Identifying and Targeting Physiological Assays of Circuit Engagement to Improve Impulsivity

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Project Summary Behavioral inhibition includes our ability to inhibit prepotent, reflexive or perseverative behaviors in the pursuit of longer-term goals. Impairments in behavioral inhibition are associated with greater levels of impulsivity. Impulsivity can be classified into at three major categories. Motor impulsivity is measured using tasks focused on waiting – impulsive subjects cannot wait as long prior to responding. Impulsivity can also be related to choice – for example, choosing a smaller immediate reward instead of a larger delayed reward. Finally, impulsive subjects tend to perseverate (i.e. act without thinking), and thus cannot flexibly shift behaviors as needed when the environment changes. Impulsivity is pan-diagnostic, occurring in attention deficit hyperactivity disorder (ADHD), drug & alcohol addiction, affective disorders and even neurologic disorders like frontotemporal dementia. Various behavioral tasks have been designed to measure the above features of impulsivity. Such models have been used to test the effects of drugs on minimizing impulsivity. Drugs used in these tasks can modulate behavior, but not always in a predictable or even replicable manner across labs, strains or species. This has precluded simple attempts at testing how pharmacologic agents can improve impulsivity. This grant, following RFA specifications, is focused on assessing whether electrophysiological measures of impulsivity can provide a more stable “intermediary” measure of circuit activity relevant to impulsivity that can be used for preclinical pharmacologic testing and development. The goals of this grant are first to identify neurophysiological (LFP-based) markers of subdomains of impulsivity described above, with a particular focus on identifying physiological markers that are translationally relevant and potentially measurable non-invasively in humans. Next, we will assess whether these physiologic measures can be used as an assay for therapeutic development by testing how the identified physiological marker changes in response to varying dosages of drugs known to affect specific subdomains of impulsivity. Finally, using optogenetics targeted at serotonin or dopamine, we will be able to directly test whether modulation of these neurotransmitter systems in a temporally refined way affects physiology and behavior.