raphe Nuclei Malfunction of the hippocampus in depression Serotonin Receptors (5-HTRs) and Signal Transduction • 5-HT innervations in the hippocampus • Signal Transduction of the pyramidal cells • Summary 2
    4. 4. What is depression? And What’s the cause Major depression is one of the most common mood disorders(over 20% of U.S. for over 18 yo during life, NIH). Symptoms: A loss of interest, Change of mood representations, Impairment of social, occupational, or educational function, Sleep problem(Insomnia or hypersomnia), indecisive, Suicidality, Worthlessness(DSM-IV, 1994) Why Serotonin?: Low levels of serotonin in the patients(Serotonin-deficiency theory)[Lacasse, Plos Med., 2005] Strong evidence: Selective Serotonin Reuptake Inhibitors(SSRI) -> induction of extracellular serotonin increase • Major antidepressant drugs(about -70%) However, detailed etiology is still unknown. 3
    5. 5. Aim of This Independent Study Some discrepancies: 1) A slow effect of SSRI on mood even after acute treatment[Harmer, BJPsychiatry, 2009] 2) SSRI is not completely effective(Dopamine theory, BDNF theory)[Dunlop, Arch Gen psychiatry, 2006;Trivedi, The New England Journal Serotonergic projections of Medicine, 2006] On the other hand….(several indication) 1)15 subgroups of Serotonin (5-HT) receptor family and different effect on neurons 2) Region-dependent distribution of the receptors 3) Strong Serotonergic innervations related with several brain regions in the depression patients(the hippocampus, the basal ganglia, and the amygdala). 4
    6. 6. Presumption of depression Presumption: • Neuronal network might cause differential effect on multiple brain regions due to different receptor types of serotonin. Purpose of this seminar • Summary of detailed survey of serotonin innervations 5
    7. 7. A table of contents • Characteristics of the Raphe Nuclei • Serotonin Receptors (5-HTRs) and Signal Transduction • Malfunction of the hippocampus in depression • 5-HT innervations in the hippocampus • Signal Transduction of the pyramidal cells • Summary 6
    8. 8. Serotonin (5-HT) • One of monoamine neurotransmitters • 5-HT, tryptophan, and melatonin are related metabolites. • Breathing rhythms, heart rate, locomotion, circadian rhythms, emotions, and neurogenesis. 7
    9. 9. General Characteristics of Raphe Nuclei Classification: The raphe nuclei: serotonin (5-HT) containing neuron clusters(Midline of the brainstem) • Subdivisions in rats: B1: Raphe Pallidus, B2: Raphe Obscurus, B3: Raphe magnus, B4: Raphe Obscurus(dorsolateral part), B5: Raphe Pontis, B6: Dorsal Raphe Nucleus(caudal part), B7: Dorsal Raphe Nucleus(Principal part), B8:Median Raphe Necules(Main party), B9:Dorsal Pontine Tegmentum • 85% of 5-HT neurons in Rostral(B7, B8) part of human brains[Hornung, J. Chemi. Neuroana. 2003] [Siegel, 2008] Fig 2 Caudal part(B13), Rostral(B7, B 8) [Stahl S., 1996] revised by CNS 8
    10. 10. General Characteristics of Raphe Nuclei DR: cell size(3040um), fusiform, darkly stained MR: cell size(1012um), oval, ligh tly stained[Verte., 20 07] [Vertes and Linley, International Congress Series, 2007] Dorsal Raphe(DR) projections in rat: the ventral tegmental area(VTA), the substantia nigra pars compacta(SNc), some regions of hypothalamus, amygdala complexes, dorsal and ventral striatum, lateral septum(LS), the entorhinal(EC), medial orbital (MO) and the medial prefrontal cortex (mPFC), the hippocampus. (anterograde tracer with PHA-L[Vertes and Linley, 2007]) Median Raphe(MR) projections in rat: the interpeduncular nucleus, VTA, medial mammillary nucleus, parts of the midline and intralaminar thalamus, the lateral habenula, septum, ventral striatum(Nucleus accumbens), the hippocampus, medial septum (MS)[Vertes J.Comp. Neurol, 1999; Vertes and Blue: dopaminergic nuclei Linley, 2007]. Red: Amygdala related Orange: Basal Ganglia Brown: hippocampus 9
