shackman psyc210 module12 naturenurture part3 032615b

PowerPoint Presentation

Nuts and Bolts Plan for Today

Lecture (Bogdan, Meaney, Dias)

No take-home assignment today!

PSYC 210:The nature & nurture of T&P, IIIGene 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)?



e.g., Individuals with higher levels of N/NE show enhanced peak activation and slower recovery in the amygdala


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)?




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?




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?


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

Caspi et al Science 2002

monoamine oxidase A (MAOA) gene

Maltreatment x MAO-A Gene

Caspi et al Science 2002

monoamine oxidase A (MAOA) 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

Stress x 5-HTT Gene

Caspi et al Science 2003, Amer J Psychiatry 2010; Monroe Psychol Sci 2008

Stress x 5-HTT Gene

Caspi et al Science 2003, Amer J Psychiatry 2010; Monroe Psychol Sci 2008

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 depressive episodes Short allele confers risk (or the Long allele confers protection)

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

Genome

Traits (Evildoing, Depression)

Intermediate Phenotype

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

Genome



What about the brain?How might we as scientists understand the neuro-molecularbuilding blocks of traits or disorders?

Genome



Caspis Suggested Strategy: 3 Easy Pieces


Start with solid evidence that MAO-A / Serotonin transporter

influences the emotional phenotype in animal models

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!


Test hypothesized mechanisms (serotonin levels in

the amygdala?) in animal model or using PET imaging


Test hypothesized mechanisms (serotonin levels in

the amygdala?) in animal model or using PET imaging


Building on this framework, other investigators have focused on linkinggenes to imaging measures of brain structure and function

Bogdan (Wash U)

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)

- then we can use noninvasive measures of SNPs (from cheek swabs), as a proxy for individual differences in neurochemistry (serotonin in the amygdala),

The Neurogenetic Strategy


Goals










Goals










Goals










Goals










Goals










Goals






- 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)




Goals






- 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 & 5-HTTLPR

Work by Hariri (prior to Caspi) suggested that amygdala reactivity is correlated with variation in the serotonin-transporter linked polymorphic region (5-HTTLPR)

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 genetically conferred differences in amygdala reactivity mediate some of the association between the 5-HTTLPR polymorphism and depression


Work by Hariri (prior to Caspi) suggested that amygdala reactivity is correlated with variation in the serotonin-transporter linked polymorphic region (5-HTTLPR)

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 genetically conferred differences in amygdala reactivity mediate some of the association between the 5-HTTLPR polymorphism and depression


S allele Enhanced Amygdala Reactivity (Sensitization)

These data suggest the following causal chain:

[GENETIC OBSERVATION] Some folks have the 5-HTTLPR 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

[EPIDEML OBSERVATION] MDD, especially among individuals exposed to stress

Hypothesized Causal Chain




































Does the gene actually predict 5-HTT expression in the amygdala (1st Assumption)?Testable hypothesis

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 adetectable 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 whether this increased risk is mediated by changes in the expression of the number of serotonin transporter molecules.

Use PET to test 5-HTT expression



our ndings are in agreement with the majority of human PET studiesthat suggest there is not adetectable 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 whether this increased risk is mediated by changes in the expression of the number of serotonin transporter molecules.


Kalin (UW)



our ndings are in agreement with the majority of human PET studiesthat suggest there is not adetectable 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 whether this increased risk [of MDD] is mediated by changes in the expression of the number of serotonin transporter molecules.

Kalin (UW)


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, suggesting that the 5-HTTLPR-amygdala association is either much smaller than previously thought, conditional on other factors, or nonexistent.

















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






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 the 5-HTTLPR-amygdala correlation is either much smaller than previously thought, conditional on other factors (like exposure to stress or trauma), or is simply nonexistent.

