Download Zach Niemann - USD Biology

DEPRESSION (MAJOR DEPRESSIVE DISORDER)
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Depressed mood most of the day, nearly every day, as indicated by either
subjective report or observation made by others.
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Markedly diminished interest or pleasure in all, or almost all, activities most of
the day, nearly every day.
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Significant weight loss when not dieting or weight gain, or decrease or increase in
appetite nearly every day.
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Insomnia or hypersomnia nearly every day
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Psychomotor agitation or retardation nearly every day
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Fatigue or loss of energy nearly every day
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Feelings of worthlessness or excessive or inappropriate guilt nearly every day
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Diminished ability to think or concentrate or indecisiveness, nearly every day
WHO GETS DEPRESSED?
People that are stressed?
Threat
Loss
Humiliation
Defeat
… Ya… I’d be depressed too
ARE THERE DIFFERENCES?
Depressed Individuals differ from Non-Depressed Individuals in the way they process
emotional cues:
• Hyperactivity of the limbic system
• Diminished ability of the prefrontal cortex to modulate limbic responses to
negative stimuli
WHERE TO START?
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Serotonin System
• Drugs already target the system
• 5-HTT particularly
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Promoter Region of the 5-HTT gene
• Located on 17q11.2
• Modified by sequence elements within the proximal 5’ regulatory region
• 5-HTTLPR)
• 2 alleles (“s” and “l”)
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The “s” allele has been associated with lower transcriptional efficiency of the
promoter than the “l” allele.
BACKGROUND 1
Altered timing of amygdala activation during sad mood
elaboration as a function of 5-HTTLPR
Furman et al. (2011) SCAN 6: 270-276
AMYGDALA ACTIVITY
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Rise Time to Peak
• Phobic patients exhibit shorter rise time in response to spiders
• Individuals high in behavioral inhibition exhibit earlier onset of activity in
response to novel faces
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Decay Rate
• Slowed in depressed individuals responding to personally negative words
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Magnitude of response was not observed to be changed
THE EXPERIMENT
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49 Girls (34 s carriers and 15 homogenous l carriers)
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Aged 10-15 years old
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No current or previous DSM-IV Axis I disorder
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Trained interviewers assessed the diagnostic status of the girls
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Saliva genotyping
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1 minute baseline
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Exposed to 1 of 3 movies
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Asked if they had experienced the scene
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1-5 sad/happy scale
TASK-RELATED ACTIVATION
Fig. 1
Fig. 2
LATENCY TO PEAK
BACKGROUND 2
Influence of Life Stress on Depression: Moderation by
a Polymorphism in the 5-HTT Gene
Caspi et al. (2003) Science 31: 386-389
GENE-BY-ENVIRONMENT
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Authors cite that “Evidence for an association between the shorter promoter
variant and depression is inconclusive.”
There is the possibility of G X E interaction
• Mice with disrupted 5-HTT (+/- and -/-) exhibited more fearful behavior and
increased adrenocorticotropin in response to stress when compared to (+/+)
controls, but in the absence of stress, no differences were observed.
• In rhesus macaques, with analogous genes, the short allele is associated with
decreased serotonergic function among monkeys reared in stressful conditions
but not among normally reared monkeys.
• Humans with one or two copies of the s allele exhibit greater amygdala neuronal
activity to exhibit greater amygdala neuronal activity to fearful stimuli compared
to individuals homozygous for the l allele.
THE EXPERIMENT
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1037 children (52% male)
Assessed at ages 3, 5, 7, 9, 11, 13, 15, 18 and 21
• 96% intact at age 26
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Separated by genotype
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Stressful life events were assessed
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Assessed for past-year depression at 26
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Contacted “someone who [knew them] well” for additional assessment
MAIN EVENT
Increased vulnerability to psychosocial stress in
heterozygous serotonin transporter knockout mice
Bartolomucci et al. (2010) Disease Models & Mechanisms 3: 459-470
THE GOAL
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Previous studies have used 5-HTT knockout mice as a model of human allelic
variation in 5-HTT function, specifically, heterozygous (+/-) 5-HTT knockout mice.
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The problem? Mice do not carry a regulatory promoter region orthologous to 5HTTLPR. Wait… what?
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The authors used these mice in an established animal model of psychosocial
stress-induced depression-related disorders. In the process, the authors hoped to
model the increased vulnerability to adult chronic psychosocial stressors
conferred by a partial genetic deficiency in 5-HTT.
FIG 1: PHYSIOLOGICAL CHANGES INDUCED BY
CHRONIC PSYCHOSOCIAL STRESS
FIG 2 DEPRESSION OF LOCOMOTOR ACTIVITY
INDUCED BY CHRONIC PSYCHOSOCIAL STRESS
FIG 3: SOCIAL AVOIDANCE IN STRESSED 5-HTT
+/- MICE
FIG 4: THE LEVEL OF AGGRESSION RECEIVED
PREDICTS BEHAVIORAL AND PHYSIOLOGICAL
CONSEQUENCES OF PSYCHOSOCIAL STRESS
FIG 5: INCREASED SOCIAL AVOIDANCE IN
5-HTT+/- MICE RECEIVING A HIGH LEVEL OF
DAILY AGGRESSION
FIG 6: DECREASED SEROTONIN TURNOVER IN
THE FRONTAL CORTEX OF STRESSED 5-HTT+/MICE
FIG 7: EFFECT OF GENOTYPE AND STRESS ON
5-HTT BINDING
Fin.