Animal Models Of Brain Disorder (Short) Notes

Animal models of brain disorder

Why do we need animal models of brain disorder?

What brain disorders can we model?

How do we test the validity of a model?

How do we construct a model?

How do we make genetic models?

Mouse vs. man

Charles Darwin, The Descent of Man – “…the difference in mind between man and the higher animals, great as it is, certainly is one of degree and not of kind…”

Why do we need animal models?

• High cost and time investment of clinical studies and trials

• Technical challenge of measuring neural function in patients

• Need to understand better the neurobiological basis of symptoms

• Investigate the role of genes and signaling pathways in disease pathophysiology

• Investigate the role of gene/environment interactions in disease pathophysiology

• Make better and more effective treatments

Examples of brain disorders that we think that we can model

PSYCHIATRIC DISORDERS:

Depression

Anxiety

Schizophrenia

Compulsive drug use

NEURODEGENERATIVE DISORDERS:

Alzheimer’s

Parkinson’s

Huntington’s

OTHER NEUROLOGICAL DISORDERS:

Epilepsy

Cerebral ischemia (stroke)

Testing the validity of a model

1. construct validity – How good is the theoretical rationale? (gene mutation, neuronal lesion, developmental origin)

2. face validity – how good are the similarities with the human condition? (behavioural symptoms, neuropathology)

3. predictive validity – how accurate are predictions made from the model (effects of treatments, disease progression)

Constructing an animal model

• Pharmacological manipulation

  • Neuronal lesion

  • Transmitter modulation

• Environmental manipulation

  • Behavioural conditioning

  • Behavioural stressors

  • Adverse early life events

• Genetic manipulation

  • Gene KO

  • Gene knock in

  • Selective breeding

  • Chemical mutagenesis

Some animal models of depression

• Environmental stress

  • Chronic mild stress

  • Social defeat

• Maternal separation

  • Rodents

  • Primates

• Selective breeding

  • “Rouen depressed mice”

• olfactory bulbectomy

• tryptophan-free diet

• stimulant-induced hyperactivity (mania)

Measurement of “depression” symptoms

• Forced swim test (learned helplessness)

• Escapable shock (learned helplessness)

• Intracranial self stimulation (anhedonia – inability to experience from pleasure from something normally enjoyable)

• Social interaction (anxiety)

Measurement of cognitive deficits in depression

Enkel et al 2009 – Ambiguous-cue interpretation is biased under stress- and depression-like states in rats – neurobiology behind negative cognitive bias (“negative outlook” on life) is unclear – this paper establishes a new ambiguous-cue interpretation paradigm and, with respect to the etiology of depression, investigated whether environmental and genetic factors contribute to a negative bias. Rats were trained to press a lever to receive a food reward contingent to one tone and to press another lever in response to a different tone to avoid punishment by electric foot-shock. A tone intermediate of the previous two was used to establish the positive or negative bias of the rat – responses to the intermediate cues were taken as indicators of the rats’ expectation of positive/negative events. A negative response biase because of decreased positive and increased negative responding was found in congenitally helpless rats, a genetic animal model of depression. Treatment with a combined noradrenergic-glucocorticoid challenge, mimicking stress-related changes in endogenous neuromodulation, biased rats away from positive responding. IN SUM, genetic and environmental risk factors for depression induce a response bias.

Some animal models of anxiety

• Environmental stress

  • Chronic mild stress

  • Social defeat

• Behavioural conditioning

  • Fear conditioning

• Selective breeding

• Pharmacological manipulation

  • Anxiogenic agents

• Genetic manipulation

  • Gene KO/KI

Measurement of “anxiety” symptoms

• Delivery of punishment (conflict)

  • Punished lever responding

  • Punished drinking

• Anticipation of punishment

  • Fear potentiated startle

• Ethologically-derived tests

  • Elevated X maze

  • Light-dark box

  • Social interaction test

• Brain stimulation

  • Periaqueductal gray, locus coeruleus

Anxiety induced by a novel environment

• Open field

• Elevated plus maze

• Elevated zero maze

• Light-dark box

Animal models of schizophrenia

• Social isolation (post weaning)

• Genetic manipulation

  • NMDA receptor knock down

  • Calcineurin KO

• Postnatal NMDA antagonist

• Postnatal neuronal lesions

Measurement of “schizophrenia” symptoms

• Hyperactivity

  • Spontaneous (open field)

  • Drug-evoked (amphetamine, NMDA antagonist)

• Sensorimotor gating deficits

  • Pre-pulse inhibition

  • Latent inhibition

• Social deficits

  • Social interaction

• Cognitive deficits

How do we make...

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