Interim Take Home

The Neurogenetic or Neurogene x Environment strategy is

potentially powerful, but assumptions need to be tested for

each candidate pathway

How might the environment and early experience getUnder the Skin andpromote 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 getUnder the Skin andpromote enduring changes in T&P?Early stress, abuse, or maltreatment Increased stress reactivity and MDD risk Maternal nurturance Decreased stress reactivity in adulthood

The key mechanistic question is how such influencesbecome longlastingTurn to a nonhuman animal model of early Nurture

Michael Meaney

The key mechanistic question is how such influencesbecome longlastingTurn to a nonhuman animal model of early Nurture

Michael Meaney

Experimenter handling has enduring consequences for stress reactivity (N/NE)

Levine Science 1962; see also Weininger Science 1954

Experimenter handling has enduring consequences for stress reactivity (N/NE)

Levels of the stress-sensitive hormone cortisol elicited by shock

M Handled

N - Not

Levine Science 1962

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






Diverts energy from longer-term priorities (such as the immune system and wound healing) to promote survival in the face of acute threat






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

Sapolsky Nature Reviews Neuroscience 2004

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



Tighter regulation of cortisol (glucocorticoids) secretion: lower baseline & poststress levels*






* Bigger early peak; quicker return to baseline; more adaptive















a more exploratory, less fearful,

and less stress-reactive adult

Decreased N/NE in offspring


What causes enduring changesin the regulation ofstress hormones in the offspring?

Mothering Style

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

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 profile 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

Mothering Style








become high moms


Mothering Style








become high moms


Mothering Style





More handling (man) More grooming (mom) less reactivity in adult offspring



become high moms


Mothering Style








become high moms

Thereby passing on the trait in a case of

multigenerational, nongenomic (i.e. outside of DNA)

inheritance

Mothering Style








themselves become high-LG-ABN moms

Thereby passing on the trait in a case of

multigenerational, nongenomic (i.e. outside of DNA)

inheritance

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 2005



The offspring of High-LG-ABN moms show much

higher expression of the benzodiazepine receptor

in the central nucleus of the amygdala (CeA)






Correlated with the amount of maternal LG / ABN








CeA activity predicts N/NE in monkeys



CeA activity predicts N/NE in monkeys

CeA activity is reduced by benzos in a

dose-dependent manner in humans

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)

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

2) Heritable changes in gene activity that are not caused by changes in DNA

Epigenetics: 2 Flavors


Differentiation: How come hair cells are different than neurons or bone cells?








Differentiation: How come your hair cells are different than neurons or bone cells (despite identical DNA)?






















non-genomic inheritance


How exactly does this work?2 key mechanisms alter the functionality of DNA

Methylation

Histone Modification

Methylation

Do epigenetic mechanismsaccount forHandling 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) Furthermore, epigenetic marks and neurochemical changes persist into adulthood

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 characteristicsbe inherited, as Lamarck posited in the 18th century?

Kerry Ressler

(Emory)

Lamarck

Hughes Nature 2014

Tantalizing affirmative evidence

but still early days

Wellberg Nat Rev Neurosci 2014

Details Are Not Important

Dias & Ressler Nature Neuro 2014

IVF

Dad is Fear Conditioned

Epigenetic marks in sperm



IVF






IVF


Mom



IVF


Mom

Enhanced Fear to Conditioned

Odor in Children

and Grandchildren




IVF


Mom

Enhanced Fear to Conditioned

Odor in Children

and Grandchildren





How are the gametes (sperm) changing???

Begs the question


Key Take Homes

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?

Key Take Homes





Traits

Genome

Epigenome

Environment / Experience

G x E or Epi x E

Proteins

(e.g., receptors)

Systems / Circuits

(e.g., amygdala,

hippocampus,

HPA axis)

Key Take Homes


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


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



and modify the brain circuits that support key features of T&P?

Key Take Homes



and modify the brain circuits that support key features of T&P?

Traits

Genome

Epigenome

Environment / Experience

G x E or Epi x E

Proteins

(e.g., receptors)

Systems / Circuits

(e.g., amygdala,

hippocampus,

HPA axis)

Key Take Homes


Key Take Homes


Maybe. Tantalizing preliminary evidence. Requires replication and extension to primates.

