Genes, the brain, and behavior

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

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

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

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

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

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

1. Sensory selectivity Rene Descartes (1664)

Julius, Patapoutian, Friedman, others

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

Many animals have strong innate odor and taste preferences Diacetyl Attractive di C. elegansReceptorSensory Neuron

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

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

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

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 DR2, DQ1 DQB1*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

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

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

Insel, Young and colleagues 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

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 Accumbens shell (Nacc) - prairie vole Lateral septum-montane vole Vasopressin V1 receptor Oxytocin receptor in accumbens- prairie 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

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

Drosophila larvae can be rovers or sitters Sokolowski and colleagues

forager locus encodes cGMP-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 N2 (England) California, Wisconsin Social feeding RC301 (Germany) California, Australia, Hawaii, Wisconsin

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

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

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

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

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

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

Increased risk of psychiatric illness over the general population Identical twin Sibling Autism 2000-fold 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

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.

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

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