Biology subjects

Fulton, S.

Publications and source records attributed to Fulton, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Dietary fructose promotes anxiety through impairment of microglia physiology

Excessive dietary fructose has been linked to metabolic and mood disorders but the underlying brain mechanisms remain unclear. In this study, we tested whether microglia, the brain resident immune cells, mediate fructose-induced anxiety. Adult C57BL/6J mice and mice knock-down for the fructose transporter Glut5 selectively in microglia (Slc2a5flox/flox:Tmem119-Cre-positive mice) were exposed to 25% fructose in drinking water for 8 weeks. We assessed metabolic parameters, anxiety- and depression-like behaviors using a battery of behavioral tests. We then performed RNA sequencing in several brain regions, including the hippocampus to characterize fructose-induced transcriptional changes. Microglial responsiveness to lipopolysaccharide (LPS) treatment was assessed in vitro and in vivo using immunohistochemistry (microglia morphology) and RT-qPCR (cytokine gene expression). Fructose feeding induced marked metabolic alterations and robust anxiety-like behavior in male mice, together with memory deficits, whereas females showed milder metabolic changes and memory impairment without clear emotional disturbances. RNA sequencing revealed that fructose alters microglial gene-expression profiles in the hippocampus. Microglial Glut5 knockdown prevented fructose-induced anxiety-like behavior in the novelty-suppressed feeding test, indicating that microglial fructose uptake is required for this effect. At the molecular level, physiological fructose exposure did not markedly increase microglial cytokine expression but blunted the cytokine response to lipopolysaccharide, consistent with a hypo-reactive microglial state. Overall, these findings identify microglia as a critical mediator of fructose-induced anxiety and suggest that chronic fructose exposure promotes a maladaptive microglial phenotype that disrupts brain circuit function, with potential implications for diet-related mental health risk.

neuroscience↗

bioRxiv2026

Lipid droplet lipolysis in POMC neurons regulates energy homeostasis in a sex-specific manner

The hypothalamus is a central regulator of glucose and energy homeostasis, with arcuate nucleus (ARC) neurons orchestrating these processes. Agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) neurons integrate metabolic cues to control feeding behavior and systemic metabolism. Among these cues, fatty acids (FA) have emerged as key modulators of ARC neuronal activity. While neuronal sensing of circulating FA has begun to be defined, the contribution of FA derived from endogenous lipid stores to ARC neuron function and energy homeostasis remains largely unexplored. We recently identified lipid droplets (LD) as regulated FA reservoirs that control FA availability and metabolism in orexigenic AgRP neurons, thereby modulating their activity and regulating feeding. This prompted us to investigate whether LD-derived FA similarly regulate POMC neuron function. To this end, we targeted adipose triglyceride lipase (ATGL), which catalyzes the first committed step of LD lipolysis, in POMC neurons. We show that LD are present in POMC neurons under basal conditions both in vitro and in vivo, and that pharmacological or genetic inhibition of ATGL increases LD abundance. ATGL deficiency enhances spontaneous firing of POMC neurons and leads to reduced body weight, fat and lean mass in males, but not females. Consistent with enhanced glucose metabolism, ATGL loss lowers glycemia and insulinemia and increases carbohydrate utilization in chow-fed males. In contrast, ATGL deficiency does not alter metabolic adaptations to cold exposure, fasting or diet-induced obesity in either sex. Collectively, these findings establish ATGL-dependent LD lipolysis in POMC neurons as a previously unrecognized, sex-dependent regulator of energy homeostasis.

neuroscience↗

bioRxiv2026

NRP1 regulates basal nociception: characterization of a peptidergic-specific NRP1 knockout mouse

