Nuts and Bolts Plan for

Today

Lecture (Bogdan, Meaney, Dias)

No take-home assignment today!

PSYC 210:
The nature & nurture of T&P, III
Gene x Environment Interactions (continued), Neurogenetics,
& Epigenetics

AJ Shackman
26 March 2015

Conceptual Roadmap, 1
Individual differences in T&P reflect the brain
e.g., Individuals with higher levels of N/NE
show enhanced activation and slower recovery
in the amygdala
Where do differences in brain activation
come from?
We cant assay tissue from the living human
amygdala but can we use the genome (DNA)
to identify candidate mechanisms (that could
be mechanistically tested in animals)?

Conceptual Roadmap, 1
Individual differences in T&P reflect the brain
e.g., Individuals with higher levels of N/NE
show enhanced peak activation and slower
recovery in the amygdala
Where do differences in brain activation
come from?
We cant assay tissue from the living human
amygdala but can we use the genome (DNA)
to identify candidate mechanisms (that could
be mechanistically tested in animals)?

Conceptual Roadmap, 1
Individual differences in T&P reflect the brain
e.g., Individuals with higher levels of N/NE
show enhanced peak activation and slower
recovery in the amygdala
Where do differences in brain activation
come from? After all, we cant assay tissue
from the living human amygdala
Can we use the genome (DNA) to
discover
candidate molecular mechanisms that could
be examined in animal models?

Conceptual Roadmap, 1
Individual differences in T&P reflect the brain
e.g., Individuals with higher levels of N/NE
show enhanced peak activation and slower
recovery in the amygdala
Where do differences in brain activation
come from? After all, we cant assay tissue
from the living human amygdala
Can we use the genome (DNA) to discover
candidate molecular mechanisms that could be
validated in animal models?

Conceptual Roadmap, 2
Genes interact with the Environment &
Experience to produce lasting changes in
T&P
How does early experience (abuse,
stress, positive maternal style) get
under the skin
and reprogram the brain circuits that
support key features of T&P?
Can these experiential modifications
be inherited by offspring?

Conceptual Roadmap, 2
Genes interact with the Environment &
Experience to produce lasting changes in
T&P
How does early experience (abuse,
stress, positive maternal style) get
under the skin
and reprogram the brain circuits that
support key features of T&P?
Can these experiential modifications
be inherited by offspring?

Conceptual Roadmap, 2
Genes interact with the Environment &
Experience to produce lasting changes in
T&P
How does early experience (abuse,
stress, positive maternal style) get
under the skin
and reprogram the brain circuits that
support key features of T&P?
Can these experiential modifications
be inherited by offspring?

Quick Recap from

the End of Last Time

Gene-Environment Interactions

Maltreatment x MAO-A
Gene

monoamine oxidase A

Caspi et al Science 200

Maltreatment x MAO-A
Gene

Abused kids with the good allele (grey:

thought to confer high levels of MAO-A
expression in the brain) showed fewer
antisocial behaviors protective

monoamine oxidase A

Caspi et al Science 200

Stress x 5-HTT Gene

Caspi et al Science 2003, Amer J Psychiatry 2010; Monroe Psychol Sc

Stress x 5-HTT Gene

Short

Long

Carriers of the Short allele of the 5-HTT

polymorphism (left) showed a strong
positive relationship between the number of
negative life events and number of
Caspi
et al
Science 2003,
Amer J Psychiatry
2010; Monroe Psychol Sc
depressive episodes
Short
allele
confers

What about the brain?

The assumption is that the genotype (MAO-A or 5-HTT gene) is
lawfully related to neurochemistry

Genome Intermediate Phenotype Traits (Evildoing, Depression)

What about the brain?

The assumption is that the genotype (MAO-A or 5-HTT gene) is
lawfully related to neurochemistry

Genome Intermediate Phenotype Traits (Evildoing, Depression)

What about the brain?

How might we as scientists understand the neuro-molecular
building blocks of traits or disorders?

Genome Intermediate Phenotype Traits (Evildoing, Depression)

Caspis Suggested Strategy: 3 Easy

Pieces

Caspis Suggested Strategy: 3 Easy

Pieces

Start with solid evidence that MAO-A / Serotonin transporter

influences the emotional phenotype in animal models

Caspis Suggested Strategy: 3 Easy

Pieces

Use human epidemiological data to address questions like:

Does the MAO / Serotonin transporter interact
with negative events to produce deleterious outcomes
(e.g., in the Dunedin sample)?
Yes!

Caspis Suggested Strategy: 3 Easy

Pieces

Test hypothesized mechanisms (serotonin levels in

the amygdala?) in animal model or using PET imaging

Caspis Suggested Strategy: 3 Easy

Pieces

Test hypothesized mechanisms (serotonin levels in

the amygdala?) in animal model or using PET imaging

Building on this framework, other investigators have focused

on linking
genes to imaging measures of brain structure and function

Bogdan (Wash U)

The Neurogenetic Strategy

Basic idea - Correlate genetic variation (SNPs) with differences in brain
structure and function (MRI)
Goals
- By correlating genetic variation with intermediate biological phenotypes (e.g.,
amygdala
activation), we can discover testable pathways for genetic influence on
behavior
- Can address questions such as, Why is the amygdala hyper-reactive in
behaviorally inhibited or neurotic individuals?

Potentially address the molecular mechanisms linking genes to brain to

behavior
- its hard to directly measure neurochemistry (e.g., serotonin levels in the
amygdala) in humans
- If we measure a genetic polymorphism with a known function (e.g., serotonin
transporter)
- and we are willing to make some assumptions (differences in the poly. have
predictable effects
on gene expression and ultimately serotonin levels in the
amygdala)

The Neurogenetic Strategy

Basic idea - Correlate genetic variation (SNPs) with differences in brain
structure and function (MRI)
Goals
- By correlating genetic variation with intermediate biological phenotypes (e.g.,
amygdala
activation), we can discover testable pathways for genetic influence on
behavior
- Can address questions such as, Why is the amygdala hyper-reactive in
behaviorally inhibited or neurotic individuals?

Potentially address the molecular mechanisms linking genes to brain to

behavior
- its hard to directly measure neurochemistry (e.g., serotonin levels in the
amygdala) in humans
- If we measure a genetic polymorphism with a known function (e.g., serotonin
transporter)
- and we are willing to make some assumptions (differences in the poly. have
predictable effects
on gene expression and ultimately serotonin levels in the
amygdala)

The Neurogenetic Strategy

Basic idea - Correlate genetic variation (SNPs) with differences in brain
structure and function (MRI)
Goals
- By correlating genetic variation with intermediate biological phenotypes (e.g.,
amygdala
activation), we can discover testable pathways for genetic influence on
behavior
- Can address questions such as, Why is the amygdala hyper-reactive in
behaviorally inhibited or neurotic individuals?

Potentially address the molecular mechanisms linking genes to brain to

behavior
- its hard to directly measure neurochemistry (e.g., serotonin levels in the
amygdala) in humans
- If we measure a genetic polymorphism with a known function (e.g., serotonin
transporter)
- and we are willing to make some assumptions (differences in the poly. have
predictable effects
on gene expression and ultimately serotonin levels in the
amygdala)

The Neurogenetic Strategy

Basic idea - Correlate genetic variation (SNPs) with differences in brain
structure and function (MRI)
Goals
- By correlating genetic variation with intermediate biological phenotypes (e.g.,
amygdala
activation), we can discover testable pathways for genetic influence on
behavior
- Can address questions such as, Why is the amygdala hyper-reactive in
behaviorally inhibited or neurotic individuals?

Potentially address the molecular mechanisms linking genes to brain to

behavior
- its hard to directly measure neurochemistry (e.g., serotonin levels in the
amygdala) in humans
- If we measure a genetic polymorphism with a known function (e.g., serotonin
transporter)
- and we are willing to make some assumptions (differences in the poly. have
predictable effects
on gene expression and ultimately serotonin levels in the
amygdala)

The Neurogenetic Strategy

Basic idea - Correlate genetic variation (SNPs) with differences in brain
structure and function (MRI)
Goals
- By correlating genetic variation with intermediate biological phenotypes (e.g.,
amygdala
activation), we can discover testable pathways for genetic influence on
behavior
- Can address questions such as, Why is the amygdala hyper-reactive in
behaviorally inhibited or neurotic individuals?

Potentially address the molecular mechanisms linking genes to brain to

behavior
- its hard to directly measure neurochemistry (e.g., serotonin levels in the
amygdala) in humans
- If we measure a genetic polymorphism with a known function (e.g., serotonin
transporter)
- and we are willing to make some assumptions (differences in the poly. have
predictable effects
on gene expression and ultimately serotonin levels in the
amygdala)

The Neurogenetic Strategy

Basic idea - Correlate genetic variation (SNPs) with differences in brain
structure and function (MRI)
Goals
- By correlating genetic variation with intermediate biological phenotypes (e.g.,
amygdala
activation), we can discover testable pathways for genetic influence on
behavior
- Can address questions such as, Why is the amygdala hyper-reactive in
behaviorally inhibited or neurotic individuals?

Potentially address the molecular mechanisms linking genes to brain to

behavior
- its hard to directly measure neurochemistry (e.g., serotonin levels in the
amygdala) in humans
- If we measure a genetic polymorphism with a known function (e.g., serotonin
transporter)
- and we are willing to make some assumptions (differences in the poly. have
predictable effects
on gene expression and ultimately serotonin levels in the
amygdala)

The Neurogenetic Strategy

Basic idea - Correlate genetic variation (SNPs) with differences in brain
structure and function (MRI)
Goals
- By correlating genetic variation with intermediate biological phenotypes (e.g.,
amygdala
activation), we can discover testable pathways for genetic influence on
behavior
- Can address questions such as, Why is the amygdala hyper-reactive in
behaviorally inhibited or neurotic individuals?

Potentially address the molecular mechanisms linking genes to brain to

behavior
- its hard to directly measure neurochemistry (e.g., serotonin levels in the
amygdala) in humans
- If we measure a genetic polymorphism with a known function (e.g., serotonin
transporter)
- and we are willing to make some assumptions (differences in the SNP have
predictable effects
on gene expression and ultimately serotonin levels in the
amygdala)

The Neurogenetic Strategy

Basic idea - Correlate genetic variation (SNPs) with differences in brain
structure and function (MRI)
Goals
- By correlating genetic variation with intermediate biological phenotypes (e.g.,
amygdala
activation), we can discover testable pathways for genetic influence on
behavior
- Can address questions such as, Why is the amygdala hyper-reactive in
behaviorally inhibited or neurotic individuals?

Potentially address the molecular mechanisms linking genes to brain to

behavior
- its hard to directly measure neurochemistry (e.g., serotonin levels in the
amygdala) in humans
- If we measure a genetic polymorphism with a known function (e.g., serotonin
transporter)
- and we are willing to make some assumptions (differences in the SNP have
predictable effects
on gene expression and ultimately serotonin levels in the
amygdala)

Drill down into the 5-HTT

example

Seminal Example: Amygdala & 5HTTLPR

Seminal Example: Amygdala & 5HTTLPR

- Work by Hariri (prior to Caspi) suggested that

amygdala reactivity is correlated with variation in the
serotonin-transporter linked polymorphic region (5HTTLPR)
- S allele is bad: Individuals with the less
transcriptionally-efficient short allele (fewer transporter
proteins available to clear serotonin from the synapse)
show heightened threat-related amygdala reactivity
relative to individuals with the long allele
- Gene Amygdala: Meta-analyses suggest that the
5-HTTLPR genotype accounts for 2-5 of the variance in
amygdala reactivity
- Gene Amygdala MDD: Evidence that these

Seminal Example: Amygdala & 5HTTLPR

- Work by Hariri (prior to Caspi) suggested that

amygdala reactivity is correlated with variation in the
serotonin-transporter linked polymorphic region (5HTTLPR)
- S allele is bad: Individuals with the less
transcriptionally-efficient short allele (fewer transporter
proteins available to clear serotonin from the synapse)
show heightened threat-related amygdala reactivity
relative to individuals with the long allele
- Gene Amygdala: Meta-analyses suggest that the
5-HTTLPR genotype accounts for 2-5 of the variance in
amygdala reactivity
S allele Enhanced Amygdala Reactivity (Sensitization)

- Gene Amygdala MDD: Evidence that these

pothesized Causal Chain

These data suggest the following causal chain:

[GENETIC OBSERVATION] Some folks have the 5HTTLPR S allele
[ASSUMPTION] less efficient 5HTT (protein)
transcription, so fewer transporters
[ASSUMPTION] too much 5HT in amygdala synapses
(chemistry)
[NEURAL OBSERVATION] increased amygdala
reactivity to threat

pothesized Causal Chain

These data suggest the following causal chain:

[GENETIC OBSERVATION] Some folks have the 5HTTLPR S allele
[ASSUMPTION] less efficient 5HTT (protein)
transcription, so fewer transporters
[ASSUMPTION] too much 5HT in amygdala synapses
(chemistry)
[NEURAL OBSERVATION] increased amygdala
reactivity to threat

pothesized Causal Chain

These data suggest the following causal chain:

