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Current Biology : CB Oct 2020A fundamental question of physiology is how gut-brain signaling stimulates appetite. While many studies have emphasized the importance of vagal afferents to the brain in...
A fundamental question of physiology is how gut-brain signaling stimulates appetite. While many studies have emphasized the importance of vagal afferents to the brain in inducing satiation, little is known about whether and how the vagal-mediated gut-brain pathway senses orexigenic signals and stimulates feeding. Here, we identified a previously uncharacterized population of fasting-activated catecholaminergic neurons in the nucleus of the solitary tract (NTS). After characterizing the anatomical complexity among NTS catecholaminergic neurons, we surprisingly found that activation of NTS epinephrine (E) neurons co-expressing neuropeptide Y (NPY) stimulated feeding, whereas activation of NTS norepinephrine (NE) neurons suppressed feeding. Monosynaptic tracing/activation experiments then showed that these NTS neurons receive direct vagal afferents from nodose neurons. Moreover, activation of the vagal→NPY/E neural circuit stimulated feeding. Our study reveals an orexigenic role of the vagal→NTS pathway in controlling feeding, thereby providing important insights about how gut-brain signaling regulates feeding behavior.
Topics: Animals; Appetite; Eating; Epinephrine; Hunger; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neural Pathways; Neurons, Afferent; Neuropeptide Y; Norepinephrine; Solitary Nucleus; Vagus Nerve
PubMed: 32822608
DOI: 10.1016/j.cub.2020.07.084 -
British Journal of Pharmacology Oct 2020A significant number of cannabinoids are known to have analgesic and anti-inflammatory properties in various diseases. Due to their presynaptic/terminal location,... (Review)
Review
A significant number of cannabinoids are known to have analgesic and anti-inflammatory properties in various diseases. Due to their presynaptic/terminal location, cannabinoid receptors can inhibit synaptic transmission and have the potential to regulate neurogenic inflammation. Neurogenic inflammation occurs when a noxious signal is detected in the periphery initiating an antidromic axon reflex in the same sensory neurone leading to depolarization of the afferent terminal. Neuropeptides are subsequently released and contribute to vasodilation, plasma extravasation and modulation of immune cells. Endocannabinoids, synthetic cannabinoids and phytocannabinoids can reduce neuroinflammation by inhibiting afferent firing and inflammatory neuropeptide release. Thus, in addition to a direct effect on vascular smooth muscle and inflammatory cells, cannabinoids can reduce inflammation by silencing small diameter neurones. This review examines the neuropharmacological processes involved in regulating antidromic depolarization of afferent nerve terminals by cannabinoids and the control of neurogenic inflammation in different diseases.
Topics: Cannabinoids; Endocannabinoids; Humans; Inflammation; Neurogenic Inflammation; Neurons, Afferent; Receptors, Cannabinoid
PubMed: 33289534
DOI: 10.1111/bph.15208 -
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 -
The Journal of Physiology May 2022
Topics: Mechanoreceptors; Muscle Spindles; Proprioception; Vibration
PubMed: 35114007
DOI: 10.1113/JP282865 -
Journal of Immunology (Baltimore, Md. :... Jan 2020The skin is innervated by numerous sensory afferent neurons that respond to a diverse array of stimuli ranging from gentle touch to noxious pain. Various features of the... (Review)
Review
The skin is innervated by numerous sensory afferent neurons that respond to a diverse array of stimuli ranging from gentle touch to noxious pain. Various features of the immune system-pathogen recognition, secretion of soluble mediators-are shared with the nervous system. This has led to the recognition that neurons share some functions with innate immune cells and have the capacity to recognize pathogens and participate in innate immune responses. Neuroimmune interactions are bidirectional. Soluble mediators from immune cells activate neurons and soluble mediators from neurons can activate immune cells. In this review, we will focus on the interplay between neurons and innate immunity in the skin in the context of host defense and inflammation.
Topics: Animals; Humans; Immunity, Innate; Neuroimmunomodulation; Sensory Receptor Cells; Skin
PubMed: 31907268
DOI: 10.4049/jimmunol.1901109 -
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 -
Cells Jul 2021A neuroimmune crosstalk is involved in somatic and visceral pathological pain including inflammatory and neuropathic components. Apart from microglia essential for... (Review)
Review
A neuroimmune crosstalk is involved in somatic and visceral pathological pain including inflammatory and neuropathic components. Apart from microglia essential for spinal and supraspinal pain processing, the interaction of bone marrow-derived infiltrating macrophages and/or tissue-resident macrophages with the primary afferent neurons regulates pain signals in the peripheral tissue. Recent studies have uncovered previously unknown characteristics of tissue-resident macrophages, such as their origins and association with regulation of pain signals. Peripheral nerve macrophages and intestinal resident macrophages, in addition to adult monocyte-derived infiltrating macrophages, secrete a variety of mediators, such as tumor necrosis factor-α, interleukin (IL)-1β, IL-6, high mobility group box 1 and bone morphogenic protein 2 (BMP2), that regulate the excitability of the primary afferents. Neuron-derived mediators including neuropeptides, ATP and macrophage-colony stimulating factor regulate the activity or polarization of diverse macrophages. Thus, macrophages have multitasks in homeostatic conditions and participate in somatic and visceral pathological pain by interacting with neurons.
