Response inhibition refers to the ability to suppress ongoing motor actions that are no longer needed or appropriate and is a fundamental feature of executive function supporting flexible and goal-oriented behaviors. Dysfunctional response inhibition is a core deficit in a variety of mental disorders including attention deficit hyperactivity disorder (ADHD), schizophrenia, autism spectrum disorders, obsessive compulsive disorder, post traumatic stress disorder, bipolar disorder and drug addiction. The neural substrates and neuromodulatory systems involved in response inhibition are well characterized in human subjects and rodent models; however, the underlying cellular and molecular mechanisms are largely unknown. To address this, we investigated a simpler model system and found that Drosophila melanogaster manifests response inhibition. This is the first observation made in invertebrates and provides an excellent model to elucidate the neurobiological basis of inhibitory control. The overarching goal of the proposed study is to elucidate the neural, cellular and molecular mechanisms underlying response inhibition in Drosophila. The preliminary data point to dopamine as an important neuromodulator for response inhibition. The flies with enhanced dopamine signaling or with deficient dopamine transporter display abnormal response inhibition. Remarkably, this phenotype is induced by simultaneous exposure to environmental and social stimuli, but not to one factor alone. The proposed research is directed at identifying the dopamine receptor and neural substrate (Aim 1), dopamine neurons (Aim 1), and intracellular signals (Aim 3) crucial for response inhibition. This will provide a baseline to further delineate comprehensive neural, cellular and molecular mechanisms. The proposed study is innovative, has great potential to provide insights into neurobiology and evolution of response inhibition and help fill the knowledge gap in our understanding of dysfunctional inhibitory control associated with diverse mental disorders.
Poor response inhibition is a core psychopathology of complex mental disorders. However, the underlying mechanisms remain largely unknown. The proposed study addresses this key issue in a powerful model system Drosophila. An innovative aspect of the proposed study is that anomalous response inhibition is triggered by simultaneous exposure to environmental and social stimuli, but not by one factor alone, in the flies with altered dopamine neurotransmission. Thus the proposed study directed at elucidating the mechanisms that genetic, environmental and social factors impinge on response inhibition is transformative and has translational potential.
