Brain complexity and disease SM MAAS

Transcription

1 Brain complexity and disease September 9, 2009 Dr. Stefan Maas, BioS Lehigh U.

2 Brain networks lehigh.edu SMAAS

3 Brain Trivia The average number of more than The adult neurons in 100,000 brain weighs the brain = kilometers of about 3 pounds. 100 billion. interconnections The average number of glial cells in the brain = times the number of neurons.

4 Complexity of the Brain 100 billion neurons plus >1 trillion glia cells connected by 100 Trillion synapses in a single human brain organized into exquisitely complex circuits responding to experience, drugs, disease, and injury

5 Generation of Complexity Areas generated = 2 n - 1 where n is the number of "things"

6 Complexity of the Brain

7 Nerve Cell Communi- cation Synapse

8 Complexity of the Brain The synapse typically has two parts: A presynaptic structure containing packets of neuro- transmitters and a postsynaptic structure of the receiving neuron

9 Cerebral cortex Sensory input Information integration cognition, thought, mood, emotion Motor output acetylcholine norepinephrine serotonin dopamine histamine

10 Neuromodulatory inputs NE Excitatory input Glutamate GluR Neuromodulatory inputs ACh DA Hist D 1 1 M 1 camp PKA Ca 2+ Ca 2+ -dependent Kinases/phosphatases Down-stream substrates IP3 + DG PKC 5-HT 2C 5-HT Hist H 2 Gene expression H 1 Short-term synaptic modification Long-term synaptic modification

11 lehigh.edu SMAAS

12 Neuromodulatory inputs NE Excitatory input Glutamate GluR Neuromodulatory inputs ACh 1 M 1 DA D 1 5-HT Hist 5-HT 2C Hist H 2 H 1

13 Gene splicing: Removal of non-coding introns Exon Intron mature splice product PROTEIN

14 h.edun lehigh SMAAS

15 RNA editing 5 A 3 transcription genomic DNA 5 A 3 pre-mrna A-to-I editing 5 I 3 splicing i + translation ti

16 Mammalian substrates of A-to to-i pre-mrna editing Gene codon amino acid editing g[ [%] GluR-B CAG/CIG Q/R 100 GluR-B, B,-C, C,-D AAG/AIG G R/G GluR-5, 5,-6 CAG/CIG G Q/R GluR-6 AUU/IUU I/V 80 UAC/UIC C Y/C 80 5-HT 2C AUA/IUA I/V Serotonin- AAU/AIU U N/S receptor AUU/IUU I/V 45-75

17 Diversity through RNA editing GluR-6 pre-mrna M1 M2 M3 5 3 AUU UAC CAG IUU UIC CIG unedited edited I / V Y / C Q / R GluR-6 N M1 M2 C

18 Diversity through RNA editing GluR-6 pre-mrna M1 M2 M3 5 3 AUU UAC CAG IUU UIC CIG unedited edited I / V Y / C Q / R GluR-6 N M1 M2 I Y Q unedited d 10 % I C V Y I Y V C I C V Y V C Q Q R Q R R R C fully edited 5 % 5 % 10 % 5% 65 %

19 Even more diversity paralytic pre-mrna 5 3 alternative splicing constitutive exon alternative exon variants

20 Even more diversity paralytic pre-mrna 5 3 alternative splicing RNA editing constitutive exon alternative exon editing site variants

21 l Networ rk k Exp ponentia h.edu Sc cale-free e Networ lehigh World Wide Web Nodes: WWW documents Links: URL links Over 3 billion documents ROBOT: ROBOT: collects all URL s found in a document and follows them recursively R. Albert, H. Jeong, A-L Barabasi, Nature, (1999). P(k) ~k k -

22 Metabolic Network Protein Interactions

23 Internet-Map lehigh.edu SMAAS

24 Figure 1.7 The Toll of Brain Disorders (Part 1)

25 Figure 1.7 The Toll of Brain Disorders (Part 2)

26 Schizophrenia lehigh.edu SMAAS

27 True or False? 1. Schizophrenia is a rare illness 2. Schizophrenia generally strikes older people 3. People with Schizophrenia have multiple or split personalities 4. More hospital beds are occupied by people with Schizophrenia h i than any other medical illness

28 Schizophrenia o Mental illness o One of the top ten causes of long term disability o currently ca. 1% of population affected across countries and cultures o same in developed and developing countries o incidence id of f per 1000 => lifetime risk of 1% for women and men

29 Schizophrenia o develops between ages 15 and 25 and mostly persists throughout h the patient s lifetime i o cause unknown => genetic factors => early environmental influences => social factors

30 Symptoms and Disease Progression Three broad types of Symptoms: Positive (psychotic) Symptoms Negative (depressive) Symptoms Cognitive and Social Impairment

31 Symptoms and Disease Progression Positive (psychotic) Symptoms > Occur last, after several years of onset > Most apparent and often lead to first psychiatric contact, tend to be episodic Loss of contact with reality Delusions (false beliefs) for example: persecutory delusions, delusions of control, grandiose delusions and somatic delusions Hallucinations (auditory, visual, olfactory, tactile) Auditory hallucinations most common

32 Symptoms and Disease Progression Negative (depressive) Symptoms Blunted affect > Occur first > Less dramatic but more pervasive and fluctuate less over time eg, immobile facial expression, monotonous voice tone Anhedonia (lack of pleasure) Apathy diminished ability to initiate and follow through on plans Alogia reduced quantity of speech

33 Symptoms and Disease Progression Cognitive and Social Impairment > Occur second Attention and Concentration deficits Problems with Learning and Memory Deficiency in executive Function abstract ac thinking, problem solving

34 Genetic factor lehigh.edu SMAAS

35 Genetic factors Genetic transmission does not follow simple Mendelian single-gene inheritance patterns Multiple susceptibility genes, each with small effect and acting in concert with environmental factors Several genes shown to be linked with schizophrenia

36 Environmental factors Biological: Prenatal events or birth complications i Infections, hypoxia, winter birth, maternal malnutrition or use of psychoactive drugs Psychosocial: Poverty and lower social class Stressful environmental conditions i Urban versus rural background

37 Pathophysiology Enlargement of the ventricular system Accompanied by overall reduction in brain volume and cortical grey matter MRI Changes are not directly linked to illness progression

38 Pathophysiology Is Schizophrenia a demyelinating disorder? Some symptoms (psychosis, cognitive impairments) are similar to MS symptoms Time of onset is similar Is Schizophrenia a neurodevelopmental disorder? prevailing pathogenic model for Schizophrenia anatomical changes due to abnormal early brain development (visible before first episode) No sign of repair or degenerative processes (glial reactions, plaques) indications of defect in neuronal migration Late onset related to processes during adolescence and early adulthood (excessive e synaptic pruning?)

39 Therapy - Management

40 Therapy - Management Also: antidepressants, mood stabilizers, benzodiazepines Combination therapy (polypharmacy) common

41 Therapy - Management Major problem: non-compliance ca. 50% (and higher soon after onset of disorder) injectible depot simplifications of regimen direct delivery..

42 Therapy - Management Early intervention prolonged untreated psychosis requires extended treatment Clinical symptoms worsen over the first several years worse prognosis after prolonged social isolation Increased efforts to detect tfi first-episode i schizophrenia h i Even better: before major symptoms appear

43 True or False? 1. Schizophrenia is a rare illness False: world-wide wide rate is 1: Schizophrenia generally strikes older people False: age of onset is People with Schizophrenia have multiple or split personalities False: they are split from reality 4. More hospital beds are occupied by people with Schizophrenia than any other medical illness True 8% of hospital beds