[GENETIC OBSERVATION] Some folks have the 5HTTLPR S allele
[ASSUMPTION] less efficient 5HTT (protein)
transcription, so fewer transporters
[ASSUMPTION] too much 5HT in amygdala synapses
(chemistry)
[NEURAL OBSERVATION] increased amygdala
reactivity to threat

pothesized Causal Chain

These data suggest the following causal chain:

[GENETIC OBSERVATION] Some folks have the 5HTTLPR S allele
[ASSUMPTION] less efficient 5HTT (protein)
transcription, so fewer transporters
[ASSUMPTION] too much 5HT in amygdala synapses
(chemistry)
[NEURAL OBSERVATION] increased amygdala
reactivity to threat

pothesized Causal Chain

These data suggest the following causal chain:

[GENETIC OBSERVATION] Some folks have the 5HTTLPR S allele
[ASSUMPTION] less efficient 5HTT (protein)
transcription, so fewer transporters
[ASSUMPTION] too much 5HT in amygdala synapses
(chemistry)
[NEURAL OBSERVATION] increased amygdala
reactivity to threat

pothesized Causal Chain

These data suggest the following causal chain:

[GENETIC OBSERVATION] Some folks have the 5HTTLPR S allele
[ASSUMPTION] less efficient 5HTT (protein)
transcription, so fewer transporters
[ASSUMPTION] too much 5HT in amygdala synapses
(chemistry)
[NEURAL OBSERVATION] increased amygdala
reactivity to threat

Does the gene actually predict 5-HTT expression in the amygdala

(1st Assumption)?
Testable hypothesis

se PET to test 5-HTT expression

No relation between polymorphism and amygdalar

5HTT expression
when you actually go in and measure the
transporter using PET
our ndings are in agreement with the majority of
human PET studiesthat suggest there is not a
detectable relationship between in vivo 5-HTT binding
and s-allele carrier status our work in the rhesus
monkey, and that of others in humans, calls into question

se PET to test 5-HTT expression

Kalin (UW)

No relation between polymorphism and amygdalar

5HTT expression
when you actually go in and measure the
transporter using PET
our ndings are in agreement with the majority of
human PET studiesthat suggest there is not a
detectable relationship between in vivo 5-HTT binding
and s-allele carrier status our work in the rhesus
monkey, and that of others in humans, calls into question

se PET to test 5-HTT expression

Kalin (UW)

No relation between polymorphism and amygdalar

5HTT expression
when you actually go in and measure the
transporter using PET
our ndings are in agreement with the majority of
human PET studiesthat suggest there is not a
detectable relationship between in vivo 5-HTT binding
and s-allele carrier status our work in the rhesus
monkey, and that of others in humans, calls into question

Others have questioned the

gene-amygdala link

Others have questioned the

gene-amygdala link

The alleged association between the serotonin-transporter-linked

polymorphic region and amygdala activation forms a cornerstone of the
common view that carrying the short (S) allele of this polymorphism is
risk factor for affective disorders [such as depression]

The authors of a recent meta-analysis showed that this association is

significant but warned that estimates might be distorted because of
publication bias (not including unpublished failures)

Here, we report a replication study of this relationship in N=120

participants. We failed to find the association

Moreover, when we conducted a meta-analysis that included unpublished

studies and data from the current study, the pooled meta-analytic effect
size was no longer significant

These findings cast doubt on previously reported substantial effects,

Others have questioned the

gene-amygdala link

The alleged association between the serotonin-transporter-linked

polymorphic region and amygdala activation forms a cornerstone of the
common view that carrying the short (S) allele of this polymorphism is
risk factor for affective disorders [such as depression]

The authors of a recent meta-analysis showed that this association is

significant but warned that estimates might be distorted because of
publication bias (not including unpublished failures)

Here, we report a replication study of this relationship in N=120

participants. We failed to find the association

Moreover, when we conducted a meta-analysis that included unpublished

studies and data from the current study, the pooled meta-analytic effect
size was no longer significant

These findings cast doubt on previously reported substantial effects,

Others have questioned the

gene-amygdala link

The alleged association between the serotonin-transporter-linked

polymorphic region and amygdala activation forms a cornerstone of the
common view that carrying the short (S) allele of this polymorphism is
risk factor for affective disorders [such as depression]

The authors of a recent meta-analysis showed that this association is

significant but warned that estimates might be distorted because of
publication bias (not including unpublished failures)

Here, we report a replication study of this relationship in N=120

participants. We failed to find the association

Moreover, when we conducted a meta-analysis that included unpublished

studies and data from the current study, the pooled meta-analytic effect
size was no longer significant

These findings cast doubt on previously reported substantial effects,

Others have questioned the

gene-amygdala link

The alleged association between the serotonin-transporter-linked

polymorphic region and amygdala activation forms a cornerstone of the
common view that carrying the short (S) allele of this polymorphism is
risk factor for affective disorders [such as depression]

The authors of a recent meta-analysis showed that this association is

significant but warned that estimates might be distorted because of
publication bias (not including unpublished failures)

Here, we report a replication study of this relationship in N=120

participants. We failed to find the association

When we conducted a meta-analysis that included unpublished studies

and data from the current study, the pooled meta-analytic effect size was
not significant

These findings cast doubt on previously reported substantial effects,

Others have questioned the

gene-amygdala link

The alleged association between the serotonin-transporter-linked

polymorphic region and amygdala activation forms a cornerstone of the
common view that carrying the short (S) allele of this polymorphism is
risk factor for affective disorders [such as depression]

The authors of a recent meta-analysis showed that this association is

significant but warned that estimates might be distorted because of
publication bias (not including unpublished failures)

Here, we report a replication study of this relationship in N=120

participants. We failed to find the association

When we conducted a meta-analysis that included unpublished studies

and data from the current study, the pooled meta-analytic effect size was
not significant

These findings cast doubt on previously reported effects, suggesting that

Interim Take Home

eurogenetic or Neurogene x Environment strategy

tially powerful, but assumptions need to be tested
andidate pathway

How might the environment

and early experience get
Under the Skin and
promote enduring changes in T&P?
Early stress, abuse, or maltreatment
Increased stress reactivity and MDD Risk
Maternal nurturance
Decreased stress reactivity in adulthood

How might the environment

and early experience get
Under the Skin and
promote enduring changes in T&P?
Early stress, abuse, or maltreatment
Increased stress reactivity and MDD risk
Maternal nurturance
Decreased stress reactivity in adulthood

Michael Meaney

The key mechanistic question is how such influences

become long
lasting
Turn to a nonhuman
animal model of early Nurture

Michael Meaney

The key mechanistic question is how such influences

become long
lasting
Turn to a nonhuman
animal model of early Nurture

Experimenter handling has enduring

consequences for stress reactivity (N/NE)

Levine Science 1962; see also Weininger Science

Experimenter handling has enduring

consequences for stress reactivity (N/NE)
Levels of the stresssensitive hormone
cortisol elicited by shock

M Handled
N - Not

Levine Science 196

Cortisol and the HPA Axis

Cortisol and the HPA Axis

Hypothalamic, Pituitary,
Adrenal
Cortisol is released from
the adrenals in response
to emotional and physical
stress
Increases glucose
availability to the brain
Generates energy from
stored reserves
Diverts energy from
longer-term priorities
(such as the immune
system and wound
healing) in order to
survive acute threats

Cortisol and the HPA Axis

Hypothalamic, Pituitary,
Adrenal
Cortisol is released from
the adrenals in response
to emotional and physical
stress
Increases glucose
availability to the brain
Generates energy from
stored reserves
Diverts energy from
longer-term priorities
(such as the immune
system and wound
healing) to promote
survival in the face of
acute threat

Cortisol and the HPA Axis

Hypothalamic, Pituitary,
Adrenal
Cortisol is released from
the adrenals in response
to emotional and physical
stress
Increases glucose
availability to the brain
Generates energy from
stored reserves
Diverts energy from
longer-term priorities
(such as the immune
system and wound
healing) to promote
survival in the face of
acute threat

What mechanisms account for

the handling effect on stress reactivity
(cortisol)?

Remarkable lifelong changes happen when

neonatal rats are removed from mom and
placed in a new cage for 15 minutes
Tighter regulation of the secretion of a class of
stress hormones, glucocorticoids (lower baseline &
poststress levels)
Lifelong increase in the number of glucocorticoid
receptors in the hippocampus, a brain region that
plays a key role in regulating cortisol release
These changes result in
a more exploratory, less fearful
, and less stress-reactive adult
Decreased N/NE, in effect

Sapolsky Nature Reviews Neuroscience 20

Remarkable lifelong changes happen when

neonatal rats are removed from mom and
placed in a new cage for 15 minutes
Tighter regulation of cortisol (glucocorticoids)
secretion: lower baseline & poststress levels*
Lifelong increase in the number of glucocorticoid
receptors in the hippocampus, a brain region that
plays a key role in regulating cortisol release
These changes result in
a more exploratory, less fearful
, and less stress-reactive adult
Decreased N/NE, in effect

gger early peak; quicker return to baseline; more adaptive

Sapolsky Nature Reviews Neuroscience 20

Remarkable lifelong changes happen when

neonatal rats are removed from mom and
placed in a new cage for 15 minutes
Tighter regulation of cortisol (glucocorticoids)
secretion: lower baseline & poststress levels*
Lifelong increase in the number of glucocorticoid
receptors in the hippocampus, a brain region that
plays a key role in regulating cortisol release
These changes result in
a more exploratory, less fearful
, and less stress-reactive adult
Decreased N/NE, in effect

gger early peak; quicker return to baseline; more adaptive

Sapolsky Nature Reviews Neuroscience 20

Remarkable lifelong changes happen when

neonatal rats are removed from mom and
placed in a new cage for 15 minutes
Tighter regulation of cortisol (glucocorticoids)
secretion: lower baseline & poststress levels*
Lifelong increase in the number of glucocorticoid
receptors in the hippocampus, a brain region that
plays a key role in regulating cortisol release
These changes result in
a more exploratory, less fearful,
and less stress-reactive adult
Decreased N/NE in offspring

gger early peak; quicker return to baseline; more adaptive

Sapolsky Nature Reviews Neuroscience 20

What causes enduring changes

in the regulation of
stress hormones in the offspring?

Mothering Style

Rats show trait-like differences in mothering style

Moms who show high levels of licking, grooming, and arched-back
nursing (high LG-ABN females) cause the handling effect
When the handled baby rat is returned to the homecage, mom
grooms returned pup
More handling More grooming Less stress reactivity in
adulthood
Cross-fostering studies (adopted by Hi or Lo mom) show that this
does not reflect an underlying common genetic cause (Genes
Mom Low N/NE prole in offspring);
Remarkably, female pups raised by high-LG-ABN moms
become high moms
Thereby passing on the trait in a case of multigenerational,
nongenomic (i.e. outside of DNA) inheritance

Sapolsky Nature Reviews Neuroscience 2004; Video @ https://www.youtube.com/watch?v=nUPm

Mothering Style

Rats show trait-like differences in mothering style

Moms who show high levels of licking, grooming, and arched-back
nursing (high LG-ABN females) cause the handling effect
When the handled baby rat is returned to the homecage, mom
grooms returned pup
More handling More grooming Less stress reactivity in
adulthood
Cross-fostering studies (adopted by Hi or Lo mom) show that this
does not reflect an underlying common genetic cause (Genes
Mom Low N/NE prole in offspring);
Remarkably, female pups raised by high-LG-ABN moms
become high moms
Thereby passing on the trait in a case of multigenerational,
nongenomic (i.e. outside of DNA) inheritance

Sapolsky Nature Reviews Neuroscience 2004; Video @ https://www.youtube.com/watch?v=nUPm

Mothering Style

Rats show trait-like differences in mothering style

Moms who show high levels of licking, grooming, and arched-back
nursing (high LG-ABN females) cause the handling effect
When the handled baby rat is returned to the homecage, mom
grooms returned pup
More handling More grooming Less stress reactivity in
adulthood
Cross-fostering studies (adopted by Hi or Lo mom) show that this
does not reflect an underlying common genetic cause (Genes
Mom Low N/NE prole in offspring);
Remarkably, female pups raised by high-LG-ABN moms
become high moms
Thereby passing on the trait in a case of multigenerational,
nongenomic (i.e. outside of DNA) inheritance

Sapolsky Nature Reviews Neuroscience 2004; Video @ https://www.youtube.com/watch?v=nUPm

Mothering Style

Rats show trait-like differences in mothering style

Moms who show high levels of licking, grooming, and arched-back
nursing (high LG-ABN females) cause the handling effect
When the handled baby rat is returned to the homecage, mom
grooms returned pup
More handling (man) More grooming (mom) less reactivity in
adult offspring
Cross-fostering studies (adopted by Hi or Lo mom) show that this
does not reflect an underlying common genetic cause (Genes
Mom Low N/NE prole in offspring);
Remarkably, female pups raised by high-LG-ABN moms
become high moms
Thereby passing on the trait in a case of multigenerational,
nongenomic (i.e. outside of DNA) inheritance

