Cosa caratterizza un buon modello animale Innanzi tutto
Cosa caratterizza un buon modello animale
Innanzi tutto, modello animale di cosa? Necessità di definire con chiarezza per quale aspetto del comportamento e delle funzioni cerebrali umane, fisiologiche o patologiche, si propone un modello animale Necessità di conoscere con chiarezza la fisiologia/anatomia del modello animale relativamente a quella funzione
Esempio: Modelli animali del funzionamento dei circuiti della corteccia visiva alla base della percezione visiva Percezione del colore (primati) Percezione del contrasto chiaro/scuro (mammiferi (per la retina anche vertebrati))
Esempio: Modelli animali del funzionamento dei circuiti dell’ippocampo alla base della memoria spaziale Mammiferi (i modelli più usati sono i roditori che hanno portato alla scoperta delle place cells, grid cells, …)
Modelli animali di patologie umane
Given the challenges of validation of animal models, it is useful for the scientific community to share criteria for judging whether a particular disease model is good enough to warrant further investments. A longstanding framework posits three types of validators: construct, face and predictive validity.
Construct (or etiologic) validity refers to the disease relevance of the methods by which a model is constructed. In the ideal situation, researchers would achieve construct validity by recreating in an animal the etiologic processes that cause a disease in humans and thus replicate neural and behavioral features of the illness.
Esempio: modelli animali per la comprensione dei circuiti cerebrali alla base delle risposte di paura e del loro controllo. Risposte di paura innate, evocate da stimoli identici nell’uomo e nell’animale Risposte di paura apprese: condizionamento classico, nell’uomo e nell’animale
A straightforward way of accomplishing construct validity would be knocking a known diseasecausing (Mendelian) genetic mutation into a mouse or, with somewhat less certainty, inserting a highly, but not fully, penetrant genetic variant that markedly increases vulnerability for a human disease. (Nestler, 2009)
Esistono buoni modelli animali di malattie umane su base genetica Esempi: Alcuni disturbi del neurosviluppo causate dalla mutazione di un singolo gene (Rett syndrome, X-fragile syndrome, . . . , non così semplice in ASD) Forme (rare) di emicrania
However, this is currently not possible for most mental illnesses, as such disease-causing genes have not been established with certainty and most disorders exhibit highly complex genetic architecture.
Il problema dei modelli animali per le demenze neurodegenerative come AD: familial AD vs sporadic AD
Secondo problema, la stessa mutazione può essere associata con sindromi differenti e con fenotipi differenti Basically, given what we now know, even for ASD, schizophrenia, bipolar disorders, which are highly geentically influenced, these syndromes are associated with both large numbers of common genetic variants of small effects and rare, more highly penetrant mutations. Thus, different individuals likely have different genetic pathways to each of these disorders. Patient stratification, biomarker clusters
Face validity indicates that a model recapitulates important anatomical, biochemical, neuropathological or behavioral features of a human disease. Biochemical abnormalities alone are not enough.
Behavioral features and neuropathological features reminiscent of a human disorder are required to achieve face validity. In addition, the temporal course of pathological sign onset must recapitulate the human one (scaled for human/animal age)
Esempi: Modelli animali sindrome di Rett (OK) Modelli di f. AD (non OK)
Come considerare un modello che ha una buona face validity ma non ha construct validity?
Predictive validity refers to the fact that the animal model responds to human known therapeutic and can correctly identify the efficacy of new putative therapeutic. Questo conferisce validità predittiva alla sperimentazione di NUOVI terapeutici
Esempi comunemente portati: modelli animali di depressione Va tenuto presente che nell’uomo i trattamenti con antidepressivi sono efficaci con protocolli di trattamenti cronico, non acuto Fin qui 27 febbraio
Quali metodiche utilizzare per fenotipizzare il modello animale?
