Cognitive inhibition is an integral component of executive control that is critically impaired in neurodegenerative disorders, such as Parkinson's and Alzheimer's disease, and even in normal cognitive aging. One task ubiquitously utilized in humans and primates to study cognitive inhibition is the Stop Signal Time task. The Stop Signal task requires subjects to cancel a planned response following the infrequent occurrence of a stop signal. In this task, it is possible to dissociate the processing underlying cognitive inhibiton and response generation. Preliminary data from my current research reveals that the responses of noncholinergic neurons in the rat basal forebrain provide a neural correlate of cognitive inhibition in a novel rodent Stop Signal task. The BF has historically received intense focus because cholinergic neurons there degenerate in Alzheimer's disease. However, the majority of neurons in the BF are noncholinergic, and most of these are GABAergic that form inhibitory connections with intra-cortical inhibitory interneurons. These neurons have been shown to provide fast, powerful modulation of the entire prefrontal cortex (PFC), which itself undergoes significant age-related changes linked to impaired cognitive inhibition. In order to better understand the neural substrate of cognitive inhibition, Specific Aim 1 of the proposed research will first probe the role of noncholinergic BF neurons in the Stop Signal task. We will test the hypothesis that noncholinergic BF neurons constitute a neural correlate of the SSRT by recording single-unit activity from the BF of awake, behaving animals in the Stop Signal task in addition to microstimulation and optogenetic photostimulation/photoinhibition to assess the causal relationship between the BF and cognitive inhibition.
Specific Aim 2 will test the hypothesis that the BF exerts control over cognitive inhibition via its connections to inhibitory intra-cortical interneurons using multi-site recording of neurons in the BF and PFC and optogenetic photostimulation/photoinhibition of the BF. Finally, in Specific Aim 3 we will examine the fine temporal course of the response of noncholinergic BF neurons in aged animals with and without cognitive inhibition deficits in order to test the hypothesis that changes in the noncholinergic BF neurons underlie age-related failures of cognitive inhibition. The proposed research represents an innovative and important step in the circuit-level exploration of age-related cognitive inhibition deficits, linking one of the most prevalent and powerful cognitive inhibition paradigms with the efficiency, power, and flexibility of rodent models. Further, the proposed research will expand our knowledge of how noncholinergic BF neurons are able to rapidly modulate cortical information processing. Finally, this research will form the basis of my dissertation, provide me with cutting-edge technical training, and allow me to develop a sophisticated skill set that will foster a career in scientific research.

Public Health Relevance

The proposed research investigates the neural basis of response inhibition, a cognitive faculty critically necessary for flexible decision making and functioning in a dynamic environment. Response inhibition, or the ability to withhold inappropriate responses, is critically impaired in many clinical conditions, including schizophrenia, drug and alcohol abuse, gambling, attention-deficit hyperactivity disorder, obsessive-compulsive disorder, Parkinson's dementia, Alzheimer's dementia, and even in normal cognitive aging. By expanding our understanding of the neural basis of response inhibition, the proposed research creates a stable foundation on which to explore possible treatment and intervention options. Further, the proposed research begins to directly address the neural basis of age-related response inhibition impairment, a key public health issue as lifespan increases and the world population ages.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Wagster, Molly V
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Johns Hopkins University
Schools of Arts and Sciences
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Mayse, Jeffrey D; Nelson, Geoffrey M; Avila, Irene et al. (2015) Basal forebrain neuronal inhibition enables rapid behavioral stopping. Nat Neurosci 18:1501-8
Mayse, Jeffrey D; Nelson, Geoffrey M; Park, Pul et al. (2014) Proactive and reactive inhibitory control in rats. Front Neurosci 8:104