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New frontiers in animal research of psychiatric illness
Arie Kaffman1, John H Krystal, John J Krystal
1Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. arie.kaffman@yale.edu
Abstract:
Alterations in neurodevelopment are thought to modify risk of numerous psychiatric disorders, including schizophrenia, autism, ADHD, mood and anxiety disorders, and substance abuse. However, little is known about the cellular and molecular changes that guide these neurodevelopmental changes and how they contribute to mental illness. In this review, we suggest that elucidating this process in humans requires the use of model organisms. Furthermore, we advocate that such translational work should focus on the role that genes and/or environmental factors play in the development of circuits that regulate specific physiological and behavioral outcomes in adulthood. This emphasis on circuit development, as a fundamental unit for understanding behavior, is distinct from current approaches of modeling psychiatric illnesses in animals in two important ways. First, it proposes to replace the diagnostic and statistical manual of mental disorders (DSM) diagnostic system with measurable endophenotypes as the basis for modeling human psychopathology in animals. We argue that a major difficulty in establishing valid animal models lies in their reliance on the DSM/International Classification of Diseases conceptual framework, and suggest that the Research Domain Criteria project, recently proposed by the NIMH, provides a more suitable system to model human psychopathology in animals. Second, this proposal emphasizes the developmental origin of many (though clearly not all) psychiatric illnesses, an issue that is often glossed over in current animal models of mental illness. We suggest that animal models are essential to elucidate the mechanisms by which neurodevelopmental changes program complex behavior in adulthood. A better understanding of this issue, in animals, is the key for defining human psychopathology, and the development of earlier and more effective interventions for mental illness.
Insights
Model organisms are crucial for understanding how neurodevelopmental changes, influenced by genes and environment, contribute to psychiatric disorders. This approach focuses on circuit development and measurable endophenotypes for better animal models.
Area of Science:
- Neuroscience
- Psychiatry
- Genetics
- Developmental Biology
Background:
- Neurodevelopmental alterations are linked to increased risk for psychiatric disorders like schizophrenia, autism, ADHD, mood disorders, anxiety, and substance abuse.
- The cellular and molecular mechanisms underlying neurodevelopmental changes and their contribution to mental illness remain poorly understood.
- Current animal models for psychiatric disorders often rely on the Diagnostic and Statistical Manual of Mental Disorders (DSM) framework, which may limit their validity.
Purpose of the Study:
- To advocate for the use of model organisms to elucidate the neurodevelopmental processes underlying psychiatric disorders in humans.
- To propose a translational research approach focusing on gene and environmental influences on neural circuit development.
- To suggest replacing the DSM system with measurable endophenotypes and the Research Domain Criteria (RDC) framework for developing more valid animal models.
Main Methods:
- Review of existing literature on neurodevelopment and psychiatric disorders.
- Advocacy for a translational research strategy using model organisms.
- Proposal for a shift from DSM-based to RDC-based and endophenotype-driven animal modeling.
Main Results:
- Model organisms are essential for understanding the mechanisms by which neurodevelopmental changes program adult behavior and contribute to psychopathology.
- Focusing on circuit development as a fundamental unit of behavior offers a distinct advantage over current modeling approaches.
- The RDC framework and measurable endophenotypes provide a more suitable basis for developing valid animal models of human mental illness.
Conclusions:
- Animal models are critical for deciphering the complex interplay of genes, environment, and neurodevelopment in shaping behavior and mental health.
- Emphasizing the developmental origins of psychiatric disorders and utilizing endophenotypes will lead to a better understanding of human psychopathology.
- This approach holds the key to developing earlier and more effective interventions for mental illness.