The End

Time-PermittingReview Questions

The (fear-potentiated or emotion-modulated) startle reflex is

Is potentiated (increased) during periods of stress, fear, and anxiety

Can be measured using similar techniques in rodents, monkeys, and humans

Is a widely used, valence-sensitive measure of conditioned and unconditioned fear

All of the above

Conventional functional MRI (fMRI) pulse sequences measure

Blood oxygenation (the hemodynamic BOLD signal); fMRI is an indirect measure of neuronal firing

Neuronal firing

The release of neurotransmitter-filled vesicles into the synapse (synpaptic cleft)

FDG metabolism

Electrical activity generated by ensembles of neurons, providing exquisite temporal resolution

Which is true?

There is one anxiety disorder

There is a whole family of anxiety disorders

The most common family of psychiatric disorders is

Anxiety

Depression

Schizophrenia

Somatoform

Anxiety disorders tend to onset

Late in life

Mid life

Early in life

Depression tends to onset

Early in life

Mid life

Late in life

The most burdensome disorder (disability, illnes, death) in the US is

Depression

Heart Disease

COPD

Cancer

Alzheimers

Elevated N/NE is a risk factor for

Anxiety disorders

Depressive disorders

Both

Anxiety and depression symptoms

Form a coherent, factor (internalizing)

Are categorically distinct

Should be thought of as natural kinds, discrete entities that exist in nature waiting to be discovered

Anxiety and depression

Are highly co-morbid

Rarely co-occur in the same individual

Treatments targeting one emotional disorder

Ameliorate (decrease) the symptoms of other emotional disorders

Decrease ratings of N/NE

Both, suggesting a common cause

Negative life events & psychological pathogens such as stress tend to

Cause individuals to cross the diagnostic boundary and experience a frank depressive disorder

Increase the risk of developing a diagnosable anxiety disorder

Increase N/NE

All of the above

Anxiety disorders, depression, and N/NE

Reflect completely separate genes

Are inherited together (shared inheritance), suggesting a common genetic underpinning

Recent meta-analyses demonstrate that

A variety of anxiety disorders, like N/NE, are associated with heightened amygdala activation to potential threat

Depression, like N/NE, is associated with increased amygdala reactivity to aversive cues

Both, providing evidence for a common biology

Barlow argues that the development of a particular Dx (diagnostic specificity) reflects

N/NE and a disorder-specific learned vulnerability (e.g., fear dogs)

N/NE and an innate vulnerability

N/NE and other non-specific risk factors

N/NE is a

Cause of emotional disorders

Symptom of emotional disorders

Identical to or synonymous with the emotional disorders

A symptom of too much anxiety

When confronted by potential threat (robot, intruder), children with high levels of behavioral inhibition (BI)

Exhibit heightened avoidance and freezing

Cease playing

Become quiet

Withdraw to the proximity of their caregiver

All of the above

Jenni Blackfords group uses a questionnaire to retrospectively assess childhood BI. This is

Much more practical than starting a new longitudinal study (waiting 20 years)

Subject to the usual concerns about mnemonic biases

Both

BI in toddlers

Parallels anxious temperament (AT) in young monkeys

Echoes theoretical descriptions of the BIS (Jeffrey Gray)

Is associated with R > L frontal EEG asymmetry, as in studies of monkeys and human adults

Is considered a facet of N/NE

Is somewhat stable (test-retest)

Is heritable (inherited)

All of the above

Most preschoolers with high levels of BI __________

Stick with it

Grow out of it

Are likely to develop an anxiety disorder

Just have an age-appropriate fear of separation or strangers

A and C

B and D

Kids with _____ & ______ are at risk for developing ___________

Consistent, high levels of BI, substance and emotional disorders

Stable, high levels of BI, schizophrenia and personality disorders

Social anxiety disorder can be characterized by

Heightened anxiety about people and performance

Pervasive worries about being judged

Avoidance

Hyper-arousal

A disconnect between what patients know to be rational vs what they feel

All of the above

BI is associated with

Less effective ways of interacting with others

Worse social outcomes

Lower quality peer relations

A loss of opportunity to acquire critical social skills

Challenges forging strong relations with new peers and schoolmates

All of the above

Over time, the repeated experience of social failure among individuals with high levels of BI may

Train them to interpret ambiguous social situations as threatening

Cause them to believe that poor social outcomes are their fault

Promote excessive anxiety about social situations and public performance

All of the above

BI is a strong (candidate) _________ for ______________; but we still need to establish ______ .