Sapolsky Nature Reviews Neuroscience 2004; Video @ https://www.youtube.com/watch?v=nUPm

Mothering Style

Rats show trait-like differences in mothering style

Moms who show high levels of licking, grooming, and arched-back
nursing (high LG-ABN females) cause the handling effect
When the handled baby rat is returned to the homecage, mom
grooms returned pup
More handling (man) More grooming (mom) less reactivity in
adult offspring
Cross-fostering studies (adopted by Hi or Lo mom) show that this
does not reflect an underlying common genetic cause (Genes
Mom Low N/NE prole in offspring);
Remarkably, female pups raised by high-LG-ABN moms
become high moms
Thereby passing on the trait in a case of
multigenerational, nongenomic (i.e. outside of DNA)
inheritance

Sapolsky Nature Reviews Neuroscience 2004; Video @ https://www.youtube.com/watch?v=nUPm

Mothering Style

Rats show trait-like differences in mothering style

Moms who show high levels of licking, grooming, and arched-back
nursing (high LG-ABN females) cause the handling effect
When the handled baby rat is returned to the homecage, mom
grooms returned pup
More handling (man) More grooming (mom) less reactivity in
adult offspring
Cross-fostering studies (adopted by Hi or Lo mom) show that this
does not reflect an underlying common genetic cause (Genes
Mom Low N/NE prole in offspring);
Remarkably, female pups raised by high-LG-ABN moms
themselves become high-LG-ABN moms
Thereby passing on the trait in a case of
multigenerational, nongenomic (i.e. outside of DNA)
inheritance

Sapolsky Nature Reviews Neuroscience 2004; Video @ https://www.youtube.com/watch?v=nUPm

LG-ABN also enhances anti-anxiety

action in the amygdala (CeA)

Caldji et al PNAS 1998; Shackman et al PNAS 2013; Paulus et al AGP

LG-ABN also enhances anti-anxiety

action in the amygdala (CeA)

The offspring of High-LG-ABN moms show mu

higher expression of the benzodiazepine rece
in the central nucleus of the amygdala (CeA)

Caldji et al PNAS 1998; Shackman et al PNAS 2013; Paulus et al AGP

LG-ABN also enhances anti-anxiety

action in the amygdala (CeA)

The offspring of High-LG-ABN moms show mu

higher expression of the benzodiazepine rece
in the central nucleus of the amygdala (CeA)

Correlated with the amount of maternal LG / A

Caldji et al PNAS 1998; Shackman et al PNAS 2013; Paulus et al AGP

LG-ABN also enhances anti-anxiety

action in the amygdala (CeA)

The offspring of High-LG-ABN moms show mu

higher expression of the benzodiazepine rece
in the central nucleus of the amygdala (CeA)

Caldji et al PNAS 1998; Shackman et al PNAS 2013; Paulus et al AGP

LG-ABN also enhances anti-anxiety

action in the amygdala (CeA)

CeA activity predicts N/NE in monkey

Caldji et al PNAS 1998; Shackman et al PNAS 2013; Paulus et al AGP

LG-ABN also enhances anti-anxiety

action in the amygdala (CeA)

CeA activity predicts N/NE in monkey

CeA activity is reduced by benzos in a

dose-dependent manner in humans

Caldji et al PNAS 1998; Shackman et al PNAS 2013; Paulus et al AGP

How does maternal behavior lead to multi-generational

transmission of reduced stress reactivity?
(we know its not mediated by genes)

Epigenetics!
Experience and nurtute can
re-program
trait-like phenotypes
(e.g., stress reactivity, N/NE)

Epigenetics: 2 Flavors
1) Non-heritable, but trait-like alterations in the
transcriptional (protein-making) potential of a cell
(such as a neuron)
Differentiation: How come hair cells are different than
neurons or bone cells?
Development: How come Micah/Hannah are small and
Alex is big?
DNA is static, but cells differentiate into many
different types, which perform different functions, and
respond differently to the environment at different
points in life
Epigenetic changes modify the activation of
certain genes
This is why differentiated cells express only the
genes that are functionally necessary

Epigenetics: 2 Flavors
1) Non-heritable, but trait-like alterations in the
transcriptional (protein-making) potential of a cell
(such as a neuron)
Differentiation: How come hair cells are different than
neurons or bone cells?
Development: How come Micah/Hannah are small and
Alex is big?
DNA is static, but cells differentiate into many
different types, which perform different functions, and
respond differently to the environment at different
points in life
Epigenetic changes modify the activation of
certain genes
This is why differentiated cells express only the
genes that are functionally necessary

Epigenetics: 2 Flavors
1) Non-heritable, but trait-like alterations in the
transcriptional (protein-making) potential of a cell
(such as a neuron)
Differentiation: How come your hair cells are different
than neurons or bone cells (despite identical DNA)?
Development: How come Micah/Hannah are small and
Alex is big?
DNA is static, but cells differentiate into many
different types, which perform different functions, and
respond differently to the environment at different
points in life
Epigenetic changes modify the activation of
certain genes
This is why differentiated cells express only the
genes that are functionally necessary

Epigenetics: 2 Flavors
1) Non-heritable, but trait-like alterations in the
transcriptional (protein-making) potential of a cell
(such as a neuron)
Differentiation: How come your hair cells are different
than neurons or bone cells (despite identical DNA)?
Development: How come Micah/Hannah are small and
Alex is big?
DNA is static, but cells differentiate into many
different types, which perform different functions, and
respond differently to the environment at different
points in life
Epigenetic changes modify the activation of
certain genes
This is why differentiated cells express only the
genes that are functionally necessary

Epigenetics: 2 Flavors
1) Non-heritable, but trait-like alterations in the
transcriptional (protein-making) potential of a cell
(such as a neuron)
Differentiation: How come your hair cells are different
than neurons or bone cells (despite identical DNA)?
Development: How come Micah/Hannah are small and
Alex is big?
DNA is static, but cells differentiate into many
different types, which perform different functions, and
respond differently to the environment at different
points in life
Epigenetic changes modify the activation of
certain genes
This is why differentiated cells express only the
genes that are functionally necessary

How exactly does this work?

2 key mechanisms alter
the functionality of DNA

Methylation

Methylation

Histone Modification

Do epigenetic mechanisms
account for
Handling Maternal Style Offspring Stress Reactivity
?

Yes! Early emerging epigenetic changes in

pups raised by High LG-ABN moms (own or
adopted)
Altered translation of the glucocorticoid
receptor in the hippocampus
Reduced stress reactivity (cortisol)
Epigenetic and neurochemical changes
persist into adulthood

Yes! Early emerging epigenetic changes in

pups raised by High LG-ABN moms (own or
adopted)
Altered translation of the glucocorticoid
receptor in the hippocampus
Reduced stress reactivity (cortisol)
Epigenetic and neurochemical changes
persist into adulthood

Yes! Early emerging epigenetic changes in

pups raised by High LG-ABN moms (own or
adopted)
Altered translation of the glucocorticoid
receptor in the hippocampus
Reduced stress reactivity (cortisol)
Epigenetic and neurochemical changes
persist into adulthood

Yes! Early emerging epigenetic changes in

pups raised by High LG-ABN moms (own or
adopted)
Altered translation of the glucocorticoid
receptor in the hippocampus
Reduced stress reactivity (cortisol)
Furthermore, epigenetic marks and
neurochemical changes persist into
adulthood

Lamarck
Kerry Ressler
(Emory)

Can we benefit (or suffer) from our

parents experience without them
teaching (or grooming) us?
Can paternal experience be transmitted
to offspring without a behavioral/social
intermediary (LG-ABN)?
Can acquired characteristics
be inherited, as Lamarck
posited in the 18th century?

Tantalizing affirmative
evidence

but still early days

Hughes Nature 2014

Details Are Not Important

Wellberg Nat Rev Neurosci 201

Dad is Fear Conditioned

IVF
Epigenetic marks in sperm

Details Are Not Important

Dias & Ressler Nature Neuro 201

Details Are Not Importan

Dad is Fear Conditioned
IVF
Epigenetic marks in sperm

Details Are Not Important

Dias & Ressler Nature Neuro 201

Dad is Fear Conditioned Mom

IVF
Epigenetic marks in sperm

Details Are Not Important

Dias & Ressler Nature Neuro 201

Dad is Fear Conditioned Mom

IVF
Epigenetic marks in sperm

Enhanced Fear to Conditioned

Odor in Children
and Grandchildren

Details Are Not Important

Dias & Ressler Nature Neuro 201

Dad is Fear Conditioned Mom

IVF
Epigenetic marks in sperm

Enhanced Fear to Conditioned

Odor in Children
and Grandchildren

Details Are Not Important

Dias & Ressler Nature Neuro 201

egs the question

How are the gametes (sperm) changing?

Details Are Not Important

Dias & Ressler Nature Neuro 201

Key Take Homes

Key Take Homes

Individual differences in T&P reflect the brain
e.g., Individuals with higher levels of N/NE
show enhanced activation and slower recovery
in the amygdala
Where do differences in brain activation
come from?
We cant assay tissue from the amygdala (in
people), but can we use the genome (DNA)
to identify candidate mechanisms (that could
be mechanistically tested in animals?

Key Take Homes

Individual differences in T&P reflect the brain
e.g., Individuals with higher levels of N/NE
show enhanced activation and slower recovery
in the amygdala
Where do differences in brain activation
come from?

We cant assay tissue from the amygdala (in

people), but can we use the
genome
(DNA)
enome
Systems
/ Circuits
igenome
(e.g., amygdala,
Proteins mechanisms
to identify candidate
(that could
Traits
vironment / Experience (e.g., receptors) hippocampus,
be mechanistically tested in
animals?
x E or Epi x E
HPA axis)

Key Take Homes

We cant assay tissue from the amygdala (in
people), but can we use the genome
(DNA) to identify candidate mechanisms
(that could be mechanistically tested in
animals?
Sometimes. Case by case basis.
Individual candidate SNPs account for
small % of variance.
Need G x E or GWASbut how do you scan
50,000 subjects?

Key Take Homes

We cant assay tissue from the amygdala (in
people), but can we use the genome (DNA)
to identify candidate mechanisms (that
could be mechanistically tested in animals?
Maybe. Test assumptions, replicate findings.
Individual candidate genetic variants
account for a small % of variance.
Need G x E (unmask effects) or GWASbut
how do you scan 100,000 subjects with the
same paradigm?

Key Take Homes

Genes interact with the Environment
& Experience to produce lasting
changes in T&P
How does early experience (abuse,
stress, positive maternal style) get
under the skin
and modify the brain circuits that
support key features of T&P?

Key Take Homes

Genes interact with the Environment
& Experience to produce lasting
changes in T&P
How does early experience (abuse,
stress, positive maternal style) get
under the skin
and modify the brain circuits that
support key features of T&P?

enome
igenome
Proteins
vironment / Experience (e.g., receptors)
x E or Epi x E

Systems / Circuits
(e.g., amygdala,
hippocampus,
HPA axis)

Traits

Key Take Homes

Can these experiential modifications
be inherited by offspring?

Key Take Homes

Can these experiential modifications
be inherited by offspring?
Maybe. Tantalizing preliminary
evidence. Requires replication and
extension to primates.

