In vivo biomarkers of GABAergic function in epileptic rats treated with the GAT-1 inhibitor E2730.

OBJECTIVE: E2730, an uncompetitive γ-aminobutyric acid (GABA) transporter-1 (GAT-1) inhibitor, has potent anti-seizure effects in a rodent model of chronic temporal lobe epilepsy, the kainic acid status epilepticus (KASE) rat model. In this study, we examined purported neuroimaging and physiological surrogate biomarkers of the effect of E2730 on brain GABAergic function. METHODS: We conducted a randomized cross-over study, incorporating 1-week treatments with E2730 (100 mg/kg/day subcutaneous infusion) or vehicle in epileptic post-KASE rats. KASE rats underwent serial 9.4 T magnetic resonance spectroscopy (MRS) measuring GABA and other brain metabolites, [18F]Flumazenil positron emission tomography (PET) quantifying GABAA receptor availability, quantitative electroencephalography (qEEG) and transcranial magnetic stimulation (TMS)-mediated motor activity, as well as continuous video-EEG recording to measure spontaneous seizures during each treatment. Age-matched, healthy control animals treated with E2730 or vehicle were also studied. RESULTS: E2730 treatment significantly reduced spontaneous seizures, with 8 of 11 animals becoming seizure-free. MRS revealed that E2730-treated animals had significantly reduced taurine levels. [18F]Flumazenil PET imaging revealed no changes in GABA receptor affinity or density during E2730 treatment. The power of gamma frequency oscillations in the EEG was decreased significantly in the auditory cortex and hippocampus of KASE and control rats during E2730 treatment. Auditory evoked gamma frequency power was enhanced by E2730 treatment in the auditory cortex of KASE and healthy controls, but only in the hippocampus of KASE rats. E2730 did not influence motor evoked potentials triggered by TMS. SIGNIFICANCE: This study identified clinically relevant changes in multimodality imaging and functional purported biomarkers of GABAergic activity during E2730 treatment in epileptic and healthy control animals. These biomarkers could be utilized in clinical trials of E2730 and potentially other GABAergic drugs to provide surrogate endpoints, thereby reducing the cost of such trials.

The effect of traumatic brain injury on learning and memory: A synaptic focus.

Deficits in learning and memory are some of the most commonly reported symptoms following a traumatic brain injury (TBI). We will examine whether the neural basis of these deficits stems from alterations to bidirectional synaptic plasticity within the hippocampus. Although the CA1 subregion of the hippocampus has been a focus of TBI research, the dentate gyrus should also be given attention as it exhibits a unique ability for adult neurogenesis, a process highly susceptible to TBI-induced damage. This review examines our current understanding of how TBI results in deficits in synaptic plasticity, as well as how TBI-induced changes in endocannabinoid (eCB) systems may drive these changes. Through the synthesis and amalgamation of existing data, we propose a possible mechanism for eCB-mediated recovery in synaptic plasticity deficits. This hypothesis is based on the plausible roles of CB1 receptors in regulating inhibitory tone, influencing astrocytes and microglia, and modulating glutamate release. Dysregulation of the eCBs may be responsible for deficits in synaptic plasticity and learning following TBI. Taken together, the existing evidence indicates eCBs may contribute to TBI manifestation, pathogenesis, and recovery, but it also suggests there may be a therapeutic role for the eCB system in TBI.

The beneficial effects of modafinil administration on repeat mild traumatic brain injury (RmTBI) pathology in adolescent male rats are not dependent upon the orexinergic system.

The sleep-wake cycle plays an influential role in the development and progression of repeat mild traumatic brain injury (RmTBI)-related pathology. Therefore, we first aimed to manipulate the sleep-wake cycle post-RmTBI using modafinil, a wake-promoting substance used for the treatment of narcolepsy. We hypothesized that modafinil would exacerbate RmTBI-induced deficits. Chronic behavioural analyses were completed along with a 27-plex serum cytokine array, metabolomic and proteomic analyses of cerebrospinal fluid (CSF), as well as immunohistochemical staining in structures important for sleep/wake cycles, to examine orexin, melanin-concentrating hormone, tyrosine hydroxylase, and choline acetyltransferase, in the lateral hypothalamus, locus coeruleus, and basal forebrain, respectively. Contrary to expectation, modafinil administration attenuated behavioural deficits, metabolomic changes, and neuropathological modifications. Therefore, the second aim was to determine if the beneficial effects of modafinil treatment were driven by the orexinergic system. The same experimental protocol was used; however, RmTBI rats received chronic orexin-A administration instead of modafinil. Orexin-A administration produced drastically different outcomes, exacerbating anxiety-related and motor deficits, while also significantly disrupting their metabolomic and neuropathological profiles. These results suggest that the beneficial effects of modafinil administration post-RmTBI, work independently of its wake-promoting properties, as activation of the orexinergic wake-promoting system with orexin-A was detrimental. Overall, these findings highlight the complexity of sleep-wake changes in the injured brain and showcase the potential of the arousal and sleep systems in its treatment.