Neuropilin-1 (NRP1) is a single pass transmembrane glycoprotein that can form a receptor complex with several tyrosine kinase receptors, including the vascular endothelial growth factor (VEGF) receptor. Previous studies have reported that binding of VEGFA to this receptor complex elicits mechanical allodynia and thermal hyperalgesia through potentiation of voltage-gated sodium and calcium channel activity. We find that Nrp1 mRNA and protein is widely distributed in naive mouse and rat DRG neurons, including peptidergic afferents. A CGRPcreER: NRP1fl/fl transgenic mice was generated to investigate the role of peptidergic NRP1 in basal nociception. Following in vivo loss of NRP1, while mice are hyposensitive to both noxious heat and mechanical stimuli. Under normal conditions, VEGFA elicits mechanical hypersensitivity, an effect that was absent in our NRP1 knockout mouse. Furthermore, VEGFA induced neuronal hyperexcitability was lost in CGRP expressing neurons isolated from this NRP1 knockout mouse. This study validates the NRP1 knockout mouse and confirms previous findings that VEGFA, often released during pathological pain conditions, requires peptidergic NRP1. Interestingly, we find that in the absence of ongoing injury or inflammation, peptidergic NRP1 regulates basal nociception and pain-like behaviors.

neuroscience↗

bioRxiv2025

Immunometabolic state modulation of sequential decision making in patch-foraging mice

Animals have evolved sophisticated behavioural and metabolic adaptations to respond to threats to homeostasis, including resource scarcity and infectious pathogens. Energy deficits associated with lack of food availability and sickness-associated anorexia elicit distinctive hypometabolic states, however how such states are integrated with higher-order cognition is largely unknown. Patch-foraging paradigms have proven useful for deciphering evolutionarily conserved and ethologically grounded insights into cost-benefit decision-making as animals continually deliberate between exploiting and exploring their environment. We developed and extensively validated a touchscreen-based patch-foraging task for mice in which food reward dynamically varied across trials, in a dataset comprising over 111,000 sequential decisions from 35 adult male mice. Contrary to predictions that emphasize the impact of inflammation to blunt effortful reward-driven behaviour, our results demonstrate that systemic lipopolysaccharides-induced inflammation promotes hyper-exploitation by attenuating exploratory choice behaviour in animals interacting with complex food environments. Such behaviour can be seen as a bias towards immediate outcomes, with impulsivity as a feature affecting the weighting of temporal factors. Given the ubiquity of systemic inflammation in numerous infectious, metabolic and psychiatric disorders featuring dysfunctional value- and cost-sensitive behaviour, these results provide insight into how immunometabolic states are linked to altered decision-making.

neuroscience↗

bioRxiv2024

Probing Nanoscale Electrochemical Phenomena with Nitrogen-Vacancy Centers inDiamond

Nitrogen-vacancy centers in nanodiamonds exhibit photo-stability and biocompatibility that make them promising candidates for versatile biological sensors. In the present work, we study the dependence of NV-nanodiamond fluorescence on the pH of the surrounding ionic aqueous solution. Band-bending effects and modified ion migration rates may be the potential mechanisms underlying the observed pH sensitivity. Our work offers insight into diamond electrochemistry and paves the way toward nanoscale pH imaging. Additionally, the methodologies developed in this work introduce a viable approach for analyzing local electrochemical environments, with potential applications in intra-cellular pH sensing, the design of electrolytic cells, and the development of alternative fuel technologies.

bioengineering↗

bioRxiv2024

Microglial engulfing of glutamatergic inputs and diminished excitability of D1 medium spiny neurons of the nucleus accumbens by peripheral inflammatory insult

