Module 1: L12-17 - animal models Flashcards
Provide examples of behavioral screening methods for animal models related to depression and anxiety: Despair-based tests in an inescapable an uncontrolable situation.
- Forced swim test (FST): animal placed in a water-filled cylinder too deep to stand in, measures latency for the animal to stop swimming
- Tail suspension test:
Explain the use and importance of face validity criteria for animal models.
“How well the model resembles the psychiatric condition”
The model has observable features – ranging from anatomy to behavior – that are (or appear) analogue to objective features of the human disorder
- how well does the model “resemble” the condition/specific features of the condition
Describe theoretical approaches in modeling depression and anxiety in animal models.
- Early life stressos
- Upredictable chronic mild stress (UCMS)
- Chronic social defeat
- Learned helplessness
Describe approaches to overcome translational failures when using animal models.
1) Acknowledge the ‘fuzziness’ and heterogeneity of MDD => use animal models of:
- depression subtypes
- treatment‑resistant depression
- recurrent depression
2) Acknowledge the limitations of short reductive behavioral tests
=> use ethologically relevant setups, longer tests in groups of rodents
Describe how optogenetic are used to manipulate the activity of selected brain cells in animals.
Example: hypercortisolic state and
blunted stress response induced
by the activation of optogenetic
protein bPAC.
Provide examples of how opto- and chemogenetics help understand the role of multiple brain regions in mediating emotional behaviors.
Precision is key: high causality
Example of opto:
- optogenetic stim of dopaminergic neurons (Chr2-DATCre- mice) in place preference
Describe how chemogenetics are used to manipulate the activity of selected brain cells in animals.
Modified human muscarinic acetylcholine receptors responding
to the modified ligand:
Clozapine-N-Oxide (CNO).
* hM3DGq: Gq - Depolarization/Activation
* hM4DGi: Gi - Hyperpolarization/inhibition
Explain the use and importance of construct validity criteria for animal models.
“How well the model is consistent with theoretical rationale”
- The model is based on known etiological or pathophysiological elements of the human disorder
Explain the use and importance of predictive validity criteria for animal models.
“How well the model responds favorably to the same drugs as humans with the condition”
Intervention effects in the model predict intervention effects in the human disorder
What are the problems with construct validity?
- Mental disorders are highly polygenic
- Genetics of mental illness are largely non-specific. E.g. familial risk for schizophrenia confers increased risk for schizophrenia+bipolar disorder and vice versa
- Environmental stressors (psychological stress) increase risk for almost all mental disorders – not just
depression/anxiety – and interact with the genetic status (gene-environment interaction)
What are the problems with face validity?
- Difficult to recreate all the behavioral features of a mental disorder in one model
- Does a simple behavior model a symptom in humans?
What are the problems with predictive validity?
- Bevarioral screens often fail to detect potential efficacy of compounds acting via novel mechanisms
What are the generel problems with translation of animal models to humans?
- Psychiatric disorders are about subjective mental phenomena that may or may not have obvious
behavioral manifestations - Psychiatric disorders are about mental dimensions that seems uniquely human, i.e. higher
reasoning, imagination, language, existential issues (suicidality), etc.
Describe the “early life stressor” approach.
- maternal deprivation - long-lasting often unpredictable seperation
- limited bedding and nesting - simulates effects of poverty
Describe the “unpredicable chronic mild stress” (UCMS) approach.
- different approaches, e.g., tilted cage, change of cage, social deprivation ect.
- both randomized stressor and variable time of day
- usually 2-8 weeks (chronic)
- “mild” is very debatable
Describe the “chronic social defeat” approach.
- resident intruder: dominant resident rodent is intruded by another rodent
Describe the “learned helplessness” approach.
- deficit in escaping from an aversive situation after exposure to
unescapable stress compared to a control group exposed to an equivalent amount of escapable stress - measures latency for the animal to escape the shock during testing
Provide examples of behavioral screening methods for animal models related to depression and anxiety: Reward-based tests for anhedonia (lack of interest in pleasure)
- Sucrose preference test: Decreased preference for sweetened water over
non-sweetened water is used as an index of anhedonia (also Cookie test) - Intracranial self stimulation test
Provide examples of behavioral screening methods for animal models related to depression and anxiety: anxiety like behavior in mice.
- Novelty suppresion of feeding: placing the animal in a situation with
a motivational conflict (eat food vs. avoidance of open space) - latency to eat in a novel environment, reflecting the level of anxiety - Open field test: more time spent at the periphery (next to the walls) indicates higher anxiety-like behaviors
- Elevated plus maze: more time spent in the dark arms indicates higher anxiety-like behaviors
How are the current validity of animals models in depression and anxiety?
Overall, good validity of current animal models of affective disorders BUT, no new pharmacological treatment found with animal models since the 1980’s
=> preclinical studies using animal models of affective disorders fail to translate
What are the features of a usefull animal model?
- it is a setup in an animal for the purpose of predicting the effect of a
manipulation on function in a human condition - It must be amenable to cross-species studies
- It must exhibit high construct validity relevant to the clinical model
- It must have predictive validity, i.e., provide a reliable signal of efficacy
across species - It can be used for confident go/no-go decisions in a drug development
program
