RESUMO
Animal studies play a central role in the identification and testing of novel drugs for CNS disorders. In his longstanding career, Berend Olivier has significantly contributed to CNS drug discovery by applying and supporting novel views and methodologies in the fields of behavioral neuroscience, pharmacology, and (epi-) genetics. Here we review and put forward some of these integrated approaches that have led to a productive collaboration and new insights into the genetic and epigenetic regulation of neurobehavioural traits related to psychiatric disorders.
Assuntos
Fármacos do Sistema Nervoso Central/farmacologia , Descoberta de Drogas/métodos , Epigênese Genética/efeitos dos fármacos , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/genética , Animais , Modelos Animais de DoençasRESUMO
Identifying the genetic and neurobiological mechanisms underlying certain behavioural traits is an important strategy to understand the aetiology of various psychiatric disorders and to find potential new treatment possibilities. It has proven a great challenge to develop paradigms that allow translational research for behavioural phenotypes that are relevant for disorders across the psychiatric spectrum. Recently, there has been increasing attention for studies that implement rodent behavioural paradigms in the home cage to assess the association between genetic backgrounds and behavioural traits. The application of interspecies genetics to unravel these traits has revealed novel insights in the genetic mechanisms that are encoding phenotypes relevant to biological processes underlying psychiatric disorders. By means of two examples, namely the stress-induced hyperthermia paradigm and the home cage environment, this review aims to show that by using individual genetic variations with phenotypes obtained from mice and across categories of neuropsychiatric disorders, novel insights in the neurobiological trajectory of psychiatric disorders can be obtained.
Assuntos
Comportamento Animal/fisiologia , Variação Genética , Transtornos Mentais/genética , Transtornos Mentais/fisiopatologia , Especificidade da Espécie , Animais , Ansiolíticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Abrigo para Animais , Humanos , Modelos Biológicos , Pesquisa Translacional Biomédica/métodosRESUMO
BACKGROUND: Identifying susceptibility genes for endophenotypes by studying analogous behaviors across species is an important strategy for understanding the pathophysiology underlying psychiatric disorders. This approach provides novel biological pathways plus validated animal models critical for selective drug development. One such endophenotype is avoidance behavior. METHODS: In the present study, novel automated registration methods for longitudinal behavioral assessment in home cages are used to screen a panel of recently generated mouse chromosome substitution strains that are very powerful in quantitative trait loci (QTL) detection of complex traits. In this way, we identified chromosomes regulating avoidance behavior (increased sheltering preference) independent of motor activity levels (horizontal distance moved). Genetic information from the mouse QTL-interval was integrated with that from the homologous human linkage region for a mood disorder. RESULTS: We genetically mapped a QTL for avoidance behavior on mouse chromosome 15, homologous with a human genome region (8q24) linked to bipolar disorder. Integrating the syntenic mouse QTL-interval with genotypes of 1868 BPD cases versus 14,311 control subjects revealed two associated genes (ADCY8 and KCNQ3). Adenylyl cyclase 8 (Adcy8) was differentially expressed in specific brain regions of mouse strains that differ in avoidance behavior levels. Finally, we showed that chronic infusion of the human mood stabilizer carbamazepine (that acts via adenylyl cyclase activity) significantly reduced mouse avoidance behavior, providing a further link between human mood disorders and this mouse home cage behavior. CONCLUSIONS: Our data suggest that Adcy8 might encode a translational behavioral endophenotype of bipolar disorder.
Assuntos
Adenilil Ciclases/genética , Mapeamento Cromossômico , Reação de Fuga/fisiologia , Transtornos do Humor/genética , Locos de Características Quantitativas/genética , Animais , Cromossomos de Mamíferos , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Genótipo , Humanos , Canal de Potássio KCNQ3/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Genéticos , Atividade Motora/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Traditional behavioral tests, such as the open field test, measure an animal's responsiveness to a novel environment. However, it is generally difficult to assess whether the behavioral response obtained from these tests relates to the expression level of motor activity and/or to avoidance of anxiogenic areas. Here, an automated home cage environment for mice was designed to obtain independent measures of motor activity levels and of sheltered feeding preference during three consecutive days. Chronic treatment with the anxiolytic drug chlordiazepoxide (5 and 10 mg/kg/day) in C57BL/6J mice reduced sheltered feeding preference without altering motor activity levels. Furthermore, two distinct chromosome substitution strains, derived from C57BL/6J (host strain) and A/J (donor strain) inbred strains, expressed either increased sheltering preference in females (chromosome 15) or reduced motor activity levels in females and males (chromosome 1) when compared to C57BL/6J. Longitudinal behavioral monitoring revealed that these phenotypic differences maintained after adaptation to the home cage. Thus, by using new automated behavioral phenotyping approaches, behavior can be dissociated into distinct behavioral domains (e.g., anxiety-related and motor activity domains) with different underlying genetic origin and pharmacological responsiveness.
Assuntos
Ansiedade/genética , Ansiedade/fisiopatologia , Automação/métodos , Comportamento Animal/fisiologia , Comportamento Exploratório/fisiologia , Atividade Motora/genética , Animais , Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Automação/instrumentação , Comportamento Animal/efeitos dos fármacos , Clordiazepóxido/uso terapêutico , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Genéticos , Atividade Motora/efeitos dos fármacos , Fatores Sexuais , Especificidade da EspécieRESUMO
The pharmacological treatment of mood and anxiety disorders has for long relied on the serendipitous findings of monoaminergic and benzodiazepine drugs more than 50 years ago. These treatments, however, are therapeutically insufficient and even though more recently developed drugs are particularly improving side effects, the efficacy or response rate of the drugs has fundamentally not improved. Therefore it is necessary to develop new methods to identify novel mechanisms not based on merely the symptomatology, but on biologically relevant (endo) phenotypes. This review examines the option of integrating mouse and human behavioural genetics to aid the identification of the putative underlying pathophysiological mechanisms and pharmacological targets for psychiatric disorders.