    11. 11. Reciprocal links between DRN and MRN “We are brothers and friends, but…” DRN affects MRN, but MDR does not affect much. DRN unknown MRN Glu application into the DRN[Mokler, 2009] Mutual connections in rats and hamster[Vertes and et al., 1988, 1991, 1999; Tisheler and Morin, Brain Res., 2003] The mean of extracellular 5-HT: DRN(15.6 ± 2.4 fmol/20ul = 0.78 ± 0.12 nmol/l; n = 16), MRN(10.6 ± 1.3 fmol/20ul = 0.53 ± 0.065 nmol/l; n=16)[Mokler, Brain Res., 2009] Putative Firing rate of 5-HT neurons: DRN(1.34 ± 0.09 Hz), MRN(0.54 ± 0.05 Hz)[Judge., etal, Neurochemi., 2006] Glu application into the MRN[Mokler, 2009] 11
    12. 12. Function of DRN -Patience and ImpulsivityPatience and Impulsivity 1. Activation 5-HT Neurons in DRN during waiting delayed rewards 2. Negative correlation between 5-HT activity and Wait Error. Omission trials counted by removal of nosepoking. [Miyazaki et al., Mol Neurobiol, 2012] 12
    13. 13. Disruption of theta rhythms by stimulation of Serotonergic neurons in MRN (cited from UCLA facility) [Hsiao et al., Behavioral Brain Resarch,2012] MS – DBB: Medial septum-diagonal band of Broca LHA: Lateral hypothalamic area Hypocretin: Orexin Theta Rhythms (4 - 10 Hz): relationship with memory consolidation in the hippocampus and possible to be induced by stress Induction of Inescapable foot shook by MS-DBB Prevention of theta rhythms by lesion of MS – DBB[] 14 [Hsiao et al., Behavioral B. Res., 2013]
    14. 14. A table of contents • • • • Characteristics of the Raphe Nuclei Function of the Raphe Nuclei Malfunction of the hippocampus in depression Serotonin Receptors (5-HTRs) and Signal Transduction • 5-HT innervations in the hippocampus • Signal Transduction of the pyramidal cells • Summary 15
    15. 15. Malfunction of hippocampal neurogenesis hypothesis Slow effect of SSRI or Antidepressant drugs (AD) -> Morphological changes (?) • Brain-Derived Neurotrophin Factor (BDNF) -> Induction of Neuro-proliferation -> Promotion of Neurogenesis • Decrease of BDNF by stress in hippocampus[Smith et al., 1995] • BDNF mRNA promotion by AD drugs[Nibuya, J. Nuro., 1995] [Berton, Nature Neuro., 2006] Chronic ADs increase neurogenesis in Rat hippocampus[Malberg, J. Neuro., 2000] 16
    16. 16. Measurement of helplessness and anxiety The Forced Swim Test: Check immovability of mice Normal: Try to avoid water Abnormal: Be quiet. Interpretation: immovability shows despair. The Novelty Suppressed Feeding (NSF) test Check amount of foods in a novel environment after removal of feeding. Interpretation: hesitation for rewards shows level of anxiety of a new environment. 17
    17. 17. Malfunction of hippocampal neurogenesis hypothesis The novelty suppressed feeding[Kuteeva, Springer, 2010]. Selective inhibition of neurogenesis -> Prevention of Antidepressant Drugs effects[Santarelli et al., Science, 2003] Hippocampal volume reduction in depression patients [Bremner JD., CNS, 2002] 18
