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September 15 – 17, 2016 | The Biltmore Hotel | Miami, FL

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Ned Kalin, MDUniversity of Wisconsin School of Medicine and Public HealthMadison, WI

Threat-Related Response: Tipping the Balance Between Appetitive and Defensive Behaviors

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Ned H. Kalin, MD

● Research/Grants: National Institutes of Health (NIH), Principal Investigator; National Institute of Mental Health (NIMH), Principal Investigator

● Stockholder: Corcept Therapeutics● Other Financial Interest: Honoraria-Pritzker

Neuropsychiatric Disorders Research Consortium;Consultant: Elsevier, Co-Editor

Disclosures

Review the neurophysiological pathways involved in emotions.

Learning Objective 1

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Describe the epigenetics of stress-related disorders.

Learning Objective 2

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Nestler EJ, et al. Neuron. 2002;34(1):13-25.

Threat and Appetitive Circuitry is Conserved Across Species

Innate Adaptive Evolutionarily Conserved Systems●Survival, avoid predation–Fear/anxiety/threat

●Reproduction, eating, finding a mate–Approach approach/appetitive

●Rearing, social support and structure–Attachment

Primates Have a Unique Ability to Regulate Emotion

Kupfer DJ, et al, Lancet. 2012;379(9820):1045-1055.

Regulation of the Expression of Innate Systems: Determinants of Psychopathology and Entrees to Treatment

●Implicit or explicit—facilitation or inhibition–Conscious or preconscious

●Chronometry of response–Rise time, amplitude, length

●Context dependent expression–When and where

Affective Dynamics1

● Emotion unfolds over time2

● Several dynamics of affect & neural responses3,4

● Habituation– Rapidity & width of neural responses– Variability

1Heller AS, et al. J Neurosci. 2015;35(29):10503-10509; 2Solomon RL, et al. Psychol Rev. 1974;81(2):119-45; 3Davidson RJ. Philos Trans R Soc Lond B Biol Sci. 2004;359(1449):1395–1411.; 4Heller AS, Casey BJ Developmental Sci. 2016;19(1):3-18.

Neural Level Psychological Level

Circuit Level

Affective Neurodynamics and Well-Being

Heller AS, et al. Psychol Sci. 2013;24(11):2191-2200.

Striatal Habituation

Using Conscious Regulation to Alter Responses to Unpleasant Stimuli

Time

Inte

nsity

of u

nple

asan

tnes

s

“It’s harmless. It’ll all be OK.”

“Fangs plunging in! Legs inching up my

arm! Aaargh!!

“Eww, creepy!!”

Conscious Emotion Regulation: Modulating Amygdala Activity

Urry HL, et al. J Neurosci. 2006;26(16):4415-4425.

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

left right

amygdala

% s

igna

l AU

C

enhance

attend

suppress

LR

vmPFC and OFC Activity During Conscious Regulation (Suppress – Attend) Negatively Correlates with Amygdala Activity

Urry HL, et al. J Neurosci. 2006;26(16):4415-4425

Genome-Wide Analysis of Over 106000 Individuals Identifies 9 Neuroticism-Associated Loci

Smith DJ, et al. Molecular Psychiatry 2016;21:749-757.

a–c) Results are shown for subjective well-being (n = 298,420) (a), depressive symptoms (n = 180,866) (b), and neuroticism (n = 170,911) (c). The x axis shows chromosomal position, and the y axis shows association significance on a −log10 scale. The upper dashed line marks the threshold for genome-wide significance (P = 5 ×10−8), and the lower dashed line marks the threshold for nominal significance (P = 1 × 10−5). Each approximately independent genome-wide significant association (lead SNP) is marked by a red ×. Each lead SNP is the SNP with the lowest P value within the locus, as defined by our clumping algorithm.

Manhattan Plots of GWAS Results for Subjective Well-Being, Depressive Symptoms, and Neuroticism

Okbay A, et al. Nat Genet. 2016;48(8):970.