Pathophysiology, blood biomarkers, and functional deficits after intimate partner violence-related brain injury: Insights from emergency department patients and a new rat model.

Intimate partner violence is a serious, but underappreciated, issue that predominantly affects women and often results in concussion (i.e., mild traumatic brain injury). However, concussion in intimate partner violence is unique because it often involves a concomitant strangulation which may exacerbate or alter the physiology and clinical presentation of the brain injury. Therefore, here we conducted human and rodent studies to provide insight into knowledge gaps related to the detection, pathophysiology, and functional consequences of intimate partner violence-related brain injury. We conducted the first study to analyze blood biomarkers and symptoms of brain injury in intimate partner violence patients presenting to an emergency department within 72 h of concussion. Intimate partner violence concussion patients, some of whom had also experienced a concomitant strangulation, had elevated serum neurofilament light and worse brain injury symptoms compared to healthy control, orthopedic trauma, and non-intimate partner violence concussion groups. We also developed the first rat model of non-fatal strangulation and examined the consequences of strangulation and concussion in isolation and in combination on pathophysiology, blood biomarkers, and behavior at 2 h and 1wk post-injury. Rats exposed to combined strangulation and concussion had exacerbated motor and cognitive deficits, neuroinflammation, and serum glial fibrillary acidic protein levels compared with either injury in isolation. Taken together, these rodent findings demonstrate that a concomitant strangulation modifies and exacerbates concussion pathophysiology, biomarkers, and functional consequences. Overall, these findings provide novel insights into intimate partner violence-related brain injury and provides a foundation for future translational studies.

Research priorities for diagnosis, prognosis, and rehabilitation following concussion: results from a national survey of Australian health professionals.

PURPOSE: Recently, the Concussion James Lind Alliance Priority Setting Partnership (JLAPSP) (Canada) identified serious research gaps regarding diagnosis, management, and access to effective rehabilitation for concussion/mild traumatic brain injury (mTBI). Our aim was to determine if the same research priorities are important to Australian health professionals working in the concussion/mTBI field. MATERIALS AND METHODS: A survey was distributed via professional networks, social media, professional group listservs, a research project noticeboard, and at conferences. It comprised of 25 of the highest ranked concussion research questions from the JLAPSP. We examined how professionals ranked the research questions and analyzed variation in ranking by clinical role and concussion/mTBI work experience. RESULTS: Our sample of 187 participants included medical and allied health professionals. Most participants were occupational therapists (22%), physiotherapists (18%), neuropsychologists (17%), and worked in Victoria (47%), New South Whales (18%), or Queensland (15%) in metropolitan areas. Health professionals ranked three research questions highest: identifying methods to predict prolonged recovery; effectiveness of early referral and treatment by a specialized concussion/mTBI team; and implementation studies on upskilling healthcare workers. CONCLUSIONS: The research priorities identified can guide research efforts to improve the assessment, management, and rehabilitation of individuals with concussion/mTBI in Australia.

Health professionals with experience in the assessment and rehabilitation of adults with concussions overwhelmingly agree that there is a need for further research to understand the prognosis and the effectiveness of specialized rehabilitation clinics.The role of healthcare providers in supporting recovery and the long-term health implications of suffering a concussion was identified as a priority.Both pre-clinical and clinical research are identified priorities to determine the effectiveness of biomarkers for concussion and return to activity.Health professionals also call for clinical trials testing management protocols, and implementation trials to support translation of clinical guidelines into practice to understand the role of healthcare providers in rehabilitation.

Breaking down silos: The Gastroenterology Immunology Neuroscience (GIN) Discovery Program - a new model for research.

