5-HT TLPR S ALLE

LE

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?ThreatLossHumiliationDefeat

… 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 ACTIVATIONFig. 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.