Introduction to neurobiology

1. Introduction to neurobiology Teacher: Neta Zach (netazach@pob.huji.ac.il, 03-5610921,052-2574626) Course site (my alice account)- alice.nc.huji.ac.il/~netazach (includes tutorials, assignments and the articles mentioned in class/tutorial) Course requirements and grade: 8 exercises, which should be submitted on the following week either via e-mail (deadline Monday 23:59) or printed. 5% of final grade 3 assignments (reading an article and answering questions about it). 15% each Final (home test) assignment �reading of a second article. 50%

2. Introduction to cellular function I- Genetics

3. Why study physiology?

4. Mechanically, however, animal is a group of cells Like unicellular organisms, animal cells can look after themselves. The shift from eukaryota to animalia is in union and specialization- they also care for one another. Before we ignore statement #1 completely, two lessons need to pass�

5. What a cell needs for us to ignore it Osmotic balance Electrical balance Ionic concentration balance This is how we will usually treat a cell- a black box with input and output

6. What a cell actually needs Maintenance Reproduction Metabolism Growth Garbage disposal And the functions that would make a body (the black box from the outside)

7. Cell- a general scheme

8. Cellular information's elementary unit is DNA Griffith 1922 S stain is lethal R stain isn�t Dead S stain isn�t lethal Dead S stain+R stain is => Lethality trait is in the DNA

9. Cellular information's elementary unit is DNA All the information necessary to replicate all cells of a particular organism is coded in its genes (meaning- later). Genes are chains of nucleic acids(DNA), which include phosphate + sugar (pentose, 5 carbon structure) + base. bases can be one of 4: adenine (A) guanine (G) cytosine (C) thymine (T)

10. The double helix model (watson & crick) a sugar+phosphate+sugar+ phosphate chain holds bases (attached to sugar) together Bases face each other to form hydrogen bonds A=T, G=C to create a coil made of intervening helixes .

11. Gene packaging

12. Why do we call it genetic information The genius of Watson and Crick: the double helix structure allows replication, i.e heredity. But it will be proven informative only if can direct protein synthesis: Unlike glucose or fatty acids, the variety of amino acids types (20 n combinations of different side chains) allows� well, every known bodily function

13. Protein synthesis-transcription RNA polymerase I/II/III attaches to DNA=>double helix opens RNA bases (AUGC) match the helix, forming a complementary RNA helix. RNA helix�s unnecessary parts (introns) are removed by splicing out, leaving only exons => messenger RNA(mRNA)

14. Protein synthesis-translation mRNA leaves the nucleus through pores to: Endoplasmatic reticulum (ER) or 2. cytosol Either way to ribosome: 3 RNA molecule form a codon. Starting codon- AUG tRNA attaches specifically to codon, carring an amino acid. Peptidyl transferase connects amino acids Ribosome jumps a codon Termination-stop codon

15. Structure of proteins From ribosome- primary structure Naturally fold to secondary structure. a-helix and b-sheets are common motifs.

16. Tertiary structure is full 3D folding, sometime requires assistive proteins- chaperons, occurs at Golgy apparatus or cytosol Quaternary structure is formed by several polypeptide subunits

17. Protein structure summary

18. Protein synthesis - summary

19. Functions of proteins- enzymes chemical reactions (intro) Laws of thermodynamics: The total energy of a system and its surroundings is constant The total entropy of a system and its surroundings always increases in a spontaneous process =>If a reaction seems to reduce entropy, then energy is released as heat (increasing surrounding disorder). Measurement: Gibbs free energy: spontaneous reaction equilibrium state requires energy input

20. Functions of proteins- enzymes (how) Binds specific substrates and accelerates specific reactions through conformational change, (Sometimes using coenzymes)

21. Functions of proteins- enzymes (what) Reaction types: Isomerization, A->B - structural rearrangement without any change in its net atomic composition Synthesis, A+B->C - combination of two or more elements (RNA polymerase, for example) Analysis( Decomposition), A->B+C � decomposition to smaller compounds Substitution (single displacement), A+BC->AC+B �shifting of one element between compounds. Substitution (double displacement), AC+BD-> AB+CD exchange of single elements between compounds.