The Gastroenterology Immunology Neuroscience (GIN) Discovery Program represents a new model for research that overcomes the limitations imposed by traditional "research silos" in science. By uniting these three fields, the GIN Program aims to enhance the understanding and treatment of chronic conditions through a system-wide perspective focusing on the gut-immune-brain axis. Key initiatives include monthly interdisciplinary seminars, an annual symposium, and GINnovate, a commercialization and entrepreneurship event. Additionally, the program offers a seed grant competition for early and mid-career researchers, promoting advancements in gut-immune-brain axis research through the power of collaboration. The GIN Program in a short period of time has facilitated the formation of a vibrant community, captivating attention from both national and international institutions. This effort to break down barriers in research aims to inspire similar models that prioritize open communication, mutual respect and a commitment to impactful science.

Adverse childhood experiences, brain efficiency, and the development of pain symptoms in youth.

BACKGROUND: Adverse childhood experiences (ACEs) are often reported by youths with chronic pain, and both ACEs and chronic pain disrupt how information is processed. However, it is unknown whether changes to shared neural networks underlie the relationship between ACEs and the development of pain symptoms. This study explored the relationships between ACEs, brain efficiency, and pain symptomology in youth. METHODS: A community sample of youths aged 14-18 years underwent MRIs, answered trauma and pain questionnaires, and underwent pain sensory testing, twice, 3 months apart (Nbaseline = 44; Nfollow-up = 42). Sensory testing determined thresholds for mechanical and thermal stimuli. Global and local network efficiencies were evaluated using graph theory. Generalized estimating equations were applied to examine whether brain efficiency moderated the relationships between ACEs, pain intensity, and pain sensitivity (i.e., mechanical detection, heat pain, and temperature change thresholds). RESULTS: There was a significant interaction between ACEs and global brain efficiency in association with pain intensity (ß = -0.31, p = 0.02) and heat pain (ß = -0.29, p = 0.004). Lower global brain efficiency exacerbated the relationship between ACEs and pain intensity (θX → Y|W = -1.16 = 0.37, p = 0.05), and heat pain sensitivity (θX → Y|W = -1.30 = 0.44, p = 0.05). Higher global brain efficiency ameliorated the relationship between ACEs and pain intensity (θX → Y|W = 1.75 = -0.53, p = 0.05). CONCLUSIONS: The relationship between ACEs and pain symptomology was comparable to chronic pain phenotypes (i.e., higher pain intensity and pain thresholds) and may vary as a function of brain efficiency in youth. This stresses the importance of assessing for pain symptoms in trauma-exposed youth, as earlier identification and intervention are critical in preventing the chronification of pain. SIGNIFICANCE: This article explores the relationship between ACEs, pain symptomology, and brain efficiency in youth. ACEs may affect how the brain processes information, including pain. Youths with lower brain efficiencies that were exposed to more ACEs have pain symptomology comparable to youths with chronic pain. Understanding this relationship is important for the earlier identification of pain symptoms, particularly in vulnerable populations such as youths exposed to trauma, and is critical for preventing the chronification of pain.

Recent developments and challenges in positron emission tomography imaging of gliosis in chronic neuropathic pain.

ABSTRACT: Understanding the mechanisms that underpin the transition from acute to chronic pain is critical for the development of more effective and targeted treatments. There is growing interest in the contribution of glial cells to this process, with cross-sectional preclinical studies demonstrating specific changes in these cell types capturing targeted timepoints from the acute phase and the chronic phase. In vivo longitudinal assessment of the development and evolution of these changes in experimental animals and humans has presented a significant challenge. Recent technological advances in preclinical and clinical positron emission tomography, including the development of specific radiotracers for gliosis, offer great promise for the field. These advances now permit tracking of glial changes over time and provide the ability to relate these changes to pain-relevant symptomology, comorbid psychiatric conditions, and treatment outcomes at both a group and an individual level. In this article, we summarize evidence for gliosis in the transition from acute to chronic pain and provide an overview of the specific radiotracers available to measure this process, highlighting their potential, particularly when combined with ex vivo / in vitro techniques, to understand the pathophysiology of chronic neuropathic pain. These complementary investigations can be used to bridge the existing gap in the field concerning the contribution of gliosis to neuropathic pain and identify potential targets for interventions.

Improving physical movement during stroke rehabilitation: investigating associations between sleep measured by wearable actigraphy technology, fatigue, and key biomarkers.

