Divergent modulation of nociception by glutamatergic and GABAergic neuronal subpopulations in the periaqueductal gray

The ventrolateral periaqueductal gray (vlPAG) constitutes a major descending pain modulatory system and is a crucial site for opioid-induced analgesia. A number of previous studies have demonstrated that glutamate and GABA play critical opposing roles in nociceptive processing in the vlPAG. It has been suggested that glutamatergic neurotransmission exerts antinociceptive effects, whereas GABAergic neurotransmission exert pronociceptive effects on pain transmission, through descending pathways. The inability to exclusively manipulate subpopulations of neurons in the PAG has prevented direct testing of this hypothesis. Here, we demonstrate the different contributions of genetically defined glutamatergic and GABAergic vlPAG neurons in nociceptive processing by employing cell type-specific chemogenetic approaches in mice. Global chemogenetic manipulation of vlPAG neuronal activity suggests that vlPAG neural circuits exert tonic suppression of nociception, consistent with previous pharmacological and electrophysiological studies. However, selective modulation of GABAergic or glutamatergic neurons demonstrates an inverse regulation of nociceptive behaviors by these cell populations. Selective chemogenetic activation of glutamatergic neurons, or inhibition of GABAergic neurons, in vlPAG suppresses nociception. In contrast, inhibition of glutamatergic neurons, or activation of GABAergic neurons, in vlPAG facilitates nociception. Our findings provide direct experimental support for a model in which excitatory and inhibitory neurons in the PAG bidirectionally modulate nociception

Battery-free, fully implantable optofluidic cuff system for wireless optogenetic and pharmacological neuromodulation of peripheral nerves

Studies of the peripheral nervous system rely on controlled manipulation of neuronal function with pharmacologic and/or optogenetic techniques. Traditional hardware for these purposes can cause notable damage to fragile nerve tissues, create irritation at the biotic/abiotic interface, and alter the natural behaviors of animals. Here, we present a wireless, battery-free device that integrates a microscale inorganic light-emitting diode and an ultralow-power microfluidic system with an electrochemical pumping mechanism in a soft platform that can be mounted onto target peripheral nerves for programmed delivery of light and/or pharmacological agents in freely moving animals. Biocompliant designs lead to minimal effects on overall nerve health and function, even with chronic use in vivo. The small size and light weight construction allow for deployment as fully implantable devices in mice. These features create opportunities for studies of the peripheral nervous system outside of the scope of those possible with existing technologies.NIH Director's Transformative Research [TR01 NS081707]; NIH SPARC Award via the NIBIB of the NIH [U18EB021793, R01 NS42595]; NIMH of the NIH [R41MH116525]; NRSA [F32 DK115122]; McDonnell Center for Cellular and Molecular Neurobiology Postdoctoral Fellowship [T32 DA007261]; Medical Scientist Training Program (MSTP) [T32 GM07200]; University of Missouri-Columbia start-up fund; NINDS NRSA [F31 NS103472]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Miniaturized, Battery‐Free Optofluidic Systems with Potential for Wireless Pharmacology and Optogenetics

Combination of optogenetics and pharmacology represents a unique approach to dissect neural circuitry with high specificity and versatility. However, conventional tools available to perform these experiments, such as optical fibers and metal cannula, are limited due to their tethered operation and lack of biomechanical compatibility. To address these issues, a miniaturized, battery-free, soft optofluidic system that can provide wireless drug delivery and optical stimulation for spatiotemporal control of the targeted neural circuit in freely behaving animals is reported. The device integrates microscale inorganic light-emitting diodes and microfluidic drug delivery systems with a tiny stretchable multichannel radiofrequency antenna, which not only eliminates the need for bulky batteries but also offers fully wireless, independent control of light and fluid delivery. This design enables a miniature (125 mm3), lightweight (220 mg), soft, and flexible platform, thus facilitating seamless implantation and operation in the body without causing disturbance of naturalistic behavior. The proof-of-principle experiments and analytical studies validate the feasibility and reliability of the fully implantable optofluidic systems for use in freely moving animals, demonstrating its potential for wireless in vivo pharmacology and optogenetics. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim1

A potential role for stress-induced microbial alterations in IgA-associated irritable bowel syndrome with diarrhea

Stress is a known trigger for flares of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS); however, this process is not well understood. Here, we find that restraint stress in mice leads to signs of diarrhea, fecal dysbiosis, and a barrier defect via the opening of goblet-cell associated passages. Notably, stress increases host immunity to gut bacteria as assessed by immunoglobulin A (IgA)-bound gut bacteria. Stress-induced microbial changes are necessary and sufficient to elicit these effects. Moreover, similar to mice, many diarrhea-predominant IBS (IBS-D) patients from two cohorts display increased antibacterial immunity as assessed by IgA-bound fecal bacteria. This antibacterial IgA response in IBS-D correlates with somatic symptom severity and was distinct from healthy controls or IBD patients. These findings suggest that stress may play an important role in patients with IgA-associated IBS-D by disrupting the intestinal microbial community that alters gastrointestinal function and host immunity to commensal bacteria

Optogenetic silencing of nociceptive primary afferents reduces evoked and ongoing bladder pain

Abstract Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) suffer from chronic pain that severely affects quality of life. Although the underlying pathophysiology is not well understood, inhibition of bladder sensory afferents temporarily relieves pain. Here, we explored the possibility that optogenetic inhibition of nociceptive sensory afferents could be used to modulate bladder pain. The light-activated inhibitory proton pump Archaerhodopsin (Arch) was expressed under control of the sensory neuron-specific sodium channel (sns) gene to selectively silence these neurons. Optically silencing nociceptive sensory afferents significantly blunted the evoked visceromotor response to bladder distension and led to small but significant changes in bladder function. To study of the role of nociceptive sensory afferents in freely behaving mice, we developed a fully implantable, flexible, wirelessly powered optoelectronic system for the long-term manipulation of bladder afferent expressed opsins. We found that optogenetic inhibition of nociceptive sensory afferents reduced both ongoing pain and evoked cutaneous hypersensitivity in the context of cystitis, but had no effect in uninjured, naïve mice. These results suggest that selective optogenetic silencing of nociceptive bladder afferents may represent a potential future therapeutic strategy for the treatment of bladder pain