environmental-modulations-number-midbrain-dopamine-neurons-adult

Environmental Modulations of the Number of Midbrain Dopamine Neurons in Adult Mice

Long-lasting changes in the brain or &#8216;brain plasticity&#8217; underlie adaptive behavior and brain repair following disease or injury. Furthermore, ...

The University of Melbourne

The complexity of the genetics underlying schizophrenia is highlighted by the multitude of molecular pathways that have been reported to be disrupted in the disorder including muscarinic, serotonergic, and glutamatergic signaling systems. It is of interest, therefore, that phospholipase C-beta1 (PLC-beta1) acts as a point of convergence for these pathways during cortical development and plasticity. These signaling pathways, furthermore, are susceptible to modulation by RGS4, one of the more promising candidate genes for schizophrenia. PLC-beta1 knockout mice were behaviorally assessed on tests including fear conditioning, elevated plus maze, and the Y maze. In situ hybridization was used to assess RGS4 expression. We found that PLC-beta1 knockout mice display abnormal anxiety profiles on some, but not all measures assessed, including decreased anxiety on the elevated plus maze. We also show memory impairment and a complete absence of acquisition of hippocampal-dependent fear conditioning. Furthermore, at a molecular level, we demonstrate dramatic changes in expression of RGS4 mRNA in selective regions of the PLC-beta1 knockout mouse brain, particularly the CA1 region of the hippocampus. These results validate the utility of the PLC-beta1 knockout mouse as a model of schizophrenia, including molecular and cellular evidence for disrupted cortical maturation and associated behavioral endophenotypes.

PLC-beta1 knockout mice as a model of disrupted cortical development and plasticity: behavioral endophenotypes and dysregulation of RGS4 gene expression.

Schizophrenia is a devastating psychiatric illness with a complex pathophysiology. We have recently documented schizophrenia-like endophenotypes in phospholipase C-β1 knockout (PLC-β1(-/-)) mice, including deficits in prepulse inhibition, hyperlocomotion, and cognitive impairments. PLC-β1 signals via multiple G-protein coupled receptor pathways implicated in neural cellular plasticity; however, adult neurogenesis has yet to be explored in this knockout model. In this study, we employed PLC-β1(-/-) mice to elucidate possible correlates between aberrant adult hippocampal neurogenesis (AHN) and schizophrenia-like behaviors. Using stereology and bromodeoxyuridine (BrdU) immunohistochemistry we demonstrated a significant increase in the density of adult-generated cells in the granule cell layer (GCL) of adult PLC-β1(-/-) mice compared with wild-type littermates. Cellular phenotype analysis using confocal microscopy revealed these cells to be mature granule neurons expressing NeuN and calbindin. Increased neuronal survival occurred concomitant with reduced caspase-3(+) cells in the GCL of PLC-β1(-/-) mice. Stereological analysis of Ki67(+) cells in the subgranular zone suggested that neural precursor proliferation is unchanged in PLC-β1(-/-) mice. We further showed aberrant migration of mature granule neurons within the GCL of adult PLC-β1(-/-) mice with excessive adult-generated mature neurons residing in the middle and outer GCL. PLC-β1(-/-) mice exhibited specific behavioral deficits in location recognition, a measure of hippocampal-dependent memory, but not novel object recognition. Overall, we have shown that PLC-β1(-/-) mice have a threefold increase in net AHN, and have provided further evidence to suggest a specific deficit in hippocampal-dependent cognition. We propose that abnormal cellular plasticity in these mice may contribute to their schizophrenia-like behavioral endophenotypes.

Increased adult hippocampal neurogenesis and abnormal migration of adult-born granule neurons is associated with hippocampal-specific cognitive deficits in phospholipase C-β1 knockout mice.

The contributions of genetic risk factors to susceptibility for brain disorders are often so closely intertwined with environmental factors that studying genes in isolation cannot provide the full picture of pathogenesis. With recent advances in our understanding of psychiatric genetics and environmental modifiers we are now in a position to develop more accurate animal models of psychiatric disorders which exemplify the complex interaction of genes and environment. Here, we consider some of the insights that have emerged from studying the relationship between defined genetic alterations and environmental factors in rodent models. A key issue in such animal models is the optimization of construct validity, at both genetic and environmental levels. Standard housing of laboratory mice and rats generally includes ad libitum food access and limited opportunity for physical exercise, leading to metabolic dysfunction under control conditions, and thus reducing validity of animal models with respect to clinical populations. A related issue, of specific relevance to neuroscientists, is that most standard-housed rodents have limited opportunity for sensory and cognitive stimulation, which in turn provides reduced incentive for complex motor activity. Decades of research using environmental enrichment has demonstrated beneficial effects on brain and behavior in both wild-type and genetically modified rodent models, relative to standard-housed littermate controls. One interpretation of such studies is that environmentally enriched animals more closely approximate average human levels of cognitive and sensorimotor stimulation, whereas the standard housing currently used in most laboratories models a more sedentary state of reduced mental and physical activity and abnormal stress levels. The use of such standard housing as a single environmental variable may limit the capacity for preclinical models to translate into successful clinical trials. Therefore, there is a need to optimize 'environmental construct validity' in animal models, while maintaining comparability between laboratories, so as to ensure optimal scientific and medical outcomes. Utilizing more sophisticated models to elucidate the relative contributions of genetic and environmental factors will allow for improved construct, face and predictive validity, thus facilitating the identification of novel therapeutic targets.