BACKGROUND: Sleep disturbance and fatigue are common in individuals undergoing inpatient rehabilitation following stroke. Understanding the relationships between sleep, fatigue, motor performance, and key biomarkers of inflammation and neuroplasticity could provide valuable insight into stroke recovery, possibly leading to personalized rehabilitation strategies. This study aimed to investigate the influence of sleep quality on motor function following stroke utilizing wearable technology to obtain objective sleep measurements. Additionally, we aimed to determine if there were relationships between sleep, fatigue, and motor function. Lastly, the study aimed to determine if salivary biomarkers of stress, inflammation, and neuroplasticity were associated with motor function or fatigue post-stroke. METHODS: Eighteen individuals who experienced a stroke and were undergoing inpatient rehabilitation participated in a cross-sectional observational study. Following consent, participants completed questionnaires to assess sleep patterns, fatigue, and quality of life. Objective sleep was measured throughout one night using the wearable Philips Actiwatch. Upper limb motor performance was assessed on the following day and saliva was collected for biomarker analysis. Correlation analyses were performed to assess the relationships between variables. RESULTS: Participants reported poor sleep quality, frequent awakenings, and difficulties falling asleep following stroke. We identified a significant negative relationship between fatigue severity and both sleep quality (r=-0.539, p = 0.021) and participants experience of awakening from sleep (r=-0.656, p = 0.003). A significant positive relationship was found between grip strength on the non-hemiplegic limb and salivary gene expression of Brain-derived Neurotrophic Factor (r = 0.606, p = 0.028), as well as a significant negative relationship between grip strength on the hemiplegic side and salivary gene expression of C-reactive Protein (r=-0.556, p = 0.048). CONCLUSION: The findings of this study emphasize the importance of considering sleep quality, fatigue, and biomarkers in stroke rehabilitation to optimize recovery and that interventions may need to be tailored to the individual. Future longitudinal studies are required to explore these relationships over time. Integrating wearable technology for sleep and biomarker analysis can enhance monitoring and prediction of outcomes following stroke, ultimately improving rehabilitation strategies and patient outcomes.

Re-examining the Mysterious Role of the Cerebellum in Pain.

Pain is considered a multidimensional experience that embodies not merely sensation, but also emotion and perception. As is appropriate for this complexity, pain is represented and processed by an extensive matrix of cortical and subcortical structures. Of these structures, the cerebellum is gaining increasing attention. Although association between the cerebellum and both acute and chronic pain have been extensively detailed in electrophysiological and neuroimaging studies, a deep understanding of what functions are mediated by these associations is lacking. Nevertheless, the available evidence implies that lobules IV-VI and Crus I are especially pertinent to pain processing, and anatomical studies reveal that these regions connect with higher-order structures of sensorimotor, emotional, and cognitive function. Therefore, we speculate that the cerebellum exerts a modulatory role in pain via its communication with sites of sensorimotor, executive, reward, and limbic function. On this basis, in this review, we propose numerous ways in which the cerebellum might contribute to both acute and chronic pain, drawing particular attention to emotional and cognitive elements of pain. In addition, we emphasise the importance of advancing our knowledge about the relationship between the cerebellum and pain by discussing novel therapeutic opportunities that capitalize on this association.

Leukocyte telomere length in multiple sclerosis: relationship between disability severity and pregnancy history.

BACKGROUND: Aging-related processes contribute to neurodegeneration and disability in multiple sclerosis (MS). Biomarkers of biological aging such as leukocyte telomere length (LTL) could help personalise prognosis. Pregnancy has been shown to be protective against disability accumulation in women with MS, though it is unclear if this effect relates to aging mechanisms or LTL. OBJECTIVES: This study aimed to cross-sectionally characterise LTL in a cohort of individuals with MS, and to correlate LTL with disability severity and pregnancy history. METHODS: We extracted DNA from the whole blood of 501 people with MS in Melbourne, Australia. Expanded Disability Status Scale (EDSS) score and demographic data, as well as pregnancy history for 197 females, were obtained at sample collection. Additional data were extracted from the MSBase Registry. LTL was determined in base pairs (bp) using real-time quantitative polymerase chain reaction. RESULTS: A relationship between EDSS score and shorter LTL was robust to multivariable adjustment for demographic and clinical factors including chronological age, with an adjusted LTL reduction per 1.0 increase in EDSS of 97.1 bp (95 % CI = 9.7-184.5 bp, p = 0.030). Adjusted mediation analysis found chronological age accounted for 33.6 % of the relationship between LTL and EDSS score (p = 0.018). In females with pregnancy data, history of pregnancy was associated with older age (median 49.7 vs 33.0 years, p < 0.001). There were no significant relationships between adjusted LTL and any history of pregnancy (LTL increase of 65.3 bp, 95 % CI = -471.0-601.5 bp, p = 0.81) or number of completed pregnancies (LTL increase of 14.6 bp per pregnancy, 95 % CI = -170.3-199.6 bp, p = 0.87). CONCLUSIONS: The correlation between LTL and disability independent of chronological age and other factors points to a link between neurological reserve in MS and biological aging, and a potential research target for pathophysiological and therapeutic mechanisms. Although LTL did not significantly differ by pregnancy history, longitudinal analyses could help identify interactions with prospectively captured pregnancy effects.

