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UPDATE ARTICLES • Rev. Bras. Psiquiatr. 35 (Suppl 2) • 2013 • https://doi.org/10.1590/1516-4446-2013-1156   copy

A critical overview of animal models of psychiatric disorders: challenges and perspectives

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Abstract

Animal models of psychiatric disorders are a challenging but highly relevant issue. Most psychiatric disorders are very heterogeneous syndromes, resulting from multiple and varied causal factors and characterized by symptoms that can only be inferred with significant limitations in non-human models. As constructing a model that reproduces a whole psychiatric syndrome seems virtually impossible, researchers have tried to focus on endophenotypes, i.e., discrete traits that are more proximal to predisposing genes than the whole syndrome. These can be explored in a wide range of approaches, such as in pharmacological, lesion, and environmental models. Another challenge is to understand how genes interact with environmental factors over time to result in the syndromic phenotype. A better understanding of the subcellular mechanisms that enhance or allow brain resistance to environmental influences is required, as is a global thesis compatible with the diversity of diseases sharing similar behavioral and biological traits. With an experimental inventory of the possible causes of minor developmental failures, we may systematically explore their consequences in the adult animal and be able to decide if this will enlighten the understanding of one or another psychiatric disease.

Animal models; psychiatric disorders; endophenotype; epigenetics

Introduction

Development of animal models of psychiatric disorders remains a challenge because of our still poor understanding of the etiopathogenesis and pathophysiology of such disorders. This results from the disparity of aims between physicians, whose interest obviously remains based on clinical features, and researchers, who need a biological foundation. There is virtually no objective measure or biological feature that could be used for psychiatric diagnosis. Progress in this field is hampered by the complexity of the human nervous system and the difficulty of studying it in detail in humans. Therefore, experimental models remain of great interest.11. Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. Nat Neurosci. 2010;13:1161-9.

A further complication is that most psychiatric disorders are very heterogeneous, probably resulting from multiple and varied causal factors leading to a similar phenotype that allows a syndromic diagnosis. In addition, most psychiatric symptoms (e.g., hallucinations, obsessions, delusions, guilt) are uniquely human and can only be inferred with significant limitations in animal models. It is not necessary or even realistic to postulate that an abnormal rat behavior should or could be analogous to an abnormal human behavior. For all these reasons, there is presently a consensual belief that development of a model that reproduces a whole psychiatric syndrome, such as schizophrenia, bipolar disorder, or major depressive disorder, is virtually impossible in a lower animal.11. Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. Nat Neurosci. 2010;13:1161-9. However, we must bear in mind that no animal model of a human disease does so, even for organic diseases such as diabetes, with all its complications.

Deconstructing mental illness: endophenotypes

As a consequence, researchers have tried to focus on discrete traits that could be studied in laboratory animals and/or be linked to genetic alterations. In this context, the term “endophenotype” was largely incorporated into psychiatric research and explored in models under the concept of heritable phenotypic features that reflect discrete components of the pathophysiologic processes more proximal to predisposing genes than the whole syndrome.22. Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003;160:636-45. Examples of tests used as endophenotypes are listed in Table 1. A major limitation of using such traits is that most are not specific to any psychiatric syndrome. For example, prepulse inhibition (PPI), a largely explored endophenotype, is disrupted in schizophrenia, Alzheimer's disease, Huntington disease, and bipolar disorder.11. Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. Nat Neurosci. 2010;13:1161-9.

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Table 1
Examples of tests used as endophenotypes in models of psychiatric disorders

Beyond their obvious role in genetic models of psychiatric disease, these traits serve as dependent variables in a wide range of approaches, such as in pharmacological, lesion, and environmental models of psychiatric disease. Such approaches have a controlled variable, based on a hypothesis about the etiopathogenesis or pathophysiology of the disease, and an endophenotype that is used as the dependent variable. For example, neurodevelopmental models are based on the assumption that a failure in brain development is involved in psychiatric diseases, using lesions (neonatal hippocampal lesion), prenatal exposure to toxins (methylazoxymethanol [MAM]), or environmental constraints (social isolation model) to elicit alterations in endophenotypes of interest.1515. Salgado JV, Hetem LA, Sandner G. [Experimental models of schizophrenia--a review]. Rev Bras Psiquiatr. 2006;28:135-41. Examples of such approaches are listed in Table 2.

