Module 1: L12-17 - animal models

Question 1

Provide examples of behavioral screening methods for animal models related to depression and anxiety: Despair-based tests in an inescapable an uncontrolable situation.

Answer 1

• 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:

Question 2

Explain the use and importance of face validity criteria for animal models.

Answer 2

“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

Question 3

Describe theoretical approaches in modeling depression and anxiety in animal models.

Answer 3

• Early life stressos
• Upredictable chronic mild stress (UCMS)
• Chronic social defeat
• Learned helplessness

Question 4

Describe approaches to overcome translational failures when using animal models.

Answer 4

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

Question 5

Describe how optogenetic are used to manipulate the activity of selected brain cells in animals.

Answer 5

Example: hypercortisolic state and
blunted stress response induced
by the activation of optogenetic
protein bPAC.

Question 6

Provide examples of how opto- and chemogenetics help understand the role of multiple brain regions in mediating emotional behaviors.

Answer 6

Precision is key: high causality
Example of opto:
- optogenetic stim of dopaminergic neurons (Chr2-DATCre- mice) in place preference

Question 7

Describe how chemogenetics are used to manipulate the activity of selected brain cells in animals.

Answer 7

Modified human muscarinic acetylcholine receptors responding
to the modified ligand:
Clozapine-N-Oxide (CNO).
* hM3DGq: Gq - Depolarization/Activation
* hM4DGi: Gi - Hyperpolarization/inhibition

Question 8

Explain the use and importance of construct validity criteria for animal models.

Answer 8

“How well the model is consistent with theoretical rationale”
- The model is based on known etiological or pathophysiological elements of the human disorder

Question 9

Explain the use and importance of predictive validity criteria for animal models.

Answer 9

“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

Question 10

What are the problems with construct validity?

Answer 10

• 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)

Question 10

What are the problems with face validity?

Answer 10

• Difficult to recreate all the behavioral features of a mental disorder in one model
• Does a simple behavior model a symptom in humans?

Question 11

What are the problems with predictive validity?

Answer 11

• Bevarioral screens often fail to detect potential efficacy of compounds acting via novel mechanisms

Question 12

What are the generel problems with translation of animal models to humans?

Answer 12

• 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.

Question 13

Describe the “early life stressor” approach.

Answer 13

• maternal deprivation - long-lasting often unpredictable seperation
• limited bedding and nesting - simulates effects of poverty

Question 14

Describe the “unpredicable chronic mild stress” (UCMS) approach.

Answer 14

• 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

Question 15

Describe the “chronic social defeat” approach.

Answer 15

• resident intruder: dominant resident rodent is intruded by another rodent

Question 16

Describe the “learned helplessness” approach.

Answer 16

• 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

Question 17

Provide examples of behavioral screening methods for animal models related to depression and anxiety: Reward-based tests for anhedonia (lack of interest in pleasure)

Answer 17

• 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

Question 18

Provide examples of behavioral screening methods for animal models related to depression and anxiety: anxiety like behavior in mice.

Answer 18

• 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

Question 19

How are the current validity of animals models in depression and anxiety?

Answer 19

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

Question 20

What are the features of a usefull animal model?

Answer 20

• 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