-
Cell Nov 2022After ingestion of toxin-contaminated food, the brain initiates a series of defensive responses (e.g., nausea, retching, and vomiting). How the brain detects ingested...
After ingestion of toxin-contaminated food, the brain initiates a series of defensive responses (e.g., nausea, retching, and vomiting). How the brain detects ingested toxin and coordinates diverse defensive responses remains poorly understood. Here, we developed a mouse-based paradigm to study defensive responses induced by bacterial toxins. Using this paradigm, we identified a set of molecularly defined gut-to-brain and brain circuits that jointly mediate toxin-induced defensive responses. The gut-to-brain circuit consists of a subset of Htr3a+ vagal sensory neurons that transmit toxin-related signals from intestinal enterochromaffin cells to Tac1+ neurons in the dorsal vagal complex (DVC). Tac1+ DVC neurons drive retching-like behavior and conditioned flavor avoidance via divergent projections to the rostral ventral respiratory group and lateral parabrachial nucleus, respectively. Manipulating these circuits also interferes with defensive responses induced by the chemotherapeutic drug doxorubicin. These results suggest that food poisoning and chemotherapy recruit similar circuit modules to initiate defensive responses.
Topics: Animals; Mice; Neurons; Neurons, Afferent; Parabrachial Nucleus; Vagus Nerve; Brain-Gut Axis
PubMed: 36323317
DOI: 10.1016/j.cell.2022.10.001 -
Neuron Sep 2015Recent advances have clarified how the brain detects CO2 to regulate breathing (central respiratory chemoreception). These mechanisms are reviewed and their significance... (Review)
Review
Recent advances have clarified how the brain detects CO2 to regulate breathing (central respiratory chemoreception). These mechanisms are reviewed and their significance is presented in the general context of CO2/pH homeostasis through breathing. At rest, respiratory chemoreflexes initiated at peripheral and central sites mediate rapid stabilization of arterial PCO2 and pH. Specific brainstem neurons (e.g., retrotrapezoid nucleus, RTN; serotonergic) are activated by PCO2 and stimulate breathing. RTN neurons detect CO2 via intrinsic proton receptors (TASK-2, GPR4), synaptic input from peripheral chemoreceptors and signals from astrocytes. Respiratory chemoreflexes are arousal state dependent whereas chemoreceptor stimulation produces arousal. When abnormal, these interactions lead to sleep-disordered breathing. During exercise, central command and reflexes from exercising muscles produce the breathing stimulation required to maintain arterial PCO2 and pH despite elevated metabolic activity. The neural circuits underlying central command and muscle afferent control of breathing remain elusive and represent a fertile area for future investigation.
Topics: Animals; Carbon Dioxide; Chemoreceptor Cells; Homeostasis; Humans; Respiration; Respiratory Center
PubMed: 26335642
DOI: 10.1016/j.neuron.2015.08.001 -
Neuron Jul 2023Vagal sensory neurons monitor mechanical and chemical stimuli in the gastrointestinal tract. Major efforts are underway to assign physiological functions to the many...
Vagal sensory neurons monitor mechanical and chemical stimuli in the gastrointestinal tract. Major efforts are underway to assign physiological functions to the many distinct subtypes of vagal sensory neurons. Here, we use genetically guided anatomical tracing, optogenetics, and electrophysiology to identify and characterize vagal sensory neuron subtypes expressing Prox2 and Runx3 in mice. We show that three of these neuronal subtypes innervate the esophagus and stomach in regionalized patterns, where they form intraganglionic laminar endings. Electrophysiological analysis revealed that they are low-threshold mechanoreceptors but possess different adaptation properties. Lastly, genetic ablation of Prox2 and Runx3 neurons demonstrated their essential roles for esophageal peristalsis in freely behaving mice. Our work defines the identity and function of the vagal neurons that provide mechanosensory feedback from the esophagus to the brain and could lead to better understanding and treatment of esophageal motility disorders.
Topics: Animals; Mice; Core Binding Factor Alpha 3 Subunit; Esophagus; Gastrointestinal Motility; Homeodomain Proteins; Mechanoreceptors; Neurons, Afferent; Sensory Receptor Cells; Stomach; Vagus Nerve
PubMed: 37192624
DOI: 10.1016/j.neuron.2023.04.025 -
Neuron Aug 2019Dorsal root ganglion (DRG) sensory neuron subtypes defined by their in vivo properties display distinct intrinsic electrical properties. We used bulk RNA sequencing of...