22. Functions of proteins- beyond enzymes The one gene one enzyme idea (Beadle & Tatum) : Advantages: Solved a lot of diseases (genetic therapy). Disadvantages: unrealistic. Two mistakes: Not one gene-polygenetic trait (from personality to cancer � all that is not clearly hereditary) Not an enzyme- most of what the body needs is not reactions, it�s regulation-signaling, markering, protein networks�

23. Reproduction (cellular)- Mitosis

24. Stage II-Mitosis

25. Reproduction (cellular) �when Formally, mitosis is part of the cell cycle, thus the tissue lives forever. However, animal cells acquire their very specific functions through differentiation and cell cycle ceases (why?). (exceptions- the liver) Solution- a stock of undifferentiated stem cells. Requires: control of the fate of a tissue ability to guide differentiation by external signals alone.

26. Neuro-genesis in the human brain Erikson 1998- new cells in the Hippocampus. 2000-also olfactory bulb. Cortex-unclear. What does it mean?

27. Sexual reproduction- meiosis One diploid cell divides to 4 haploid cells(gametas): Replication-like mitosis(46 pairs of sister cromatids) Division I - 23 pairs on each daughter cell. Division II-pair separation (like mitosis)

28. Where genetic variability kicks in-Mutations Source: Structural change in the replicated DNA strand (radiation, oxidative damage...mutagen) or replication error. Types: 1)Attaching the wrong base or deletion/insertion of one base- point mutation. Can be neutral, silent, missense or nonsense. 2)Changes of many bases: deletion/insertion or Defects in Okazaki fragment attachment- translocation, deletion, inversion (fragile X, Down syndrome�)

29. Where genetic variability kicks in-effects of mutations Point mutation can eliminate /create /increase /decrease /reverse a certain function. Occurs in transcription>mitosis>meiosis (better control) Importance: Recombination, chromosomal translocation occurring in meiosis between mother�s chromatid and father�s cromatid (�crossing over�)- breaking the linkage between genes to create new combinations of traits.

30. Examples of induced �natural� selection 20 generations

31. Expression For all but X and Y we have 2 homologies chromosomes=>two alleles. Same is called Homozygote, different-Heterozygote. Heterozygote-We are interested in what will the trait be Phenotype vs. Genotype) : One gene is dominant over the other- Dominant expresses-examples-normal enzyme vs defected, pigment vs. albino. (mechanism- one gene is quite enough or stronger (pigment) or mechanically favorable

32. Both are evidenced in phenotype-�blend�/mixed (Incomplete dominance)- Mechanisms-1.both expressed (examples-carnation, snapdragon and roses, when pink, are �daughters� of red and white parents. 2. Only one expressed in each cell completely randomly (examples-grey pets have black and white hair cells). Mechanism-mechanically favoring one allele. 3. If expression is in patches- selection of one allele but done early in development. Note: not always one allele is favorable!

34. Introduction to cellular function II- cellular processes

35. What a cell actually needs Maintenance Reproduction Metabolism Growth Garbage disposal And the functions that would make a body (the black box from the outside)

36. Cell- a general scheme

37. Nutrition-general Requirements: substrates, energy. Substrate, how: polymers (food) ->monomer->polymer Catabolism- break down, energy released. Anabolism-building up, energy required, Substrate, what: Protein (amino acids)-mostly muscles, energy Fat (fatty acids)-membranes, energy Carbohydrate (glucose)-energy only. Few-minerals and vitamins for co-enzymes

38. Nutrition-energy Cell receives glucose and through glycolysis (in cytosol) produces pyrovate + ATP

40. The tie between nutrition and respiration- mitochondria

43. Respiration is good for you Improvement from(2 ATP): Glucose 2 ATP, 2 lactate (useless) To(30 ATP) Glucose +6O2 6CO2+6H2O+~30ATP

