Genes, the brain, and behavior

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Genes, the brain, and behavior
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Phenylketonuria (PKU) Identified in 1934 Mental
retardation, delayed social skills,
hyperactivity Movement disorders, rocking,
seizures
Phenylalanine Hydroxylase
L-Phenylalanine
L-Tyrosine
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Gene
Cell (neuron)
Brain
Person
Smaller, fewer neurons
Mutation in phenylalanine hydroxylase
Altered function
Altered behavior
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Genes and neurological diseases e.g.
Alzheimers disease Parkinsons
disease Huntingtons disease Amyelotropic lateral
sclerosis Some simple genetic cases Some
complex Some non-genetic
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What is the genetic influence on behavior?
How many genes? What molecules and pathways? What
kinds of modifications? How do they affect
behavior?
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Environmental information
Sensory selectivity
Internal states
Nervous system
Behavioral decisions
Output motor response
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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 gt
60C 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)
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1. Sensory selectivity
Rene Descartes (1664)
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Julius, Patapoutian, Friedman, others
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Julius and colleagues
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Many animals have strong innate odor and taste
preferences
Diacetyl
C. elegans
Receptor
Sensory Neuron
di
Attractive
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How is an attractive response specified?
Diacetyl
C. elegans
Receptor
Sensory Neuron
di
Attractive
odr-10 mutant C. elegans
di
Ignored
(Odorant and taste receptors evolve very rapidly)
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How is an attractive response specified?
Diacetyl
C. elegans
Receptor
Sensory Neuron
di
Attractive
odr-10 mutant C. elegans
di
Ignored
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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
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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)
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2. Internal states (sleep)
Reduced motor activity Decreased sensory
threshold Characteristic posture Easy
reversibility Homeostasis / rebound Metastability
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Narcolepsy/Cataplexy Reduced sleep
latency Premature entry into REM sleep Waking
hallucinations Loss of muscle control with
excitement Linkage mapping HLA DR2, DQ1
DQB10602 Autoimmune disease?
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(No Transcript)
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Mutations in the Hypocretin 2 receptor (Orexin
receptor) cause canine narcolepsy
Mutations in hypocretin/orexin cause mouse
narcolepsy
Cell 98365 (1999) Mignot lab Cell 98437 (1999)
Yanagisawa lab
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• 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

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2000 hypocretin/orexin-producing neurons in the
hypothalamus project to many regions involved in
sleep and arousal
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Hypocretin-containing neurons are lost in human
narcolepsy
Neuron 27469 (2000) J. Siegel
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Internal states Characteristic structure,
features Characteristic brain regions and
modulators Can be induced by sensory input, but
self-sustain Modify strength of intrinsic
pathways
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3. Species-specific behaviors sociability
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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
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Oxytocin/vasopressin neuropeptides Osmotic
regulation (hypertonic) Social behaviors
earthworms, fish, birds, mammals
Both montane and prairie voles have, express
peptides
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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
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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)
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4. Differences within a species
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Why have multiple behavioral strategies?
Risk-averse, or Specialist
Frequency
Risk-prone, or Generalist
Calories ingested
90
10
70
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Calories required
Calories required
Giraldeau and Livoreil, Game theory and social
foraging (1998)
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Drosophila larvae can be rovers or sitters
Sokolowski and colleagues
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forager locus encodes cGMP-dependent kinase
HighRover, LowSitter, OffDead Activation
sensory, physiological pathways Targets
channels, signaling, neuronal excitability
Sokolowski and colleagues
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Natural variation in feeding behavior
Solitary feeding N2 (England) California,
Wisconsin
Social feeding RC301 (Germany) California,
Australia, Hawaii, Wisconsin
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Social and solitary strains have different
alleles of the neuropeptide receptor gene npr-1
social
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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
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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
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Polygenic effects are the rule (probably)
Drosophila geotaxis 500 generations Hirsch and
colleagues, 1950s
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Gene expression patterns lead to genes for
geotaxis
Greenspan and others, 2002
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Differences within a species Probably not in
core pathways (rapid transmission, action
potential, development) More likely in
modulatory pathways tolerate highs/lows Sensor
y control in an individual Genetic variation
between individuals Fixation between species
Discussion paper Ben-Shahar et al., 2002
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Most human genes are shared with other organisms
Humans only 1
Humans Vertebrates 22
Eukaryotes Prokaryotes 21
All animals 24
All eukaryotes 32
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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
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SSRI antidepressants block reuptake of the
neurotransmitter serotonin after release
SSRI increased serotonin accumulation
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The Dunedin Multidisciplinary Health and
Development Study
1037 children Tracked from ages 3-26
Silva, Poulton et al.
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Genetic sensitivity to the environment Serotonin
reuptake transporter genotype and traumatic
events interact in human depressive illness
Caspi et al., 2003 Science 301386
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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