Neuroimmune responses to systemic inflammation can generate anxiodepressive behaviors and psychomotor slowing. The nucleus accumbens (NAc) is a neural hub encoding mood and motivation that contributes to the locomotor and mood dampening effects of neuroinflammation. Dopamine receptor 1 mediums spiny neurons (D1-MSNs) of the NAc regulate locomotor activity, motivated behavior and emotional states and are modulated by microglial reactivity. Here, we evaluated sickness- and anxiety-like behaviors along with D1-MSN activity and microglial responses in the NAc to systemic lipopolysaccharide (LPS) administration. LPS stimulated anxiety-like behavior, blunted locomotion and reduced cFos expression in D1-MSNs of the NAc core and shell of male mice. These effects associated with reduced excitatory inputs (EPSCs) onto D1-MSNs as measured by whole cell patch-clamp. To determine if microglia contribute to changes in MSN activity, Ca2+ imaging of primary cultures containing NAc neurons with or without primary NAc microglia was performed. The presence of microglia decreased the activity of LPS-treated MSNs in response to dopamine and glutamate application and LPS stimulated microglial phagocytosis of MSN processes in co-cultures. Immunohistochemical analyses revealed that in vivo LPS treatment enhanced morphological indices of microglia reactivity and engulfment of vesicular glutamate transporter 1 (VGLUT1) inputs in the NAc. Our results suggest that LPS reduces locomotion and stimulates anxiety via increasing microglia engulfment of excitatory inputs onto D1-MSNs, and highlight changes in NAc microglia phagocytic activity in the behavioral consequences of neuroinflammation.

neuroscience↗

bioRxiv2024

Densely Populated Cell and Organelles Segmentation With Multi-Plane Deep Learning Pipeline

The complex and highly intertwined morphology of activated platelets within blood clot thrombi poses significant challenges for segmentation. Here we develop a robust machine vision pipeline for cell and organelle segmentation within volume electron microscope (vEM) datasets and validate that against both model CREMI neuron segmentation challenge data and focused isotropic FIB-SEM imaged platelets and their organelles within a series of ferric chloride indued murine occlusive clots Neural network predictions were collected along multiple planes, capturing 3D correlations using only 2D neural networks. Using a workstation class computer, we segmented and analyzed hundreds of platelets and report quantitative morphological measurements of platelets and their thousands of included organelles. CREMI neuron segmentation challenge analysis produced state-of-the-art outcomes as did platelet data in comparison to manual segmentation. Our work paves the way for large-scale, single cell, 3D studies across multiple examples and lends initial single cell level insights into occlusive thrombus structure and platelet heterogeneity therein. We include a lightweight Jupyter notebook for initializing and running the neural network (Data and Materials Availability). We also provide Amira Avizo protocols for converting neural network outputs to cell and organelle instances and subsequent morphological measurements.

bioengineering↗

bioRxiv2024

Neuronal lipid droplets play a conserved and sex-biased role in maintaining whole-body energy homeostasis

ABSTRACTLipids are essential for neuron development and physiology. Yet, the central hubs that coordinate lipid supply and demand in neurons remain unclear. Here, we combine invertebrate and vertebrate models to establish the presence and functional significance of neuronal lipid droplets (LD) in vivo. We find that LD are normally present in neurons in a non-uniform distribution across the brain, and demonstrate triglyceride metabolism enzymes and lipid droplet-associated proteins control neuronal LD formation through both canonical and recently-discovered pathways. Appropriate LD regulation in neurons has conserved and male-biased effects on whole-body energy homeostasis across flies and mice, specifically neurons that couple environmental cues with energy homeostasis. Mechanistically, LD-derived lipids support neuron function by providing phospholipids to sustain mitochondrial and endoplasmic reticulum homeostasis. Together, our work identifies a conserved role for LD as the organelle that coordinates lipid management in neurons, with implications for our understanding of mechanisms that preserve neuronal lipid homeostasis and function in health and disease. HIGHLIGHTSO_LILipid droplets (LD) normally form in neurons across species Neuronal LD are regulated by a conserved gene network C_LIO_LINeuronal LD regulation plays a conserved and sex-biased role in maintaining energy homeostasis C_LIO_LILD regulation supports ER and mitochondrial function in hunger-activated neurons C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/613929v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1936e92org.highwire.dtl.DTLVardef@40478aorg.highwire.dtl.DTLVardef@18d5faorg.highwire.dtl.DTLVardef@882ee9_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Astrocyte glucocorticoid receptors mediate sex-specific changes in activity following stress

