developmental test Flashcards
(18 cards)
Define the following
- construct validity
- face validity
- predictive validity
construct - does the animal model represent the same underlying causes and mechanisms of the mental disorder in humans?
face - Does the animal model look like the disorder?
predictive - Can the animal model predict treatment responses accurately for humans?
Outline Willner’s criteria for construct validity
Clear interpretation of both the model’s behavior and the features of the disorder.
A homologous relationship between model behavior and human depression symptoms → refined to a similarity in behavioral/cognitive dysfunctions and similarity in etiology between the model and the disorder.
Outline Willner’s criteria for face validity
Antidepressant effects should only present with chronic administration.
Symptoms should be specific to the disorder the animal model replicates.
The symptoms should coexist in a specific subgroup of individuals with that disorder => the model should not display features that are absent in real life groups with that disorder.
Outline Willner’s criteria for predictive validity
Correctly identifying antidepressants of pharmacologically diverse types.
Avoiding false negatives— should not miss known effective drugs.
Avoiding false positives — should not identify ineffective drugs as effective.
Potency in the model should correlate with clinical potency.
Outline the examples Willner used to explain each type of validity
Construct - maternal separation model - baby chimps and babies acted similarly due to separation
Face - learned helplessness in dogs - looks similar to learned helplessness of depression
Predictive - Learned helplessness in dogs - both showed similar effects to antidepressants
Outline the differences between the previous and current approaches of animal model validity:
Before:
Focus on face validity.
Animal model expected to exhibit all the symptoms of the disorder.
Matches the description in DSM.
After:
Move away from DSM matching: Researchers no longer aim to replicate entire DSM diagnoses in animal models.
Focus on underlying cause: Emphasis is now on identifying core biological or behavioral traits (not all symptoms).
Use of endophenotypes: Models target specific features rather than full disorders (Zachar, 2022, as cited in Van den Berg, 2022).
Outline the challenges of face and construct validity:
Face Validity Issues
Human psychiatric diagnoses are imprecise, making it hard to match animal behaviors to human symptoms.
This ambiguity makes it difficult to judge whether an animal model truly reflects human mental disorders.
Construct Validity Issues
Genetic models:
Inserting a “disease-causing” gene seems ideal, but not feasible:
No single gene causes psychiatric disorders.
Most disorders have complex genetic roots.
Environmental models:
Exposing animals to stress or trauma doesn’t ensure construct validity.
These risks are non-specific and can lead to both mental illness and normal outcomes.
The perinatal ketamine model of schizophrenia: STRENGTHS
Models All Three Symptom Domains
Mimics Core Pathophysiology
Neurodevelopmentally Relevant
Simple, Fast, and Cost-Effective
Amenable to Pharmacological Testing
The perinatal ketamine model of schizophrenia: LIMITATIONS
Dose and Timing Sensitivity
Limited Etiological Insight
Inconsistency in Predictive Validity
Species and Complexity Gaps
Risk of Overgeneralization
No Chronic Progression
What is the perinatal ketamine model of schizophrenia? Why ketamine?
It’s an animal model that mimics schizophrenia by disrupting NMDA receptor function during early brain development. Ketamine, an NMDA antagonist, is used to impair PV-expressing GABAergic interneurons, which are crucial for inhibitory control in the prefrontal cortex (PFC) — a system known to be dysfunctional in schizophrenia.
Ketamine blocks NMDA receptors, which are essential for the development of PV interneurons. Early-life NMDAR blockade leads to long-lasting brain and behavioral changes relevant to schizophrenia.
The perinatal ketamine model of schizophrenia: method
Ketamine treatment: Male mice were randomly assigned to receive either ketamine or saline during the second postnatal week (postnatal days 7, 9, and 11). This developmental window is critical for prefrontal cortex maturation
Upon reaching adulthood, multiple behavioral and other tests were conducted:
PV Expression in PFC: Immunohistochemistry was performed to quantify the number of PV-expressing GABAergic interneurons in the medial prefrontal cortex. This assessed whether ketamine treatment induced long-lasting disruptions in inhibitory interneuron populations, which are implicated in schizophrenia.
Attentional Set-Shifting Task: Animals were tested in a T-maze paradigm requiring them to shift from an egocentric response strategy to a visual-cue-based strategy. This paradigm specifically probes cognitive flexibility and PFC-dependent executive function, both of which are often impaired in schizophrenia.
Latent Inhibition (LI) Test: A conditioned taste aversion paradigm was used to measure LI, an attentional process known to be disrupted in schizophrenia.