Dorsal root ganglion (DRG) sensory neuron subtypes defined by their in vivo properties display distinct intrinsic electrical properties. We used bulk RNA sequencing of genetically labeled neurons and electrophysiological analyses to define ion channel contributions to the intrinsic electrical properties of DRG neuron subtypes. The transcriptome profiles of eight DRG neuron subtypes revealed differentially expressed and functionally relevant genes, including voltage-gated ion channels. Guided by these data, electrophysiological analyses using pharmacological and genetic manipulations as well as computational modeling of DRG neuron subtypes were undertaken to assess the functions of select voltage-gated potassium channels (Kv1, Kv2, Kv3, and Kv4) in shaping action potential (AP) waveforms and firing patterns. Our findings show that the transcriptome profiles have predictive value for defining ion channel contributions to sensory neuron subtype-specific intrinsic physiological properties. The distinct ensembles of voltage-gated ion channels predicted to underlie the unique intrinsic physiological properties of eight DRG neuron subtypes are presented.
Topics: Action Potentials; Afferent Pathways; Animals; Computer Simulation; Ganglia, Spinal; Gene Expression Profiling; Gene Expression Regulation; High-Throughput Nucleotide Sequencing; Ion Channels; Mechanoreceptors; Mice; Mice, Transgenic; Models, Neurological; Nerve Tissue Proteins; Patch-Clamp Techniques; Potassium Channels, Voltage-Gated; RNA; Sensory Receptor Cells; Transcriptome
PubMed: 31248728
DOI: 10.1016/j.neuron.2019.05.039 -
Cold Spring Harbor Perspectives in... May 2019Cholinergic efferent neurons originating in the brainstem innervate the acoustico-lateralis organs (inner ear, lateral line) of vertebrates. These release acetylcholine... (Review)
Review
Cholinergic efferent neurons originating in the brainstem innervate the acoustico-lateralis organs (inner ear, lateral line) of vertebrates. These release acetylcholine (ACh) to inhibit hair cells through activation of calcium-dependent potassium channels. In the mammalian cochlea, ACh shunts and suppresses outer hair cell (OHC) electromotility, reducing the essential amplification of basilar membrane motion. Consequently, medial olivocochlear neurons that inhibit OHCs reduce the sensitivity and frequency selectivity of afferent neurons driven by cochlear vibration of inner hair cells (IHCs). The cholinergic synapse on hair cells involves an unusual ionotropic ACh receptor, and a near-membrane postsynaptic cistern. Lateral olivocochlear (LOC) neurons modulate type I afferents by still-to-be-defined synaptic mechanisms. Olivocochlear neurons can be activated by a reflex arc that includes the auditory nerve and projections from the cochlear nucleus. They are also subject to modulation by higher-order central auditory interneurons. Through its actions on cochlear hair cells, afferent neurons, and higher centers, the olivocochlear system protects against age-related and noise-induced hearing loss, improves signal coding in noise under certain conditions, modulates selective attention to sensory stimuli, and influences sound localization.
Topics: Animals; Cochlea; Efferent Pathways; Hair Cells, Auditory, Inner; Hair Cells, Auditory, Outer; Humans; Ion Channels; Mice; Mice, Knockout; Neurotransmitter Agents; Synapses; Synaptic Transmission
PubMed: 30082454
DOI: 10.1101/cshperspect.a033530 -
Trends in Neurosciences Mar 2023Chronic pain caused by injury or disease of the nervous system (neuropathic pain) has been linked to persistent electrical hyperactivity of the sensory neurons... (Review)
Review
Chronic pain caused by injury or disease of the nervous system (neuropathic pain) has been linked to persistent electrical hyperactivity of the sensory neurons (nociceptors) specialized to detect damaging stimuli and/or inflammation. This pain and hyperactivity are considered maladaptive because both can persist long after injured tissues have healed and inflammation has resolved. While the assumption of maladaptiveness is appropriate in many diseases, accumulating evidence from diverse species, including humans, challenges the assumption that neuropathic pain and persistent nociceptor hyperactivity are always maladaptive. We review studies indicating that persistent nociceptor hyperactivity has undergone evolutionary selection in widespread, albeit selected, animal groups as a physiological response that can increase survival long after bodily injury, using both highly conserved and divergent underlying mechanisms.