The End

Time-Permitting
Review Questions

The (fear-potentiated or emotionmodulated) startle reflex is

A. Is potentiated (increased)
during periods of stress,
fear, and anxiety
B. Can be measured using
similar techniques in
rodents, monkeys, and
humans
C. Is a widely used,
valence-sensitive
measure of conditioned
and unconditioned fear
D. All of the above

Conventional functional MRI (fMRI)

pulse sequences measure
A. Blood oxygenation (the
hemodynamic BOLD signal);
fMRI is an indirect measure
of neuronal ring
B. Neuronal ring
C. The release of
neurotransmitter-lled
vesicles into the synapse
(synpaptic cleft)
D. FDG metabolism
E. Electrical activity generated
by ensembles of neurons,
providing exquisite temporal
resolution

Which is true?
A. There is one
anxiety disorder
B. There is a whole
family of
anxiety
disorders

The most common family of

psychiatric disorders is
A. Anxiety
B. Depression
C. Schizophrenia
D. Somatoform

Anxiety disorders tend to onset

A. Late in life
B. Mid life
C. Early in life

Depression tends to onset

A. Early in life
B. Mid life
C. Late in life

The most burdensome disorder

(disability, illnes, death) in the US is
A. Depression
B. Heart Disease
C. COPD
D. Cancer
E. Alzheimers

Elevated N/NE is a risk

factor for
A. Anxiety
disorders
B. Depressive
disorders
C. Both

Anxiety and depression

symptoms
A. Form a coherent,
factor (internalizing)
B. Are categorically
distinct
C. Should be thought
of as natural kinds,
discrete entities that
exist in nature
waiting to be
discovered

Anxiety and depression

A. Are highly comorbid
B. Rarely co-occur
in the same
individual

Treatments targeting one emotional

disorder
A. Ameliorate
(decrease) the
symptoms of
other emotional
disorders
B. Decrease
ratings of N/NE
C. Both,
suggesting a
common cause

Negative life events & psychological

pathogens such as stress tend to
A. Cause individuals to
cross the diagnostic
boundary and
experience a frank
depressive disorder
B. Increase the risk of
developing a
diagnosable anxiety
disorder
C. Increase N/NE
D. All of the above

Anxiety disorders, depression, and

N/NE
A. Reflect
completely
separate genes
B. Are inherited
together
(shared
inheritance),
suggesting a
common genetic
underpinning

Recent meta-analyses demonstrate

that
A. A variety of anxiety
disorders, like N/NE, are
associated with
heightened amygdala
activation to potential
threat
B. Depression, like N/NE, is
associated with increased
amygdala reactivity to
aversive cues
C. Both, providing evidence
for a common biology

Barlow argues that the development of a

particular Dx (diagnostic specicity) reflects

A. N/NE and a
disorder-specic
learned
vulnerability (e.g.,
fear dogs)
B. N/NE and an innate
vulnerability
C. N/NE and other
non-specic risk
factors

N/NE is a
A. Cause of emotional
disorders
B. Symptom of
emotional disorders
C. Identical to or
synonymous with
the emotional
disorders
D. A symptom of too
much anxiety

When confronted by potential threat (robot, intruder),

children with high levels of behavioral inhibition (BI)

A. Exhibit heightened
avoidance and
freezing
B. Cease playing
C. Become quiet
D. Withdraw to the
proximity of their
caregiver
E. All of the above

Jenni Blackfords group uses a questionnaire to

retrospectively assess childhood BI. This is

A. Much more
practical than
starting a new
longitudinal study
(waiting 20 years)
B. Subject to the
usual concerns
about mnemonic
biases
C. Both

BI in toddlers
A. Parallels anxious temperament
(AT) in young monkeys
B. Echoes theoretical
descriptions of the BIS (Jeffrey
Gray)
C. Is associated with R > L frontal
EEG asymmetry, as in studies
of monkeys and human adults
D. Is considered a facet of N/NE
E. Is somewhat stable (testretest)
F. Is heritable (inherited)
G. All of the above

Most preschoolers with

high levels of BI __________
A. Stick with it
B. Grow out of it
C. Are likely to develop
an anxiety disorder
D. Just have an ageappropriate fear of
separation or
strangers
E. A and C
F. B and D

Kids with _____ & ______ are at risk

for developing ___________
A. Consistent, high
levels of BI,
substance and
emotional disorders
B. Stable, high levels
of BI, schizophrenia
and personality
disorders

Social anxiety disorder can be

characterized by
A. Heightened anxiety
about people and
performance
B. Pervasive worries about
being judged
C. Avoidance
D. Hyper-arousal
E. A disconnect between
what patients know to
be rational vs what they
feel
F. All of the above

BI is associated with
A. Less effective ways of
interacting with others
B. Worse social outcomes
C. Lower quality peer
relations
D. A loss of opportunity to
acquire critical social
skills
E. Challenges forging
strong relations with new
peers and schoolmates
F. All of the above

Over time, the repeated experience of social failure

among individuals with high levels of BI may

A. Train them to interpret

ambiguous social
situations as
threatening
B. Cause them to believe
that poor social
outcomes are their fault
C. Promote excessive
anxiety about social
situations and public
performance
D. All of the above

BI is a strong (candidate) _________ for

______________; but we still need to establish ______ .

A. Intermediate
phenotype,
dysthmia, causation
B. Endophenotype,
social anx disorder,
causation
C. Biomarker, emotional
disorders, heritability
D. Marker, overactive
insula, heritability

T&P reflect
A. Nature
B. Nurture
C. Both

Genes (nature) can influence

A. Environments
and experience
B. Neither. Nature
and nurture are
distinct and
independent
forces

Nature (heritability) is
A. Fixed and
immutable
B. Plastic and can
change in
response to
growing
autonomy or
due to
cumulative
impact

Heritability is
A. The proportion of
variation in a trait,
such as C/SC, that
is accounted for
by the pedigree
(family tree)
B. GV / Total PV = GV
/ GV + EV
C. A and B

Estimates of heritability
A. Are xed
B. Can be influenced by
social and
environmental
influences (e.g., living
in a conservative
religious community)
that increase or
decrease the amount
of variation in the trait
(e.g., disinhibition,
partying, smoking)

Heritability
A. Is the % of
variation in a trait,
such as E/PE, that
is passed down
from your parents
B. Reflects the
inheritance of
genes, not
phenotypes or
traits

Heritability describes
A. The % of my trait that
is inherited (nature)
vs. environmental
(nurture)
B. The % of phenotypic
variation across a
group of individuals
that is influenced by
genetic factors
C. Individuals within a
population (e.g., Alex)

Highly heritable traits, such as

height
A. Are our destiny
B. Can potentially
be powerfully
influenced by
interventions
(environment)

Ryan Bogdan: The neurogenetic strategy

A. Involves correlating variation
in genetic polymorphisms
(SNPs) with variation in
intermediate phenotypes,
such as differences in
amygdala activation
B. Promises to address WHY
individuals differ in brain
activation (e.g., why do
individuals high in N/NE show
heightened amygdala
reactivity)
C. Opens the door to discovering
testable mechanisms for
genetic influence on behavior
D. All of the above

Which is false about the serotonin

transporter genetic polymorphism
A. Amygdala reactivity is correlated
with variation in the serotonintransporter linked polymorphic
region (5-HTTLPR) on the SLC6A4
gene
B. The L allele is bad: Individuals
with the more transcriptionallyefficient long allele (more
transporter proteins available to
clear serotonin from the synapse)
show heightened threat-related
amygdala reactivity relative to
individuals with the short allele
C. Meta-analyses suggest that this
allele accounts for 20-50% of the
variance in amygdala reactivity
D. B and C

Which is false?
A.

B.

C.

D.

Some have suggested that the

neurogenetics strategy can address
the molecular mechanisms linking
genes to brain to traits, such as N/NE
Some have suggested that if we
measure a genetic polymorphism with
a known function (e.g., serotonin
transporter) and we are willing to
make some assumptions, then we can
use SNPs as a proxy for individual
differences in brain chemistry
(serotonin in the amygdala). Which is
awesome because we usually cannot
measure neurochemistry in living
human brains.
In relation to the serotonin transporter
allele, a key assumption of this
strategy is that differences in the
allele are actually associated with
differences in the expression of the
serotonin transporter in the brain
Several groups (e.g., Kalin) have used
PET to show that there is in fact an
association between the allele
transporter expression in the

Which is true
A. The HPA axis is involved in
the release of cortisol,
epinephrine/adrenaline,
and
norepinephrine/noradrenali
ne in response to physical
and psychological stress,
which increases the
availability of energy for
the brain as well as
defensive behaviors
(ght/flight)
B. HPA = hippocampal,
pituitary, amygdala

Which is false
A. Remarkable life-long changes
happen to stress-reactivity when
neonatal rats are exposed to
experimenter handling, providing
a nonhuman animal model of
early experience & temperament
B. Handling leads to tighter, more
precise regulation of cortisol
C. Handling leads to increased
expression of the glucocortisoid
receptor in the hippocampus in
adulthood
D. As adults, rats who were handled
as pups are less exploratory,
more fearful, and more stress
reactive (N/NE)

Which is false: Michael Meaneys group

has provided evidence that the impact of
handling on temperament (N/NE or stress
reactivity) is
A. Related to increased
expression of benzodiazepine
receptors in the amygdala
B. Mediated by a social factor,
namely, maternal style (LGABN: licking, grooming, and
arched-back nursing)
C. Mediated by genes that
increase maternal LG-ABN and
decrease offspring reactivity
D. Not genetically transmitted
(i.e., moms can alter
adopted/cross-fostered pups)

Which is false about

epigenetics
A.

B.
C.

D.

E.

Refers to trait-like alterations in

the transcriptional (proteinmaking) potential of a cell (such
as a neuron) that are not due to
changes in the genome (DNA);
turning certain genes on/off,
without changing the genes
themselves
Often reflects methylation or
histone modication of the DNA
Explains cell differentiation (liver
vs brain cell) & developmentally
appropriate changes in the brain
and body
Can never be heritable
(transmitted to subsequent
generations)
Can be heritable, violating a key
tenet of modern biology
(inherited traits, such as T&P,

Which is false: How does maternal behavior produce

lasting changes in (rodent) temperament (N/NE)

A. Meaneys team showed that

maternal behavior (LG-ABN)
produces epigenetic
changes
B. Epigenetic changes lead to
increased expression of
glucocorticoid receptors in
the hippocampus,
supporting enduring
changes in stress reactivity
C. Epigenetic changes induced
by maternal behavior only
persist during the neonatal
period

Can paternal experience be transmitted to offspring without a

behavioral/social intermediary? Can we benet (or suffer) from
our parents experience without them teaching (or grooming)
us? Can acquired characteristics be inherited, as Lamarck
posited in the 18th century?
A. Yes!
B. No!
C. Ressler and others have
provided tantalizing
evidence suggesting that
this is possible, but much
remains unclear (e.g., how
fear learning in the brain
influences epigenetics in the
sperm/gametes)

Which is false: Trait-like differences in T&P

reflect the brain. Differences in brain
structure and function reflect the influence
of
A. Genome/DNA
B. Epigenome
C. Experience/Enviro
nment
D. Experience
interacting with
the genome and
epigenome
E. None of the above

Which is false: Trait-like differences in T&P reflect

the brain. Nature (genome/DNA, epigenome) and
nurture (experience) interact to change

A. Protein expression
B. DNA methylation
C. Neurochemical
receptor expression
and binding
D. Hippocampal
structure and
function
E. Histone status
F. None of the above

How does early experience (abuse, stress,

caregiver behavior) get into the brain
A. Changes in the
genetic code
B. Changes in the
epigenome that
alter the
expression of
genes, leading to
changes in protein
synthesis and,
ultimately, activity

* Taylors question in class

GWAS pretends that

A. Alleles (i.e.,
genetic variants)
do not interact
with or influence
one another (only
independent
effects are
considered)
B. Alleles do interact
with one another

GWAS genome-wide association

study
A. Brute force approach to
identifying correlations
between alleles and
phenotypes, such as N/NE
B. Often relies on SNP chips
C. Suffers from low statistical
sensitivity, because of the
very large number of tests
performed
D. Opens the door to
discovering new and
potentially important
molecular pathways
E. All of the above

Showing that a trait, such as E/PE, is

heritable indicates
A. A single,
coherent or
unied
biological cause
B. Nothing
whatsoever with
regard to the
number or kind
of substrates

Kagans model of BI
A. Shows a number of
parallels with N/NE and
Grays BIS, reinforcing the
idea that childhood
temperament and adult
personality are closely
related
B. Shows a number of
important differences from
N/NE and Grays BIS,
reinforcing the idea that
childhood temperament
and adult personality are
distinct kinds

An allele is
A. A genetic
polymorphism
B. A genetic variant
C. The thing; that gives
rise to geneticallydetermined
individual differences
in trait-like
phenotypes
D. All of the above

Family, twin, and adoption studies

(aka behavioral genetics) are
A. Correlational
B. Mechanistic
C. Provide a tool
for discovering
the molecular
substrates of
T&P

Family, twin, and adoption studies (aka

behavioral genetics) teach us that
A. Psychiatric disorders,
like T&P, aggregate
in families
B. Are heritable
C. Things that blood
relatives share (e.g.,
SES, toxin exposure,
stress, habits) are
important
determinants of
psychopathology

Which is true
A. In humans, DNA is organized
into 23 pairs of chromosomes,
one descended from Mom and
one from Dad
B. Chromosomes are organized
into genes, regions of DNA
corresponding to the
instructions for a protein
C. These proteins form neurons,
axons, the myelin sheath
covering axons, neurochemicals,
synapses and every other
component of our brains, the
wetware that gives rise to our
T&P
D. All of the above

Developing a mechanistic understanding of the

molecular neurobiology of T&P and associated
psychiatric disorders promises to
A.

B.

C.
D.

E.
F.

G.