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Table 2
Examples of approaches used to explore endophenotypes as dependent variables in models of psychiatric disorders

The great challenge: reconstructing mental illness in models

Another challenge is the construction of models to understand how genetic alterations interact with environmental factors over time to result in the syndromic phenotype. Clear epidemiological information is a prerequisite for construction of such models, which have been on a quest for a genetic determinism for most psychiatric diseases. Despite indisputable achievements, discoveries in this field have been disappointing.3131. DeRosse P, Malhotra AK, Lencz T. Molecular genetics of the psychosis phenotype. Can J Psychiatry. 2012;57:446-53. We suggest that this could be due to a mistake in the a priori assumption of such studies. They postulate, often implicitly, the occurrence of rare mutations with a weak expression of their corresponding phenotype, except in some individuals in which an unfortunate environmental feature acts as a trigger. The opposite assumption was not considered - namely, that psychiatric disorders are sustained by a very frequent modification of the genotype, but to which the majority of subjects would be resilient. Some specific failure in this resilience would allow the disease to occur. Such an assumption could even explain why the same genotype contributes to depression in some subjects and schizophrenia in others, as observed in a family in the case of the famous DISC1 mutation.3232. Blackwood DH, Fordyce A, Walker MT, St Clair DM, Porteous DJ, Muir WJ. Schizophrenia and affective disorders--cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet. 2001;69:428-33. This general assumption could be of importance for the mathematical basis of future epidemiological investigations and for fundamental investigations, the latter having then to consider the mechanisms of resilience rather than the causes of vulnerability of the brain to its environment.

Perspectives

A better understanding of the subcellular mechanisms that enhance or allow brain resistance to environmental influence - i.e., more basic research into the mechanisms of epigenesis - is required to reconcile these different approaches to genetic-environment interaction. A recent study in rats showed that maternal separation modifies genome expression.3333. Dimatelis JJ, Pillay NS, Mutyaba AK, Russell VA, Daniels WM, Stein DJ. Early maternal separation leads to down-regulation of cytokine gene expression. Metab Brain Dis. 2012;27:393-7. This is a crucial gate to the interplay between genotype and social environment. In addition, we need a global thesis compatible with the diverse range of diseases that share similar behavioral and biological traits. Friston's “disconnection hypothesis” may serve as a link between the diversity of causes and biological and behavioral manifestations.3434. Friston KJ. The disconnection hypothesis. Schizophr Res. 1998;30:115-25.,3535. Stephan KE, Friston KJ, Frith CD. Dysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring. Schizophr Bull. 2009;35:509-27. Briefly, it proposes that abnormal functional integration among different brain regions is a feature of several psychiatric disorders. This “disconnectivity” would be linked to altered N-methyl-D-aspartate (NMDA) receptor-mediated synaptic plasticity (or even wiring of fibers during brain development) and/or altered regulation of these receptors by neuromodulatory transmitters such as dopamine, serotonin, and acetylcholine. There is a diversity of possibilities for neuronal connections to become particular, which would account for the diversity of their clinical or biological outcomes. Rather than considering more models of depression or schizophrenia, we suggest that an experimental inventory of the possible causes of minor developmental failures be taken and that the biological and behavioral consequences of these developmental failures in the adult animal be explored systematically, with no a priori endponts for this research. Only later on will we be able to decide if the corresponding observations will enlighten our understanding of any given psychiatric disease.

Conclusions

Animal models of psychiatric disorders remain a challenging but highly relevant issue. Progress has been made by the deconstruction of mental syndromes into endophenotypes. The great challenge remains to reconstruct them by understanding how the interplay between genes and environment results, over time, in the full syndrome. In this regard, a promising approach could be the search for possible causes of minor developmental failures and the assessment of their biological and behavioral consequences in the adult animal.

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