2011.10.15.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 1 Development of Complex Curricula for Molecular Bionics and Infobionics Programs within a consortial* framework** Consortium leader PETER PAZMANY CATHOLIC UNIVERSITY Consortium members SEMMELWEIS UNIVERSITY, DIALOG CAMPUS PUBLISHER The Project has been realised with the support of the European Union and has been co-financed by the European Social Fund *** **Molekuláris bionika és Infobionika Szakok tananyagának komplex fejlesztése konzorciumi keretben ***A projekt az Európai Unió támogatásával, az Európai Szociális Alap társfinanszírozásával valósul meg. PETER PAZMANY CATHOLIC UNIVERSITY SEMMELWEIS UNIVERSITY sote_logo.jpg dk_fejlec.gif INFOBLOKK 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 2 Peter Pazmany Catholic University Faculty of Information Technology BEVEZETÉS A FUNKCIONÁLIS NEUROBIOLÓGIÁBA INTRODUCTION TO FUNCTIONAL NEUROBIOLOGY www.itk.ppke.hu By Imre Kalló Contributed by: Tamás Freund, Zsolt Liposits, Zoltán Nusser, László Acsády, Szabolcs Káli, József Haller, Zsófia Maglóczky, Nórbert Hájos, Emilia Madarász, György Karmos, Miklós Palkovits, Anita Kamondi, Lóránd Erőss, Róbert Gábriel, Kisvárdai Zoltán Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 3 www.itk.ppke.hu Operation and operation failures of complex systems Anxiety Depression Psychiatric DisordersImre Kalló & József HallerPázmány Péter Catholic University, Faculty of Information Technology Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 4 www.itk.ppke.hu Behavior, behavioral disturbances BehaviorActions and reactions of the individual(humanoranimal) under the influence of internal and external stimuli Behavioral disturbanceAbnormal behavior developing under the influence of internal and/orexternal stimuli Abnormal behavior -inadequate for the situation -involves suffering -persistent Bahavioral disturbances in humans neurological disturbances (dementia, epilepsy, Alzheimer disease, brain injury, etc.) psychiatric disorders personality disorders (eg. psychopathy) clinical disorders (eg. anxiety and depression) Serious injury and/or functional disturbance of the CNS Mild functional deficits developing in response to stimuli of the CNS Mild developmental malformations, functional deficit of CNS Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 5 www.itk.ppke.hu How can behavioral disturbancesbe corrected? -1sthypothesis Reflex arches Reflex arch systems If behavior is action (or reaction), then it is related to movement …consequently, if there was something wrong with behavior than movement-control needed correction Planning and organizing of the voluntary movements Prefrontal ctx Thalamus Basal ganglia Sensory cortex Motor cortex Spinal cord Behavior is not just movement; it is emotion-driven movement Emotions, motivations Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 6 www.itk.ppke.hu Behavior, behavioral disturbance -corrected definitions, 2ndhypothesis BehaviorThe individual (human, animal) is emotionally motivated; emotions,actions and reactions are under the influence of internal and external stimuli Behavioral disturbanceAbnormal behavior and abnormal emotions developing under the influence of internal and external stimuli -Mismatch with the situation -Cause sufferings (equal with sufferings) -Chronic Emotional changes are expressed at the level of behavior 2ndhypothesis: Emotions need to be "corrected”, and the behavioral disturbance will be rectified Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 7 www.itk.ppke.hu Behavior, emotion, function Anxiety Depression Emotions Definite or uncertain fear Depression, dejectedness Circumstances of formation Novel situations Hopeless crisis Behavioral consequences Avoidance of risky places, and behaviors Behavioral reactions reduced to minimum Biological function Avoidance of un-necessary risks Ensuring survival Both can be abnormal if,: (1) areexpressed in inadequate situations (2) last too long, or occur frequently (3) involve suffering Both emotions are "self-defensive" Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 8 www.itk.ppke.hu Behavioral disturbance, emotion, function Anxiety Depression Types: generalized anxiety(context-independent fear) panic(short-term fear attacks) PTSD, ATSD(trauma-induced fear accompanied by many other symptoms) phobia (agoraphobia, zoophobia, horror of height, etc)(fear of well-defined objects, living beings or situations) obsessive-compulsive disorder(obsessive-compulsive actions driven byanxiety) Behavioral consequences:normal lifestylehindered Prevalencemen: 6-8%women: 10-15% Types:Minor(hopelessness, self pitiness, irritability, pessimistic view of future, symptoms of diseases without illness) Major(extreme sadness, self reproach, lack of self-esteem, avoidance of pleasantexperiences, memory-, sleeping-, and eating problems)Bipolar:Major + Maniac (euphoria, feelings