Annually, more than a million persons experience traumatic brain injury (TBI) in the US and a substantial proportion of this population develop debilitating neurological disorders, such as, paralysis, cognitive deficits and epilepsy. Despite the long-standing knowledge of the risks associated with TBI, no effective biomarkers or interventions exist. Recent evidence suggests a role for inflammatory modulators in TBI-induced neurological impairments. Current technological advances allow for the simultaneous analysis of the precise spatial and temporal expression patterns of numerous proteins in single samples which ultimately can lead to the development of novel treatments. Thus, the present study examined 23 different cytokines, including chemokines, in the ipsi and contralateral cerebral cortex of rats at 24 hours after a Fluid Percussion Injury (FPI). Furthermore, the estimation of cytokines were performed in a newly developed multiplex assay instrument, MAGPIX (Luminex Corp) and compared with an established instrument, Bio-Plex (Bio-Rad), in order to validate the newly developed instrument. The results show numerous inflammatory changes in the ipsi and contralateral side after FPI that were consistently reported by both technologies.

Despite extensive research on astrocytic Ca²⁺ in synaptic transmission, its contribution to the modulation of sensory transmission during different brain states remains largely unknown. Here, by using two-photon microscopy and whole-cell recordings, we show two distinct astrocytic Ca²⁺ signals in the murine barrel cortex: a small, long-lasting Ca²⁺ increase during sleep and a large, widespread but short-lasting Ca²⁺ spike when aroused. The large Ca²⁺ wave in aroused mice was inositol trisphosphate (IP3)-dependent, evoked by the locus coeruleus-norepinephrine system, and enhanced sensory input, contributing to reliable sensory transmission. However, the small Ca²⁺ transient was IP3-independent and contributed to decreased extracellular K⁺, hyperpolarization of the neurons, and suppression of sensory transmission. These events respond to different pharmacological inputs and contribute to distinct sleep and arousal functions by modulating the efficacy of sensory transmission. Together, our data demonstrate an important function for astrocytes in sleep and arousal states via astrocytic Ca²⁺ waves.

Traumatic brain injury (TBI) precedes the onset of epilepsy in up to 15–20% of symptomatic epilepsies and up to 5% of all epilepsy. Treatment of acquired epilepsies, including post-traumatic epilepsy (PTE), presents clinical challenges, including frequent resistance to anti-epileptic therapies. Considering that over 1.6 million Americans present with a TBI each year, PTE is an urgent clinical problem. Neuroinflammation is thought to play a major causative role in many of the post-traumatic syndromes, including PTE. Increasing evidence suggests that neuroinflammation facilitates and potentially contributes to seizure induction and propagation. The inflammatory cytokine, macrophage migration inhibitory factor (MIF), is elevated after TBI and higher levels of MIF correlate with worse post-traumatic outcomes. MIF was recently demonstrated to directly alter the firing dynamics of CA1 pyramidal neurons in the hippocampus, a structure critically involved in many types of seizures. We hypothesized that antagonizing MIF after TBI would be anti-inflammatory, anti-neuroinflammatory and neuroprotective. The results show that administering the MIF antagonist ISO1 at 30 min after TBI prevented astrocytosis but was not neuroprotective in the peri-lesion cortex. The results also show that ISO1 inhibited the TBI-induced increase in γδT cells in the gut, and the percent of B cells infiltrating into the brain. The ISO1 treatment also increased this population of B cells in the spleen. These findings are discussed with an eye towards their therapeutic potential for post-traumatic syndromes, including PTE.

Gulf war illness (GWI), is a chronic multi-symptom illness that has impacted approximately one-third of the veterans who served in the 1990 to 1991 Gulf War. GWI symptoms include cognitive impairments (eg, memory and concentration problems), headaches, migraines, fatigue, gastrointestinal and respiratory issues, as well as emotional deficits. The exposure to neurological chemicals such as the anti-nerve gas drug, pyridostigmine bromide (PB), and the insecticide permethrin (PER), may contribute to the etiologically related factors of GWI. Various studies utilizing mouse models of GWI have reported the interplay of these chemical agents in increasing neuroinflammation and cognitive dysfunction. Astrocytes are involved in the secretion of neuroinflammatory cytokines and chemokines in pathological conditions and have been implicated in GWI symptomology. We hypothesized that exposure to PB and PER causes lasting changes to hippocampal astrocytes, concurrent with chronic cognitive deficits that can be reversed by cervical vagus nerve stimulation (VNS). GWI was induced in CD1 mice by injecting the mixture of PER (200 mg/kg) and PB (2 mg/kg), i.p. for 10 consecutive days. VNS stimulators were implanted at 33 weeks after GWI induction. The results show age-related cognitive alterations at approximately 9 months after exposure to PB and PER. The results also showed an increased number of GFAP-labeled astrocytes in the hippocampus and dentate gyrus that was ameliorated by VNS.

Epilepsy affects over 80 million people worldwide, with approximately 40% experiencing refractory seizures. Despite some progress in deciphering the complex process of epileptogenesis, which transforms a healthy brain into one susceptible to epilepsy, there are still no therapies available to prevent this condition. Traumatic brain injury (TBI) is a leading cause of epilepsy in both military and civilian populations, often leading to the complex condition of posttraumatic epilepsy (PTE). Defined as recurrent seizures following TBI, PTE lacks effective treatment options, highlighting the need for improved experimental models and translational interventions. Unveiling disease-modifying therapeutics for epilepsy is a top priority in the field of neurology research. One major obstacle in PTE research is the lack of robust models that accurately reflect the multifaceted and heterogeneous nature of human PTE. Hence, developing disease-modifying treatments requires innovative models that facilitate the identification of novel therapeutic approaches. Establishing clinically relevant animal models is critical for elucidating the pathophysiological mechanisms of epileptogenesis and identifying effective therapies for PTE management. This article describes the opportunities and challenges associated with advances in PTE experimental models, including the call for common data elements to be developed for PTE. Inspired by insights from a 2023 workshop supported by the American Epilepsy Society, this review explores progress in animal models, experimental protocols, biomarkers, and principles of therapeutic interventions for TBI-induced seizures and posttraumatic epileptogenesis. It evaluates the PTE research landscape and critically discusses current strategies, innovations, hurdles and future directions for establishing models that ultimately lead to the development of disease-modifying agents and targeted therapeutic approaches for PTE prevention. SIGNIFICANCE STATEMENT: Posttraumatic epilepsy (PTE) lacks specific therapies due to limited experimental models. Here, we outline the proceedings of the 2023 American Epilepsy Society-supported National Workshop on PTE, covering small and large animal models for PTE research. This article provides insights into recent advancements in experimental paradigms and analyzes the validity and application of these models in identifying interventions to prevent epileptogenesis following traumatic brain injury. We address challenges and obstacles in discovering PTE therapies, offering clinical data context and common themes.