Gene-environment interactions and construct validity in preclinical models of psychiatric disorders.

There is an enormous demand for new therapeutic interventions for a range of major disorders. The majority of clinical trials in recent years have been unsuccessful despite highly promising preclinical data. Therefore, an urgent issue confronting both the academic and commercial medical research sectors is how to optimize translation of preclinical studies. The vast majority of preclinical studies are currently performed using laboratory mice and rats. We will discuss the various opportunities for optimization of animal models of CNS disorders. One limitation of current approaches is that most studies are conducted on sedentary, unstimulated animals with unlimited access to food in the home cage, thus leading to metabolic and physiological compromise. Environmental enrichment, which enhances sensory stimulation, cognitive activity and physical exercise, has been demonstrated to induce dramatic effects on brain and behavior in both wild-type and genetically modified rodent models, relative to standard-housed littermate controls. Environmental enrichment also exerts beneficial effects outside the CNS, such as a reduction in excess body fat. We propose that therapeutic interventions which are found to show promise in standard-housed preclinical models should be subsequently tested under conditions of greater environmental enrichment to identify therapeutics which continue to show efficacy in housing contexts of superior 'environmental construct validity'. Other possible approaches to optimize the quality, validity and reporting of preclinical studies in animal models are also discussed.

Towards environmental construct validity in animal models of CNS disorders: optimizing translation of preclinical studies.

Fragile X syndrome, the leading inherited cause of mental retardation and autism spectrum disorders worldwide, is caused by a tandem repeat expansion in the FMR1 (fragile X mental retardation 1) gene. It presents with a distinct behavioral phenotype which overlaps significantly with that of autism. Emerging evidence suggests that tandem repeat polymorphisms (TRPs) might also play a key role in modulating disease susceptibility for a range of common polygenic disorders, including the broader autism spectrum of disorders (ASD) and other forms of psychiatric illness such as schizophrenia, depression, and bipolar disorder [1]. In order to understand how TRPs and associated gene mutations mediate pathogenesis, various mouse models have been generated. A crucial step in such functional genomics is high-quality behavioral and cognitive phenotyping. This chapter presents a basic behavioral battery for standardized tests for assaying social phenotypes in mouse models of brain disorders, with a focus on aggression.

Characterizing social behavior in genetically targeted mouse models of brain disorders.

Decanalization mediating gene-environment interactions in schizophrenia and other psychiatric disorders with neurodevelopmental etiology.

Psychiatric disorders affect a substantial proportion of the population worldwide. This high prevalence, combined with the chronicity of the disorders and the major social and economic impacts, creates a significant burden. As a result, an important priority is the development of novel and effective interventional strategies for reducing incidence rates and improving outcomes. This review explores the progress that has been made to date in establishing valid animal models of psychiatric disorders, while beginning to unravel the complex factors that may be contributing to the limitations of current methodological approaches. We propose some approaches for optimizing the validity of animal models and developing effective interventions. We use schizophrenia and autism spectrum disorders as examples of disorders for which development of valid preclinical models, and fully effective therapeutics, have proven particularly challenging. However, the conclusions have relevance to various other psychiatric conditions, including depression, anxiety and bipolar disorders. We address the key aspects of construct, face and predictive validity in animal models, incorporating genetic and environmental factors. Our understanding of psychiatric disorders is accelerating exponentially, revealing extraordinary levels of genetic complexity, heterogeneity and pleiotropy. The environmental factors contributing to individual, and multiple, disorders also exhibit breathtaking complexity, requiring systematic analysis to experimentally explore the environmental mediators and modulators which constitute the 'envirome' of each psychiatric disorder. Ultimately, genetic and environmental factors need to be integrated via animal models incorporating the spatiotemporal complexity of gene-environment interactions and experience-dependent plasticity, thus better recapitulating the dynamic nature of brain development, function and dysfunction.

Identifying novel interventional strategies for psychiatric disorders: integrating genomics, 'enviromics' and gene-environment interactions in valid preclinical models.

Article	Year
PLC-beta1 knockout mice as a model of disrupted cortical development and plasticity: behavioral endophenotypes and dysregulation of RGS4 gene expression. Hippocampus\| PubMed ID: 18493969	2008
Increased adult hippocampal neurogenesis and abnormal migration of adult-born granule neurons is associated with hippocampal-specific cognitive deficits in phospholipase C-β1 knockout mice. Hippocampus\| PubMed ID: 21080410	2012
Gene-environment interactions and construct validity in preclinical models of psychiatric disorders. Progress in neuro-psychopharmacology & biological psychiatry\| PubMed ID: 21168465	2011
Towards environmental construct validity in animal models of CNS disorders: optimizing translation of preclinical studies. CNS & neurological disorders drug targets\| PubMed ID: 23574171	2013
Characterizing social behavior in genetically targeted mouse models of brain disorders. Methods in molecular biology (Clifton, N.J.)\| PubMed ID: 23719910	2013
Decanalization mediating gene-environment interactions in schizophrenia and other psychiatric disorders with neurodevelopmental etiology. Frontiers in behavioral neuroscience\| PubMed ID: 24312026	2013
Identifying novel interventional strategies for psychiatric disorders: integrating genomics, 'enviromics' and gene-environment interactions in valid preclinical models. British journal of pharmacology\| PubMed ID: 24846457	2014

Emma L. Burrows

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