Download or read book Endophenotypes Of Psychiatric And Neurodegenerative Disorders In Rodent Models written by Sylvie Granon and published by . This book was released on 2009-01-01 with total page 358 pages. Available in PDF, EPUB and Kindle. Book excerpt: Psychiatric disorders are uniquely human. Yet we need animal models to test hypotheses about biological mechanisms. Treatment development relies on model systems to evaluate the efficacy of therapeutics. How can such a profound paradox be resolved? Dr. Sylvie Granon of the Institute Pasteur in Paris has successfully assembled a collection of fifteen review chapters that address multiple aspects of rodent models of neuropsychiatric disorders. Outstanding experts describe paradigms relevant to Alzheimer s disease, mental retardation, schizophrenia, autism, attentional deficit hyperactivity disorder, impulsivity, drug addiction, post-traumatic stress disorder, multiple sclerosis, and sudden infant death syndrome. Traditional lesioning and pharmacological methods are contrasted with newer targeted gene mutation strategies for generating rodent models. Strengths and limitations of transgenic and knockout mouse models are discussed by many of the insightful authors. In Alice in Wonderland, the Cheshire Cat speaks English and tell us We re all mad here. Unfortunately, real animals do not talk, and cannot tell us about their abnormal internal emotional or mental states, if any. It is essential to recognize that researchers will never be able to replicate schizophrenia or autism or depression in a mouse. Many psychiatric dysfunctions appear to originate primarily in the human frontal cerebral cortex, a highly developed structure that dramatically eclipses the modest frontal cortex of rodents. Numbers of synapses and available pathways for making neural connections that permit higher executive functions are enormously greater in humans as compared to other species. Expansion of the human prefrontal cortex is an evolutionary recent phenomenon. There has not been enough time for thorough trouble-shooting and beta-testing of its neural circuitry. No wonder so much can go so wrong. Endophenotypes offer a neat solution to our conundrum. Rather than trying to replicate the full human syndrome, specific components of behavioral symptoms and neuroanatomical abnormalities can be modeled in rodents. While mental illnesses that are primarily caused by incorrect developmental neuroanatomy or aberrant neurotransmitter pharmacology in the prefrontal cortex may be difficult to model in mice, whose prefrontal cortex is minimal, connections between frontal cortex and other brain regions such as thalamus are similar across species. Homologies between rodents and primates in frontal cortex connections and specific behavioral functions have been extensively described by Bryan Kolb. The inability of Alzheimer s patients to store new memories represents a discrete characteristic that can be paralleled in rats and mice, who store new memories using similar neurophysiological mechanisms. Schizophrenic patients display deficits in sensorimotor gating and errors in working memory. Very similar procedures and equipment are available to assay prepulse inhibition and working memory in humans, monkeys, rats, and mice. Neuropharmacological pathways mediating the biological actions of abused drugs are similar in humans and rats. Drug addicts show poor impulse control and poor decision making in tasks that are analogous to some forms of errors in the five choice serial reaction time task for rats and mice. Genetic mutations that produce synaptic dysfunctions or amyloid plaques in the human brain are inserted into the mouse genome to create mouse models of mental retardation, which are then evaluated on learning and memory tasks. Thus, a simpler focus on individual endophenotype components of a human disease permits reasonable analogies to be generated in model organisms. The ideal animal model of a human syndrome is quantitative, readily replicated across laboratories, and incorporates three types of validity. Face validity is the conceptual analogy to a human symptom or endophenotype. Some unusual social behaviors in mice offer a conceptual analogy to the first diagnostic symptom of autism, abnormal reciprocal social interactions. Construct validity employs the same cause or precipitating event in the animal model and the human disease. Inflammatory demyelination presents construct validity for a rodent model of multiple sclerosis. Predictive validity confirms the specific therapeutic response. Treatments that work in the human disease also work in the animal model. For example, antidepressants that are effective in treating post-traumatic stress disorder should effectively reverse the behavioral traits of a rat model of this syndrome. Very few animal models of neuropsychiatric diseases incorporate all three types of validity. The authors contributing to this volume explain the challenges, failures and successes of an impressively wide range of model organisms. As the true causes of mental illnesses are identified, neuroscientists and pharmaceutical researchers will design more targeted model systems with true construct validity to the etiologies of neuropsychiatric syndromes. Behavioral assays will continue to be invented and refined to optimize face validity to the endophenotypes of the human disease. Ultimately these endeavors will result in model organisms with high predictive validity and translational value, to enhance the discovery of effective cures for debilitating major mental illnesses.