Redene diagnostic categories and

T&P traits in terms of quantiable
etiology (root causes)
Accelerate the development of novel
treatments or prevention efforts
targeting links in the etiological chain
Identify at-risk individuals early (e.g.,
carriers of a particular polymorphism)
Predict treatment response or more
quickly pick the best treatment (e.g.,
carriers of a particular polymorphism)
Enhance prognosis: You have 3
months to live
Provide a novel discovery tool for
addressing some of the most
fundamental question about the
nature of T&P
All of the above

Children with elevated behavioral

inhibition (BI)
A. Are more likely to develop anxiety,
mood, and co-morbid substance
abuse disorders later in life
B. Are more likely to develop
psychopathology if they show
stable, high levels of BI across
development
C. Are shy and reticent in the face of
novelty and potential threat (e.g.,
scary robot, human intruder)
D. May show elevated levels of the
stress hormone cortisol
E. Show a R > L pattern of frontal EEG
F. Show heightened amygdala
reactivity to novel faces in
adulthood
G. All of the above

If a trait is highly heritable, this means that group

differences at one point in history will always be that
way

A. Yes
B. No

What are the long-term prospects for linking genes to

intermediate neural phenotypes to traits, such as
C/SC?
A. Awesome!
B. Terrible! What a waste
of taxpayer money!
C. It depends on the nature
of the linkages, which
we do not yet know
D. Current evidence
suggests somewhere in
between awesome and
terrible, but we do not
yet know
E. C and D

Which is true
A. Common genetic polymorphisms
(the SNPs measured by SNP
chips) have, at most, weak effects
on brain function and behavior
(e.g., 2-5%)
B. Such small effects are small and
hard to reliably detect without
using very large and expensive
samples
C. Such small effects have led to
many non-replications
D. Such small effects have led many
to wonder whether this research
strategy is worth the money
E. All of the above

Which is true
A. Hannah is a 6
y.o. boy
B. Micah is an 18
m.o. girl
C. Both of Dr. Ss
kids are cute as
all get out
D. All of the above

The Big 3 superfactors are

about
A. 10% heritable
B. 45% heritable
C. 90% heritable

In class, we discussed several arguments for why

even these small effects are potentially important
A. Small is mis-leading; a limited
number (on the order of a few
tens) of SNPs, each accounting for
a small % of the variance, can add
up to meaningful differences (as in
the height example)
B. The expense to date of this
research is modest compared to
military expenditures or even
large-scale physics projects
(colliders)
C. The discoveries are truly novel,
opening the door to models and
treatments that we probably never
would have predicted or
developed based on our existing
knowledge and intuitions

Which is inherited
(heritable)?
A. Genes
B. Trait-like
phenotypes,
such as E/PE
C. All of the above

Heritability reflects
A. The % of betweenindividual variation
predictable from
pedigree
B. The % of a trait
within an individual
(you!) that is
inherited from your
forebears

A wide variety of environmental

factors can
A. Trigger genetic
predispositions (e.g.,
to high levels of N/NE)
B. Compensate for or
regulate the
expression of genetic
predispositions
C. Enhance or
accentuate genetic
predispositions
D. All of the above

Heritability
A. Is probabilistic and
predictive of
average outcomes
B. Is deterministic if
you know the
parents, you know
exactly what to
expect of the
offspring regardless
of environment or
experience

Anxiety disorders, such as GAD, and

major depression are
A. Categorically different
B. Often co-morbid and
show a number of
other similarities, in
terms of therapeutic
response, heritability,
and do on, suggesting
that they are closely
related to one another
and form a spectrum

Treatments targeting anxiety

disorders
A. Tend to influence
N/NE as well as
depression
B. Selectively
influence the
targeted disorder
C. Only help some
patients
D. A and C
E. B and C

Anxiety disorders, depression, and

N/NE appear to share
A. Genes
B. Neural
substrates (e.g.,
amygdala
hyper-reactivity)
C. Both

Lesion studies in rodents, monkeys, and

humans demonstrate that the amygdala
A. Is required for the
normal acquisition
of new fear learning
(conditioned
emotional
response)
B. Not required
C. Is required for the
retention of already
learned fears

Elevated N/NE
A. Is common
among anxiety
patients
B. Is common
among
depression
patients
C. Both

Psychological pathogens, such as

stress and family conflict
A. Exert similar
effects on
depression, anxiety
disorders, and
N/NE, suggesting a
common substrate
B. Have distinct
effects on T&P vs.
depression vs.
anxiety disorders

In a widely cited paper published in Science in 2003, Caspi

and colleagues provided evidence that Individual differences
in the serotonin transporter SNP

A. predicted depression
B. interacted with life
stress to predict
depression, providing
evidence of a G x E
interaction and
suggesting a
neurochemical substrate
for psychiatric risk
C. Was completely and
utterly unrelated to
depression

Amygdala lesions in
monkeys block
A. The acquisition
of new
conditioned
fears
B. Innate anxiety
about snakes
C. Both

Height is
A. Trait-like
B. Among the most
heritable traits,
although offspring will
show considerable
variation
C. Can be markedly
affected by
interventions (diet,
nutrition, and
healthcare access)

Jerry Kagan argues that the root cause

of childhood behavioral inhibition (BI) is
A. An over-reactive
amygdala
B. Maladaptive
cognitive coping
mechanisms
C. Worry
D. Disress
E. Social reticence
F. Shyness

The administration of a benzodiazepine

(anti-anxiety medication)

A. Causes a dosedependent
reduction in
amygdala
activation
B. Causes a dosedependent
increase in
amygdala
activation

Why do some individuals develop particular

disorders, such as specic phobia of dogs?
A. Learning and experience
B. Core vulnerability
(heightened
neuroticism, hyperreactive amygdala,
inadequate regulation of
the amygdala)
C. Both, neither is
sufficient to explain the
development of specic
emotional disorders

The RoboGator Experiment: Amygdala

lesions in rodents attenuate
A. Reticence to get the food
pellet in the presence of
the remote-control
robogator, suggesting a
substrate for the reticence
demonstrated by BI kids,
consistent with lesioned
monkeys and the human
intruder
B. The amount of time hiding
in the nest area (outside
the arena containing the
Rgator)
C. All of the above

Heritability
A. Is informative
about the nature
and plasticity of
group differences
(men/women,
black/white) in
traits
B. Is not informative
about such mean
differences

Amygdala damage
A. Increases ratings
of trust and
approachability to
faces that are
normally deemed
untrustworthy
B. Has no
consequence of
social interactions
or social cognition

N/NE is
A. A specic risk
factor for
anxiety
disorders
B. A nonspecic
risk factor for a
broad range of
psychiatric
disease

Patient SM has circumscribed bilateral

destruction of her amygdalae. She
A. Picks up snakes and
spiders, despite
professing anxiety
B. Shows no fear in the
haunted house
C. Is unable to acquire
new conditioned fears
in the lab
D. Quickly returned to
the park where she
was assaulted

Is BI a viable intermediate phenotype

for social anxiety disorder
A. Yes
B. No

Emotional disorders and

N/NE
A. Are
fundamentally
different
B. Reflect a
common cause
C. Are
categorically
distinct

Exam Review:
Material Covered During the
First Third of Course

How can we identify the cause(s) of

T&P (e.g., low C/SC)?
A. Forge a link between
individual differences in a
trait and variation in a
relevant behavioral or
biological measure
B. Correlate traits and fMRI
activation
C. Compute a regression
(correlation) between task
performance (e.g., BART)
and traits of interest
D. Directly manipulate the
hypothesized cause.
E. All of the above

What's the problem with reducing a complex,

broad-band trait to a single number?

A. Mixes distinct
processes
B. Hinders our
ability to clearly
resolve the
underlying
substrates
C. Too simplistic
D. All of the above

One strategy for discovering the cause of

phenomenologically complex traits (and mental
disorders) is to

A. Decompose them
into simpler,
more manageable
intermediate
phenotypes
B. Give up
C. Search for
endophenotypes
D. A and C

Which of the following can we plausibly model in

nonhuman animal models (where we can perform
mechanistic experiments to determine causation)

A. Anti-social behavior
B. C/SC
C. Delay of
gratication
D. Turn-taking and
emotional irritability
E. Hyper-sensitivity to
reward-related cues
F. C and E

With respect to neurological soft signs

(trait), elevated lead levels in the hair are
A. Noncausal
symptom/marker of
the process that
causes the trait or
phenotype
B. Marker or scar of
the trait or the
organisms response
to the trait
C. Endophenotype

We discussed 2 kinds of intermediate

phenotypes. Both kinds are
A. Causal
B. Heritable
C. Aggregate in
families
D. Co-segregate in
families

Endophenotypes are
A. Simpler than the
trait one seeks to
understand
B. Causal
C. A bridge between
the genotype and
phenotype
D. Heritable
E. All of the above

Which is true
A. Intermediate
phenotypes cause
traits, markers do not
B. Markers cause traits,
intermediate
phenotypes do not
C. Endophenotypes
cause traits,
biomarkers do not
D. A and C
E. B and C

Remarkably
A. We know quite a bit
about the mechanisms
linking genes to
endophenotypes
B. We know quite a bit
about the mechanisms
linking endophenotypes
to traits (and disorders)
C. We know next to nothing
about either mechanism
for any established
endophenotype

EEG/ERP affords
A. Exquisite spatial
resolution
B. Exquisite
temporal
resolution
C. Neither
D. Both

Conventional fMRI signals

reflect
A. Blood
oxygenation
levels
B. Neuronal ring

Conceptually, activation in both ERPs

and event-related fMRI is estimated by

A. Computing the
average
response
evoked by a
particular
condition or
kind of event
B. Computing the
cross-correlation
among sensors

Which is true
A. EEG is relatively cheap,
tolerant of motion, and
reflects neuronal
electrical activity
(EPSPs)
B. fMRI is relatively
expensive, sensitive to
motion artifacts, and
does not directly
measure neuronal
activity
C. Both

EEG and fMRI are

A. Causal (like lesion
studies)
B. Mechanistic (like
manipulating brain
activity in rodents
with drug infusions)
C. Correlational (like
longitudinal studies
of behavior)

In his 1968 book Personality and Assessment, Walt

Mischel argued that the primary determinant of
moods, thoughts, and behavior is

A. The situation,
because T&P at
most predict
outcomes r = .
30 (9%
variance)
B. T&P
C. Both

But contemporary science suggests that moods,

thoughts, and behavior are determined by

A. The situation
B. T&P
C. Both

Trait-like individual differences in T&P are strongly

predictive of

A. Academic
performance (above
& beyond IQ)
B. Marital stability &
satisfaction
C. Mental & physical
health and wellbeing
(morbidity)
D. Death (mortality)
E. All of the above

Correlation and variance explained: If

two variables are correlated R = .50, the
amount of variance accounted for is:

A. 0.50 * 0.50 = .25 =

25%
B. 0.50 / 0.50 = 1 =
100%
C. Sqrt(.50) = .7071 =
70%

Longitudinal research studies

A. Provide strong evidence that

antecedants (childhood)
predict consequences
(adulthood), a precondition
for establishing causation
B. Complex, costly, and timeconsuming
C. Can not prove causation,
because they do not
manipulate the putative
cause of the outcome
D. All of the above

Moffitt et al PNAS: What is C/SC?

A. Do things by the book;

follow rules
B. Prefer order and neatness
C. Planful; not impulsive
D. Able to delay gratication;
self-disciplined
(marshmallow test)
E. Focused; not easily
distracted
F. All of the above

Which features of modern culture tend to magnify the

impact of individual differences in T&P, such as C/SC?

A. Longevity
B. Risk exposure (fast
food nation)
C. The relatively high
prevalance of
psychiatric disorders,
such as depression,
anxiety, and
substance abuse
D. All of the above

Moffitt et al PNAS: Key results:

Childhood C/SC predicted mid-life

A. Composite measure
of health
B. Composite measure
of personal wealth
C. Incarceration,
criminal conviction
and other indices of
public safety
D. All of the above

Moffitt et al PNAS: Key results:

Which is true?

A. Kids with low C/SC are prone to

smoke, become parents, and
drop out of school as teens
B. Teen snares explain the
negative adult outcomes
experienced by many kids with
low C/SC
C. Teen snares are only part of the
story. Might make more sense to
target the root cause (low
childhood C/SC) for intevention,
rather than teen symptoms
D. All of the above

Moffitt et al showed that childhood self-control predicts health, wealth &

public safety in midlife. What was one intervening mechanism during
adolescence that partially explained the link from kid temperament to
deleterious adult outcomes?

A. Smoking
B. Becoming a parent
C. Excessive video
game playing
D. Violence in the
media
E. High-caffeine energy
drinks
F. A & B
G. C & D

Correlation and variance explained: If

two variables are correlated R = .50, the
amount of variance accounted for is:

A. 0.50 * 0.50 = .25 =

25%
B. 0.50 / 0.50 = 1 =
100%
C. Sqrt(.50) = .7071 =
70%

T&P reflect trait-like individual differences in

emotional and cognitive biases that
A. First emerge early in life
B. Continue to evolve for many
years
C. Account for consistency in
behavior, inner experience,
and risk across time and
contexts. Can be relatively
simple (e.g., anxious distress)
or complex and multiply
determined (orderliness).
Excessive video game playing
D. Can be relatively simple
E. Can be complex and
multidimensional
F. All of the above

T&P are not different in kind (according to Shackman)

because they are both

A. Biological
B. Emotional
C. Cognitive
D. Somewhat
heritable
E. All of the above

What are the 3 fundamental dimensions of T&P?

