Purinergic signaling mediates neuroglial interactions to generate sighs

Sighs prevent the collapse of alveoli in the lungs, initiate arousal under hypoxic conditions, and even express sadness and relief. Sighs are periodically superimposed on normal breaths, known as eupnea. Implicated in the generation of these rhythmic behaviors is the preBötzinger complex (preBötC)1. Yet how this small microcircuit can produce two rhythms with strikingly different periodicities remains unresolved. Our computational simulations predict that sighs are generated by the coincidence of two temporally distinct calcium oscillations and are in agreement with experimental evidence suggesting that astrocytes drive sigh behavior through slower, extrinsically driven calcium oscillations that link the eupnea and sigh rhythms. We found that purinergic signaling is necessary to generate spontaneous and hypoxia- induced sighs, and photo-activation of preBötC astrocytes is sufficient to elicit sigh activity. We conclude that sighs are an emergent property of the preBötC network generated by neuroglial interactions, where the distinct modulatory responses of neurons and glia allow for both rhythms to be independently regulated.

Glial Connexins and Pannexins in the Healthy and Diseased Brain

Over the past several decades a large amount of data have established that glial cells, the main cell population in the brain, dynamically interact with neurons and thus impact their activity and survival. One typical feature of glia is their marked expression of several connexins, the membrane proteins forming intercellular gap junction channels and hemichannels. Pannexins, which have a tetraspan membrane topology as connexins, are also detected in glial cells. Here, we review the evidence that connexin and pannexin channels are actively involved in dynamic and metabolic neuroglial interactions in physiological as well as in pathological situations. These features of neuroglial interactions open the way to identify novel non-neuronal aspects that allow for a better understanding of behavior and information processing performed by neurons. This will also complement the “neurocentric” view by facilitating the development of glia-targeted therapeutic strategies in brain disease.

Modulation of neuroglial interactions using differential target multiplexed spinal cord stimulation in an animal model of neuropathic pain

The development and maintenance of chronic neuropathic pain involves distorted neuroglial interactions, which result in prolonged perturbations of immune and inflammatory response, as well as disrupted synapses and cellular interactions. Spinal cord stimulation (SCS) has proven effective and safe for more than 40 years, but comprehensive understanding of its mode of action remains elusive. Previous work in our laboratory provided evidence that conventional SCS parameters modulate biological processes associated with neuropathic pain in animals. This inspired the development of differential target multiplexed programming (DTMP) in which multiple electrical signals are used for modulating glial cells and neurons in order to rebalance their interactions. This work compares DTMP with both low rate and high rate programming using an animal model of neuropathic pain. The spared nerve injury model was implemented in 48 rats equally randomized into four experimental groups: No-SCS, DTMP, low rate, and high rate. Naive animals (N = 7) served as a reference control. SCS was applied continuously for 48 h and pain-related behavior assessed before and after SCS. RNA from the spinal cord exposed to SCS was sequenced to determine changes in gene expression as a result of injury (No-SCS vs. naïve) and as a result of SCS (SCS vs. No-SCS). Bioinformatics tools (Weighted Gene Co-expression Network Analysis and Gene Ontology Enrichment Analysis) were used to evaluate the significance of the results. All three therapies significantly reduced mechanical hypersensitivity, although DTMP provided statistically better results overall. DTMP also reduced thermal hypersensitivity significantly. RNA-sequencing corroborated the complex effects of nerve injury on the transcriptome. In addition, DTMP provided significantly more effective modulation of genes associated with pain-related processes in returning their expression toward levels observed in naïve, noninjured animals. DTMP provides a more effective way of modulating the expression of genes involved in pain-relevant biological processes associated with neuroglial interactions.