Skillen, E. | Search bioRxiv

bioRxiv2026

Non-invasive Vagal Nerve Stimulation as a Potential Treatment for Repetitive Blast Trauma

BackgroundPolytrauma caused by exposure to high explosives (blast) is increasingly common among military personnel and civilians yet treatment for related post-concussive symptoms and chronic behavioral dysfunction is limited. Therapeutic targets following these injuries are typically focused on the central nervous system, with less attention placed on potentially more accessible peripheral targets. Vagus nerve stimulation (VNS) has recently gained traction as a potential therapeutic modality but has yet to be examined in a blast trauma setting. MethodsOur well-established blast overpressure model was utilized to induce repetitive (3x) blast trauma, followed by treatment with non-invasive transcutaneous VNS one hour following each blast exposure in male mice. Acutely following repetitive blast exposure, we measured serum and brain cytokine levels, fecal microbial abundance, and locomotion and anxiety-like behavior in the open field assay. Chronically (1-3 months post blast), mice were assessed for behavioral outcomes related to mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD), including acoustic startle (hyperreactivity), probabilistic discounting (risky decision making), and two-bottle choice test (voluntary alcohol consumption). ResultsVNS treatment following blast exposure decreased acute blast-induced inflammatory response in the blood and brain, especially serum IL-9 and IP-10, and brain MPC-1. Chronic behavior tests demonstrated a VNS-dependent reduction in blast-induced risky decision-making and a decreased intake and preference for ethanol. Conversely, VNS was not effective in preventing acute blast effects on the microbiome or chronic hyperreactivity behaviors measured with acoustic startle. DiscussionThis study identifies the vagus nerve as a novel peripheral target for treating acute and chronic blast-induced dysfunction.

neuroscience↗

bioRxiv2024

Anxiety and risk-taking behavior maps onto opioid and alcohol polysubstance consumption patterns in male and female mice

Polysubstance use is prevalent in the population but remains understudied in preclinical models. Alcohol and opioid polysubstance use is associated with negative outcomes, worse treatment prognosis, and higher overdose risk; but underlying mechanisms are still being uncovered. Examining factors that motivate use of one substance over another in different contexts in preclinical models will better our understanding of polysubstance use and improve translational value. Here we assessed baseline anxiety-like and locomotive behavior and then measured voluntary consumption of multiple doses of alcohol and fentanyl in group housed male and female mice using our novel Socially Integrated Polysubstance (SIP) system. Fifty-six male (n=32) and female (n=24) adult mice were housed in groups of 4 for one week with continuous access to food, water, two doses of ethanol (5% and 10%) and two doses of fentanyl (5 ug/ml and 20 ug/ml). Our analyses revealed sex differences across multiple domains - female mice consumed more liquid in the dark cycle, had higher activity, a higher preference for both ethanol and fentanyl over water, and their fentanyl preference increased over the seven days. Furthermore, both male and female mice displayed polysubstance consumption patterns, with female mice displaying more prolonged polysubstance use across days in the SIP chambers. We then used machine-learning techniques to reveal underlying relationships between baseline behavioral phenotypes and subsequent polysubstance consumption patterns, where anxiety- and risk-taking-like behavioral phenotypes mapped onto discrete patterns of polysubstance use, preference, and escalation. By simulating more translationally relevant substance use and improving our understanding of the motivations for different patterns of consumption, this study contributes to the developing preclinical literature on polysubstance use with the goal of facilitating better treatment outcomes and novel therapeutic strategies.

neuroscience↗