Epigenetics of Stress-Related Disorders: Gene X Environment Interactions

Klengel T, Binder EB. Neuron. 2015;86(6):1343-1357.

Nestler EJ, et al. Neuroscientist. 2016;22(5):447-463.

Epigenetic Regulation in Brain

Epigenetics of Stress-Related Disorders: Gene X Environment Interactions

Klengel T, Binder EB. Neuron. 2015;86(6):1343-1357.

Early Maternal Stress Increases Children’s Stress Hormones

Essex MJ, et al. Biol Psychiatry. 2002;52(8):776-784.

● High levels of maternal stress during the first year of life alters children’s stress response later in life

● At 4.5 yrs. children have increased cortisol

● In the 1st grade these children have significantly more psychiatric symptoms

Basis for Psychopathology: Evolutionarily Conserved Systems Gone Awry●Fear/anxiety – survival–Fear disorders – PTSD, phobias, panic–Anxiety disorders – GAD

●Approach/appetitive – reproduction–Depression, addictions, eating disorders

●Attachment – social support and structure–Separation anxiety disorder, depression,

autism, borderline personality disorder

The Threat System: Fear and Anxiety

Correlation with AT, bonferroni corrected

t=5.24 t>8

t=-5.24 t<-8

Positive

Negative

Right

OFC

BST

Amygdala

Anterior Hippocampus

PAG

Anxiety-Related Regions

n = 592 young rhesus monkeysFox AS, et al. Proc Natl Acad Sci U S A. 2015;112(29):9118-9122.

The Amygdala is Critical for Fear and Anxiety

Ledoux AA, et al. Front Behav Neurosci. 2014;8:88.

Cortical pathway“high road”

Subcortical pathway “low road”

Fear/Anxiety: Central Extended Amygdala Diagram

Fox AS, Kalin NH. Am J Psychiatry. 2014;171(11):1162-1173.

Kupfer DJ, et al. Lancet. 2012;379(9820):1045-1055.

Johnstone T, et al. J Neurosci. 2007;27(33):8877-8884.

Differential Regulation of Amygdala by vmPFC in Controls and Depressed Patients (Suppress – Attend)

r = -0.63

r = 0.57

The Appetitive System: Reward and Reinforcement

A simplified schematic of the major dopaminergic, glutamatergic and GABAergic connections to and from the ventral tegmental area (VTA) and nucleus accumbens (NAc) in the rodent brain. The primary reward circuit includes dopaminergic projections from the VTA to the NAc, which release dopamine in response to reward-related stimuli (and in some cases, aversion-related stimuli). There are also GABAergic projections from the NAc to the VTA; projections through the direct pathway (mediated by D1-type medium spiny neurons (MSNs)) directly innervate the VTA, whereas projections through the indirect pathway (mediated by D2-type MSNs) innervate the VTA via interveningGABAergic neurons in the ventral pallidum (not shown). The NAc also contains numerous types of interneurons

Neural Circuitry Underlying Reward and Motivation

Russo SJ, Nestler EJ. Nat Rev Neurosci. 2013;14(9):609-625.

Heller AS, et al. Proc Natl Acad Sci U S A. 2009;106(52)22445-22450.

Alterations in Reward Circuit when Depressed Subjects Attempt to Upregulate Positive Emotion

Changes in Response of Reward Circuitry Predict Treatment Response

Heller AS, et al. Am J Psychiatry. 2013;170(2);197-206.

Clinical Connections

● Evolution of survival systems– threat and appetitive- is conserved across species

● Innate approach and avoidance systems underlie adaptive and maladaptive emotional responses

● Primates have a remarkable capacity to regulate threat and appetitive responses with well developed prefrontal cortex

● Genetic and epigenetics underlie individual differences as well as psychopathology

● Interactions between threat and appetitive systems determine the type of stress-related psychopathology and should give clues to individualized treatments

Questions Answers &

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