Interactions between orexin neurons and astrocytes in the lateral hypothalamus influence activity levels including circadian and motivated behaviour. These behaviors are disrupted by stress in rodents and form a hallmark of stress-related neuropsychiatric disorders. Here we set out to understand how stress influences activity and the underlying cellular mechanisms. We report that the long-term effects of stress on activity levels correlate with spontaneous firing of orexin neurons with hyperactivity in males and hypoactivity presented by female mice. These neuronal changes were accompanied by extensive astrocyte remodelling. Causal manipulations identified lateral hypothalamic astrocytes as key regulators of activity patterns. In the context of stress, genetic deletion of glucocorticoid receptors in lateral hypothalamic astrocytes rescued the effects of stress on orexin neuron firing, restoring activity to control levels in both males and females. Overall, these data suggest that astrocytic regulation of orexin neuron firing enables the maintenance of activity levels, and their dysfunction drives stress-induced activity dysregulation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=185 HEIGHT=200 SRC="FIGDIR/small/613499v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@1e4b3b9org.highwire.dtl.DTLVardef@1d35774org.highwire.dtl.DTLVardef@12a168org.highwire.dtl.DTLVardef@122d9dc_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Remote automated delivery of mechanical stimuli coupled to brain recordings in behaving mice

The canonical framework for testing pain and mechanical sensitivity in rodents is manual delivery of stimuli to the paw. However, this approach is time consuming, produces variability in results, requires significant training, and is ergonomically unfavorable to the experimenter. To circumvent limitations in manual delivery of stimuli, we have created a device called the ARM (Automated Reproducible Mechano-stimulator). Built using a series of linear stages, cameras, and stimulus holders, the ARM is more accurate at hitting the desired target, delivers stimuli faster, and decreases variability in delivery of von Frey hair filaments. We demonstrate that the ARM can be combined with traditional measurements of pain behavior and automated machine-learning based pipelines. Importantly, the ARM enables remote testing of mice with experimenters outside the testing room. Using remote testing, we found that mice habituated more quickly when an experimenter was not present and experimenter presence leads to significant sex-dependent differences in paw withdrawal and pain associated behaviors. Lastly, to demonstrate the utility of the ARM for neural circuit dissection of pain mechanisms, we combined the ARM with cellular-resolved microendoscopy in the amygdala, linking stimulus, behavior, and brain activity of amygdala neurons that encode negative pain states. Taken together, the ARM improves speed, accuracy, and robustness of mechanical pain assays and can be combined with automated pain detection systems and brain recordings to map central control of pain.

neuroscience↗

bioRxiv2024

Sediment-associated processes drive spatial variation in ecosystem respiration in the Yakima River basin

Hyporheic zones (HZ) can contribute substantially to total stream ecosystem respiration (ERtot). HZ-focused process-based models may, therefore, effectively predict ERtot across sites, yet this remains untested under variable environmental conditions. Here we evaluate whether spatial variation in HZ respiration predicted via a process-based model explains spatial variation in field-estimates of ERtot across 33 sites in the Yakima River basin in Washington State, USA. We found that HZ respiration predictions did not explain spatial variation in field estimates of ERtot. To investigate further, we partitioned ERtot contributions into water column respiration (ERwc) and sediment-associated respiration (ERsed). ERsed contributed >50% of ERtot at 88% of sites, though relative contributions varied substantially. Despite this dominance, modeled HZ respiration explained neither spatial variation in ERtot nor in ERsed, suggesting that the HZ model alone does not capture the drivers of sediment-associated respiration across these sites. Instead, ERsed spatial variation was primarily explained by gross primary production, stream slope, velocity, and total dissolved nitrogen rather than median grain size, a primary control of HZ respiration predicted by the process-based model. Consistent with recent studies, our results indicate that improving basin-scale ERtot predictions requires integrating hydrologic and biogeochemical processes across hyporheic, benthic, and water column zones.