of urgency, excitement, aggression, etc. Behavioral consequences: normal lifestylehindered suiciderisk Prevalencemen: 10-12%women: 15-20% The two disorders are often comorbid Function: unknown Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 9 www.itk.ppke.hu Behavioral disturbance, emotion, function Anxiety Depression Types: generalized anxiety(context-independent fear) panic(short-term fear attacks) PTSD, ATSD(trauma-induced fear accompanied by many other symptoms) phobia (agoraphobia, zoophobia, horror of height, etc)(fear of well-defined objects, living beings or situations) obsessive-compulsive disorder(obsessive-compulsive actions driven byanxiety) Behavioral consequences:normal lifestylehindered Prevalencemen: 6-8%women: 10-15% Types:Minor(hopelessness, self pitiness, irritability, pessimistic view of future, symptoms of diseases without illness) Major(extreme sadness, self reproach, lack of self-esteem, avoidance of pleasantexperiences, memory-, sleeping-, and eating problems)Bipolar:Major + Maniac (euphoria, feelings of urgency, excitement, aggression, etc. Behavioral consequences: normal lifestylehindered suiciderisk Prevalencemen: 10-12%women: 15-20% The two disorders are often comorbid Function: unknown Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 10 www.itk.ppke.hu Prefrontal ctx Olphactory bulb Gyrus Cinguli Hippocampus Amygdala Hypothalamus Thalamus Central Gray Matter Papez circuit Mechanisms of emotional control –major components and functions Prefrontal cortexcontrol of voluntary movementsprocessing of informations attentionemotional attitude„personality" Cingular cortexcoordination of perception and emotions (eg. emotional component of pain) Thalamuscontrol of movementprocessing of sensory informations and relay to the cerebral cortex Hippocampusspatial orientation and memorynavigationemotions, emotional memory Amygdalavigilance, movement controlemotional responses (fear, aggression, reward)control of hormonal responses Hypothalamusaction programs of emotional behaviorsendocrine functionsautonomic control Periaqueductal grey matterautonomic controlmovement controlemotional behaviors Olphactory bulbcomplex role in emotions and behavior (mostly non-humanspecies) How will all these result in emotions and movement? Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 11 www.itk.ppke.hu Prefrontal ctx Olphactory bulb Gyrus Cinguli Hippocampus Amygdala Hypothalamus Thalamus Central Gray Matter Papez circuit Mechanisms of emotional control –major components and functions Prefrontal cortexcontrol of voluntary movementsprocessing of informations attentionemotional attitude„personality" Cingular cortexcoordination of perception and emotions (eg. emotional component of pain) Thalamuscontrol of movementprocessing of sensory informations and relay to the cerebral cortex Hippocampusspatial orientation and memorynavigationemotions, emotional memory Amygdalavigilance, movement controlemotional responses (fear, aggression, reward)control of hormonal responses Hypothalamusaction programs of emotional behaviorsendocrine functionsautonomic control Periaqueductal grey matterautonomic controlmovement controlemotional behaviors Olphactory bulbcomplex role in emotions and behavior (mostly non-humanspecies) How will all these result in emotions and movement? Sensory cortex Motor cortex Spinal cord Prefrontális ktx Thalamus Bazális ganglionok Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 12 www.itk.ppke.hu System of the emotional control -diffuse effects Prefrontal ctx Olphactory bulb Gyrus Cinguli Hippocampus Amygdala Hypothalamus Thalamus Central grey matter Papez circuit raphe (serotonin) limbic system Introduction to functional neurobiology: Psychiatric Disorders Prefrontal ctx Olphactory bulb Gyrus Cinguli Hippocampus Amygdala Hypothalamus Thalamus Central grey matter Papez circuit 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 13 www.itk.ppke.hu System of the emotional control -diffuse effects raphe (serotonin) locus coeruleus (noradrenalin) limbic system motoros rendszer Senzory cortex Motor cortex Spinal cord Introduction to functional neurobiology: Psychiatric Disorders Prefrontal ctx Olphactory bulb Gyrus Cinguli Hippocampus Amygdala Hypothalamus Thalamus Central grey matter Papez circuit 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 14 www.itk.ppke.hu System of the emotional control -diffuse effects raphe (serotonin) locus coeruleus (noradrenaline) limbic system motor system Senzory cortex Motor cortex Spinal cord Introduction to functional neurobiology: Psychiatric Disorders Prefrontal ctx Olphactory bulb Gyrus Cinguli Hippocampus Amygdala Hypothalamus Thalamus Central grey matter Papez circuit 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 15 www.itk.ppke.hu System of the emotional control -diffuse effects raphe (serotonin) locus coeruleus (noradrenaline) limbic system motor