Il problema dei test comportamentali per i modelli animali di disturbi umani è molto sentito in letteratura
Esempi di valutazioni comportamentali utilizzate nel campo della ricerca sulla depressione
Learned helplessness, defines the condition of a human person or of another animal who has learned to behave helplessly, even when the opportunity is restored for it to help itself by avoiding an unpleasant or harmful circumstance to which it has been subjected. Put in a cage with an easy escape way, animals in the yoked groups did not attempt to escape (learned helplessness) and exhibited some behaviour typical of human depression (anhedonia). The strongest predictor of a depressive response was lack of control over the aversive stimulus. Note: not all the animals in the yoked group developed learned helplessness
A major weakness of all three tests (forced swimming, tail suspension and learned helplessness) is that they involve short-term stress applied to normal rodents, which is very different from human depression, in which an underlying genetic vulnerability combines with stochastic and chronic environmental exposures to produce long-lasting behavioral pathology. Similarly, the ability of antidepressants to produce a rapid response after single doses in these tests contrasts markedly with the well-established need to use antidepressants chronically (weeks to months) to obtain a clinical response in humans.
A second major class of tests of depression-related behavior involves measuring anhedonia or homeostatic symptoms. This approach has the advantage of being based on symptoms of depression, and therefore yielding more convincing face validity, rather than on properties of current antidepressants. Most frequently examined is an animal’s interest in pleasurable activities, such as preference for a sucrose solution over water or engaging in social or sexual behavior. Models with decreased sucrose preference, not resulting from a motor or sensory deficit, are interpreted as demonstrating anhedonia and thus depressionlike behavior. Although anhedonia is not specific to depression, it is a core symptom of depression about which there are testable neurobiological hypotheses, making it an attractive target for investigation in animal models.
A range of homeostatic symptoms (alterations in sleep, circadian rhythms and feeding with attendant metabolic parameters) that are common in depressed humans, but only infrequently examined in animal models, would add a useful objective dimension to rodent studies.
Esempi di valutazioni comportamentali utilizzate n campo della ricerca sulla schizofrenia
More recently, cognitive deficits characteristic of schizophrenia have been used to evaluate animal models. Although deficits in attention, working memory and executive function are not individually specific to schizophrenia, they are important and disabling features of the disorder; thus, animal models that reproduce such symptoms have some claim on face validity.
Another test recently used in animal models of schizophrenia is Pre Pulse Inhibition (PPI). An advantage of PPI is that deficits are documented in many individuals with schizophrenia. A limitation is that PPI deficits are not specific; they occur in other conditions, including Alzheimer’s disease.
Thus, PPI can contribute to establishment of face validity, but does not, by itself, make the case.
Prepulse inhibition (PPI) In the prepulse inhibition (PPI) procedure, the rodent is placed in a small chamber and exposed to a brief pulse of noise. The test is used to assess the subject’s ability to "gate" or filter environmental information. In the acoustic (startle model) of sensorimotor gating, a weak acoustic stimulus (ie, the prepulse) decreases the reflexive flinching response (startle) produced by a second, more intense, stimulus (the pulse). Prepulse inhibition is a cross-species phenomenon (ie, it is present in mammals ranging from mice to humans), yet it is relatively absent among schizophrenic patients and, more recently discovered, among patients with Alzheimer’s disease. The reduced ability to filter out irrelevant auditory stimulation is a characteristic thought to contribute to certain manifestations of these conditions including inattention, distractibility, and cognitive deficits.
Deficits of prepulse inhibition manifest in the inability to filter out the unnecessary information; they have been linked to abnormalities of sensorimotor gating. Pulse-alone results are compared to prepulse-plus-pulse, and the percentage of the reduction in the startle reflex represents prepulse inhibition.
La presenza di deficit nel PPI test NON fa si che un modello animale sia un modello di schizofrenia (può contribuire alla face validity). Va inoltre considerato COME è stato ottenuto (construct validity).
In totale: Un buon modello animale deve: Incorporare comportamenti che caratterizzano la condizione umana Essere basati su fattori eziologici noti (o fortemente probabili) Essere molecolarmente congruenti con biomarcatori della malattia nell’uomo Rispondere in maniera prevedibile e con modalità di trattamento analoghe ai trattamenti clinici disponibili
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