Genes the brain and behavior Phenylketonuria PKU Identified

Genes, the brain, and behavior

Phenylketonuria (PKU) Identified in 1934 Mental retardation, delayed social skills, hyperactivity Movement disorders, rocking, seizures OH Phenylalanine Hydroxylase NH 3 CH 2 CH CH COO- L-Phenylalanine NH 3 COO- L-Tyrosine

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

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

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

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

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 R = 0. 99 R=0 Circadian rhythm, Heat > 60°C genetic, trans-species, fixed pathways Odor of coyote urine genetic, intra-species Odor of kitchen cleaner learned behavior (unpredictability is statistically predictable)

1. Sensory selectivity Rene Descartes (1664)

Julius, Patapoutian, Friedman, others

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

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

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

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

Mammalian taste responses are hard-wired too Sugars Amino acids Toxins Alkaloids “RASSL” artificial receptor in T 1 R cells: Mice drink ligand “RASSL” artificial receptor in T 2 R cells: Mice reject ligand Zuker and colleagues

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)

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

Narcolepsy/Cataplexy Reduced sleep latency Premature entry into REM sleep Waking hallucinations Loss of muscle control with excitement Linkage mapping HLA DR 2, DQ 1 DQB 1*0602 Autoimmune disease?

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

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

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

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

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

3. Species-specific behaviors: sociability

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

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

Vasopressin/oxytocin receptors are expressed differently in monogamous and polygamous voles Vasopressin V 1 receptor Accumbens shell (Nacc) - prairie vole Lateral septum-montane vole Oxytocin receptor in accumbensprairie vole, not montane vole Insel, Young and colleagues

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)

4. Differences within a species

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

Drosophila larvae can be rovers or sitters Sokolowski and colleagues

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

Natural variation in feeding behavior Solitary feeding Social feeding N 2 (England) RC 301 (Germany) California, Wisconsin California, Australia, Hawaii, Wisconsin

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

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

Social behavior is induced by stress High stress Social feeding Low stress Solitary feeding Moderate stress = high O 2: npr-1(social) strains are stressed npr-1(solitary) strains are relaxed

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

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

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

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

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

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

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

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

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