Startled flies may provide insight into ADHD

A state of arousal can be defined as in increase in activity or sensitivity and is central to many behaviors in all sorts of organisms. It has not been fully established whether arousal is a generalized state that can be heightened by specific stimuli or is more multidimensional. Further, although many studies have implicated key neurochemicals in arousal, the specific roles of these neuromodulators are unclear. "Previous studies with the fruit fly, Drosophila, have provided evidence that dopamine plays a role in arousal from sleep, known as endogenous arousal. However, evidence for a role for dopamine in exogenously generated arousal, that which is stimulated by a factor in the environment, is less consistent," explains senior study author Dr. David J. Anderson from the California Institute of Technology.

Dr. Anderson and colleagues developed a novel behavioral paradigm for startle-induced arousal in fruit flies and screened for genetic mutations that potentiated this emotion-like behavior. The researchers identified one loss-of-function mutation in a dopamine receptor, DopR, which potentiated the startle response but decreased endogenous arousal. Essentially, the flies slept more but were hypersensitive to being startled. Additional studies supported the finding that these independent and opposite influences of DopR are exerted in different neural circuits. "Taken together, our data suggest that environmentally stimulated arousal and sleep-wake transitions reflect distinct forms of arousal that are genetically, anatomically, and behaviorally separate," says Dr. Anderson.

Intriguingly, the hyper-reactivity to environmental stimuli seen in the flies with the DopR mutation is similar to some of the symptoms seen in humans with ADHD, which has also been linked to dopamine. The genetic basis of emotional behavior is significant because it is believed that abnormalities in such behaviors may underlie psychiatric disorders. Further, it is important to note that Drosophila shares most of its genes in common with humans and also has many of the same brain chemicals that have been implicated in psychiatric disorders, including dopamine.

"If humans, like flies, have distinct brain circuits mediating environmentally stimulated and endogenous arousal, then it is possible that ADHD may specifically involve dopaminergic dysfunction in circuits mediating the former rather than the latter type of arousal," suggests Dr. Anderson. "This view of ADHD as a disorder of arousal circuits suggests that further elucidation of such circuits may deepen our understanding of this disorder and potentially lead to more targeted therapies."

Most of the genes found in the fruit fly—more accurately referred to as the vinegar fly—are found in humans as well, including those neurons that produce brain chemicals like dopamine and serotonin, which have been implicated in psychiatric disorders.

The researchers include Tim Lebestky, California Institute of Technology, Pasadena, CA, Howard Hughes Medical Institute; Jung-Sook C. Chang, California Institute of Technology, Pasadena, CA, Howard Hughes Medical Institute; Heiko Dankert, California Institute of Technology, Pasadena, CA; Lihi Zelnik, California Institute of Technology, Pasadena, CA; Young-Cho Kim, Pennsylvania State University, University Park, PA; Kyung-An Han, Pennsylvania State University, University Park, PA; Fred W. Wolf, University of California, San Francisco, Emeryville, CA; Pietro Perona, California Institute of Technology, Pasadena, CA; and David J. Anderson, California Institute of Technology, Pasadena, CA, Howard Hughes Medical Institute.