CRCNS: Evidence-based modeling of neuromodulatory action on network properties
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Principal Investigator: Yangyang Wang Organization: BRANDEIS UNIVERSITY Fiscal Year: 2024 Award: $357,884 Funding agency: National Institute on Drug Abuse PROJECT SUMMARY (See instructions): Overview: The preBotzinger Complex (preBotC) is the neuronal network that drives inspiratory rhythmogenesis whose activity is orchestrated in response to changes in homeostasis and is critical for maintaining and adapting breathing to the demands of the organism. Respiratory networks are constantly modulated by numerous neuromodulators through altering properties of neurons, synapses and networks. Understanding action of neuromodulation on respiratory networks is critical to understanding control of breathing. While there is extensive experimental effort on studying network effects of neuromodulation, the mechanisms underlying neuromodulatory action on respiratory network properties cannot be easily understood just by experimental work alone. Despite the well-established utility of computational approaches to studying the neural control of breathing, a knowledge gap exists for a computational understanding of the detailed mechanisms underlying how different neuromodulators interact to impact respiratory rhythmogenesis. The overall objective of this proposal is to uncover the mechanism by which the temporal order of neuromodulation with opposing actions (i.e., inhibitory and excitatory) differentially impact respiratory network dynamics. Our preliminary data suggest that such temporal sequencing can induce bifurcations and bistability in network states. We hypothesize that temporal order of opposing neuromodulators yields different changes in intrinsic and synaptic properties of a network which together produce qualitatively different network behaviors when the order is reversed. We will combine electrophysiological experiments and computational modeling across the levels of molecules (glutamates), neurons and networks to test this hypothesis via a focus on respiration, with three Specific Aims: (1) Identify how changes in inhibitory neuromodulation (e.g., opioids) impacts synaptic dynamics and properties in glutamatergic synapse. (2) Dissect the mechanisms by which excitatory neuromodulation (e.g., norepinephrine) regulates respiratory network dynamics through changes in both intrinsic and synaptic properties. (3) Examine the synaptic and intrinsic mechanisms by which temporal order of opposing neuromodulators produces different network states. We will explore and identify relevant bifurcations induced by temporal order of neuromodulators using dynamical systems theory. Terms: <Affect><Autoregulation><Behavior><Behavioral><Biologic Models><Biological Models><Blood gas><Brain><Brain Nervous System><Breathing><CNS Nervous System><Central Nervous System><Cessation of life><Collaborations><Computer Models><Computerized Models><Data><Death><Diffusion><EPSP><Electrophysiology><Electrophysiology (science)><Encephalon><Excitatory Postsynaptic Potentials><Experimental Models><Glutamate Receptor><Glutamates><Homeostasis><Individual><Instruction><Investigators><Knowledge><L-Glutamate><Levarterenol><Levonorepinephrine><Measures><Model System><Modeling><Nature><Nerve Cells><Nerve Unit><Neural Cell><Neuraxis><Neurobiology><Neurocyte><Neuromodulator><Neurons><Neurophysiology / Electrophysiology><Noradrenaline><Norepinephrine><Opiates><Opioid><Organism><Persons><Physiological Homeostasis><Population><Property><Receptor Activation><Receptor Protein><Research Personnel><Researchers><Respiration><Respiratory Aspiration><Respiratory Depression><Respiratory Inspiration><Scientist><Synapses><Synaptic><Systems Theory><Testing><Transmission><United States><Ventilatory Depression><Work><computational modeling><computational models><computational neuroscience><computer based models><computerized modeling><depressed breathing><depression of breathing><diffused><diffuses><diffusing><diffusions><drug action><dynamic system><dynamical system><electrophysiological><evidence base><glutamatergic><inspiration><living system><mortality><mu opioid receptors><neural control><neural regulation><neurobiological><neuromodulation><neuromodulatory><neuronal><neurophysiological><neurophysiology><neuroregulation><opiate crisis><opiate deaths><opiate mortality><opiate use disorder><opioid crisis><opioid deaths><opioid epidemic><opioid mortality><opioid overdose death><opioid related death><opioid use disorder><postsynaptic><preBotzinger complex><presynaptic><receptor><respiratory><respiratory mechanism><response><synapse><transmission process><μ opioid receptors><μ-OR><μOR>