Intermediate phenotype, dysthmia, causation

Endophenotype, social anx disorder, causation

Biomarker, emotional disorders, heritability

Marker, overactive insula, heritability

T&P reflect

Nature

Nurture

Both

Genes (nature) can influence

Environments and experience

Neither. Nature and nurture are distinct and independent forces

Nature (heritability) is

Fixed and immutable

Plastic and can change in response to growing autonomy or due to cumulative impact

Heritability is

The proportion of variation in a trait, such as C/SC, that is accounted for by the pedigree (family tree)

GV / Total PV = GV / GV + EV

A and B

Estimates of heritability

Are fixed

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

Is the % of variation in a trait, such as E/PE, that is passed down from your parents

Reflects the inheritance of genes, not phenotypes or traits

Heritability describes

The % of my trait that is inherited (nature) vs. environmental (nurture)

The % of phenotypic variation across a group of individuals that is influenced by genetic factors

Individuals within a population (e.g., Alex)

Highly heritable traits, such as height

Are our destiny

Can potentially be powerfully influenced by interventions (environment)

Ryan Bogdan: The neurogenetic strategy

Involves correlating variation in genetic polymorphisms (SNPs) with variation in intermediate phenotypes, such as differences in amygdala activation

Promises to address WHY individuals differ in brain activation (e.g., why do individuals high in N/NE show heightened amygdala reactivity)

Opens the door to discovering testable mechanisms for genetic influence on behavior

All of the above

Which is false about the serotonin transporter genetic polymorphism

Amygdala reactivity is correlated with variation in the serotonin-transporter linked polymorphic region (5-HTTLPR) on the SLC6A4 gene

The L allele is bad: Individuals with the more transcriptionally-efficient 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

Meta-analyses suggest that this allele accounts for 20-50% of the variance in amygdala reactivity

B and C

Which is false?

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 amygdala, confirming this key assumption

Which is true

The HPA axis is involved in the release of cortisol, epinephrine/adrenaline, and norepinephrine/noradrenaline in response to physical and psychological stress, which increases the availability of energy for the brain as well as defensive behaviors (fight/flight)

HPA = hippocampal, pituitary, amygdala

Which is false

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

Handling leads to tighter, more precise regulation of cortisol

Handling leads to increased expression of the glucocortisoid receptor in the hippocampus in adulthood

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

Related to increased expression of benzodiazepine receptors in the amygdala

Mediated by a social factor, namely, maternal style (LG-ABN: licking, grooming, and arched-back nursing)

Mediated by genes that increase maternal LG-ABN and decrease offspring reactivity

Not genetically transmitted (i.e., moms can alter adopted/cross-fostered pups)

Which is false about epigenetics

Refers to trait-like alterations in the transcriptional (protein-making) 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 modification 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, reflect the intergenerational transmission of DNA)

Which is false: How does maternal behavior produce lasting changes in (rodent) temperament (N/NE)

Meaneys team showed that maternal behavior (LG-ABN) produces epigenetic changes

Epigenetic changes lead to increased expression of glucocorticoid receptors in the hippocampus, supporting enduring changes in stress reactivity

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 benefit (or suffer) from our parents experience without them teaching (or grooming) us? Can acquired characteristics be inherited, as Lamarck posited in the 18th century?

Yes!

No!

