Lecture 2: 5’ VNTR + Meta-Analysis + Induced Animal Models + deltaFosB + MKP-1

Hereditary Depression

more within relatives, 50% risk in identical twins, could be due to vulnerability

5-HTT Gene MDD

longitudinal, depression gene, serotonin transporter, long vs short (bad) -> susceptibility

5-HTT Short Gene

VNTR region with deletion -> TATA/TF binding -> translated region; prone to depression

5-HTT Mechanism

short gene -> less transporter; stressor -> NT deficiency -> less to recycle; vulnerability/stress

Meta-Analysis

statistical process that combines data from multiple studies to draw conclusion about a topic, trend

Summary Triangle

overall strong interaction that s allele = developing depression when stressed

Meta-Analysis Graph

left -> strong s allele; middle -> no difference, right -> strong l allele; forest plot data

Animal Models

mimic human stress, induction models -> CUS (chronic unpredictable stress), C57 inbred mice

C57 Inbred Mice

express difference stress due to CUS -> 50-75% experience depression, some are resilient

Chronic Unpredictable Stress Production

wet bedding, flooding, foot shocks, tilted cage, restrict food/water

Tests for Depression

FST (don’t swim), TST (hang), foot shock (still), forced separation (won’t interact)

Social Defeat Models

defeat by large mice, AP increase Ventral Tegmental Area (VTA) -> nucleus accumbens

Learned Helplessness Models

some don’t succumb -> increase in deltaFosB in various areas of brain

Resilience

brain’s capacity to cope with stress + stable psychological functioning in response to prolonged stress

Promote Resilience

active coping strategy (reassessment of stress) + avoidant coping (behavioral adaptability)

DeltaFosB

nucleus accumbens (reward), transcriptional activator, low = depression, antidepressants = increase

ΔFosB Function

brain reward circuit, mediates stress resilience + antidepressant responses

ΔFosB Observations

isolated mice (depressed mice) demonstrate a decrease in ΔFosB in nucleus accumbens

Increase ΔFosB in Isolated Mice Experiment

took herpes simplex virus (delivers to diff areas of brain, causes neurons to express protein) -> injected into GFP; packaged ΔFosB -> nucleus accumbens -> neurons overexpress ΔFosB -> depressed animals interact more (swim/struggle more = less depressed); HSV-ΔFosB

Decrease ΔFosB in Grouped Mice Experiment

deliver decoy delta-c-JunD -> forms AP-1 complex, prevents ΔFosB binding + increases CREB activation; non-depressed mice -> depression (decreased ΔFosB); AVV-ΔJunD

Post-Mortem Human Studies

depressed + age-matched control -> increase in mRNA of MKP-1 in DG/CA1

MKP-1 Experiment

use adeno-associated virus deliver MKP-1 -> anhedonia (decreased preference) + increased escape failures + delayed feeding (appetite changes)

Escape Failure

taught to escape box -> times they fail; depressed fail more = reduced cognitive function

MKP-1 Phosphatase

removes phosphates/inhibits ERK1/2; stops the RAS/MEK/ERK/CREB pathway

MKP-1 Knockout Mice

no depression, knockouts resistant to CUS

MEK/CREB Pathway

GF -> GFRs -> dimerize -> Ras -> Raf -> MEK -> ERK -> kinases MSK/RSK -> CREB -> BDNF/VEGF (GF-related genes) -> active, healthy cell; ALWAYS ACTIVE, otherwise cells die

VEGF Receptor

vascular endothelial growth factor, FLK-1

FGF

fibroblast growth factor - FGFR1-4