A. N/NE
B. P/TA
C. E/PE
D. S/RE
E. C/SC
F. A, C, and E
G. A, B, and C

N/NE can be dissected into which 2 facet traits

A. Distress
(fear/anxiety)
and Irritation
(anger)
B. Guilt and Shame

Which statistical test is used to quantify

the continuity (temporal or test-retest stability) of
traits

A. Students t test
B. ANOVA
C. Correlation

T&P is

A. Fixed and
immutable
B. Moderately stable
(R = 0.4 to 0.6
over periods of
one to several
years)
C. Completely plastic
and malleable

Which features of modern culture tend to

magnify the impact of individual differences in
T&P, such as C/SC?

A. Longevity
B. Risk exposure (fast
food nation)
C. The relatively high
prevalance of
psychiatric disorders,
such as depression,
anxiety, and
substance abuse
D. All of the above

The Five Factor Model (FFM) is predicated on

the lexical hypothesis, the assumption that
the deep structure of T&P is embedded in our
natural language, waiting to be discovered.
What are some concerns with this
assumption?

A. Meaningful aspects of T&P may

not be captured by single word
adjectives (e.g., relationships
or processes). Key aspects of
T&P might be too complex for
single words, requiring
phrases, sentences, or even
whole paragraphs of words
B. No guarantee that words
(natural language) will permit
the expression of scientically
crucial aspects of personality
C. Both

The FFM assumes that responses obtained

from untrained lay individuals (e.g., military
personnel, undergraduates) are an adequate
means of uncovering the core dimensions of
personality. What are potential concern with
this assumption?
A.

B.

C.

D.

Lay individuals are sloppy

and inconsistent in their use
of language (e.g.
aggressive, critical)
Untrained raters may not
have sufficiently
sophisticated mental models
of T&P
Untrained judges are more
likely to be biased or even to
lie
All of the above

Tomarken argued that biological

measures of T&P need to be
A. Reliable: Show
adequate internal
consistency reliability
B. Reliable: Show
adequate test-retest
stability (trait-like)
C. Reliable and Valid

Establishing the construct validity of a

measure requires that we demonstrate that it is

A.Sensitive to
some process,
such as fear
B. Specific to
some process
(fear & no other
process)
C. Sensitive and
Specific

he FFM was derived using factor analysis.

Factor analysis is a useful technique for

A. Reducing the
dimensionality of a
dataset
B. Compressing data
C. Identifying a relatively
small number of
factors that describe a
dataset
D. Creating new
questionnaires
E. All of the above

Can factor analysis be used to

objectively discover the nature of T&P?

A. Yes
B. No

In terms of discovery, potential

limitations of factor analysis include
A. Garbage In/Garbage Out;
Dependent on the kinds of inputs;
Cant identify factors that are not
sampled or represented in the data
B. Subjective decisions about the
number of factors to retain (degree
of acceptable lossiness); Splitter
or lumper
C. Requires the analyst to decide at
the outset whether dimensions are
independent or correlated (i.e.,
needs to pick the rotation
technique)

The FFM is largely based on factor analyses of

adjectives. Was the pool of words

A. representative of
the English
language
B. selected on the
basis of
preconceived
notions about the
importance and
understandability
of particular words?

Were the methods that were used to reduce

the ~400,000 words comprising the
unabridged dictionary to a more manageable
pool of adjectives (personality descriptors)

A. replicable,
objective, and
atheoretical
B. subjective,
idiosyncratic,
and
theoretically
biased?

The key take home point from

Blocks critique is that the FFM
A. Is a bunch of hooey
B. Reflects the
fundamental nature
of T&P
C. Is a convenient
short-hand, a
sometimes useful
ction that begs for
additional research

Moffitt et al PNAS: Key results: Which

is true?
A. Kids with low C/SC are
prone to smoke, become
parents, and drop out of
school as teens
B. Teen snares explain the
negative adult outcomes
(reduced health, wealth,
public safety)
experienced by many kids
with low C/SC
C. Teen snares are only part
of the story.
D. All of the above

Establishing the construct validity of a

measure requires that we demonstrate that it is

A.Sensitive to
some process,
such as fear
B. Specific to
some process
(fear & no other
process)
C. Sensitive and
Specific

Which item would NOT be found on a

paper-and-pencil measure of N/NE?

A. Emotionally labile
(unstable)
B. Bothered by
change
C. Prone to sadness
D. Prone to anxiety
E. Blue or depressed
F. Punctual

While they tend to show good internal-consistency

reliability and test-retest stability, self-report measures of
T&P can be limited by biases and artifacts, including

A. Social desirability
(looking good)
B. Lying or
malingering
C. Mnemonic
distortions (e.g.,
peak-end rule)
D. All of the above

Behavior is guided by
A. Conscious processes
B. Automatic habits and
implicit attitudes that
lie outside of
awareness and which
opaque to
introspection, hence
not measureable using
standard paper-andpencil measures of T&P
C. Both conscious and
unconscious processes

Behavior is guided by
A. Conscious processes
B. Automatic habits and
implicit attitudes that
lie outside of
awareness and which
opaque to
introspection, hence
not measureable using
standard paper-andpencil measures of T&P
C. Both conscious and
unconscious processes

Which is true?
A. Amygdala lesions block the
conditioned fear response (SCR)
B. The Story We Tell Ourselves:
Hippocampal lesions block selfreported contingency learning
C. This double dissociation provides
direct evidence for separable
substrates and indicates the need for
using both ratings and other kinds of
measures (e.g., physiological)
D. All of the above

McNulty provided
evidence that
A. Implicit & explicit attitudes
toward spouses are uncorrelated,
suggesting that they reflect
distinct neural circuitry
B. Implicit attitudes (measured
behaviorally) predicted marital
satisfaction 4 years later
C. Whereas, explicit ratings of
attitudes toward ones spouse
did not
D. All of the above

There is considerable
evidence that
A. Trait-like differences in
T&P interact with traitrelevant cues to
produce states
B. Trait measures predict
state ratings
C. E/PE predicts pos affect
elicited by humorous
lm clips; N/NE predicts
fear and anxiety elicited
by aversive lm clips
D. All of the above

Traits predict
A. More intense
states in the
presence of
relevant cues
B. This reflects
heightened peak
activation in the
underlying neural
systems
C. Both

But, T&P also predicts

A. Motivated behavior: Approach
or avoid
B. Emotion regulation & recovery
following challenges
C. Anticipatory thoughts and
feelings (e.g., worry) before
challenges
D. All of the above; the common
denominator is the ABSENCE of
trait-relevant cues in the
immediate environment;
therefore, the T&P x Context
= States model is true but
incomplete

Moods, thoughts, and behavior are

determined by

A. The situation
B. T&P
C. Both

Longitudinal research studies

A. Provide strong evidence that

antecedants (childhood)
predict consequences
(adulthood), a precondition
for establishing causation
B. Complex, costly, and timeconsuming
C. Can not prove causation,
because they do not
manipulate the putative
cause of the outcome
D. All of the above

The key take home point from

Blocks critique is that the FFM
A. Is a bunch of hooey
B. Reflects the
fundamental nature
of T&P
C. Is a convenient
short-hand, a
sometimes useful
ction that begs for
additional research

The Five Factor Model (FFM) is predicated on

the lexical hypothesis, the assumption that
the deep structure of T&P is embedded in our
natural language, waiting to be discovered.
What are some concerns with this
assumption?

A. Meaningful aspects of T&P

may not be captured by single
word
B. Key aspects of T&P might be
too complex for single words,
requiring phrases, sentences,
or even whole paragraphs of
words
C. No guarantee that words
(natural language) will permit
the expression of scientically
crucial aspects of personality
D. All of the above

Are trait-like differences in T&P embodied

in the on-going, spontaneous activity of
the brain?
A.

B.

No, traits interact with

trait-relevant cues to
produce more transient
thoughts, feelings, and
behaviors (i.e., states)
Yes, individuals with
elevated N/NE
(dispositional anxiety)
show increased FDG
metabolism (indexed using
PET) and perfusion imaging
(ASL fMRI) in the
amygdala, even at rest.

Oftentimes, physiological measures, such as EEG, PET, and

functional MRI are collected "at rest" (i.e., when subjects are not
asked to perform any particular task). Are subjects necessarily in
an emotionally-neutral state of quiet quiescence?

A.

B.

Yes, they're quietly lying in

the scanner looking at a
xation cross
No, not necessarily. Many
features of the scanning
procedures could
potentially elicit anxiety
(e.g., novelty, conned
conditions, absence of
normal freedom of
movement, claustrophobia,
noise stress, etc.)

Can we discern temperament &

personality when rewards and
punishments are absent (at rest)?
A.

B.

No, traits interact with

trait-relevant cues to
produce more transient
thoughts, feelings, and
behaviors (i.e., states)
Yes, research using EEG,
PET, and functional MRI
demonstrate that
differences in T&P are
associated with systematic
differences in the activity
and functional connectivity
of the brain in the absence
of explicit rewards and
punishments.

Is the brain ever really at

rest?
A.

Yes.

B.

No, although it only

comprises ~2% of the
adult body mass, the brain
consumes ~20% of the
body's oxygen and glucose
at rest. Importantly, this
consumption is only
modestly altered when
subjects are actively
engaged in performing
mental tasks.

in the serotonin-transporter
linked polymorphic region (5HTTLPR) on the SLC6A4 gene. In
particular, individuals with the
__________ allele tend to be
characterized by heightened
N/NE.
A.
B.

Short
Long

special kind of functional MRI

(arterial sping labeling or
perfusion imaging) to
demonstrate that individuals
with the short ("bad") allele of
the 5-HTTLPR (serotonin
transporter polymorphism) show:
A.

B.

Elevated amygdala
reactivity to threat-related
images.
Elevated activity
(perfusion) in the
amygdala and
hippocampus at rest.

Conventional functional MRI (blood

oxygenation level dependent signal) is
good for:

A.

Assessing differences in
activity, because it's in
arbitrary units that vary
from subject to subject

B.

Assessing trait-like
differences in resting
activity, because it's
calibrated to a real
physical scale.

Amygdala metabolism predicts individual

differences in N/NE (anxious temperament
or negative affectivity) in

A.
B.
C.

Young rhesus macaque

monkeys
Human adults
Both

dispositional anxiety that were

conducted in young monkeys by Ned
Kalin's lab. In these studies, the
monkeys are allowed to respond
naturally to various mild stressors
(e.g., novel testing cage, human
intruder's prole), anesthetized, and
then positioned in the PET scanner.
Activity
in the PET scanner reflects
A. The anesthetized brain.
Therefore, activity does not
reflect a reaction to the
scanner environment.
B.

Regions that were more

metabolically active and,
hence, took up more of the
radiolabeled glucose,
during the preceding 30-

can be used to quantify individual

differences in functional connectivity
(co-activation over time). In humans,
rs-fMRI is collected at rest. In
monkeys, it is typically collected
under light anesthesia. Unlike FDGPET, fMRI
measures of functional connectivity
acquired
under anesthesia
reflect
A. The anesthetized
brain.
Therefore, differences
functional connectivity
does not reflect a reaction
to the scanner
environment, they reflect
the brain's intrinsic
organization or
architecture.

B.

Regions that were more or

Anxious temperament (AT; increased freezing, increased levels of the stress

hormone cortisol, and less frequent coo vocalizations) in young monkeys shows
a number of parallels with _______________. Indeed, individual differences in AT
and __________ can be assayed using similar experimental procedures.

A.

Childhood behavioral
inhibition (BI)

B.

Behavioral Activation
System (BAS)

C.

Conscientiousness/Self-

Drew Fox and colleagues in the Kalin lab demonstrated

that amygdala metabolism predicted differences in
dispositional anxiety (anxious temperament) when it
was collected

A.

In stressful contexts (alone

in the novel testing cage,
human intruder)

B.

In more secure contexts

(home cage alone, home
cage with usual cagemate)

C.

Both stressful and secure

contexts

These results suggest that the "Traits x

Trait-Relevant Cues = States" model is

A.
B.
C.

True
False
True but incomplete

Individuals high in N/NE

tend to
A.

B.

C.

Show elevated reactions to

threat (bigger peak, slower
recovery)
Show chronically elevated
metabolism in regions of
the brain that help to
orchestrate states of
anxiety and arousal
Both

Trait-like differences in N/NE reflect [pick

the most correct & complete response]

A.
B.

C.

The amygdala
The amygdala and other regions
(e.g., the bed nucleus of the stria
terminalis (BNST), hippocampus,
and periaqueductal gray (PAG)).
Elevated metabolism in the
amygdala and other regions
(e.g., the bed nucleus of the stria
terminalis (BNST), hippocampus,
and periaqueductal gray (PAG))
as well as altered functional
connectivity between the
amygdala and prefrontal cortex
(PFC).

T&P potentially reflects

A.

Differences in the peak

response to perturbation

B.

Differences in the
threshold, rise time, peak
amplitude, and recovery to
baseline.

fundamental dimensions of T&P,

one based on sensitivity to
reward-predicting cues
('incentives'), the other based on
sensitivity to punishment or
threat-predicting cues. These
reflect differences in the BAS and
BIS, respectively. High-BAS
individuals
tend
A. Be more sociable,
socially to
B.