ecology↗

bioRxiv2023

Microglial adipose triglyceride lipase regulates neuroinflammatory and behavioural responses to LPS

Adipose triglyceride lipase (ATGL), the enzyme that catalyses the rate-limiting step of triglyceride lipolysis, regulates inflammation in peripheral tissues. ATGL has been associated with both pro- and anti-inflammatory responses in different tissues suggesting its actions are dependent on cell type. Recent studies in microglia and macrophages suggest that lipid droplets (LD), a triglyceride storing organelle, and LD lipolysis via ATGL are important components of inflammatory responses. Here, we determined the impact of ATGL inhibition and microglia-specific ATGL loss-of-function on inflammatory and behavioural responses to acute pro-inflammatory insult. First, we evaluated the impact of lipolysis inhibition on lipopolysaccharide (LPS)-induced expression and secretion of cytokines in mouse primary microglia cultures. LPS led to LD accumulation in microglia and altered the expression of lipolysis regulators. The pan-lipase inhibitor ORlistat alleviated LPS-induced expression of IL-1{beta} and IL-6. Specific inhibition of ATGL by ATGListatin had similar anti-inflammatory action on cytokines expression and secretion in both neonatal and adult microglia cultures. Second, targeted and untargeted lipidomic studies revealed that ATGL inhibition reduced LPS-induced generation of pro-inflammatory prostanoids and affected ceramide profile. Finally, the role of ATGL in neuroinflammation was assessed in a novel mouse model with inducible ATGL deletion specifically in microglia. Loss of microglial ATGL in adult male mice dampened LPS-induced expression of IL-6 and reduced LPS-induced sickness behaviour. Together, our results demonstrate that pharmacological inhibition or loss of ATGL-mediated triglyceride lipolysis reduces LPS-induced inflammation to suggest that inhibition of lipolysis plays a beneficial role in neuroinflammation.

neuroscience↗

bioRxiv2023

Anesthesia suppressed gastric myoelectric power in the ferret

BackgroundGastrointestinal myoelectric signals have been the focus of extensive research; although it is unclear how general anesthesia affects these signals, studies have often been conducted under general anesthesia. Here, we explore this issue directly by recording gastric myoelectric signals during awake and anesthetized states in the ferret and also explore the contribution of behavioral movement to observed changes in signal power. MethodsFerrets were surgically implanted with electrodes to record gastric myoelectric activity from the serosal surface of the stomach, and, following recovery, were tested in awake and isoflurane-anesthetized conditions. Video recordings were also analyzed during awake experiments to compare myoelectric activity during behavioral movement and rest. Key ResultsA significant decrease in gastric myoelectric signal power was detected under isoflurane anesthesia compared to the awake condition. Moreover, a detailed analysis of the awake recordings indicates that behavioral movement is associated with increased signal power compared to rest. Conclusions & InferencesThese results suggest that both general anesthesia and behavioral movement can affect the amplitude of gastric myoelectric. In summary, caution should be taken in studying myoelectric data collected under anesthesia. Further, behavioral movement could have an important modulatory role on these signals, affecting their interpretation in clinical settings.

neuroscience↗

bioRxiv2022

Role of astroglial ACBP in energy metabolism flexibility and feeding responses to metabolic challenges in male mice

