Neurobiology of Intrinsic Primary Afferent Neurons
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Principal Investigator: David R. Linden Organization: MAYO CLINIC ROCHESTER Fiscal Year: 2024 Award: $538,004 Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases Project Summary / Abstract The gastrointestinal (GI) tract is the only organ system that is capable of intrinsic neural reflexes. These are initiated by a unique neuron type called intrinsic primary afferent neurons (IPANs). IPANs are key to orchestrating neural reflexes that allow efficient processing of meals for nutrient uptake by rapidly adapting to changing luminal content to alter vascular, secretory and motor function. In the guinea pig, IPANs use multiple mechanisms of neuroplasticity to adapt to inflammatory, hormonal and neural stimuli. From these studies it is clear that IPAN neuroplasticity mediates digestive disease. Even though the mouse has become the vertebrate animal model of choice for digestive disease, murine IPANs have lacked consensus markers making precise studies of mouse IPANs inconceivable. These issues are now resolved by our recent transcriptome and morphological analysis of the ENS, which challenges the dogma that IPANs are a single class of neuron, and suggest that rather there are four classes of IPANs. In combination with recent advances in morphological (i.e. tissue clearing) and physiological approaches (i.e. genetically-encoded markers and activity indicators) we are now able to study mouse IPANs in a relatively high throughput manner. The objective of this proposal is to test the overall hypothesis that different classes of IPANs possess morphologies and physiology that uniquely contribute to intestinal function. This hypothesis will be tested in a series of experiments designed to address three specific aims: Specific Aim 1: determine the structure of receptive fields and connectivity of murine IPANs; Specific Aim 2: determine responses of murine IPANs to mechanical and chemical stimuli; Specific Aim 3: determine the role of IPANs in gastrointestinal physiology. Collectively, these studies address a critical gap in our knowledge on the basic neural control of gut functions. Deciphering sensory capabilities and functional responses of molecularly defined IPANs are likely to pave the way for future improvements in diagnostic and therapeutic strategies of digestive disease. Terms: <Address><Afferent Neurons><Alimentary Canal><Animal Model><Animal Models and Related Studies><Auerbach's Plexus><Axon><Blood Vessels><Body System><Body Tissues><CCK><CNS plasticity><Cavia><Cell Body><Cells><Chemical Stimulation><Chemicals><Cholecystokinin><Code><Coding System><Colon><Connector Neuron><Consensus><Data><Diagnostic><Diagnostic Method><Diagnostic Procedure><Diagnostic Technique><Digestive Diseases><Digestive System Diseases><Digestive System Disorders><Digestive Tract><Disease><Disorder><Drug Targeting><Electrophysiology><Electrophysiology (science)><Endowment><Enteral><Enteric><Enteric Nervous System><Environment><Epithelium><Experimental Designs><Future><GI Tract><GI tract disorder><Ganglia><Gastrointestinal Physiology><Gastrointestinal Tract><Gastrointestinal tract structure><Guinea Pigs><Guinea Pigs Mammals><Health><Hormonal><Human><Inflammatory><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Intestinal><Intestines><Ion Channel><Ion Transport><Ionic Channels><Knowledge><Mechanical Stimulation><Mechanics><Mediating><Membrane Channels><Mice><Mice Mammals><Modern Man><Molecular><Morphology><Motor><Motor Cell><Motor Neurons><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Muscle><Muscle Tissue><Myenteric Plexus><Nerve Cells><Nerve Impulse Transmission><Nerve Transmission><Nerve Unit><Nervous System><Neural Cell><Neural Ganglion><Neurobiology><Neurocyte><Neurologic Body System><Neurologic Organ System><Neuronal Plasticity><Neuronal Transmission><Neurons><Neuropeptides><Neurophysiology / Electrophysiology><Nutrient><Organ System><Pancreozymin><Physiologic><Physiological><Physiology><Process><Publishing><Reflex><Reflex action><Reporter><Reporting><Role><Sensory><Sensory Neurons><Series><Stimulus><Stretching><Structure><Submucosa><Testing><Therapeutic><Tissues><Uropancreozymin><Vertebrate Animals><Vertebrates><afferent nerve><alimentary tract><axon signaling><axon-glial signaling><axonal signaling><bowel><central nervous system plasticity><digestive canal><digestive disorder><digestive tract disease><dysmotility><dysmotility syndrome><electrophysiological><experiment><experimental research><experimental study><experiments><gastrointestinal function><gastrointestinal tract disease><gastrointestinal tract disorder><glia signaling><glial signaling><global gene expression><global transcription profile><improved><inflammatory disease of the intestine><inflammatory disorder of the intestine><innervation><innovate><innovation><innovative><intestinal autoinflammation><jejunum><mechanic><mechanical><mechanical stimulus><model of animal><motility disorder><motoneuron><muscular><nerve signaling><nerve supply><neural><neural control><neural initiation><neural plasticity><neural regulation><neural signaling><neurobiological><neuromodulation><neuromodulatory><neuronal><neuronal signaling><neuroplastic><neuroplasticity><neuroregulation><neurotransmission><receptive field><response><scRNA-seq><sensory nerve><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><transcriptome><uptake><vascular><vertebrata>