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

Genome/DNA

Epigenome

Experience/Environment

Experience interacting with the genome and epigenome

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

Protein expression

DNA methylation

Neurochemical receptor expression and binding

Hippocampal structure and function

Histone status

None of the above

How does early experience (abuse, stress, caregiver behavior) get into the brain

Changes in the genetic code

Changes in the epigenome that alter the expression of genes, leading to changes in protein synthesis and, ultimately, activity

GWAS pretends that

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

Alleles do interact with one another

* Taylors question in class

GWAS genome-wide association study

Brute force approach to identifying correlations between alleles and phenotypes, such as N/NE

Often relies on SNP chips

Suffers from low statistical sensitivity, because of the very large number of tests performed

Opens the door to discovering new and potentially important molecular pathways

All of the above

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

A single, coherent or unified biological cause

Nothing whatsoever with regard to the number or kind of substrates

Kagans model of BI

Shows a number of parallels with N/NE and Grays BIS, reinforcing the idea that childhood temperament and adult personality are closely related

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 genetic polymorphism

A genetic variant

The thing; that gives rise to genetically-determined individual differences in trait-like phenotypes

All of the above

Family, twin, and adoption studies (aka behavioral genetics) are

Correlational

Mechanistic

Provide a tool for discovering the molecular substrates of T&P

Family, twin, and adoption studies (aka behavioral genetics) teach us that

Psychiatric disorders, like T&P, aggregate in families

Are heritable

Things that blood relatives share (e.g., SES, toxin exposure, stress, habits) are important determinants of psychopathology

Which is true

In humans, DNA is organized into 23 pairs of chromosomes, one descended from Mom and one from Dad

Chromosomes are organized into genes, regions of DNA corresponding to the instructions for a protein

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

All of the above

Developing a mechanistic understanding of the molecular neurobiology of T&P and associated psychiatric disorders promises to

Redefine diagnostic categories and T&P traits in terms of quantifiable 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)

Are more likely to develop anxiety, mood, and co-morbid substance abuse disorders later in life

Are more likely to develop psychopathology if they show stable, high levels of BI across development

Are shy and reticent in the face of novelty and potential threat (e.g., scary robot, human intruder)

May show elevated levels of the stress hormone cortisol

Show a R > L pattern of frontal EEG

Show heightened amygdala reactivity to novel faces in adulthood

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

Yes

No

What are the long-term prospects for linking genes to intermediate neural phenotypes to traits, such as C/SC?

Awesome!

Terrible! What a waste of taxpayer money!

It depends on the nature of the linkages, which we do not yet know

Current evidence suggests somewhere in between awesome and terrible, but we do not yet know

C and D

Which is true

Common genetic polymorphisms (the SNPs measured by SNP chips) have, at most, weak effects on brain function and behavior (e.g., 2-5%)

Such small effects are small and hard to reliably detect without using very large and expensive samples

Such small effects have led to many non-replications

Such small effects have led many to wonder whether this research strategy is worth the money

All of the above

Which is true

Hannah is a 6 y.o. boy

Micah is an 18 m.o. girl

Both of Dr. Ss kids are cute as all get out

All of the above

The Big 3 superfactors are about

10% heritable

45% heritable

90% heritable

In class, we discussed several arguments for why even these small effects are potentially important

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)

The expense to date of this research is modest compared to military expenditures or even large-scale physics projects (colliders)

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)?

Genes

Trait-like phenotypes, such as E/PE

All of the above

Heritability reflects

The % of between-individual variation predictable from pedigree

The % of a trait within an individual (you!) that is inherited from your forebears

A wide variety of environmental factors can

Trigger genetic predispositions (e.g., to high levels of N/NE)

Compensate for or regulate the expression of genetic predispositions

Enhance or accentuate genetic predispositions

All of the above

Heritability

Is probabilistic and predictive of average outcomes

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

Categorically different

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

Tend to influence N/NE as well as depression

Selectively influence the targeted disorder

Only help some patients

A and C

B and C

Anxiety disorders, depression, and N/NE appear to share

Genes

Neural substrates (e.g., amygdala hyper-reactivity)

Both

Lesion studies in rodents, monkeys, and humans demonstrate that the amygdala

Is required for the normal acquisition of new fear learning (conditioned emotional response)

Not required

Is required for the retention of already learned fears

Elevated N/NE

Is common among anxiety patients

Is common among depression patients

Both

Psychological pathogens, such as stress and family conflict

Exert similar effects on depression, anxiety disorders, and N/NE, suggesting a common substrate

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

predicted depression

interacted with life stress to predict depression, providing evidence of a G x E interaction and suggesting a neurochemical substrate for psychiatric risk

