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Genes, the brain, and behavior
Phenylketonuria (PKU)
Identified in 1934
Mental retardation, delayed social skills, hyperactivity
Movement disorders, rocking, seizures
OH
Phenylalanine
Hydroxylase
NH3
CH2
CH2
CH
CH
COO-
L-Phenylalanine
NH3
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 T1R cells: Mice drink ligand
“RASSL” artificial receptor in T2R 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 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
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 V1 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 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
Social feeding
N2 (England)
RC301 (Germany)
California, Wisconsin California, Australia,
Hawaii, Wisconsin
Social and solitary strains
have different alleles of the neuropeptide receptor gene npr-1
social
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
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
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
Most human genes are shared with other organisms
Humans only
1%
Eukaryotes +
Prokaryotes
21%
All eukaryotes
32%
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 V1R
Internal states
cry/pdf loci
Orexin/hypocretin
Serotonin transport
forager locus
Behavioral decisions
Output motor response