Novel Object Recognition Task: Mice were exposed to both familiar and novel objects. Time spent investigating each object was recorded to determine object recognition performance.
Social Interaction Task: Investigation time of a familiar versus a novel conspecific was measured over multiple trials. This evaluated symptoms such as social withdrawal
The perinatal ketamine model of schizophrenia: findings
- Reduced PV Expression in mPFC: ketamine treatment led to a significant reduction in PV expression in the medial prefrontal cortex (mPFC) of adult mice.
- Impaired Attentional Set-Shifting: KET-treated mice were able to learn an initial response strategy (egocentric turning) similarly to controls. However, they were significantly impaired in shifting to a new strategy based on visual cues, taking more trials and making more errors.
- Impaired Latent Inhibition: The ability to ignore irrelevant stimuli, was reduced in KET mice.
- Novel Object Recognition Deficits: SAL-treated mice spent more time exploring a novel object, showing intact recognition memory. KET-treated mice did not show this preference, indicating deficits in attention and memory.
- Social Interaction Deficits: KET-treated mice showed reduced social investigation behaviors. Unlike SAL-treated mice, who decreased interest in a familiar stimulus and showed renewed interest in a novel mouse, KET mice did not.
The perinatal ketamine model of schizophrenia: conclusion
Administering ketamine (an NMDAR antagonist) during early development in mice causes persistent schizophrenia-like symptoms in adulthood. This includes impairments in cognitive flexibility, recognition memory, and social behavior, all linked to reduced PV-expressing interneurons in the medial prefrontal cortex.
Schizophrenia-like effects are not due to generalized anxiety as ketamine-treated animals showed no significant differences in anxiety-related tasks compared to control animals.
While ketamine, PCP, and MK-801 (all NMDAR antagonists) differ pharmacologically, they all produce similar schizophrenia-like deficits, highlighting their usefulness in modeling the disorder. However, the exact neurophysiological mechanisms through which these drugs induce symptoms at different developmental stages remain unclear and need further study.
Findings support the notion that early NMDAR antagonism can disrupt brain circuits responsible for cognition and behavior, offering insights into the pathophysiology of schizophrenia.
Drug self-administration model (addiction): background
The self-administration model is widely used to investigate the brain mechanisms underlying addictive behaviours.
Animals learn to press a lever to receive a drug (e.g., cocaine, heroin, or nicotine)
Is instrumental in understanding the neurobiology of addiction and testing treatments that might reduce drug-seeking or relapse
drug self-administration model: outline its face, construct and predictive validity
face validity: high, animals voluntarily take drugs, show relapse behaviours similar to humans
construct: high, involves key human addiction pathways (e.g mesolimbic dopamine system, VTA-NAc circuit - The same neurobiological substrates involved in drug use in humans are implicated in drug intake and reinforcement in rodents
predictive: high, responds to pharmacological treatments similarly to humans
perinatal ketamine model: outline its face, construct and predictive validity
face: moderate, mimics early-life NMDA receptor disruption linked to schizophrenia-like symptoms - Ketamine-exposed rodents show three core schizophrenia-like behaviors: hyperactivity (positive), social withdrawal (negative), and memory loss (cognitive).
construct: moderate-high, targets glutamatergic dysfunction relevant to Sz. Models neurodevelopmental risk factors -
Prenatal ketamine affects NMDA receptor function — a key pathway in the glutamate hypothesis of schizophrenia. It also reduces PV+ interneurons and BDNF levels, and raises inflammation — all findings that align with postmortem schizophrenia data.
predictive: moderate - some treatments (e.g antipsychotics) reverse behavioural deficits - but not always. Results vary depending on ketamine dose, timing, and the specific behavior tested.
limited nesting and bedding model: outline its face, construct and predictive validity
face - moderate; models early life adversity leading to anxiety and depression behaviours in offspring - maternal behaviours (e.g., fragmented care, rough handling) that mimic human caregiving disruptions seen in neglect or adverse environments.
construct - high; replicates environmental stress effects HPA-axis dysregulation, including elevated corticosterone and altered glucocorticoid receptor expression,
changes in brain regions (e.g., hippocampus, amygdala, prefrontal cortex) parallel known neurodevelopmental impacts of early life stress in humans.
predictive - moderate-high; rodents exposed to limited often respond to antidepressants and anxiolytics, such as SSRIs or CRF receptor antagonists, environmental enrichment, in ways that mirror human clinical responses.
