Institute of Experimental Medicine Anxiety, agression, depression Functions and disfunctions of complex systems József Haller

Three phases of coping with challenges Potential threat „Defeat" Environmental events Anxiety Alarm "Depression" Emotional responses Behavioral responses Risk avoidance („precutionary programs") Fight/flight („action programs") Activity avoidance („survival programs")

(„precutionary programs") Coping and psychiatric problems Emotional responses Conditions ... psychopathology Anxiety Risk avoidance („precutionary programs") Axiety disorders Aggression-related psychopathologies Depression These occur inadequately are persistent cause suffering Alarm Fight/flight („action programs") "Depression" Activity avoidance („survival programs")

Dysregulated coping – list of psychiatric disorders Anxiety Generalized Panic Agoraphobia Specific phobias Social phobia Post-traumatic stress disorder Agression-related Intermittent Explosive disorder Conduct disorder Oppositional-defiant disorder Antisocial personality disorder Borderline personality disorder Other disorders Schizophrenia Drug dependence (including alcohol) Attention deficit-hyperactivity disorder Neurological diseases Brain damage Epilepsy Alzheimer disease Depression Minor Major Bipolar General features comorbidity large frequency challenging in terms of suffering and costs Solutions Psychotherapy recognition of the problem (cognitíve therapy) problem-solving strategies (behavioral therapy) Pharmacotherapy understanding brain mechanisms identifying targets of intervention drug development

The first step of pharmacotherapy: understanding brain mechanisms The scientific model is a simplified artificial system, which is isomorphic in key features of the modelled phenomenon (alike but not the same) What makes psychiatric modelling possible? the universality of neural functions the universality of emotions the unversality of the stress-emotions relationship the homology of etiological factors

* Agression models Models of the natural phenomenon Psychopathology models Hypothalamic aggression The resident/intruder test Trait selection Stress models Developmental models 2 4 6 8 10 Soft bites Hard bites All bites Attack counts *

Circuits of aggression - „phenomenon" and psychopathology Are people different? Mainly electrophysiologic techniques (1960-2000) Psychosurgery Brain imaging Hess (1928) Siegel et al. (1960-1970) Activated by fighting Over-activatied in socially isolated rats Three-dimensional representation of the right-hand side of the brain by the Blender software, based on Paxinos and Watson (1998) PrL Cg1 MO IL VO LO NacSh LS BNST PVN HAA LH MeA CeA LA BLA dmPAG lPAG vlPAG dlPAG LC VTA Bregma -5.0 mm Bregma 0.0 mm +5.0 Mainly immuncytochemistry and pharmacology (1980-2000) Kruk et al. (1970-2000)

Anterior limbic cortex Aggression-related psychopathologies – treatments based on the natural phenomenon 1 2 Prefrontal cortex Anterior limbic cortex N. accumbens Amygdala Forebrain bundle Striatum Substantia nigra (dopamine) 1= nigrostriatal pathway (motor functions) 2= mezolimbic pathway (rewards) ventrális tegmentl area (dopamine) Dorsal raphe (serotonin) Locus coeruleus (noradrenaline) Current pharmacotherapies are based on these pathways Therapies based on psychopathologic models?

Anxiety models Models of the natural phenomenon Psychopatology models Selection lines, transgenic animals, etc... Vogel test

The circuits of anxiety Internal cues Raph Lc Agyk NE CRF hip Emotional memory Environmental cues Am processing Thal Thal ht sgc flight /avoidance perseverence panic

global inhibition (GABA) Anxiety – treatments based on the natural phenomenon global inhibition (GABA) anxiety decreases global excitation (glutamate, glicine) anxiety increases The dynamics of global excitation and inhibition 1 2 Prefrontal cortex Anterior limbic cortex N. accumbens Amygdala Forebrain bundle Striatum Substantia nigra (dopamine) 1= nigrostriatal pathway (motor functions) 2= mezolimbic pathway (rewards) ventrális tegmentl area (dopamine) Dorsal raphe (serotonin) Locus coeruleus (noradrenaline) Current pharmacotherapies are based on these pathways Therapies based on psychopathologic models?

Depression models – psychopatological symptom models Chronic mild stress - anhedonia

Circuits of depression

Anterior limbic cortex The treatment of depression sleep deprivation combined melatonin-serotonin therapy light therapy electroshock 1 2 Prefrontal cortex Anterior limbic cortex N. accumbens Amygdala Forebrain bundle Striatum Substantia nigra (dopamine) 1= nigrostriatal pathway (motor functions) 2= mezolimbic pathway (rewards) ventrális tegmentl area (dopamine) Dorsal raphe (serotonin) Locus coeruleus (noradrenaline)

Environmental effects Developmental conditions The treatment of psychiatric disorders – current strategies Environmental effects neuromodulation anxiolytics anti-agressive drugs antidepressant Prefrontális ktx Szaglógumó Gyrus Cinguli Hippocampus Amygdala Hypothalamus Thalamus Centrális szürkeállomány Developmental conditions "Background" (endocrine, metabolic, etc.) Genetic background

Strategies of the future Search for mechanisms Search for targets Testing Treatment what was changed in the brain (pathology!) are changes causative? does the „repairing” of brain changes „repair” behavior? is it applicable to humans? new generation of therapies

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