Animal Models of Mood Disorders Flashcards
Is there a comob with anxiety and depression?
Yes; plot MDRAS with anxiety rating scale
Positive correlation
And therefore, it may be valuable for antidepressants to have anxiolytic properties
Describe the basic mechanism of antidepressant action
Monoaminergic drugs take weeks/ months to ameliorate symptoms of depression with secondary neoplastic changes involving transcription and translation
Reduced neurogenesis implicated in MDD; SSRIs increase neurogenesis in rodent hippocampus
Anti-depressants may also exert their effects by stimulating BDNF = neuronal growth and survival
Remission rates are low after SSRI (30%)
What is meant by an animal model of a human disease?
Mimic the physiology and symptoms of human disease in animals
Based on a number of interventions: Pharma Genetic alteration Experience (e.g. ELA) Surgical adaptation
Describe the different concepts of validity in animal models
Face validity; does the model capture some or all of the symptoms of human disease
Construct validity; do the pathophysiology and aetiology mirror human disease
Predictive validity; does the model predict which treatments will be effective in human patients
Describe animal models vs behavioural tests
Animal models;
Attempt to reproduce disease state in animal
Changes in physiology and behaviour observed
Focus on construct validity
Behavioural test:
Attempt to assess impact of tx on disease symptoms
Focus on predictive validity
Describe animal models of MDD
Learned helplessness (chronic despair) Unpredictable chronic mild stress ELA Social defeat Olfactory bulbectomy Genetic models (GR -/-)
Describe the tests of depression like behaviour in animal models
Resignation/ despair: forced swimming, tail suspension
Anhedonia: sucrose preference test, reduced intra-cranial self-stimulation
Lack of motivation; decreased grooming, decreased nest building
Describe the forced swimming test (resignation test)
Mice/ rats in glass cylinders
After a time, the animals will give up swimming/ attempt to escape and remain immobile
Antidepressants will increase the time before immobility
Pros: easy and cheap, good predictive value for monoaminergic drugs
Cons: measures response to acute stressor but not necessarily depressive symptoms, sensitive to acute treatment with monoaminergic drugs (SSRIs), predictive value for non-monoaminergic drugs is uncertain
Describe the tail suspension test
Conceptually similar to forced swilling test
Antidepressants will increase engaging in escape behaviour
Pros; easy, cheap. Good predictive validity
Cons; measures response to an acute stressor but not necessarily MDD. Sensitive to acute treatment of monoaminergic drugs, predictive validity for non-monoaminergic drugs uncertain. Suitable for mice only
Describe the sucrose preference test (anhedonia)
Rodents presented with choice between sucrose and water
Amount of each consumed is measured
Models of depression may cause a reduced preference for sucrose
Describe the intra-cranial self stimulation test as a measure of anhedonia in animal models
Rodents with chronically implanted electrodes that activate VTA - accumbens find self-stimulation rewarding and will work for reward
A reduction in self-stimulation provides a measure of reduced interest in rewarding stimuli
Describe the light/ dark box as a measure of anxiety in animal models
Number of entries and time spent in lighted area recorded
More anxious; more time spent in dark
Pits the natural desire to explore against the anxiety assoc area with bright, open areas
Describe the open field test as a measure of anxiety in animal models
Animals allowed to explore a brightly lit open field area
Time in centre vs periphery is recorded
Anxious animals stick to sides and avoid centre
Describe the elevated plus maze as a measure of anxiety in animal models
Animals tracked as they explore an elevated maze with 2 enclosed arms and 2 open arms
Anxious rats/ mice spend less time in open arms and more in enclosed arms
Describe the model for social interaction in animals?
Mice exposed to another animal, interacting freely or through a barrier
Social interactions scored
Measure of anhedonia
What is novelty induced hypophagia?
Animal in a novel environment (vs home) will show a reduction in feeding in response to anxiety
What was the first animal model of depression
Learned helplessness
Dogs received a series of unpredictable and uncontrollable electric shocks
Dogs subsequently placed in shuttle box in which escape from electric shock is possible by jumping over barrier when auditory stimulus occurs
Dogs subjected to uncomfortable shock failed to escape, remaining passively in shock compartment
Suggests that lack of control over aversive stimuli leads to a state of helplessness
How can learned helplessness be modelled in rodents?
Very similar to work with dogs
Exposure to uncontrollable, unpredictable shocks. Failure to escape shock in a shuttle box
Pros: good face validity
Cons; requires very strong stressors. Symptoms may not last long after cessation of uncontrollable shock
Is there a role of BDNF in learned helplessness?
BDNF dose dependent reduces the number of failures and escape latency in a learned helplessness shuttle box task
TCAs and SSRIs will both reduce the learned helplessness behaviour
How do animal models aim to create a chronic mild stress?
Stresses include (over at least 2 weeks)
Mild water and food deprivation
Temperature changes
Change of cage-mates
Causes long lasting changes in behaviour and physiology that mirror MDD (e.g. decrease in sucrose preference, grooming, locomotion, sexual behaviour)
Pros; excellent face, construct and predictive validity
Cons; very time consuming and expensive
Describe the effect of 3 drugs on immobility times in a tail suspension test after chronic mild stress
Used; fluoxetine, tianeptine and olanzapine
In chronic mild stress animal; inability in saline control
All 3 drugs cause a large reduction in the immobile time in tail suspension test
Is ELA a good model for depression in animal models?