Pain and Post-traumatic Stress Disorder Symptoms: Dyadic Relationships Between Canadian Armed Forces Members/Veterans With Chronic Pain and Their Offspring.

Chronic pain and mental health issues occur at higher rates in Veterans than the general population. One widely recognized mental health issue faced by Veterans is post-traumatic stress disorder (PTSD). Trauma symptoms and pain frequently co-occur and are mutually maintained due to shared mechanisms. Many Veterans are also parents. Parental physical and mental health issues significantly predict children's chronic pain and related functioning, which can continue into adulthood. Only 1 U.S.-based study has examined pain in the offspring of Veterans, suggesting a heightened risk for pain. Research to date has not examined the associations between trauma and pain and the dyadic influences of these symptoms, among Veterans, and their children. The current study aimed to describe pain characteristics in Canadian Armed Forces Members/Veterans with chronic pain and their offspring (youth and adult children aged 9-38). Cross-lagged panel models were conducted to examine dyadic relationships between pain interference and trauma symptoms of Canadian Armed Forces Members/Veterans and their offspring. Over half of adult offspring and over one-quarter of youth offspring reported chronic pain. Results revealed effects between one's own symptoms of PTSD and pain interference. No significant effects of parents on offspring or offspring on parents were found. The findings highlight the interconnection between pain and PTSD consistent with mutual maintenance models and a lack of significant interpersonal findings suggestive of resiliency in this unique population. PERSPECTIVE: We characterized chronic pain in the offspring of Canadian Armed Forces Members/Veterans with chronic pain and examined dyadic relationships between PTSD symptoms and chronic pain interference. Findings revealed that PTSD symptoms and pain interference were related within Veterans and offspring, but no dyadic relationships were found, which could reflect resiliency.

Shaking Up Our Approach: The Need for Characterization and Optimization of Pre-clinical Models of Infant Abusive Head Trauma.

Traumatic brain injuries (TBIs) are a large societal and individual burden. In the first year of life, the vast majority of these injuries are the result of inflicted abusive events by a trusted caregiver. Abusive head trauma (AHT) in infants, formerly known as shaken baby syndrome, is the leading cause of inflicted mortality and morbidity in this population. In this review we address clinical diagnosis, symptoms, prognosis, and neuropathology of AHT, emphasizing the burden of repetitive AHT. Next, we consider existing animal models of AHT, and we evaluate key features of an ideal model, highlighting important developmental milestones in children most vulnerable to AHT. We draw on insights from other injury models, such as repetitive, mild TBIs (RmTBIs), post-traumatic epilepsy (PTE), hypoxic-ischemic injuries, and maternal neglect, to speculate on key knowledge gaps and underline important new opportunities in pre-clinical AHT research. Finally, potential treatment options to facilitate healthy development in children following an AHT are considered. Together, this review aims to drive the field toward optimized, well-characterized animal models of AHT, which will allow for greater insight into the underlying neuropathological and neurobehavioral consequences of AHT.

Infraorbital nerve injury triggers sex-specific neuroimmune responses in the peripheral trigeminal pathway and common pain behaviours.

Trigeminal neuropathic pain is emotionally distressing and disabling. It presents with allodynia, hyperalgesia and dysaesthesia. In preclinical models it has been assumed that cephalic nerve constriction injury shows identical molecular, cellular, and sex dependent neuroimmune changes as observed in extra-cephalic injury models. This study sought empirical evidence for such assumptions using the infraorbital nerve chronic constriction model (ION-CCI). We compared the behavioural consequences of nerve constriction with: (i) the temporal patterns of recruitment of macrophages and T-lymphocytes at the site of nerve injury and in the trigeminal ganglion; and (ii) the degree of demyelination and axonal reorganisation in the injured nerve. Our data demonstrated that simply testing for allodynia and hyperalgesia as is done in extra-cephalic neuropathic pain models does not provide access to the range of injury-specific nociceptive responses and behaviours reflective of the experience of trigeminal neuropathic pain. Similarly, trigeminal neuroimmune changes evoked by nerve injury are not the same as those identified in models of extra-cephalic neuropathy. Specifically, the timing, magnitude, and pattern of ION-CCI evoked macrophage and T-lymphocyte activity differs between the sexes.