Was completely and utterly unrelated to depression

Amygdala lesions in monkeys block

The acquisition of new conditioned fears

Innate anxiety about snakes

Both

Height is

Trait-like

Among the most heritable traits, although offspring will show considerable variation

Can be markedly affected by interventions (diet, nutrition, and healthcare access)

Jerry Kagan argues that the root cause of childhood behavioral inhibition (BI) is

An over-reactive amygdala

Maladaptive cognitive coping mechanisms

Worry

Disress

Social reticence

Shyness

The administration of a benzodiazepine (anti-anxiety medication)

Causes a dose-dependent reduction in amygdala activation

Causes a dose-dependent increase in amygdala activation

Why do some individuals develop particular disorders, such as specific phobia of dogs?

Learning and experience

Core vulnerability (heightened neuroticism, hyper-reactive amygdala, inadequate regulation of the amygdala)

Both, neither is sufficient to explain the development of specific emotional disorders

The RoboGator Experiment: Amygdala lesions in rodents attenuate

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

The amount of time hiding in the nest area (outside the arena containing the Rgator)

All of the above

Heritability

Is informative about the nature and plasticity of group differences (men/women, black/white) in traits

Is not informative about such mean differences

Amygdala damage

Increases ratings of trust and approachability to faces that are normally deemed untrustworthy

Has no consequence of social interactions or social cognition

N/NE is

A specific risk factor for anxiety disorders

A nonspecific risk factor for a broad range of psychiatric disease

Patient SM has circumscribed bilateral destruction of her amygdalae. She

Picks up snakes and spiders, despite professing anxiety

Shows no fear in the haunted house

Is unable to acquire new conditioned fears in the lab

Quickly returned to the park where she was assaulted

Is BI a viable intermediate phenotype for social anxiety disorder

Yes

No

Emotional disorders and N/NE

Are fundamentally different

Reflect a common cause

Are categorically distinct

Exam Review: Material Covered During theFirst Third of Course

How can we identify the cause(s) of T&P (e.g., low C/SC)?

Forge a link between individual differences in a trait and variation in a relevant behavioral or biological measure

Correlate traits and fMRI activation

Compute a regression (correlation) between task performance (e.g., BART) and traits of interest

Directly manipulate the hypothesized cause.

All of the above

What's the problem with reducing a complex, broad-band trait to a single number?

Mixes distinct processes

Hinders our ability to clearly resolve the underlying substrates

Too simplistic

All of the above

One strategy for discovering the cause of phenomenologically complex traits (and mental disorders) is to

Decompose them into simpler, more manageable intermediate phenotypes

Give up

Search for endophenotypes

A and C

Which of the following can we plausibly model in nonhuman animal models (where we can perform mechanistic experiments to determine causation)

Anti-social behavior

C/SC

Delay of gratification

Turn-taking and emotional irritability

Hyper-sensitivity to reward-related cues

C and E

With respect to neurological soft signs (trait), elevated lead levels in the hair are

Noncausal symptom/marker of the process that causes the trait or phenotype

Marker or scar of the trait or the organisms response to the trait

Endophenotype

We discussed 2 kinds of intermediate phenotypes. Both kinds are

Causal

Heritable

Aggregate in families

Co-segregate in families

Endophenotypes are

Simpler than the trait one seeks to understand

Causal

A bridge between the genotype and phenotype

Heritable

All of the above

Which is true

Intermediate phenotypes cause traits, markers do not

Markers cause traits, intermediate phenotypes do not

Endophenotypes cause traits, biomarkers do not

A and C

B and C

Remarkably

We know quite a bit about the mechanisms linking genes to endophenotypes

We know quite a bit about the mechanisms linking endophenotypes to traits (and disorders)

We know next to nothing about either mechanism for any established endophenotype

EEG/ERP affords

Exquisite spatial resolution

Exquisite temporal resolution

Neither

Both

Conventional fMRI signals reflect

Blood oxygenation levels

Neuronal firing

Conceptually, activation in both ERPs and event-related fMRI is estimated by

Computing the average response evoked by a particular condition or kind of event

Computing the cross-correlation among sensors

Which is true

EEG is relatively cheap, tolerant of motion, and reflects neuronal electrical activity (EPSPs)

fMRI is relatively expensive, sensitive to motion artifacts, and does not directly measure neuronal activity

