Subdiaphragmatic vagal nerve stimulation attenuates the development of hypertension and alters nucleus of the solitary tract transcriptional networks in the spontaneously hypertensive rat.

Augmented vagal signaling may be therapeutic in hypertension. Most studies to date have used stimulation of the cervical vagal branches. Here, we investigated the effects of chronic intermittent electric stimulation of the ventral subdiaphragmatic vagal nerve branch (sdVNS) on long-term blood pressure, immune markers, and gut microbiota in the spontaneously hypertensive rat (SHR), a rodent model of hypertension characterized by vagal dysfunction, gut dysbiosis, and low-grade inflammation. We evaluated the effects of sdVNS on transcriptional networks in the nucleus of the solitary tract (NTS), a major cardioregulatory brain region with direct gut vagal projections. Male juvenile SHRs were implanted with radiotelemetry transmitters and vagal nerve cuffs for chronic intermittent electric sdVNS, applied three times per day for 7 consecutive weeks followed by 1 wk of no stimulation. Blood pressure was measured once a week using telemetry in the sdVNS group as well as age-matched sham-stimulated SHR controls. At the endpoint, colonic and circulating inflammatory markers, corticosterone, and circulating catecholamines were investigated. Bacterial 16 s sequencing measured gut bacterial abundance and composition. RNA sequencing evaluated the effects of sdVNS on transcriptional networks in the NTS. SHRs that received sdVNS exhibited attenuated development of hypertension compared with sham animals. No changes in peripheral inflammatory markers, corticosterone, or catecholamines and no major differences in gut bacterial diversity and composition were observed following sdVNS, apart from decreased abundance of Defluviitaleaceale bacterium detected in sdVNS SHRs compared with sham animals. RNA sequencing revealed significant sdVNS-dependent modulation of select NTS transcriptional networks, including catecholaminergic and corticosteroid networks.NEW & NOTEWORTHY We show that stimulation of the ventral subdiaphragmatic vagal nerve branch may be a promising potential approach to treating hypertension. The data are especially encouraging given that rodents received only 30 min per day of intermittent stimulation therapy and in view of the potential of long-term blood pressure effects that are not stimulus-locked.

Acute vagus nerve stimulation enhances reversal learning in rats.

Cognitive flexibility is a prefrontal cortex-dependent neurocognitive process that enables behavioral adaptation in response to changes in environmental contingencies. Electrical vagus nerve stimulation (VNS) enhances several forms of learning and neuroplasticity, but its effects on cognitive flexibility have not been evaluated. In the current study, a within-subjects design was used to assess the effects of VNS on performance in a novel visual discrimination reversal learning task conducted in touchscreen operant chambers. The task design enabled simultaneous assessment of acute VNS both on reversal learning and on recall of a well-learned discrimination problem. Acute VNS delivered in conjunction with stimuli presentation during reversal learning reliably enhanced learning of new reward contingencies. Enhancement was not observed, however, if VNS was delivered during the session but was not coincident with presentation of to-be-learned stimuli. In addition, whereas VNS delivered at 30 HZ enhanced performance, the same enhancement was not observed using 10 or 50 Hz. Together, these data show that acute VNS facilitates reversal learning and indicate that the timing and frequency of the VNS are critical for these enhancing effects. In separate rats, administration of the norepinephrine reuptake inhibitor atomoxetine also enhanced reversal learning in the same task, consistent with a noradrenergic mechanism through which VNS enhances cognitive flexibility.

Intrastriatal injection of pre-formed mouse α-synuclein fibrils into rats triggers α-synuclein pathology and bilateral nigrostriatal degeneration.