system Senzory cortex Motor cortex Spinal cord Introduction to functional neurobiology: Psychiatric Disorders Prefrontal ctx Olphactory bulb Gyrus Cinguli Hippocampus Amygdala Hypothalamus Thalamus Central grey matter Papez circuit 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 16 www.itk.ppke.hu System of the emotional control -diffuse effects raphe (serotonin) locus coeruleus (noradrenaline) limbic system motor system Senzory cortex Motor kortex Spinal cord (Stress)hormones Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 17 www.itk.ppke.hu How does a complex system operate well? –a systems theory approach Emotion complex interactions Movement „wiring” stimulus-response stimulus -will-response Fine tuning diffuse effects General functional state Global effects Treatment options Hormones, hormone antagonists (testosterone, estrogen, cortizol) Compounds modifying serotonergic, nordrenergic, and dopaminergic neurotransmission Compound stimulating GABA neurotransmission Partial glutamate receptor agonists Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 18 www.itk.ppke.hu How does a complex system operate well? –systems theory approach Emotion complex interactions Movement „wiring stimulus-response stimulus -will-response Fine tuning diffuse effects General functional state Global effects Main risk: interference from bodily functions High risk approach, not recommended Limited possibilities The most frequently used option Treatment options Hormones, hormone antagonists (testosterone, estrogen, cortizol) Compounds modifying serotonergic, nordrenergic, and dopaminergic neurotransmission Compound stimulating GABA neurotransmission Partial glutamate receptor agonists Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 19 www.itk.ppke.hu Drug targets and treatment options synthesis precursor (eg. tyrosine) synthesis (enzymatic activity) storage in vesicles release signal transduction (receptors) reuptake/degradation Inhibition: lesions neurotoxins inhibition of synthetic enzymes inhibition of vezicular uptake stimulation of reuptake receptor antagonists Stimulation: increasing the amount of precursors facilitation of depletion inhibition of reuptake inhibition of degradation receptor agonists Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 20 www.itk.ppke.hu Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 21 www.itk.ppke.hu Systems theory approach Trouble real,potential, or hypothetical If envisoned If realised If sustained Anxiety Alarm Depression Precaution: Avoid risks (precaution "turned on") Mobilising „dormant" energies: Energy stores mobilized Active behavioral programs turned on(eg. fight or flight) Activity cutback : Some programs run at minimum Other programs suspended Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 22 www.itk.ppke.hu Neuronal pathways of anxiety Anxiety of animals environmental factors Am CTX Thal processing internal factors Lc emotionalmemory Se hip Thal sgc sustained fear, panic ht escape CRF NE Raph GLU GABA Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 23 www.itk.ppke.hu Neuronal pathways of anxiety Anxiety of animals environmental factors Am CTX Thal processing internal factors Lc emotionalmemory Se hip Thal sgc sustained fear, panic ht escape CRF NE Raph GLU GABA 10% CCK, GABA Raphe (5/HT) GABAA, alfa-2 subunits DORSALHIPPOCAMPUS Benzodiazepines, serotonergic anxiolytics Amygdala Locus coeruleus CRF NE Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 24 www.itk.ppke.hu GLU GABA CL- Barbiturates small doses opening probabilityincreases inhibition of anxiety large doses opening the channel hypnoticeffect toxicity Human: The most frequently used anxiolyticsare thebenzodiazepines, although they are addictive. Barbituratesare still used (relatively rarely). Aminoacids GABA complex Benzodiazepines modulation of channel-opening frequency agonists inhibition of anxiety antagonists preventingthe effects of anxiolytics inverse agonists increase of anxiety Excitatory aminoacids Glutamate, aspartate (glycine) Agonist effects: increase of anxietyHope: partial antagonism sustainanxiety states(posttraumatic stress disorder; SGC, NMDA/glycine) inhibition of benzodiazepine effects Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 25 www.itk.ppke.hu Most important benzodiazepine anxiolytics (thousands were synthesized) CompoundHalf life*Effects** Triazolam2-4hypnotic Lorazepam8-12anxiolytic, hypnotic Oxazepam Temazepam Lormetazepam Alprazolam6-12anxiolytic, antidepressant Nitrazepam16-40 Diazepam20-40 (Nordiazepam 60)anxiolytic, anticonvulsive Chlordiazepoxide4-5 Flurazepam1anxiolytic, Clonazepam50anticonvulsive, anxiolytic, *Effect can be significantly longer ** All reduce aggressiveness Side effects sedation muscle tone relaxation, movement coordinationproblems addiction Flumezanil: competitive benzodiazepine antagonist used to overcome the effects of overdosed benzodiazepines Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 26 www.itk.ppke.hu Amygdala Locus coeruleus CRF NE Hope Beta adrenergic antagonists Serotonergic anxiolytics Beta adrenergic antagonists Prefrontális ktx Szaglógumó Gyrus Cinguli Hippocampus Amygdala Hypothalamus Thalamus Centrális szürkeállomány Papez gyűrű Prefrontális ktx Szaglógumó Gyrus Cinguli Hippocampus Amygdala Hypothalamus Thalamus Centrális szürkeállomány Papez circuit raphe (serotonin) locus coeruleus (noradrenaline) Anxiolyzis Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 27 www.itk.ppke.hu 10% CCK, GABA Raphe (5/HT3) GABAA, alfa-2 subunit DORZAL HIPPOCAMPUS Benzodiazepines, serotonergicanxiolytics Hope hope hope ... Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 28 www.itk.ppke.hu Experimental modelling of anxiety light/dark box hole board elevated plus maze social interaction other, eg. shock-prod Vogel-test passive avoidance open field Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 29 www.itk.ppke.hu Experimental modelling of anxiety black/whitebox light/dark box hole board hole board elevated plus maze elevated plus-maze social interaction other, eg. shock-prod Vogel-test passive avoidance passive avoidance open field open field Such tests and models are used to Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 30 www.itk.ppke.hu Neuronal pathways of depression Pathway OlphAmygdala bulb Raphe 5HT1A, MR/GR Hippocampus alfa-1 Locus coeruleusalfa-2 LocusCentral coeruleusamygdala Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 31 www.itk.ppke.hu Neuronal pathways of depression Pathway OlphAmygdala bulb Raphe 5HT1A, MR/GR Hippocampus alfa-1 Locus coeruleusalfa-2 LocusCentral coeruleusamygdala Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 32 www.itk.ppke.hu The monoamine theory of depression Depression can be traced back to reduced monoamine (noradrenergic and serotonergic) functions in the brain. Arguments: Depression has a strong genetic component (biochemical abnormality) Symptoms of depression arereduced or blocked by compounds, which stimulate the monoaminergic system Norepinephrine metabolites are reduced inthe blood and cerebrospinal fluid of depressive patients Serotoninemetabolites are reduced in thecerebrospinal fluid of depressive patients Serotonin uptake is reduced in platelets Counter arguments: Biochemical effects of monoaminergic antidepressants are fastwhilebehavioral effectsdevelop slowly Data on monomamine metabolism are controversial Based on biochemical activity, certain compounds (e.g. amphetamine, cocaine) should decreasesymptoms of depression but the do not have such effects Certain compoundsdecrease depression without affecting the monoaminergicsystem Conclusion: Compounds that stimulatemonoaminergic neurotransmission also decrease the symptoms of depression; Their behavioral effects are not necessarily direct consequences of theirprimary biochemical effects. Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 33 www.itk.ppke.hu Antidepressants Tricyclicantidepressants (TCA) compounds:imipramine, amitriptillin, clomipramine, desipramin, nortryptillin, protriptillin, doxipramin effects: inhibition of NE, 5-HT reuptake side effects: sedation, disturbed motorcoordination (weakens with time), dry mouth, constipation,urine retention Monoamine oxidaseinhibitors (MAOI) compounds:phenelzine, tranylcypromine, iproniazid effects:reduction of enzymatic degradation of NE, 5-HT, DA side effects: reduction of blood pressure, tremor, excitation, insomnia, weight increase, hepatotoxicity (rare) Selective Serotonin Reuptake Inhibitors (SSRI) compounds:fluoxetine, fluvoxamine, paroxetine, sertraline, nefopan effects:inhibition of 5-HT reuptake side effects: nausea, insomnia, weight increase Selective NoradrenalineReuptake Inhibitors (SNRI) compounds:nomifensine, maprotiline effects: inhibition of NE reuptake side effects: sedation, dry mouth, disturbed vision, etc Alpha-2 adrenergic blockers compounds:mianserine effects:increase of NE release side effects: sedation, dry mouth, disturbed vision, etc Tyaneptin Iprindole Litium Electroshock Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 34 www.itk.ppke.hu Experimental modelling of depression Chronic mild stress Bulbectomy Flinder's sensitive line Sleep deprivation Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 35 www.itk.ppke.hu Experimental modelling of depression Chronic mild stress Bulbectomy Flinder's senzitive line Sleep deprivation Such tests and models are used to Introduction to functional neurobiology: Psychiatric Disorders 2011.10.15. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 36 www.itk.ppke.hu Emotion complex interactions Movement „wiring stimulus-response stimulus -will-response Fine tuning diffuse effects General functional state Global effects 10% CCK, GABA Raphe (5/HT3) GABAA, alfa-2 subunit Subcellular/molecular mechanisms