5-HT T

LPR S

ALL

ELE

SHORTY

SADNESS

DEPRESSION (MAJOR DEPRESSIVE DISORDER)• Depressed mood most of the day, nearly every day, as indicated

by either subjective report or observation made by others.

• Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day.

• Significant weight loss when not dieting or weight gain, or decrease or increase in appetite nearly every day.

• Insomnia or hypersomnia nearly every day

• Psychomotor agitation or retardation nearly every day

• Fatigue or loss of energy nearly every day

• Feelings of worthlessness or excessive or inappropriate guilt nearly every day

• 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?

• Serotonin System• Drugs already target the system• 5-HTT particularly

• 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”)

• 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

• 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

• Decay Rate• Slowed in depressed individuals responding to personally negative

words

• Magnitude of response was not observed to be changed

THE EXPERIMENT

• 49 Girls (34 s carriers and 15 homogenous l carriers)

• Aged 10-15 years old

• No current or previous DSM-IV Axis I disorder

• Trained interviewers assessed the diagnostic status of the girls

• Saliva genotyping

• 1 minute baseline

• Exposed to 1 of 3 movies

• Asked if they had experienced the scene

• 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

• 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

• 1037 children (52% male)

• Assessed at ages 3, 5, 7, 9, 11, 13, 15, 18 and 21 • 96% intact at age 26

• Separated by genotype

• Stressful life events were assessed

• Assessed for past-year depression at 26

• 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

• 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.

• The problem? Mice do not carry a regulatory promoter region orthologous to 5-HTTLPR. Wait… what?

• 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.