An Introduction Considering Animal Models Major Depressive Disorder Clinical Depression Clinical Symptoms vary reduced mood pleasure and concentration disturbed sleep increased fatigue irritability ID: 1043775
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1. Causes and Mechanisms of DepressionAn IntroductionConsidering Animal Models
2. Major Depressive DisorderClinical DepressionClinical Symptoms varyreduced mood, pleasure and concentrationdisturbed sleep, increased fatigue, irritabilityloss of self-worth, suicide riskMay represent unique disordersStruggle to Cope with daily personal and social livesOften has a Social componentComorbid with other health conditions
3. Heritability of DepressionGenetic Factors contribute up to 50%Complex array of stress-related genesCarrying a gene does not confer expressionDoes not determine symptomsEpigeneticsHeritable biochemical signalsBind to specific DNA sequences or linked proteinsDo not alter the DNA sequenceAlter the likelihood of Gene Expression
4. Epigenetic MechanismsGene by Environment Interactions
5. Environmental EpigeneticsThe Genome of an Individual is invariableBut…Environmental Factors influence Gene ActionHow?Epigenetic Factors change exposure of GenesDNA methylation Histone methylation, acetylation, phosphorylation (more)Increase or decrease Gene ExpressionSpecific genes onlyOften related to stress
6. Environmental Epigeneticsand DepressionChronic Stress → DNA methylation Promoter: corticotropin-releasing factor (CRF) gene Result: increased levels of this stress hormoneEarly Adversity → Histone + DNA methylation glucocorticoid receptor (GR) gene in hippocampusResult: reduced negative feedback during stressIncreased stress hormone (cortisol)Increased vulnerability to stressIncreased susceptibility to Depression
7. Not mutually exclusiveMajor Theories of Depression
8. Depression Theories(from Treatments and Research)Monoamine (serotonin = 5-HT) deficiencyFirst and Most widely accepted theoryBased on 5-HT reuptake inhibitor efficacy (SRI)Most modern antidepressant drugs also includenorepinephrine (NE) reuptake inhibition (NRI)And/or dopamine (DA) reuptake inhibition (DRI)< 50% are satisfactorily treatedNo clear mechanism6-8 wk delay precludes deficiency as the cause5-HTT linked polymorphic region gene is related
9. Depression Theories(from Treatments and Research)Neurotrophic (Brain-Derived Neurotrophic Factor)↑BDNF in Hippocampus →↓ Depressive Behaviors↓BDNF linked to ↑Depressive symptoms↑BDNF associated with clinical recoveryStimulates neuroplasticity and neurogenesisAssociated with reduced depressionBDNF → ↓ 5-HT reuptake (similar to SRIs)BDNF → 5-HTT regulation↑BDNF in Nucleus Accumbens → ↑Depressive Behaviors Val66Met BDNF mutant →↑ vulnerability to Depression
10. Depression Theories(from Treatments and Research)NeuroinflammationActivated by social stress↑ cytokines: IL1, IL6, TNFαSimilar to Major Depression→ ↓ BDNF and other neurotrophinsDepression induces ↑ inflammatory responses to stressGut-Brain ConnectionProbiotic diversity reduces depression
11. Depression Theories(from Treatments and Research)Chronic Social StressClinically linked to depression in humansLinks Childhood Trauma to DepressionDramatically effects 5-HT, DA, and NE concentrationsPromotes epigenetic changesEnhances expression of 5-HTT-LPR (short version)For carriers of the gene mutant↓ 5-HTT expression → ↑ synaptic 5-HT↑ Amygdala response to fear and stressGreater susceptibility to Depression
12. Chronic Social stressLinks many of the other theories
13. Pre-clinical modelsCurrent Animal Models of Depression
14. Pre-Clinical Models should haveConstruct, Face, & Predictive ValidityConstruct ValidityExperimental Conditions replicate Cause of the diseaseDifficult when causes are not completely knownFace ValidityModel Symptoms replicate Clinical Indications of the diseasePredictive ValidityAnimal response to therapy predicts clinical success
15. Pre-Clinical Models should haveConstruct, Face, & Predictive ValidityFactor Administratione.g. Retinoids (Stress Axis)Cytokines (Immune Function)Genetic knockouts SurgeryOlfactory Bulbectomy
16. Pre-Clinical Models should haveConstruct, Face, & Predictive ValidityLearned Helplessness Inescapable foot shock; short-term onlyChronic Mild Stress 6-7 stressors changed daily and randomlyH2O deprivation, wet bedding, tilting cage, isolation, crowding, changed lighting rhythm, cage vibration, food deprivation, forced swim, intermittent white noise…no social componentModels with a social componentAre the most translatable to Clinical SuccessChronic Social Isolation
17. Social Models have greaterConstruct, Face, & Predictive ValidityChronic Social Stress10 days of defeatPaired with a Novel for 10 min each dayCohabits with Aggressor, separated by wire meshFollowed by tests of despair and anhedoniaStress-Alternatives Model (Summers Lab)Depression and Anxiety4 days of novel social aggressionEscape is possible for the test animal only
18. Where the rubber meets the road for ValidityTests of Depressive Behavior
19. Tests of Behavioral Despair Forced Swim TestTail SuspensionTestMeasured by how long it takes the test animal to stop movingMore movement: supposed to equate to less despair
20. Tests of AnhedoniaMeasured by preference for sugar water over plain H2O or time to show interest in sexual activity with a receptive partnerMore interest: supposed to equate to greater interest in pleasureSucrose PreferenceSexual Interest
21. Tests of Social AvoidanceMeasured by ratio of time in proximity to social versus non-social conditionsMore Social Contact: Less Depressive Behavior
22. Research in Depression must considerThese Critical ElementsEpigenetic &