Forward genetic approach for behavioral neuroscience using animal models

Abstract

Forward genetics is a powerful approach to understand the molecular basis of animal behaviors. Fruit flies were the first animal to which this genetic approach was applied systematically and have provided major discoveries on behaviors including sexual, learning, circadian, and sleep-like behaviors. The development of different classes of model organism such as nematodes, zebrafish, and mice has enabled genetic research to be conducted using more-suitable organisms. The unprecedented success of forward genetic approaches was the identification of the transcription-translation negative feedback loop composed of clock genes as a fundamental and conserved mechanism of circadian rhythm. This approach has now expanded to sleep/wakefulness in mice. A conventional strategy such as dominant and recessive screenings can be modified with advances in DNA sequencing and genome editing technologies.

High-throughput measurement of fibroblast rhythms reveals genetic heritability of circadian phenotypes in diversity outbred mice and their founder strains

“…Genetic diversity is the primary driver for differences in molecular rhythms, which ultimately regulate physiological and behavioral rhythms. Previous studies have shown that genetic variants or mutations in canonical circadian genes lead to marked changes in circadian rhythm phenotypes across many different organisms 3 , 4 , 30 . Single base mutations in Per2 31 or Clock 32 genes altered period of behavioral rhythms in mice 31 .…”

“…Efforts to identify new genes or variants that modulate the amplitude, phase, or period of the clock have heavily relied on mice to leverage their genetic diversity and availability of genetics tools 3 , 4 . While these efforts have been valuable, many of these studies have used common inbred mouse strains or conventional inbred crosses that are constrained by their narrow genetic and phenotypic range.…”

Hunt for mammalian sleep-regulating genes

“…Unfortunately, these deletion in mice causes embryonic lethality and developmental abnormalities, making these mutants unsuitable for studying sleep/wakefulness. Please consult our previous review on this topic for more details [21].…”

Total Wake: Natural, Pathological, and Experimental Limits to Sleep Reduction

“…Another case of surviving without sleep came from fruit fly studies. In Drosophila melanogaster , natural inactivity states are commonly defined as “sleep” ( Funato, 2020 ). Drosophila locomotor inactivity lasting at least 5 min shares behavioral hallmarks of sleep in humans such as specific posture, increased arousal threshold, reversibility, and homeostatic regulation, and when following rest (“sleep”) deprivation, flies showed an increase in consecutive “sleep” ( Hendricks et al, 2000 ; Shaw et al, 2000 ; Funato, 2020 ).…”

“…In Drosophila melanogaster , natural inactivity states are commonly defined as “sleep” ( Funato, 2020 ). Drosophila locomotor inactivity lasting at least 5 min shares behavioral hallmarks of sleep in humans such as specific posture, increased arousal threshold, reversibility, and homeostatic regulation, and when following rest (“sleep”) deprivation, flies showed an increase in consecutive “sleep” ( Hendricks et al, 2000 ; Shaw et al, 2000 ; Funato, 2020 ). Some studies have reported that sleep deprivation in flies could be lethal or decrease lifespan ( Shaw et al, 2002 ; Ly et al, 2018 ; Vaccaro et al, 2020 ).…”