C.

dominant, and enjoy social

attention
Are predisposed to engage
in appetitively-motivated
(approach) behaviors.
Experience less anger when
their goals are thwarted.

In principle, high-BAS
individuals tend to
experience more intense
A.

"Wanting" related
emotional states
(excitement, joy, anger)

B.

"Liking" related emotional

states (contentment,
hedonic or sensual
pleasure)

BAS and BIS have been linked to

stable individual differences in
frontal EEG asymmetry. High-BIS
individuals tend to show ______,
whereas High-BAS individuals
tend to show ________ .
A.

B.

Right >> Left asymmetry

and Left >> Right
asymmetry.
Right << Left asymmetry
and Left << Right
asymmetry.

Pharmacological manipulations
(e.g., anti-anxiety drugs) and
neurofeedback manipulations
targeting frontal EEG asymmetry
don't just change the EEG, they
also change reactions to emotional
challenges.
This
suggests
that
A. The neural mechanisms that
underlie the scalp-recorded
EEG asymmetry make a
CAUSAL contribution to T&P.
B.

The neural mechanisms that

underlie the scalp-recorded
EEG asymmetry reflect a
CORRELATE of T&P

C.

The neural mechanisms that

underlie the scalp-recorded
EEG asymmetry reflect a
CONCOMITANT of T&P

Nicotine-deprived smokers anticipating a puff and

infants anticipating a reunion with their mother both
show

A.

L >> R frontal EEG

asymmetry, suggesting
that this biological
measure reflects appetitive
drive (wanting)

B.

L << R frontal EEG

asymmetry, suggesting
that this biological
measure reflects liking and
pleasure

Using daily diary techniques, Gable and

colleagues provided evidence that
differences in T&P reflect

A.

B.

C.

Differential reactivity to
motivationally-signicant
daily events
Differential exposure to
motivationally-signicant
daily events
Both

Converging with the results of the "resting" brain

activity studies, Gable's results suggest that T&P can
bias transient moods, feelings, and behaviors when

A.
B.
C.

Trait-relevant cues are

absent (or present)
Trait-relevant cues are
actively ignored
Both

Implicit/automatic and explicit

(declarative knowledge) processes can

A.

Be uncorrelated,
suggesting distinct neural
circuits
B. Guide behavior
C. Be disrupted by
circumscribed hippocampal
and orbitofrontal lesions,
respectively
D. A & B
E. A, B & C

Electrodermal activity (a.k.a.

EDA/SCR/GSR)
A.

Reflects changes in the

skin's resistance. Sweaty
palms (arousal) reduce the
skin's resistance,
increasing conductance.

B.

Is a measure of arousal and

can be amplied by
positive stress
(excitement), negative
stress (fear), and cognitive
challenges.

C.

Is valence-sensitive:
maximal when one is
experiencing a negative
emotional state,
intermediate for neutral

Extra Slides

GWAS genome-wide association

study
A. Brute force approach to
identifying correlations
between alleles and
phenotypes, such as N/NE
B. Often relies on SNP chips
C. Suffers from low statistical
sensitivity, because of the
very large number of tests
performed
D. Opens the door to
discovering new and
potentially important
molecular pathways
E. All of the above

Showing that a trait, such as E/PE, is

heritable indicates
A. A single,
coherent or
unied
biological cause
B. Nothing
whatsoever with
regard to the
number or kind
of substrates

Kagans model of BI
A. Shows a number of
parallels with N/NE and
Grays BIS, reinforcing the
idea that childhood
temperament and adult
personality are closely
related
B. Shows a number of
important differences from
N/NE and Grays BIS,
reinforcing the idea that
childhood temperament
and adult personality are
distinct kinds

An allele is
A. A genetic
polymorphism
B. A genetic variant
C. The thing; that gives
rise to geneticallydetermined
individual differences
in trait-like
phenotypes
D. All of the above

Family, twin, and adoption studies

(aka behavioral genetics) are
A. Correlational
B. Mechanistic
C. Provide a tool
for discovering
the molecular
substrates of
T&P

Family, twin, and adoption studies (aka

behavioral genetics) teach us that
A. Psychiatric disorders,
like T&P, aggregate
in families
B. Are heritable
C. Things that blood
relatives share (e.g.,
SES, toxin exposure,
stress, habits) are
important
determinants of
psychopathology

Which is true
A. In humans, DNA is organized
into 23 pairs of chromosomes,
one descended from Mom and
one from Dad
B. Chromosomes are organized
into genes, regions of DNA
corresponding to the
instructions for a protein
C. These proteins form neurons,
axons, the myelin sheath
covering axons, neurochemicals,
synapses and every other
component of our brains, the
wetware that gives rise to our
T&P
D. All of the above

Developing a mechanistic understanding of the

molecular neurobiology of T&P and associated
psychiatric disorders promises to
A.

B.

C.
D.

E.
F.

G.

Redene diagnostic categories and

T&P traits in terms of quantiable
etiology (root causes)
Accelerate the development of novel
treatments or prevention efforts
targeting links in the etiological chain
Identify at-risk individuals early (e.g.,
carriers of a particular polymorphism)
Predict treatment response or more
quickly pick the best treatment (e.g.,
carriers of a particular polymorphism)
Enhance prognosis: You have 3
months to live
Provide a novel discovery tool for
addressing some of the most
fundamental question about the
nature of T&P
All of the above

Children with elevated behavioral

inhibition (BI)
A. Are more likely to develop anxiety,
mood, and co-morbid substance
abuse disorders later in life
B. Are more likely to develop
psychopathology if they show
stable, high levels of BI across
development
C. Are shy and reticent in the face of
novelty and potential threat (e.g.,
scary robot, human intruder)
D. May show elevated levels of the
stress hormone cortisol
E. Show a R > L pattern of frontal EEG
F. Show heightened amygdala
reactivity to novel faces in
adulthood
G. All of the above

If a trait is highly heritable, this means that group

differences at one point in history will always be that
way

A. Yes
B. No

What are the long-term prospects for linking genes to

intermediate neural phenotypes to traits, such as
C/SC?
A. Awesome!
B. Terrible! What a waste
of taxpayer money!
C. It depends on the nature
of the linkages, which
we do not yet know
D. Current evidence
suggests somewhere in
between awesome and
terrible, but we do not
yet know
E. C and D

Which is true
A. Common genetic polymorphisms
(the SNPs measured by SNP
chips) have, at most, weak effects
on brain function and behavior
(e.g., 2-5%)
B. Such small effects are small and
hard to reliably detect without
using very large and expensive
samples
C. Such small effects have led to
many non-replications
D. Such small effects have led many
to wonder whether this research
strategy is worth the money
E. All of the above

Which is true
A. Hannah is a 6
y.o. boy
B. Micah is an 18
m.o. girl
C. Both of Dr. Ss
kids are cute as
all get out
D. All of the above

The Big 3 superfactors are

about
A. 10% heritable
B. 45% heritable
C. 90% heritable

In class, we discussed several arguments for why

even these small effects are potentially important
A. Small is mis-leading; a limited
number (on the order of a few
tens) of SNPs, each accounting for
a small % of the variance, can add
up to meaningful differences (as in
the height example)
B. The expense to date of this
research is modest compared to
military expenditures or even
large-scale physics projects
(colliders)
C. The discoveries are truly novel,
opening the door to models and
treatments that we probably never
would have predicted or
developed based on our existing
knowledge and intuitions

Which is inherited
(heritable)?
A. Genes
B. Trait-like
phenotypes,
such as E/PE
C. All of the above

Heritability reflects
A. The % of betweenindividual variation
predictable from
pedigree
B. The % of a trait
within an individual
(you!) that is
inherited from your
forebears

A wide variety of environmental

factors can
A. Trigger genetic
predispositions (e.g.,
to high levels of N/NE)
B. Compensate for or
regulate the
expression of genetic
predispositions
C. Enhance or
accentuate genetic
predispositions
D. All of the above

Heritability
A. Is probabilistic and
predictive of
average outcomes
B. Is deterministic if
you know the
parents, you know
exactly what to
expect of the
offspring regardless
of environment or
experience

Anxiety disorders, such as GAD, and

major depression are
A. Categorically different
B. Often co-morbid and
show a number of
other similarities, in
terms of therapeutic
response, heritability,
and do on, suggesting
that they are closely
related to one another
and form a spectrum

Treatments targeting anxiety

disorders
A. Tend to influence
N/NE as well as
depression
B. Selectively
influence the
targeted disorder
C. Only help some
patients
D. A and C
E. B and C

Anxiety disorders, depression, and

N/NE appear to share
A. Genes
B. Neural
substrates (e.g.,
amygdala
hyper-reactivity)
C. Both

Lesion studies in rodents, monkeys, and

humans demonstrate that the amygdala
A. Is required for the
normal acquisition
of new fear learning
(conditioned
emotional
response)
B. Not required
C. Is required for the
retention of already
learned fears

Elevated N/NE
A. Is common
among anxiety
patients
B. Is common
among
depression
patients
C. Both

Psychological pathogens, such as

stress and family conflict
A. Exert similar
effects on
depression, anxiety
disorders, and
N/NE, suggesting a
common substrate
B. Have distinct
effects on T&P vs.
depression vs.
anxiety disorders

In a widely cited paper published in Science in 2003, Caspi

and colleagues provided evidence that Individual differences
in the serotonin transporter SNP

A. predicted depression
B. interacted with life
stress to predict
depression, providing
evidence of a G x E
interaction and
suggesting a
neurochemical substrate
for psychiatric risk
C. Was completely and
utterly unrelated to
depression

Amygdala lesions in
monkeys block
A. The acquisition
of new
conditioned
fears
B. Innate anxiety
about snakes

Height is
A. Trait-like
B. Among the most
heritable traits,
although offspring will
show considerable
variation
C. Can be markedly
affected by
interventions (diet,
nutrition, and
healthcare access)

Jerry Kagan argues that the root cause

of childhood behavioral inhibition (BI) is
A. An over-reactive
amygdala
B. Maladaptive
cognitive coping
mechanisms
C. Worry
D. Disress
E. Social reticence
F. Shyness

The administration of a benzodiazepine

(anti-anxiety medication)

A. Causes a dosedependent
reduction in
amygdala
activation
B. Causes a dosedependent
increase in
amygdala
activation

Why do some individuals develop particular

disorders, such as specic phobia of dogs?
A. Learning and experience
B. Core vulnerability
(heightened
neuroticism, hyperreactive amygdala,
inadequate regulation of
the amygdala)
C. Both, neither is
sufficient to explain the
development of specic
emotional disorders

The RoboGator Experiment: Amygdala

lesions in rodents attenuate
A. Reticence to get the food
pellet in the presence of
the remote-control
robogator, suggesting a
substrate for the reticence
demonstrated by BI kids,
consistent with lesioned
monkeys and the human
intruder
B. The amount of time hiding
in the nest area (outside
the arena containing the
Rgator)
C. All of the above

Heritability
A. Is informative
about the nature
and plasticity of
group differences
(men/women,
black/white) in
traits
B. Is not informative
about such mean
differences

Amygdala damage
A. Increases ratings
of trust and
approachability to
faces that are
normally deemed
untrustworthy
B. Has no
consequence of
social interactions
or social cognition

N/NE is
A. A specic risk
factor for
anxiety
disorders
B. A nonspecic
risk factor for a
broad range of
psychiatric
disease

Patient SM has circumscribed bilateral

destruction of her amygdalae. She
A. Picks up snakes and
spiders, despite
professing anxiety
B. Shows no fear in the
haunted house
C. Is unable to acquire
new conditioned fears
in the lab
D. Quickly returned to
the park where she
was assaulted

Is BI a viable intermediate phenotype

for social anxiety disorder
A. Yes
B. No

Emotional disorders and

N/NE
A. Are
fundamentally
different
B. Reflect a
common cause
C. Are
categorically
distinct

End of Clicker Questions

The End

Material to Consider
Adding in Future Terms

Perhaps add this for spring

2015

Add this

http://www.nature.com/neuro/journal/
vaop/ncurrent/full/nn.3778.html

Although we did not directly map

methylation in peripheral tissues onto
methylation levels in brain in the
same cohort, cross-cohort
convergence among tissues (saliva,
blood, brain) is consistent with recent
work demonstrating a substantial
correlation between the blood and
brain methylomes16. Furthermore,
prior work has mapped variability in a
similar range of SLC6A4 promoter
methylation values onto individual

Extra Slides

Brief Aside on How the Environment

Gets Under the Skin
Students:
whats a plausible mechanism?
How might parenting or exposure to other risks influence behavior (phenotype)?

How Does E Get Under the Skin?