Topics: Humans; Animals; Nociceptors; Sensory Receptor Cells; Neuralgia; Adaptation, Physiological
PubMed: 36610893
DOI: 10.1016/j.tins.2022.12.007 -
Neuroscience Letters Apr 2021Neural changes underly hyperresponsiveness in asthma and other airway diseases. Afferent sensory nerves, nerves within the brainstem, and efferent parasympathetic nerves... (Review)
Review
Neural changes underly hyperresponsiveness in asthma and other airway diseases. Afferent sensory nerves, nerves within the brainstem, and efferent parasympathetic nerves all contribute to airway hyperresponsiveness. Inflammation plays a critical role in these nerve changes. Chronic inflammation and pre-natal exposures lead to increased airway innervation and structural changes. Acute inflammation leads to shifts in neurotransmitter expression of afferent nerves and dysfunction of M muscarinic receptors on efferent nerve endings. Eosinophils and macrophages drive these changes through release of inflammatory mediators. Novel tools, including optogenetics, two photon microscopy, and optical clearing and whole mount microscopy, allow for improved studies of the structure and function of airway nerves and airway hyperresponsiveness.
Topics: Animals; Asthma; Humans; Neurons, Afferent; Optogenetics; Parasympathetic Nervous System; Receptors, Muscarinic; Signal Transduction
PubMed: 33667601
DOI: 10.1016/j.neulet.2021.135795 -
Annual Review of Vision Science Sep 2018The thalamocortical pathway is the main route of communication between the eye and the cerebral cortex. During embryonic development, thalamocortical afferents travel to... (Review)
Review
The thalamocortical pathway is the main route of communication between the eye and the cerebral cortex. During embryonic development, thalamocortical afferents travel to L4 and are sorted by receptive field position, eye of origin, and contrast polarity (i.e., preference for light or dark stimuli). In primates and carnivores, this sorting involves numerous afferents, most of which sample a limited region of the binocular field. Devoting abundant thalamocortical resources to process a limited visual field has a clear advantage: It allows many stimulus combinations to be sampled at each spatial location. Moreover, the sampling efficiency can be further enhanced by organizing the afferents in a cortical grid for eye input and contrast polarity. We argue that thalamocortical interactions within this eye-polarity grid can be used to represent multiple stimulus combinations found in nature and to build an accurate cortical map for multidimensional stimulus space.
Topics: Brain Mapping; Eye; Humans; Neural Pathways; Neurons, Afferent; Retinal Neurons; Thalamus; Visual Cortex; Visual Fields; Visual Pathways; Visual Perception
PubMed: 29856937
DOI: 10.1146/annurev-vision-091517-034122 -
Cold Spring Harbor Perspectives in... Dec 2019To provide a meaningful representation of the auditory landscape, mammalian cochlear hair cells are optimized to detect sounds over an incredibly broad range of... (Review)
Review
To provide a meaningful representation of the auditory landscape, mammalian cochlear hair cells are optimized to detect sounds over an incredibly broad range of frequencies and intensities with unparalleled accuracy. This ability is largely conferred by specialized ribbon synapses that continuously transmit acoustic information with high fidelity and sub-millisecond precision to the afferent dendrites of the spiral ganglion neurons. To achieve this extraordinary task, ribbon synapses employ a unique combination of molecules and mechanisms that are tailored to sounds of different frequencies. Here we review the current understanding of how the hair cell's presynaptic machinery and its postsynaptic afferent connections are formed, how they mature, and how their function is adapted for an accurate perception of sound.
Topics: Animals; Calcium Channels, L-Type; Hair Cells, Auditory; Humans; Membrane Potentials; Neurons, Afferent; Receptors, Glutamate; Synapses
PubMed: 30617058
DOI: 10.1101/cshperspect.a033175 -
Journal of Neurophysiology Dec 2017Large-diameter myelinated phrenic afferents discharge in phase with diaphragm contraction, and smaller diameter fibers discharge across the respiratory cycle. In this... (Review)
Review
Large-diameter myelinated phrenic afferents discharge in phase with diaphragm contraction, and smaller diameter fibers discharge across the respiratory cycle. In this article, we review the phrenic afferent literature and highlight areas in need of further study. We conclude that ) activation of both myelinated and nonmyelinated phrenic sensory afferents can influence respiratory motor output on a breath-by-breath basis; ) the relative impact of phrenic afferents substantially increases with diaphragm work and fatigue; ) activation of phrenic afferents has a powerful impact on sympathetic motor outflow, and ) phrenic afferents contribute to diaphragm somatosensation and the conscious perception of breathing. Much remains to be learned regarding the spinal and supraspinal distribution and synaptic contacts of myelinated and nonmyelinated phrenic afferents. Similarly, very little is known regarding the potential role of phrenic afferent neurons in triggering or modulating expression of respiratory neuroplasticity.
Topics: Animals; Diaphragm; Humans; Neuronal Plasticity; Neurons, Afferent; Nociception; Phrenic Nerve; Respiration
PubMed: 28835527
DOI: 10.1152/jn.00484.2017