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5-HT T LPR S allele

5-HT T LPR S allele. 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.

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5-HT T LPR S allele

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  1. 5-HTTLPR S allele Shorty Sadness

  2. 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

  3. Who gets depressed? • People that are stressed? • Threat • Loss • Humiliation • Defeat • … Ya… I’d be depressed too

  4. 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

  5. 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.

  6. 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

  7. 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

  8. 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

  9. Task-Related Activation Fig. 1 Fig. 2

  10. Latency to Peak

  11. 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

  12. 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.

  13. 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

  14. Main Event • Increased vulnerability to psychosocial stress in heterozygous serotonin transporter knockout mice • Bartolomucci et al. (2010) Disease Models & Mechanisms 3: 459-470

  15. 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.

  16. Fig 1: Physiological changes induced by chronic psychosocial stress

  17. Fig 2 Depression of locomotor activity induced by chronic psychosocial stress

  18. Fig 3: Social avoidance in stressed 5-HTT +/- mice

  19. Fig 4: The level of aggression received predicts behavioral and physiological consequences of psychosocial stress

  20. Fig 5: Increased social avoidance in 5-HTT+/- mice receiving a high level of daily aggression

  21. Fig 6: Decreased serotonin turnover in the frontal cortex of stressed 5-HTT+/- mice

  22. Fig 7: Effect of genotype and stress on 5-HTT binding

  23. Fin.

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