Genes, the brain, and behavior

1. Genes, the brain, and behavior

2. OH CH2 CH2 CH CH COO- NH3 COO- NH3 Phenylketonuria (PKU) Identified in 1934 Mental retardation, delayed social skills, hyperactivity Movement disorders, rocking, seizures Phenylalanine Hydroxylase L-Phenylalanine L-Tyrosine

3. Diet Gene Cell (neuron) Brain Person Mutation in phenylalanine hydroxylase Smaller, fewer neurons Altered function Altered behavior

4. Genes and neurological diseases: e.g. Alzheimer’s disease Parkinson’s disease Huntington’s disease Amyelotropic lateral sclerosis Some simple genetic cases Some complex Some non-genetic

5. What is the genetic influence on behavior? How many genes? What molecules and pathways? What kinds of modifications? How do they affect behavior?

6. Environmental information Sensory selectivity Internal states Nervous system Behavioral decisions Output motor response

7. Natural selection will approximately optimize response to statistically predictable features of the natural environment Environmental information is statistical = Behavioral strategies will be statistical R 0.9999 Circadian rhythm, Heat > 60°C genetic, trans-species, fixed pathways R = 0.99 Odor of coyote urine genetic, intra-species R = 0 Odor of kitchen cleaner learned behavior (unpredictability is statistically predictable)

8. 1. Sensory selectivity Rene Descartes (1664)

9. Julius, Patapoutian, Friedman, others

10. 35°C Inflammation Even the most basic pathways can be modulated Julius and colleagues

11. Many animals have strong innate odor and taste preferences C. elegans Receptor Sensory Neuron Diacetyl di Attractive

12. di ODR-10(AWB) C. elegans Repulsive How is an attractive response specified? C. elegans Receptor Sensory Neuron Diacetyl di Attractive odr-10 mutant C. elegans di Ignored (Odorant and taste receptors evolve very rapidly)

13. di ODR-10(AWB) C. elegans Repulsive How is an attractive response specified? C. elegans Receptor Sensory Neuron Diacetyl di Attractive odr-10 mutant C. elegans di Ignored

14. Mammalian taste responses are hard-wired too Toxins Alkaloids Sugars Amino acids “RASSL” artificial receptor in T1R cells: Mice drink ligand “RASSL” artificial receptor in T2R cells: Mice reject ligand Zuker and colleagues

15. Sensory pathways filter the enviroment Basic, conserved machinery (TRPs, rhodopsin) Innate pathways for preference Flexibility in peripheral reception -- new filters (Cats have lost sweet receptors) Flexibility of modulatory pathways (inflammation)

16. 2. Internal states (sleep) Reduced motor activity Decreased sensory threshold Characteristic posture Easy reversibility Homeostasis / rebound Metastability

17. Narcolepsy/Cataplexy Reduced sleep latency Premature entry into REM sleep Waking hallucinations Loss of muscle control with excitement Linkage mapping HLA DR2, DQ1 DQB1*0602 Autoimmune disease?

19. Mutations in the Hypocretin 2 receptor (Orexin receptor) cause canine narcolepsy Mutations in hypocretin/orexin cause mouse narcolepsy Cell 98:365 (1999) Mignot lab Cell 98:437 (1999) Yanagisawa lab

20. Classical neurotransmitters: rapid, precise, local • Neuropeptide neurotransmitters: • act over seconds to hours • can act over a distance • dozens or hundreds • each expressed by specific neurons • many specific receptors • modulatory

21. ~2000 hypocretin/orexin-producing neurons in the hypothalamus project to many regions involved in sleep and arousal

22. Hypocretin-containing neurons are lost in human narcolepsy Neuron 27:469 (2000) J. Siegel

23. Internal states Characteristic structure, features Characteristic brain regions and modulators Can be induced by sensory input, but self-sustain Modify strength of intrinsic pathways

24. 3. Species-specific behaviors: sociability

25. Polygamous and monogamous social behavior in voles Montane vole: Colonial High maternal, paternal care High pair-bonding Territorial, aggressive High separation stress Prairie vole: Mostly solitary Limited maternal care No paternal care Non-territorial, non-aggressive Low separation stress Insel, Young and colleagues

26. Oxytocin/vasopressin neuropeptides Osmotic regulation (hypertonic) Social behaviors: earthworms, fish, birds, mammals Both montane and prairie voles have, express peptides

27. Vasopressin/oxytocin receptors are expressed differently in monogamous and polygamous voles Vasopressin V1 receptor Accumbens shell (Nacc) - prairie vole Lateral septum-montane vole Oxytocin receptor in accumbens- prairie vole, not montane vole Insel, Young and colleagues

28. Differences between species Can involve new genes (pheromone receptors) More likely to reconfigure existing genes Relationship between sensory input, internal state, decision Often begin with behavioral isolation (songbirds, stickleback fish) Discussion paper: Fergusen et al (2000)

29. 4. Differences within a species

30. Why have multiple behavioral strategies? Risk-averse, or Specialist Frequency Risk-prone, or Generalist Calories ingested 90% 10% 70% 30% Calories required Calories required Giraldeau and Livoreil, Game theory and social foraging (1998)

31. Drosophila larvae can be rovers or sitters Sokolowski and colleagues

32. forager locus encodes cGMP-dependent kinase: High=Rover, Low=Sitter, Off=Dead Activation: sensory, physiological pathways Targets: channels, signaling, neuronal excitability Sokolowski and colleagues

33. Natural variation in feeding behavior Solitary feeding N2 (England) California, Wisconsin Social feeding RC301 (Germany) California, Australia, Hawaii, Wisconsin

34. Social and solitary strains have different alleles of the neuropeptide receptor gene npr-1 social

35. npr-1(215V) is necessary for solitary behavior: If the gene is inactivated, solitary strains become social npr-1 (215V) is sufficient for solitary behavior: Introducing this one gene makes wild social strains become solitary

36. Social behavior is induced by stress High stress Social feeding Low stress Solitary feeding Moderate stress = high O2: npr-1(social) strains are stressed npr-1(solitary) strains are relaxed

37. Polygenic effects are the rule (probably) Drosophila geotaxis 500 generations Hirsch and colleagues, 1950s

38. Gene expression patterns lead to genes for geotaxis Greenspan and others, 2002

39. Differences within a species Probably not in core pathways (rapid transmission, action potential, development) More likely in modulatory pathways: tolerate highs/lows Sensory control in an individual Genetic variation between individuals Fixation between species Discussion paper: Ben-Shahar et al., 2002

40. Most human genes are shared with other organisms Humans only 1% Humans + Vertebrates 22% Eukaryotes + Prokaryotes 21% All animals 24% All eukaryotes 32%

41. Increased risk of psychiatric illness over the general population Identical twin Sibling Autism 2000-fold 50-150 fold Schizophrenia 48-fold 9-fold Bipolar disorder 60-fold 7-fold Depression 8-fold 2-5 fold Type 2 diabetes 16-fold 2-3 fold

42. SSRI antidepressants block reuptake of the neurotransmitter serotonin after release SSRI: increased serotonin accumulation

43. The Dunedin Multidisciplinary Health and Development Study 1037 children Tracked from ages 3-26 Silva, Poulton et al.

44. Genetic sensitivity to the environment: Serotonin reuptake transporter genotype and traumatic events interact in human depressive illness Caspi et al., 2003 Science 301:386

45. Environmental information Sensory selectivity Taste/odor receptors Vasopressin V1R Internal states Nervous system Orexin/hypocretin Serotonin transport cry/pdf loci npr-1 locus forager locus Behavioral decisions Output motor response