Previous studies demonstrate that intrastriatal injections of fibrillar alpha-synuclein (α-syn) into mice induce Parkinson's disease (PD)-like Lewy body (LB) pathology formed by aggregated α-syn in anatomically interconnected regions and significant nigrostriatal degeneration. The aim of the current study was to evaluate whether exogenous mouse α-syn pre-formed fibrils (PFF) injected into the striatum of rats would result in accumulation of LB-like intracellular inclusions and nigrostriatal degeneration. Sprague-Dawley rats received unilateral intrastriatal injections of either non-fibrillized recombinant α-syn or PFF mouse α-syn in 1- or 2- sites and were euthanized at 30, 60 or 180 days post-injection (pi). Both non-fibrillized recombinant α-syn and PFF α-syn injections resulted in phosphorylated α-syn intraneuronal accumulations (i.e., diffuse Lewy neurite (LN)- and LB-like inclusions) with significantly greater accumulations following PFF injection. LB-like inclusions were observed in several areas that innervate the striatum, most prominently the frontal and insular cortices, the amygdala, and the substantia nigra pars compacta (SNpc). α-Syn accumulations co-localized with ubiquitin, p62, and were thioflavin-S-positive and proteinase-k resistant, suggesting that PFF-induced pathology exhibits properties similar to human LBs. Although α-syn inclusions within the SNpc remained ipsilateral to striatal injection, we observed bilateral reductions in nigral dopamine neurons at the 180-day time-point in both the 1- and 2-site PFF injection paradigms. PFF injected rats exhibited bilateral reductions in striatal dopaminergic innervation at 60 and 180 days and bilateral decreases in homovanillic acid; however, dopamine reduction was observed only in the striatum ipsilateral to PFF injection. Although the level of dopamine asymmetry in PFF injected rats at 180 days was insufficient to elicit motor deficits in amphetamine-induced rotations or forelimb use in the cylinder task, significant disruption of ultrasonic vocalizations was observed. Taken together, our findings demonstrate that α-syn PFF are sufficient to seed the pathological conversion and propagation of endogenous α-syn to induce a progressive, neurodegenerative model of α-synucleinopathy in rats.

The effects of targeted vagus nerve stimulation on glucose homeostasis in STZ-induced diabetic rodents.

During type 1 diabetes, an autoimmune attack destroys pancreatic ß-cells leading to the inability to maintain glucose homeostasis. These ß-cells are neuroresponsive endocrine cells which normally secrete insulin partially in response to input from the vagus nerve. This neural pathway can be utilized as a point of therapeutic intervention by delivering exogenous stimulation to drive increased insulin secretion. In this study, a cuff electrode was implanted on the pancreatic branch of the vagus nerve just prior to pancreatic insertion in rats, and a continuous glucose meter was implanted into the descending aorta. Streptozotocin (STZ) was used to induce a diabetic state, and changes in blood glucose were assessed using various stimulation parameters. Stimulation driven changes in hormone secretion, pancreatic blood flow, and islet cell populations were assessed. We found increased changes in the rate of blood glucose change during stimulation which subsided after stimulation ended paired with increased concentration of circulating insulin. We did not observe increased pancreatic perfusion, which suggests that the modulation of blood glucose was due to the activation of b-cells rather than changes in the extra-organ transport of insulin. Pancreatic neuromodulation showed potentially protective effects by reducing deficits in islet diameter, and ameliorating insulin loss after STZ treatment.

Designing a bioelectronic treatment for Type 1 diabetes: targeted parasympathetic modulation of insulin secretion.

The pancreas is a visceral organ with exocrine functions for digestion and endocrine functions for maintenance of blood glucose homeostasis. In pancreatic diseases such as Type 1 diabetes, islets of the endocrine pancreas become dysfunctional and normal regulation of blood glucose concentration ceases. In healthy individuals, parasympathetic signaling to islets via the vagus nerve, triggers release of insulin from pancreatic ß-cells and glucagon from α-cells. Using electrical stimulation to augment parasympathetic signaling may provide a way to control pancreatic endocrine functions and ultimately control blood glucose. Historical data suggest that cervical vagus nerve stimulation recruits many visceral organ systems. Simultaneous modulation of liver and digestive function along with pancreatic function provides differential signals that work to both raise and lower blood glucose. Targeted pancreatic vagus nerve stimulation may provide a solution to minimizing off-target effects through careful electrode placement just prior to pancreatic insertion.

