Our current understanding of the mechanisms that allow the nervous system to function as a sensorimotor integrator and incorporate recent experiences into the induction of an appropriate behavioral response is limited. Fundamental insights into these processes are likely to be achieved in multidisciplinary studies that span the levels of circuit analysis, characterization of actions of first messengers, and characterization of integrative properties of second messengers. We propose a series of experiments that will be conducted in a preparation in which this type of integrated approach is possible. We will characterize an arousal state we refer to as build-up that is manifested as progressive increases in the strength and/or articulation of responses as they are repeatedly evoked. Our work seeks to explain both the induction and persistence of this phenomenon. We will test a hypothesis that is strongly supported by previous findings and preliminary data. This hypothesis postulates that as higher order neurons that initiate behavior are repeatedly activated, they release modulatory peptide cotransmitters. These peptides exert second messenger-mediated effects on motor neurons and interneurons that are activated in a behavior specific manner. The excitability and firing frequency of these cells is progressively increased and the ongoing behavior is progressively strengthened. To test our hypotheses, we will perform experiments in the isolated nervous system that will evaluate effects of released peptides. For example, we will characterize biophysical and biochemical mechanisms of actions. Analytical work will utilize identified neurons and will include experiments that assess consequences of peptide release during motor program generation. Additionally, to further probe the behavioral role of the characterized mechanisms, we will perform experiments in semi-intact preparations in which we will block or activate specific second messenger mediated effects and quantify resulting changes in movements. This work is relevant to public health in that impairments in behavior initiation and execution are associated with a number of serious psychiatric disorders, e.g., autism, adult attention deficit pathologies, compulsive obsessive disorders, and depression. Additionally, these types of pathologies are associated with neurological disorders, e.g., Parkinson's disease and a number of other pathologies that results from trauma- or neurodegeneration- induced lesions of the CNS.

Public Health Relevance

The phenomenon we study, network arousal, facilitates the initiation of a behavior and insures that the behavior is executed in a well articulated manner. Impairments in behavior initiation are associated with a number of serious psychiatric disorders, e.g., adult attention deficit pathologies, compulsive obsessive disorders, and depression. Additionally, these types of impairments are associated with neurological disorders, e.g., Parkinson's disease and other conditions involving lesions of the CNS;studies that characterize mechanisms that mediate network arousal are likely to provide insights that will facilitate the development of novel therapeutic approaches for these pathological conditions.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-A (04))
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Gnadt, James W
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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Yang, Chao-Yu; Yu, Ke; Wang, Ye et al. (2016) Aplysia Locomotion: Network and Behavioral Actions of GdFFD, a D-Amino Acid-Containing Neuropeptide. PLoS One 11:e0147335
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Dacks, Andrew M; Weiss, Klaudiusz R (2013) Release of a single neurotransmitter from an identified interneuron coherently affects motor output on multiple time scales. J Neurophysiol 109:2327-34

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