Both

EEG and fMRI are

Causal (like lesion studies)

Mechanistic (like manipulating brain activity in rodents with drug infusions)

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

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

T&P

Both

But contemporary science suggests that moods, thoughts, and behavior are determined by

The situation

T&P

Both

Trait-like individual differences in T&P are strongly predictive of

Academic performance (above & beyond IQ)

Marital stability & satisfaction

Mental & physical health and wellbeing (morbidity)

Death (mortality)

All of the above

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

0.50 * 0.50 = .25 = 25%

0.50 / 0.50 = 1 = 100%

Sqrt(.50) = .7071 = 70%

Longitudinal research studies

Provide strong evidence that antecedants (childhood) predict consequences (adulthood), a precondition for establishing causation

Complex, costly, and time-consuming

Can not prove causation, because they do not manipulate the putative cause of the outcome

All of the above

Moffitt et al PNAS: What is C/SC?

Do things by the book; follow rules

Prefer order and neatness

Planful; not impulsive

Able to delay gratification; self-disciplined (marshmallow test)

Focused; not easily distracted

All of the above

Which features of modern culture tend to magnify the impact of individual differences in T&P, such as C/SC?

Longevity

Risk exposure (fast food nation)

The relatively high prevalance of psychiatric disorders, such as depression, anxiety, and substance abuse

All of the above

Moffitt et al PNAS: Key results: Childhood C/SC predicted mid-life

Composite measure of health

Composite measure of personal wealth

Incarceration, criminal conviction and other indices of public safety

All of the above

Moffitt et al PNAS: Key results: Which is true?

Kids with low C/SC are prone to smoke, become parents, and drop out of school as teens

Teen snares explain the negative adult outcomes experienced by many kids with low C/SC

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

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?

Smoking

Becoming a parent

Excessive video game playing

Violence in the media

High-caffeine energy drinks

A & B

C & D

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

0.50 * 0.50 = .25 = 25%

0.50 / 0.50 = 1 = 100%

Sqrt(.50) = .7071 = 70%

T&P reflect trait-like individual differences in emotional and cognitive biases that

First emerge early in life

Continue to evolve for many years

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

Can be relatively simple

Can be complex and multidimensional

All of the above

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

Biological

Emotional

Cognitive

Somewhat heritable

All of the above

What are the 3 fundamental dimensions of T&P?

N/NE

P/TA

E/PE

S/RE

C/SC

A, C, and E

A, B, and C

N/NE can be dissected into which 2 facet traits

Distress (fear/anxiety) and Irritation (anger)

Guilt and Shame

Which statistical test is used to quantify the continuity (temporal or test-retest stability) of traits

Students t test

ANOVA

Correlation

T&P is

Fixed and immutable

Moderately stable (R = 0.4 to 0.6 over periods of one to several years)

Completely plastic and malleable

Which features of modern culture tend to magnify the impact of individual differences in T&P, such as C/SC?

Longevity

Risk exposure (fast food nation)

The relatively high prevalance of psychiatric disorders, such as depression, anxiety, and substance abuse

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?

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

No guarantee that words (natural language) will permit the expression of scientifically crucial aspects of personality

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?

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

Reliable: Show adequate internal consistency reliability

Reliable: Show adequate test-retest stability (trait-like)

Reliable and Valid

Construct validity (functional significance) entails the assessment of a measures _______________ and ___________________ .

Sensitivity and specificity, effectively the reverse and forward inference

Put simply, a measure should be very sensitive to the target construct and no other

238

Establishing the construct validity of a measure requires that we demonstrate that it is

Sensitive to some process, such as fear

Specific to some process (fear & no other process)

Sensitive and Specific

The FFM was derived using factor analysis. Factor analysis is a useful technique for

Reducing the dimensionality of a dataset

Compressing data

Identifying a relatively small number of factors that describe a dataset

Creating new questionnaires

All of the above

Can factor analysis be used to objectively discover the nature of T&P?