Targeted Vagus Nerve Stimulation does not Disrupt Cardiac Function in the Diabetic Rat.

In this study, we acutely identified a target branch of the vagus nerve known as the pancreatic branch of the vagus nerve, which exclusively innervates the pancreas by applying electrical stimulus to the known cervical vagus nerve and observing compound neural action potentials at the target nerve. In a set of chronically implanted rats, the target nerve was again cuffed using an electrode and also implanted with a continuous glucose monitor. A model of type 1 diabetes (T1D) was chemically induced and hyperglycemic state confirmed. After induction, stimulation was applied to the pancreatic branch of the vagus nerve and heart rate variability measured to assess the targeted nature of the stimulation. Pancreatic vagus nerve stimulation in a diabetic model was not found to influence heart rate demonstrating the ability of targeted stimulation to be used as for organ-specific neuromodulation while minimizing side effects.

The effect of Mg-Ca-Sr alloy degradation products on human mesenchymal stem cells.

Biodegradable Mg alloys have the potential to replace currently used metallic medical implant devices, likely eliminating toxicity concerns and the need for secondary surgeries, while also providing a potentially stimulating environment for tissue growth. A recently developed Mg-Ca-Sr alloy possesses advantageous characteristics over other Mg alloys, having a good combination of strength and degradation behavior, while also displaying potentially osteogenic properties. To better understand the effect of alloy degradation products on cellular mechanisms, in vitro studies using human bone marrow-derived mesenchymal stem cells were conducted. Ionic products of alloy dissolution were found to be nontoxic but changed the proliferation profile of stem cells. Furthermore, their presence changed the progress of osteogenic development, while concentrations of Mg in particular appeared to induce stem cell differentiation. The work presented herein provides a foundation for future alloy design where structures can be tailored to obtain specific implant performance. These potentially bioactive implants would reduce the risks for patients by shortening their healing time, minimizing discomfort and toxicity concerns, while reducing hospital costs. © 2017 The Authors Journal of Biomedical Materials Research Part B: Applied Biomaterials Published by Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 697-704, 2018.

Development of poly (1,8 octanediol-co-citrate) and poly (acrylic acid) nanofibrous scaffolds for wound healing applications.

Wound care is one of the leading health care problems in the United States costing billions of dollars yearly. Annually, millions of acute wounds occur due to surgical procedures or traumas such as burns and abrasions, and these wounds can become non-healing due to bacterial infection or underlying pathologies. Current wound care treatments include the use of bioinert constructs combined with topical administration of anti-bacterial agents and growth factors. However, there is a growing need for the development of bioactive wound dressing materials that are able to promote wound healing and the regeneration of healthy tissue. In this work, we evaluate and report the use of a novel electrospun polymeric scaffold consisting of poly (1,8 octanediol-co-citrate) and poly (acrylic acid) for wound healing applications. The scaffold exhibits intrinsic antibacterial activity, hydrogel-like water uptake abilities, and the ability to deliver physiologically relevant concentrations of growth factor. Additionally, the scaffold shows antibacterial function when tested with bacteria relevant to wound healing applications. Biological characterization of the electrospun scaffold shows excellent cellular adhesion, low cytotoxicity, and enhanced proliferation of skin fibroblasts. This work has potential towards the development of novel bioactive scaffolds for prevention of bacterial infiltration into the wound bed and enhanced healing.

The Effect of Simulated Microgravity on Differentiation of Porcine Blood-Derived Vascular Stem Cells.

The negative effects of space flight on cardiovascular health of astronauts have been demonstrated and documented over many years. Endothelial cells (ECs) play an important role in regulating weightlessness-induced cardiovascular dysfunction. This project seeks to study the effect of microgravity on the differentiation of endothelial progenitor cells (EPCs) into ECs and the downstream functions of the differentiated cells. Initial exposure of EPCs to microgravity indicated an inhibition of migratory, proliferative, and antithrombogenic capacity of the differentiated ECs. However, our results indicate a potential recovery of proliferative and antithrombogenic functions on prolonged exposure to microgravity.