Acyl-CoA Binding Protein (ACBP), also known as Diazepam Binding Inhibitor (DBI), has recently emerged as a hypothalamic and brainstem gliopeptide regulating energy balance. Previous work has shown that the ACBP-derived octadecaneuropeptide exerts strong anorectic action via POMC neuron activation and the melanocortin-4 receptor. Importantly, targeted ACBP loss-of-function in astrocytes promotes hyperphagia and diet-induced obesity while its overexpression in arcuate astrocytes reduces feeding and body weight. Despite this knowledge, the role of astroglial ACBP in adaptive feeding and metabolic responses to acute metabolic challenges has not been investigated. Using different paradigms, we found that ACBP deletion in Glial Fibrillary Acidic Protein (GFAP)-positive astrocytes does not affect diet-induced weight loss in obese male mice nor metabolic parameters in chow-fed mice (e.g. energy expenditure, body temperature) during fasting, cold exposure and at thermoneutrality. In contrast, astroglial ACBP deletion impairs meal pattern and feeding responses during refeeding after a fast and during cold exposure, thereby showing that ACBP is required to mount an appropriate feeding response in states of increased energy demand. These findings challenge the general view that astroglial ACBP exerts anorectic effects and suggest that regulation of feeding by ACBP is dependent on metabolic status.

physiology↗

bioRxiv2022

Towards transboundary networks of climate-smart marine reserves in the Southern California Bight

Climate-smart conservation addresses the vulnerability of biodiversity to climate change impacts but may require transboundary considerations. Here, we adapt and refine 16 biophysical guidelines for climate-smart marine reserves for the transboundary California Bight ecoregion. We link several climate-adaptation strategies (e.g., maintaining connectivity, representing climate refugia, and forecasting effectiveness of protection) by focusing on kelp forests and associated species. We quantify transboundary larval connectivity along [~]800 km of coast and find that the number of connections and the average density of larvae dispersing through the network under future climate scenarios could decrease by [~]50%, highlighting the need to protect critical steppingstone nodes. We also find that although focal species will generally recover with 30% protection, marine heatwaves could hinder subsequent recovery in the following 50 years, suggesting that protecting climate refugia and expanding the coverage of marine reserves is a priority. Together, these findings provide a first comprehensive framework for integrating climate resilience for networks of marine reserves and highlight the need for a coordinated approach in the California Bight ecoregion.

ecology↗

bioRxiv2021

Spontaneous Neural Activity Changes after Bariatric Surgery: a resting-state fMRI study

1.BackgroundMetabolic disorders associated with obesity could lead to alterations in brain structure and function. Whether these changes can be reversed after weight loss is unclear. Bariatric surgery provides a unique opportunity to address these questions because it induces marked weight loss and metabolic improvements which in turn may impact the brain in a longitudinal fashion. Previous studies found widespread changes in grey matter (GM) and white matter (WM) after bariatric surgery. However, findings regarding changes in spontaneous neural activity following surgery, as assessed with the fractional amplitude of low frequency fluctuations (fALFF) and regional homogeneity of neural activity (ReHo), are scarce and heterogenous. In this study, we used a longitudinal design to examine the changes in spontaneous neural activity after bariatric surgery (comparing pre- to post-surgery), and to determine whether these changes are related to cardiometabolic variables. MethodsThe study included 57 participants with severe obesity (mean BMI=43.1{+/-}4.3kg/m2) who underwent sleeve gastrectomy (SG), biliopancreatic diversion with duodenal switch (BPD), or Roux-en-Y gastric bypass (RYGB), scanned prior to bariatric surgery and at follow-up visits of 4 months (N=36), 12 months (N=29), and 24 months (N=14) after surgery. We examined fALFF and ReHo measures across 1022 cortical and subcortical regions (based on combined Schaeffer-Xiao parcellations) using a linear mixed effect model. Voxel-based morphometry (VBM) based on T1-weighted images was also used to measure GM density in the same regions. We also used an independent sample from the Human Connectome Project (HCP) to assess regional differences between individuals who had normal-weight (N=46) or severe obesity (N=46). ResultsWe found a global increase in the fALFF signal with greater increase within dorsolateral prefrontal cortex, precuneus, inferior temporal gyrus, and visual cortex. This effect was more significant 4 months after surgery. The increase within dorsolateral prefrontal cortex, temporal gyrus, and visual cortex was more limited after 12 months and only present in the visual cortex after 24 months. These increases in neural activity measured by fALFF were also significantly associated with the increase in GM density following surgery. Furthermore, the increase in neural activity was significantly related to post-surgery weight loss and improvement in cardiometabolic variables, such as insulin resistance index and blood pressure. In the independent HCP sample, normal-weight participants had higher global and regional fALFF signals, mainly in dorsolateral/medial frontal cortex, precuneus and middle/inferior temporal gyrus compared to the obese participants. These BMI-related differences in fALFF were associated with the increase in fALFF 4 months post-surgery especially in regions involved in control, default mode and dorsal attention networks. ConclusionsBariatric surgery-induced weight loss and improvement in metabolic factors are associated with widespread global and regional increases in neural activity, as measured by fALFF signal. These findings alongside the higher fALFF signal in normal-weight participants compared to participants with severe obesity in an independent dataset suggest an early recovery in the neural activity signal level after the surgery.