Yes

No

In terms of discovery, potential limitations of factor analysis include

Garbage In/Garbage Out; Dependent on the kinds of inputs; Cant identify factors that are not sampled or represented in the data

Subjective decisions about the number of factors to retain (degree of acceptable lossiness); Splitter or lumper

Requires the analyst to decide at the outset whether dimensions are independent or correlated (i.e., needs to pick the rotation technique)

242

The FFM is largely based on factor analyses of adjectives. Was the pool of words

representative of the English language

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)

replicable, objective, and atheoretical

subjective, idiosyncratic, and theoretically biased?

The key take home point from Blocks critique is that the FFM

Is a bunch of hooey

Reflects the fundamental nature of T&P

Is a convenient short-hand, a sometimes useful fiction that begs for additional research

Moffitt et al PNAS: Key results: Which is true?

Kids with low C/SC are prone to smoke, become parents, and drop out of school as teens

Teen snares explain the negative adult outcomes (reduced health, wealth, public safety) experienced by many kids with low C/SC

Teen snares are only part of the story.

All of the above

Establishing the construct validity of a measure requires that we demonstrate that it is

Sensitive to some process, such as fear

Specific to some process (fear & no other process)

Sensitive and Specific

Which item would NOT be found on a paper-and-pencil measure of N/NE?

Emotionally labile (unstable)

Bothered by change

Prone to sadness

Prone to anxiety

Blue or depressed

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

Social desirability (looking good)

Lying or malingering

Mnemonic distortions (e.g., peak-end rule)

All of the above

Behavior is guided by

Conscious processes

Automatic habits and implicit attitudes that lie outside of awareness and which opaque to introspection, hence not measureable using standard paper-and-pencil measures of T&P

Both conscious and unconscious processes

Behavior is guided by

Conscious processes

Automatic habits and implicit attitudes that lie outside of awareness and which opaque to introspection, hence not measureable using standard paper-and-pencil measures of T&P

Both conscious and unconscious processes

Which is true?

Amygdala lesions block the conditioned fear response (SCR)

The Story We Tell Ourselves: Hippocampal lesions block self-reported contingency learning

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)

All of the above

McNulty provided evidence that

Implicit & explicit attitudes toward spouses are uncorrelated, suggesting that they reflect distinct neural circuitry

Implicit attitudes (measured behaviorally) predicted marital satisfaction 4 years later

Whereas, explicit ratings of attitudes toward ones spouse did not

All of the above

There is considerableevidence that

Trait-like differences in T&P interact with trait-relevant cues to produce states

Trait measures predict state ratings

E/PE predicts pos affect elicited by humorous film clips; N/NE predicts fear and anxiety elicited by aversive film clips

All of the above

Traits predict

More intense states in the presence of relevant cues

This reflects heightened peak activation in the underlying neural systems

Both

But, T&P also predicts

Motivated behavior: Approach or avoid

Emotion regulation & recovery following challenges

Anticipatory thoughts and feelings (e.g., worry) before challenges

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

The situation

T&P

Both

Longitudinal research studies

Provide strong evidence that antecedants (childhood) predict consequences (adulthood), a precondition for establishing causation

Complex, costly, and time-consuming

Can not prove causation, because they do not manipulate the putative cause of the outcome

All of the above

The key take home point from Blocks critique is that the FFM

Is a bunch of hooey

Reflects the fundamental nature of T&P

Is a convenient short-hand, a sometimes useful fiction 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?

Meaningful aspects of T&P may not be captured by single word

Key aspects of T&P might be too complex for single words, requiring phrases, sentences, or even whole paragraphs of words

No guarantee that words (natural language) will permit the expression of scientifically crucial aspects of personality

All of the above

Are trait-like differences in T&P embodied in the on-going, spontaneous activity of the brain?

No, traits interact wi

shackman psyc210 module12 naturenurture part3 032615b

Documents

brain activation

conceptual roadmap

enhanced activation

individual differences

environment experience

brain circuits

enhanced peak activation

key features of tp