Controlled and localized genetic manipulation in the brain

Abstract

Establishing the contributions of inherited genes relative to experience in brain function forms a central theme of neuroscience. There is little doubt that both activity-dependent neuronal plasticity and genetically determined programs generate important influences on the developing and the adult nervous system. The ability to change behaviour in response to new environmental hazards and AbstractBrain structure and function are determined in part through experience and in part through our inherited genes. A powerful approach for unravelling the balance between activity-dependent neuronal plasticity and genetic programs is to directly manipulate the genome. Such molecular genetic studies have been greatly aided by the remarkable progress of large-scale genome sequencing efforts. Sophisticated mouse genetic manipulations allow targeted point-mutations, deletions and additions to the mouse genome. These can be regulated through inducible promoters expressing in genetically specified neuronal cell types. However, despite significant progress it remains difficult to target specific brain regions through transgenesis alone. Recent work suggests that transduction vectors, like lentiviruses and adeno-associated viruses, may provide suitable additional tools for localized and controlled genetic manipulation. Furthermore, studies with such vectors may aid the development of human genetic therapies for brain diseases.

Development of the retinal vasculature

“…This is because genetic mutations affecting the vasculature are often embryonically lethal and mutant mice never reach adulthood. Techniques that allow the targeting of specific genes in adult retina such as RNAi [123] or inducible transgenic systems [124] have therefore great potential in this field. Such approaches could be used to investigate the mechanisms that control vessel maturation and drive vessels into quiescence in the retina.…”

Long‐range connectivity of mouse primary somatosensory barrel cortex

“…, 2005; Zhang et al. , 2007) combined with new viral tools and the increasing number of cell‐type‐specific genetically engineered mice (Aronoff & Petersen, 2006; Gong et al. , 2007; Livet et al.…”

“…In addition, the specific functional roles that different brain areas contribute to whiskerdependent behaviors can now be examined with unprecedented precision. The recent development of optogenetic tools (Nagel et al, 2003;Boyden et al, 2005;Zhang et al, 2007) combined with new viral tools and the increasing number of cell-type-specific genetically engineered mice (Aronoff & Petersen, 2006;Gong et al, 2007;Livet et al, 2007;Wickersham et al, 2007a&,b;Luo et al, 2008;Cardin et al, 2009;O'Connor et al, 2009;Sohal et al, 2009) is likely to help significant progress be made over the coming decades into the causal analysis of which neurons in the brain serve which functions during whisker behaviors.…”

Genetically Modified Mouse Models

“…In recent years, the Cre/loxP system has been significantly improved and variations have been introduced, making this technology even more flexible in terms of developmental time and tissue-dependent expression (the reader is referred to review articles such as Aronoff & Petersen (2006)). The Cre/loxP system.…”