    18. 18. A table of contents • • • • Characteristics of the Raphe Nuclei Function of the Raphe Nuclei Malfunction of the hippocampus in depression Serotonin Receptors (5-HTRs) and Signal Transduction • 5-HT innervations in the hippocampus • Signal Transduction of the pyramidal cells • Summary 19
    19. 19. Subtypes Agonists 5-HT1A Tetalin, 5-MeODMT, BAY, 8-OHDOAT 5-HT1B 5-HT1D Antagonists G protein Localization Serotonin Receptors Function Spiperone, WAY-100135 Gi(AC↓, open K+), Go(close Ca2+) Hippocumpus,the lateral septum,entorhinal and cingular cortices, dorsal raphe nucleus Autoreceptor, Heteroreceptor (unselective) TFMPP, CGS12066B,Sumat riptan, L694247 Isamoltane, GR-55562, SB 224289, SB236057 Gi(AC↓) SN,globus pallidus,caudate putamen,ventral pallidum,entopeduncular nucleus,hippocampus, cortex,VTA Autoreceptor Sumatriptan, PNU 109291, BRL 15572 GR-127935 Gi(AC↓) SN,globus pallidus,caudate putamen,ventral pallidum,entopeduncular nucleus,hippocampus, cortex,VTA Autoreceptor 5-HT1E Gi(AC↓) The caudate,putamen amygdala,and cortical areas(Bruinvels, 1994) 5-HT1F Gi(AC↓) hippocumpus cortical areas 5-HT2A DOI, DOB, α-Me5HT ritanserin(vged o ,1989) Gq(PLC)↑ Cortex, claustrum, hippocampus, hypothalamus, basal ganglia 5-HT2C SB-243213(Blackbu rn et al., 2002) Mesulergine, SB-242084, RS-102221 Gq(PLC)↑ the chroid plexus, the frontal cortex,the limbic system,hippocumpus,septum,hypot halamus, striatum,nucleus accumbens,rhombencephalon,spin al cord Post synaptically expressed [Filip, 2009;Hoyer, 20 2002]
    20. 20. Subtypes Agonist s Antagonists G protein Localization 5-HT3 α-Me-5HT DAU 6215 Zacopride, Odanserton, Granisotron Zatosetron None(Ion channels-influx Na+, Ca2+, efflux K+) the caudal medulla, forebrain, SN, N. AC, prefrontl cortex, striatum SDZ-205557 GR-125487 Gs(AC↑) limbic regions, the olfactory system, striatum, medial habenula, hippocampus 5-HT5A Gi/o(AC↓) Hippocampus, hypothalamus, olfactory bulb, cortex, thalamus, striatum, pons 5-HT5B ? Habenula, raphe nucleui, hippocampus(in rodents); pseudogene(in humans) Lisuride, Colozapine SB271046 Gs(AC↑) Striatum, olfactory tubercle, N. Acc, Clozapine, Amitryptline Gs(AC↑) hypothalamus, thalamus, brain stem, striatum, cerebral cortex. 5-HT4 SC53116 5-HT6 5-HT7 LSD GABA-containing cells in neocortex, olfactory cortex, hippocampus, amygdala 21 [Filip, 2009;Hoyer, 2002]
    21. 21. Serotonin receptors and Signal Transduction a 22 [Berumen et al., The Scientific World Journal,2012]
    22. 22. Serotonin Receptors and Signal Transduction • a [Berumen et al., The Scientific World Journal,2012] 23
    23. 23. Serotonin Receptors and Signal Transduction • a 24 [Berumen et al., The Scientific World Journal,2012]
    24. 24. 25
    25. 25. 26
    26. 26. A table of contents • • • • Characteristics of the Raphe Nuclei Function of the Raphe Nuclei Malfunction of the hippocampus in depression Serotonin Receptors (5-HTRs) and Signal Transduction • 5-HT innervations in the hippocampus • Signal Transduction of the pyramidal cells • Summary 27
    27. 27. Hippocampus and 5-HT Ascending Projections MR fibers in dorsal Hippocampu s[Vertes, 199 9] Mouse Brain(cited from NeuroDigi) PHA-L MR fibers in ventral Hippocampus[Vertes, 1999] PHA-L 5-HT fibers[Morin et al., 1999] PHA-L MR fibers to hippocampus[Morin et al., 1999] CC: Central Gray GCL: granule cell layer Mo: Molecular layer of Dentate Gyrus PCL: Pyramidal Layer SLM: Stratum lacunosummoleculare SR: Stratum radiatum 28 SOr: Stratum oriens