Epigenetics provides a biological explanation for how E (parenting, therapy, life
events) alters behavior
-

The environment (e.g., learning, stress) can alter gene expression (protein synthesis)
without altering the genome (DNA; hence, not heritable)

Gene expression is influenced by transcription factors, which bind to sequences of DNA

Binding of transcription factors turns genes on or off

Epigenetic mechanisms involve changes to how readily transcription factor can access
the DNA
E.g., methylation: addition of a methyl group onto a cytosine (1 of the 4 base
pairs that make up DNA) silences the gene because methyl hinders the
transcription factors
-

Epigenetic modications of the genome have long been known to exist e.g., all cells in
the body share the same DNA; accordingly, there must be a mechanism whereby
different genes are active in liver cells vs. neurons

Work in rodents by Michael Meaneys group demonstrates that maternal behavior can
influence the adult T&P of offspring and that this is epigenetic dependent

How Does E Get Under the Skin?

Epigenetics provides a biological explanation for how E (parenting, therapy, life
events) alters behavior
-

The environment (e.g., learning, stress) can alter gene expression (protein synthesis)
without altering the genome (DNA; hence, not heritable)

Gene expression is influenced by transcription factors, which bind to sequences of DNA

Binding of transcription factors turns genes on or off

Epigenetic mechanisms involve changes to how readily transcription factor can access
the DNA
E.g., methylation: addition of a methyl group onto a cytosine (1 of the 4 base
pairs that make up DNA) silences the gene because methyl hinders the
transcription factors
-

Epigenetic modications of the genome have long been known to exist e.g., all cells in
the body share the same DNA; accordingly, there must be a mechanism whereby
different genes are active in liver cells vs. neurons

Work in rodents by Michael Meaneys group demonstrates that maternal behavior (xfostered) can influence the adult T&P of offspring and that this is epigenetic dependent

How Does E Get Under the Skin?

Epigenetics provides a biological explanation for how E (parenting, therapy, life
events) alters behavior
-

The environment (e.g., learning, stress) can alter gene expression (protein synthesis)
without altering the genome (DNA; hence, not heritable)

Gene expression is influenced by transcription factors, which bind to sequences of DNA

Binding of transcription factors turns genes on or off

Epigenetic mechanisms involve changes to how readily transcription factor can access
the DNA
E.g., methylation: addition of a methyl group onto a cytosine (1 of the 4 base
pairs that make up DNA) silences the gene because methyl hinders the
transcription factors
-

Epigenetic modications of the genome have long been known to exist e.g., all cells in
the body share the same DNA; accordingly, there must be a mechanism whereby
different genes are active in liver cells vs. neurons

Elegant mechanistic work in rodents by Michael Meaneys group demonstrates that one
aspect of the early environment , maternal behavior (x-fostered), can influence the T&P
of offspring and that this is epigenetic dependent

This is exceedingly hard to study in humans because epigenetic mechanisms vary across
the brain and body, so measuring epigenetic effects in blood or saliva may not tell you

PSYC 612 R08B:

G-E Correlations:
How Genes Get Outside the Skin

AJ Shackman
9 December 2013

PSYC 612 R08B:

G-E Correlations:
How Genes Get Outside the Skin

Students?

Lemery (ASU)

Jaffee (Penn)

Translational Promise
Sara argues that, in principle, if one could identify with high sensitivity and
specificity at-risk G-E pairs
- At-risk kids paired with risky environments (parental style, peers, adversity, abuse,
etc.)
You could target them for precision interventions BEFORE the onset of cumulative
damage
- in effect, she argues for a more nuanced extension of the Moffitt PNAS strategy
- instead of identifying kids with low C/SC
- identify kids with low C/SC and other environmental risk factors
- this is akin, as I understand it, to what Andreas lab does (ADHD kid + parent with
sub-optimal skill)
- potentially, one could use biomarkers (gene screens) to identify high-risk parent-kid
dyads

G-E Correlations Defined (Plomin

77)
Many sources of influence that we might consider environmental are actually
non-random and genetic
1. Passive G-E correlation (nature and nurture are confounded)
- among biologically related parents and offspring, the parents provide genotypes
AND rearing environment; thus many parent-child outcome correlations may
actually reflect passive G-E effects
-

E.g., the reason children who are spanked or smacked are more aggressive than
children who are not may be that parents and kids share a genetic risk for
aggressive behavior (common cause)

2. Evocative G-E correlation

- e.g., a child who is predisposed to having an outgoing, cheerful T&P is more likely to
evoke positive attention from others than a child who is predisposed to N/NE
E.g., Individuals with a grumpy, abrasive temperament (N/NE) tend to evoke
unpleasant responses
from coworkers and others than cheerful, friendly individuals
-

3. Active G-E correlation

- Individuals actively select environments
- E.g., individuals predisposed to high E/PE seeking may be more prone to attend
parties, go to bars, meet new people, be exposed to or to try substances of abuse

G-E Correlations Defined (Plomin

77)
Many sources of influence that we might consider environmental are actually
non-random and genetic

1. Passive G-E correlation (nature and nurture are confounded)

- among biologically related parents and offspring, the parents provide genotypes
AND rearing environment; thus many parent-child outcome correlations reflect
passive G-E effects
-

E.g., the reason children who are spanked or smacked are more aggressive than
children who are not may be that parents and kids share a genetic risk for
aggressive behavior (common cause)

2. Evocative G-E correlation

- e.g., a child who is predisposed to having an outgoing, cheerful T&P is more likely to
evoke positive attention from others than a child who is predisposed to N/NE
E.g., Individuals with a grumpy, abrasive temperament (N/NE) tend to evoke
unpleasant responses
from coworkers and others than cheerful, friendly individuals
-

3. Active G-E correlation

- Individuals actively select environments
- E.g., individuals predisposed to high E/PE seeking may be more prone to attend
parties, go to bars, meet new people, be exposed to or to try substances of abuse

G-E Correlations Defined (Plomin

77)
Many sources of influence that we might consider environmental are actually
non-random and genetic

1. Passive G-E correlation (nature and nurture are confounded)

- among biologically related parents and offspring, the parents provide genotypes
AND rearing environment; thus many parent-child outcome correlations reflect
passive G-E effects
-

E.g., the reason children who are spanked or smacked are more aggressive than
children who are not may be that parents and kids share a genetic risk for
aggressive behavior (common cause)

2. Evocative G-E correlation

- e.g., a child who is predisposed to having an outgoing, cheerful T&P is more likely to
evoke positive attention from others than a child who is predisposed to N/NE
-

E.g., Infant behavioral inhibition evokes parental insensitivity, which then

potentiates
maladaptive parentchild interactions over time, exacerbating fear of novelty

3. Active G-E correlation

- Individuals actively select environments
- E.g., individuals predisposed to high E/PE seeking may be more prone to attend
parties, go to bars, meet new people, be exposed to or to try substances of abuse

G-E Correlations Defined (Plomin

77)
Many sources of influence that we might consider environmental are actually
non-random and genetic

1. Passive G-E correlation (nature and nurture are confounded)

- among biologically related parents and offspring, the parents provide genotypes
AND rearing environment; thus many parent-child outcome correlations reflect
passive G-E effects
-

E.g., the reason children who are spanked or smacked are more aggressive than
children who are not may be that parents and kids share a genetic risk for
aggressive behavior (common cause)

2. Evocative G-E correlation

- e.g., a child who is predisposed to having an outgoing, cheerful T&P is more likely to
evoke positive attention from others than a child who is predisposed to N/NE
-

E.g., Infant behavioral inhibition evokes parental insensitivity, which then

potentiates
maladaptive parentchild interactions over time, exacerbating fear of novelty

3. Active G-E correlation (Niche Building)

- Individuals actively select environments
-

E.g., individuals predisposed to high E/PE seeking may be more prone to attend
parties, go to bars, meet new people, be exposed to delinquent peers, and try

Evidence for G-E Correlations

Evidence for G-E Correlations

Mostly from FTA studies demonstrating that environmental measures are
heritable, including many linked to psychopathology
e.g., marital quality, social support, parental discipline/warmth, family environment,

peer relationships, negative life events such as divorce and exposure to trauma
Environments are heritable because genotype influences behaviors that evoke,
select, and modify features of the environment
- Environments less amenable to behavioral modication are less heritable, e.g., the
death of a loved one, losing ones home in a natural disaster
- Than those that depend on the individuals behavior, e.g., divorce, getting red
Take home: Genetic risk factors do not necessarily have direct effects on phenotypes (T&P,
Dx), but can work indirectly by modifying sensitivity to environmental risk factors (active GE) or by influencing exposure
to risk (passive, evocative G-E)

Evidence for G-E Correlations

Mostly from FTA studies demonstrating that environmental measures are
heritable, including many linked to psychopathology
e.g., marital quality, social support, parental discipline/warmth, family environment,

peer relationships, negative life events such as divorce and exposure to trauma
Environments are heritable because genotype influences behaviors that evoke,
select, and modify features of the environment
- Environments less amenable to behavioral modication are less heritable, e.g., the
death of a loved one, losing ones home in a natural disaster
- Than those that depend on the individuals behavior, e.g., divorce, getting red
Take home: Genetic risk factors do not necessarily have direct effects on phenotypes (T&P,
Dx), but can work indirectly by modifying sensitivity to environmental risk factors (active GE) or by influencing exposure
to risk (passive, evocative G-E)

G-E Correlation Take Homes

3 Kinds of G-E Correlations: Passive, Evocative,
and Active
Take home: Genetic risk factors do not necessarily have
direct effects on phenotypes (T&P, Dx), but can work
indirectly by modifying exposure to environmental risks
(e.g., stress, substances, delinquent peers) that reinforce
particular personality traits or precipitate frank
psychopathology
More fundamentally, these data emphasize that
Nature/Genotype and Nurture/Environment are not
mutually exclusive forces, but often work together to
increase or decrease the likelihood of important
outcomes

Long Term Prospects, The Good

We could get lucky
In the most optimistic scenario, nearly all of the veried risk genes identied
through GWAS or sequencing will map to a single coherent inter-connected
biological pathway.
This will occur only if the genetic underpinnings of the disorder reflect a high
degree of etiological homogeneity. i.e. a single disease process
(equinality)
Intermediate scenarios (neither Ugly nor Good) are possible

Long Term Prospects, The Ugly

There are many many ways to make a neuron hypofunction
(shrunken
dendrites, too few or dysfunctional receptors, downregulated 2 nd
messenger systems, or decient transport mechanisms.
There are even more pathways to make a complex
circuit dysfunction
This scenario is likely if there are hundreds of distinct biochemical
changes that individually contribute to Dx (neither necessary nor
sufficient) with independent pathways to the phenotype.
Perhaps there are too many ways for the human brain to produce
symptoms/signs of psychiatric disorders (for example, sad mood, auditory
hallucinations, grandiosity) for a limited number of biologically coherent
pathways to emerge from the 100s or 1000s of genes that make small
contributions to risk.
Here, psychiatric disorders (or T&P) arise at such a high level within the
mindbrain system that we have no way to integrate GWAS or sequencing
ndings.

Strategy for Linking FTA to

Molecules
Dick notes that it is useful to first search for G*E interactions in FTA studies
There are a huge number of environmental factors that could potentially be assessed
Useful to build off the already well-developed developmental literature
In cases where there is an interaction between Genes (in aggregate) and Environment (e.g.,
peer delinquency exposure), that is, a hit in the FTA literature
It makes sense to drill down into specic genes, either candidate variants or GWAS

More Sophisticated Approaches:

Gene*Gene & Multilocus Profiles
The phenotype (T&P/Dx) reflects the cumulative effect of all
the genes; traits are massively polygenic
In principle, it would be helpful to model gene*gene
interactions or develop more complex additive (many main
effects) proles (high on this, medium on that, low on the
other and so on)
In practice, this is challenging given the combinatorial
complexity
Also, prole scores that combine many genes eliminates the
possibility of testing specic mechanistic hypotheses in animal
models, back to black box of aggregate heritability
There is considerable excitement about the development of
more sophisticated analytic tools (e.g., machine learning of

More Sophisticated Approaches:

Gene*Gene & Multilocus Profiles
The phenotype (T&P/Dx) reflects the cumulative effect of all
the genes; traits are massively polygenic
In principle, it would be helpful to model gene*gene
interactions or develop more complex additive (many main
effects) proles (high on this, medium on that, low on the
other and so on)
In practice, this is challenging given the combinatorial
complexity
Also, prole scores that combine many genes eliminates the
possibility of testing specic mechanistic hypotheses in animal
models, back to black box of aggregate heritability
There is considerable excitement about the development of
more sophisticated analytic tools (e.g., machine learning of

Grade Distribution

Grade Components

3 Scenarios

What If I Got a Low B and Want an

A

What If I Got a Low B and Want an

A

What If I Got a Low C and Want a B

What If I Got a Low C and Want a B

What If I Got a D and Want a B

What If I Got a D and Want a B

Extra Credit

Cumulative Exam #2
60 items (instead of 40)
33% (20/60) from the material covered
on the 1st exam
66% (40/60) focused on the new
material
Please contact Tara if you have any
questions or concerns with the class,
extra credit, etc. ASAP.