Topics: Animals; Cell Communication; Cytokines; Ganglia, Spinal; Humans; Inflammation Mediators; Macrophages; Neuroimmunomodulation; Neurons; Neuropeptides; Pain; Pain Threshold; Phenotype; Signal Transduction
PubMed: 34440650
DOI: 10.3390/cells10081881 -
The Journal of Neuroscience : the... May 2023The spinal dorsal horn contains vesicular glutamate transporter-2 (VGluT2)-expressing excitatory neurons and vesicular GABA transporter (VGAT)-expressing inhibitory...
The spinal dorsal horn contains vesicular glutamate transporter-2 (VGluT2)-expressing excitatory neurons and vesicular GABA transporter (VGAT)-expressing inhibitory neurons, which normally have different roles in nociceptive transmission. Spinal glutamate NMDAR hyperactivity is a crucial mechanism of chronic neuropathic pain. However, it is unclear how NMDARs regulate primary afferent input to spinal excitatory and inhibitory neurons in neuropathic pain. Also, the functional significance of presynaptic NMDARs in neuropathic pain has not been defined explicitly. Here we showed that paclitaxel treatment or spared nerve injury (SNI) similarly increased the NMDAR-mediated mEPSC frequency and dorsal root-evoked EPSCs in VGluT2 dorsal horn neurons in male and female mice. By contrast, neither paclitaxel nor SNI had any effect on mEPSCs or evoked EPSCs in VGAT neurons. In mice with conditional (gene encoding GluN1) KO in primary sensory neurons (-cKO), paclitaxel treatment failed to induce pain hypersensitivity. Unexpectedly, SNI still caused long-lasting pain hypersensitivity in -cKO mice. SNI increased the amplitude of puff NMDA currents in VGluT2 neurons and caused similar depolarizing shifts in GABA reversal potentials in WT and -cKO mice. Concordantly, spinal knockdown diminished SNI-induced pain hypersensitivity. Thus, presynaptic NMDARs preferentially amplify primary afferent input to spinal excitatory neurons in neuropathic pain. Although presynaptic NMDARs are required for chemotherapy-induced pain hypersensitivity, postsynaptic NMDARs in spinal excitatory neurons play a dominant role in traumatic nerve injury-induced chronic pain. Our findings reveal the divergent synaptic connectivity and functional significance of spinal presynaptic and postsynaptic NMDARs in regulating cell type-specific nociceptive input in neuropathic pain with different etiologies. Spinal excitatory neurons relay input from nociceptors, whereas inhibitory neurons repress spinal nociceptive transmission. Chronic nerve pain is associated with aberrant NMDAR activity in the spinal dorsal horn. This study demonstrates, for the first time, that chemotherapy and traumatic nerve injury preferentially enhance the NMDAR activity at primary afferent-excitatory neuron synapses but have no effect on primary afferent input to spinal inhibitory neurons. NMDARs in primary sensory neurons are essential for chemotherapy-induced chronic pain, whereas nerve trauma causes pain hypersensitivity predominantly via postsynaptic NMDARs in spinal excitatory neurons. Thus, presynaptic and postsynaptic NMDARs at primary afferent-excitatory neuron synapses are differentially engaged in chemotherapy- and nerve injury-induced chronic pain and could be targeted respectively for treating these painful conditions.
Topics: Rats; Mice; Male; Female; Animals; Receptors, N-Methyl-D-Aspartate; Chronic Pain; Rats, Sprague-Dawley; Synapses; Neuralgia; Paclitaxel; Posterior Horn Cells; Neurons; Antineoplastic Agents
PubMed: 37185237
DOI: 10.1523/JNEUROSCI.0183-23.2023 -
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 -
Frontiers in Immunology 2023The immune system has evolved to protect the host from infectious agents, parasites, and tumor growth, and to ensure the maintenance of homeostasis. Similarly, the... (Review)
Review
The immune system has evolved to protect the host from infectious agents, parasites, and tumor growth, and to ensure the maintenance of homeostasis. Similarly, the primary function of the somatosensory branch of the peripheral nervous system is to collect and interpret sensory information about the environment, allowing the organism to react to or avoid situations that could otherwise have deleterious effects. Consequently, a teleological argument can be made that it is of advantage for the two systems to cooperate and form an "integrated defense system" that benefits from the unique strengths of both subsystems. Indeed, nociceptors, sensory neurons that detect noxious stimuli and elicit the sensation of pain or itch, exhibit potent immunomodulatory capabilities. Depending on the context and the cellular identity of their communication partners, nociceptors can play both pro- or anti-inflammatory roles, promote tissue repair or aggravate inflammatory damage, improve resistance to pathogens or impair their clearance. In light of such variability, it is not surprising that the full extent of interactions between nociceptors and the immune system remains to be established. Nonetheless, the field of peripheral neuroimmunology is advancing at a rapid pace, and general rules that appear to govern the outcomes of such neuroimmune interactions are beginning to emerge. Thus, in this review, we summarize our current understanding of the interaction between nociceptors and, specifically, the myeloid cells of the innate immune system, while pointing out some of the outstanding questions and unresolved controversies in the field. We focus on such interactions within the densely innervated barrier tissues, which can serve as points of entry for infectious agents and, where known, highlight the molecular mechanisms underlying these interactions.
Topics: Humans; Nociceptors; Sensory Receptor Cells; Pain; Peripheral Nervous System; Myeloid Cells
PubMed: 37006298
DOI: 10.3389/fimmu.2023.1127571