44. Cleaning up after the meal-lysosomes Organelles containing enzymes to digest macromolecules (lipase, Carbohydrase, protease, nuclease� ). Purpose: Garbage, bacteria, necrosis Mechanism-hydrolysis. PH 4.8 (cytosol 7)- Leakage less harmful (proton pump in (single) membrane) Importance: Tay-Sachs causes blindness, deafness, paralysis and death (due to ganglioside GMS accumulation)

45. Cleaning up after the meal-peroxisomes Oxidative stress (free radicals) is the main cause of mutation and cell death (in apoptosis): To eliminate oxidative stress-(single-membrane) organelles: 2H2O2 (catalase)? 2H2O + O2. No peroxisomes- Zellweger syndrome (mental retardation and death). But also in cytosol-no superoxide mismutase-ALS Anyway, oxidative stress still accumulates:� Apples brown. Butter turns rancid. Iron rusts. brain degenerates.� Solutions?

46. Transport-protein transport The way of the protein: Nucleus-rER-(golgi), transport from rER to golgi- vesicles (created-with other lipids- in sER). In golgi(cis-> lumen-> trans ): protein modification- folding, attaching glucose, phosphate�and out in new vesicles Secretion in vesicles:

47. Transport-cellular transport-cytoskeleton

48. Transport-cellular transport-cytoskeleton II 2.neurofilaments-10nm most common. cytokratins alzhaimer-neurofilmentary tangles (senile plaques). stable 3.Microfilaments- 3-5 nm made of actin. Cell periphery/membrane, for secretion (and muscle contraction). Changes dynamically.

49. Cell boundaries- membranes (briefly) Membranes are lipid bilayers(phospholipids form close shapes naturally in aqueous solutions), hydrophobic and therefore impermeable to all polar substances. Membranes are crossed by proteins, some act as transporters of polar or large substances: channels (open/close), pores (�holes�), active pumps (ATP), transporters (gradient dependent). Other proteins do not transport materials but transmit their presence-receptors

50. Cell boundaries-neuron shape Cell body-soma Dendrite (generally many) Axon

51. Cell boundaries- shape divergences The most diverse human tissue

52. Cell boundaries - Glia Non - neuronal cells, 50:1 more prevalent in the brain than neurons. Do not possess neurons� electrical signaling ability but do respond to/secrete neurotransmitters. Believed to provide: structural support, nutrition but mostly electrical isolation by wrapping neurons with myelin. Myelin-fatty acid coating that improves electrical conductance

53. Glia in CNS- oligodendrocytes Myelin coating, only in higher vertebrates each �Arm� wraps about 1mm of axons

54. Glia in CNS-astrocytes The most common glial cell, surround neurons and blood vessels and form scar tissue Can control neurotransmitter levels �a second neural network" -slower, electrically coupled and communicates through calcium waves.

55. Glia in PNS-schwann cells Wrap myelin by spiraling around the axon, sometimes with as many as 100 revolutions. A well-developed Schwann cell is shaped like a rolled-up sheet of paper of 1mm diameter.

56. Quantum theory of mind First assumption- the mind is a quantum object. Therefore, it should be comprised of quantal mechanisms Rational: In Quantum Mechanics a particle can take up several states at once and then �collapse� to one state. The mind has normally several states at once (subconsciously) and collapses to one-This is the threshold of consciousness. Evidence : none. Not for the mind description, nor for the mechanisms. Problems: numerous. One of them: If metaphors were always to be followed, we wouldn�t need the word �like� in our dictionaries. (�minimization of mystery-both are mystery, therefore related�-David Chalmers)

57. Second assumption: microtubuli are a good candidate to be the quantal elements Rational- 1.unlike neurons, they are small enough. 2. They are constantly being constructed and deconstructed (the stability point is the consciousness) 3. They, like consciousness, are effected by anesthetics. Evidence: the above is all correct. The rest is un-researchable.

58. Problems: 1.in 37 degrees, quantal process should take 10-20 sec. Neuron changes in milliseconds. 2. microtubulis of different cells aren�t connected. 3. Many microtubuli problems are known, none are related to consciousness. 4. All microtubule effects are well described by regular mechanics,. 5. Many other things are related to anesthetics. 6. If they had any evidence, maybe we could argue about it, but they have NONE.