Yes; ELA can make people vulnerable to depression
Pups separated from dam for 1-24 hrs per day during first 2 PN weeks
Results in increase anxiety and depression
Good construct validity
Describe studies involving ELA models and depressive behaviours
Maternal separation in rats results in anhedonia in later life indicated by a reduced ICSS:
Lever pressing for stimulation of MFB was reduced in female maternally separated rats but not males
Are there hormone changes in ELA mice (in terms of MDD)?
Yes; prior ELA will increase CRF in the PVN
Increased response to stress
Describe social defeat as an animal model for MDD
Chronic stress based model; mice/ rats repeatedly exposed to a dominant animal
Leads to social aversion in subsequent social interaction tests
Small number of days = anxiety
Longer time period = depression
Pros; good predictive validity (chronic tx with SSRIs required for depressive symptoms), good face validity (symptoms of depression reproduced), good construct validity (relevant to chronic perceptions of social failure)
Cons; very time consuming so expensive and slow, can only be used with male mice as female mice are less aggressive
Describe a study of social defeat and its links to MDD
14 days of social defeat in mice leads to anhedonia as indicated by a reduced preference to sucrose (and reduced social interaction)
Describe olfactory bulbectomy as a model for MDD
Removal of olfactory bulbs in rodents results in depressive symptoms, and a range of physiological changes
Bulbectomy may cause chronic stress owing to sensory deprivation/ hippocampal dysfunction
Model has poor construct validity but good predictive validity incl a delayed response to ADs
Describe genetic models for depression in terms of HPA hyperactivity
Evidence for HPA-axis hyperactivity and elevated cortisol levels in depressed patients
Reduced glucorticoid receptor (GR) expression may cause deficient feedback = incr HPA axis activity
Describe the heterozygous mice models for GR
Reduced GR expression; increased HPA axis activity
These GR +/- mice show:
Incr learned helplessness after stress
Incr corticosteroid release in response to stress
Downregulation of hippocampal BDNF
Decreased neurogenesis, particularly when stressed
Model has good face and construct validity
GR +/- mice show an increased escape latency and escape failures in shuttle-box task
BrdU+ cells (neurogenesis marker in hippocampus) in dentate gyrus are significantly reduced in GR +/- stressed mice
Describe the role of tests of despair in normal animals
Not a model of depression; used by pharma companies
Allows for drug screening to assess the acute effects of drug treatments
Many drugs with AD properties will cause an acute change in depressive behaviour test
Describe the role of ketamine in depression?
Stress = decreases in synaptic stress and spine loss with AMPAR activation increasing synaptic strength and synaptogenesis
Ketamine = NMDA receptor antagonist
Metabolite of ketamine enhances AMPAR mediated transmission but inactive at NMDA receptor
What is the theory of ketamine’s mode of action as an antidepressant
Blocks NMDA on interneurons reducing inhibition of presynaptic glutamergic terminals = increased glutamate and AMAPR
Ketamine metabolite NHNK is sufficient to exert antidepressant effects (reduced escape failures in a shuttle box paradigm)
Does HNK (ketamine metabolite) have a role in hippcampal fEPSPs?
Yes; it enhances them
Stimulate schaffer collaterals to CA1 = evoked response
Primarily a measure of AMPAR activity
Describe the role of ketamine and its metabolites in ant depression action
Ketamine; blocks inhibition of interneurons
Metabolite; activates AMPAR (sequence of downstream changes such as BDNF and synaptogenesis)
Does tianeptine play a role in hippocampal function?
Yes; can enhance place recognition memory in mice
Enhances AMPAR mediated synaptic transmission and long term potentiation
How does tianeptine exert its effect on the hippocampus?
Tianeptine is a mu and delta opioid receptor agonist
Action on these receptors may underlie its AMPA modulating properties
What is the main cell type in the N. Acc?
Medium Spiny Neuron (MSN)
What is the role of the PFC in depression?
Connection between MPC and N. Acc mediate associations between environmental stimuli and reward
PFC action and spine density is decreased in depression using fMRI
Anhedonia and depression = reduced glutamatergic activation of N. Acc
Resilience = increased activity/ synaptic strength in PFC-N. Acc
What studies have been performed to demonstrated a decrease in PFC activity in MDD?
IEG (markers of neuronal activity - genes expressed when neurons are active) markers of prefrontal activity are reduced in post-mortem brain tissue from depressed patients
IEG markers are also reduced in a mouse social defect stress model of depression
What is the role of the hippocampus in depression?
According to Deaken and Graeff’s theory = depression involves underactivity in the MRN to hippocampus during aversive events
This under activation results in a reduction of the inhibition of hippocampal activity via 5-HT1A receptors
The hippocampus is therefore overactive during aversive events, and the consolidation of aversive memories (rumination)
Hippocampal activity is abnormally high during loss events in treatment resistant depression
Describe the role of the hippocampus vs prefrontal inputs in depression
Optogenetic depression of synaptic stress in Hippocampal - N. Acc reverses chronic social defeat stress CSDS induced depressive symptoms
High frequency stimulation of Hippocampal - N. Acc afferents increases depressive symptoms
High frequency stimulation of the PFC- N. Acc decreases depressive symptoms
PFC underactive in depression
Hippocampus overactive
Do novel antidepressants that modulate AMPAR function have pathway specific effects on synaptic strength?
HNK and tianeptine enhance AMPAR mediated transmission in the hippocampus
Describe hippocampal-N. Acc projections vs PFC-N. Acc projections
Hippocampal to nucleus accumbens = increased synaptic strength results in a pro-depressive state
Prefrontal cortex to nucleus accumbens = increased synaptic stress results in a pro-resilient state