    28. 28. Serotonin Receptor Expression in the mouse hippocampus • a 5Hippo. Localization HTR 1A granular, pyramidal N., and some glia (Presynaptic R as well) 1B Presynaptic N. of DRN or MRN 2A granular, pyramidal, and astrocytes 2C CA3 pyramidal. 3A CA2 and C3 Pyramidal N. 4 Cholinergic axon 5A Astrocytes 5B CA1 pyramidal cells 7 CA1 neurons 29
    29. 29. Serotonin Receptor Expression in the mouse hippocampus • a GCL: Granule cell layer, Glu ML: molecular layer, Hilus: 30
    30. 30. SSRI induces neurogenesis[Santralli, 2003] -> 5-HT increase in DG. • a [Berumen et al., The Scientific World Journal,2012] Q1. Which receptor is dominant? Assumption(As) . Maybe 5-HT1AR, and linking to inhibition of AC. 31
    31. 31. SSRI induces neurogenesis[Santralli, 2003] -> 5-HT increase in DG. • a Q1. Which receptor is dominant? Assumption(As). Maybe 5-HT1AR, and linking to inhibition of AC. Q2. Express where? [Berumen et al., The Scientific World Journal,2012] 32
    32. 32. SSRI induces neurogenesis[Santralli, 2003] -> 5-HT increase in DG. • a Q1. Which receptor is dominant? Assumption(As). Maybe 5HT1AR, and linking to inhibition of AC. Q2. Express where? a) Induction of neurogenesis by 5HT1A agonist in DG[Grabiec, 2009]. b) Inhibition of cell proliferation by 5-HT1A antagonist[Radley, JJ., 2002]. [Berumen et al., The Scientific World Journal,2012] 33
    33. 33. SSRI induces neurogenesis[Santralli, 2003] -> 5-HT increase in DG. • a Q1. Which receptor is dominant? Assumption(As). Maybe 5-HT1AR, and linking to inhibition of AC. Q2. Express where? a) Induction of neurogenesis by 5HT1A agonist in DG[Grabiec, 2009]. b) Inhibition of cell proliferation by 5-HT1A antagonist[Radley, JJ., 2002]. As: 1. GABA > Pyramidal How b) happen? [Berumen et al., The Scientific World Journal,2012] 34
    34. 34. SSRI induces neurogenesis[Santralli, 2003] -> 5-HT increase in DG. • a Q1. Which receptor is dominant? Assumption(As). Maybe 5-HT1AR, and linking to inhibition of AC. Q2. Express where? a) Induction of neurogenesis by 5HT1A agonist in DG[Grabiec, 2009]. b) Inhibition of cell proliferation by 5-HT1A antagonist[Radley, JJ.]. As: 1. GABA > Pyramidal How b) happen? 2. Pyramidal > GABA 5-HT1A G protein activates cAMP? [Berumen et al., The Scientific World Journal,2012] 35
    35. 35. SSRI induces neurogenesis[Santralli, 2003] -> 5-HT increase in DG. • a Q1. Which receptor is dominant? Assumption(As). Maybe 5-HT1AR, and linking to inhibition of AC. Q2. Express where? a) Induction of neurogenesis by 5HT1A agonist in DG[Grabiec, 2009]. b) Inhibition of cell proliferation by 5-HT1A antagonist[Radley, JJ.]. As: 1. GABA > Pyramidal How b) happen? 2. Pyramidal > GABA 5-HT1A G protein activates cAMP? 3. Other receptors? Other G proteins? 4. 5-HT increase in DG? [Berumen et al., The Scientific World Journal,2012] 36
    36. 36. Signal Transduction of Pyramidal neurons Unknow n 37 [Dumen et al., 2012]
    37. 37. Summary • 1. Serotonergic neurons project to the basal ganglia, the amygdala complex, the hippocampus, and others. • 5-HT affect neurogenesis as well as anxiety. • Differential 5-HTRs’ expression in hippocampus. • A causal receptor is still unknown. 38
    38. 38. Discussion Time Dance of the Rats[17c, Germany] 39

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