neuroscience↗

bioRxiv2021

Selective stimulation of the ferret abdominal vagus nerve with multi-contact nerve cuff electrodes

Dysfunction and diseases of the gastrointestinal (GI) tract are a major driver of medical care. The vagus nerve innervates and controls multiple organs of the GI tract and vagus nerve stimulation (VNS) could provide a means for affecting GI function and treating disease. However, the vagus nerve also innervates many other organs throughout the body, and off-target effects of VNS could cause major side effects such as changes in blood pressure. In this study, we aimed to achieve selective stimulation of populations of vagal afferents using a multi-contact cuff electrode wrapped around the abdominal trunks of the vagus nerve. Four-contact nerve cuff electrodes were implanted around the dorsal (N=3) or ventral (N=3) abdominal vagus nerve in six ferrets, and the response to stimulation was measured via a 32-channel microelectrode array (MEA) inserted into the nodose ganglion. Selectivity was characterized by the ability to evoke responses in MEA channels through one bipolar pair of cuff contacts but not through the other bipolar pair. We demonstrated that is was possible to selectively activate subpopulations of vagal afferents using abdominal VNS. Additionally, we quantified the conduction velocity of evoked responses to determine what types of nerve fibers (i.e. A{delta} vs. C) responded to stimulation. We also quantified the spatial organization of evoked responses in the nodose MEA to determine if there is somatotopic organization of the neurons in that ganglion. Finally, we demonstrated in a separate set of three ferrets that stimulation of the abdominal vagus via a four-contact cuff could selectively alter gastric myoelectric activity, suggesting that abdominal VNS can potentially be used to control GI function.

bioengineering↗

bioRxiv2020

Tuning electrical stimulation of the cervical vagus nerve for abdominal signaling while reducing cardiovascular side effects

Electrical vagus nerve stimulation (VNS) has the potential to treat a wide variety of diseases by modulating afferent and efferent communication to the heart, lungs, esophagus, stomach, and intestines. Although distal vagal nerve branches, close to end organs, could provide a selective therapeutic approach, these locations are often surgically inaccessible. In contrast, the cervical vagus nerve has been targeted for decades using surgically implantable cuff electrodes to treat epileptic seizures and depression; however, to date, clinical implementation of VNS has relied on an electrode with contacts that fully wrap around the nerve, producing non-selective activation of the entire nerve. Here we demonstrate selective cervical VNS using cuff electrodes with multiple contacts around the nerve circumference to target different functional pathways. These flexible probes were adjusted to the diameter of the nerve using an adhesive hydrogel wrap to create a robust electrode interface. Our approach was verified in a rat model by demonstrating that cervical VNS produces neural activity in the abdominal vagus nerve while limiting effects on the cardiovascular system (i.e., changes in heart rate or blood pressure). This study demonstrates the potential for selective cervical VNS as a therapeutic approach for modulating distal nerve branches while reducing off target effects. This methodology could potentially be refined to treat gastrointestinal, metabolic, inflammatory, cardiovascular, and respiratory diseases amenable to vagal neuromodulatory control.

neuroscience↗