Investigating the Association Between Extended Participation in Collision Sports and Fluid Biomarkers Among Masters Athletes.

Traumatic brain injuries (TBIs) and concussions are prevalent in collision sports, and there is evidence that levels of exposure to such sports may increase the risk of neurological abnormalities. Elevated levels of fluid-based biomarkers have been observed after concussions or among athletes with a history of participating in collision sports, and certain biomarkers exhibit sensitivity toward neurodegeneration. This study investigated a cohort of 28 male amateur athletes competing in "Masters" competitions for persons >35 years of age. The primary objective of this study was to compare the levels of blood and saliva biomarkers associated with brain injury, inflammation, aging, and neurodegeneration between athletes with an extensive history of collision sport participation (i.e., median = 27 years; interquartile range = 18-44, minimum = 8) and those with no history. Plasma proteins associated with neural damage and neurodegeneration were measured using Simoa® assays, and saliva was analyzed for markers associated with inflammation and telomere length using quantitative real-time polymerase chain reaction. There were no significant differences between collision and non-collision sport athletes for plasma levels of glial fibrillary acidic protein, neurofilament light, ubiquitin C-terminal hydrolase L1, tau, tau phosphorylated at threonine 181, and brain-derived neurotrophic factor. Moreover, salivary levels of genes associated with inflammation and telomere length were similar between groups. There were no significant differences between groups in symptom frequency or severity on the Sport Concussion Assessment Tool-5th Edition. Overall, these findings provide preliminary evidence that biomarkers associated with neural tissue damage, neurodegeneration, and inflammation may not exhibit significant alterations in asymptomatic amateur athletes with an extensive history of amateur collision sport participation.

Microbiome depletion prior to repeat mild TBI differentially alters social deficits and prefrontal cortex plasticity in adolescent and adult rats.

Although aging, repeat mild traumatic brain injury (RmTBI), and microbiome modifications independently change social behavior, there has been no investigation into their cumulative effects on social behavior and neuroplasticity within the prefrontal cortex. Therefore, we examined how microbiome depletion prior to RmTBI affected social behavior and neuroplasticity in adolescent and adult rats. Play, temperament analysis, elevated plus maze, and the hot/cold plate assessed socio-emotional function. Analyses of perineuronal nets (PNNs) and parvalbumin (PV) interneurons was completed. Social-emotional deficits were more pronounced in adults, with microbiome depletion attenuating social behavior deficits associated with RmTBI in both age groups. Microbiome depletion increased branch length and PNN arborization within the PFC but decreased the overall number of PNNs. Adults and males were more vulnerable to RmTBI. Interestingly, microbiome depletion may have attenuated the changes to neuroplasticity and subsequent social deficits, suggesting that the microbiome is a viable, but age-specific, target for RmTBI therapeutics.

A pre-existing Toxoplasma gondii infection exacerbates the pathophysiological response and extent of brain damage after traumatic brain injury in mice.

Traumatic brain injury (TBI) is a key contributor to global morbidity that lacks effective treatments. Microbial infections are common in TBI patients, and their presence could modify the physiological response to TBI. It is estimated that one-third of the human population is incurably infected with the feline-borne parasite, Toxoplasma gondii, which can invade the central nervous system and result in chronic low-grade neuroinflammation, oxidative stress, and excitotoxicity-all of which are also important pathophysiological processes in TBI. Considering the large number of TBI patients that have a pre-existing T. gondii infection prior to injury, and the potential mechanistic synergies between the conditions, this study investigated how a pre-existing T. gondii infection modified TBI outcomes across acute, sub-acute and chronic recovery in male and female mice. Gene expression analysis of brain tissue found that neuroinflammation and immune cell markers were amplified in the combined T. gondii + TBI setting in both males and females as early as 2-h post-injury. Glutamatergic, neurotoxic, and oxidative stress markers were altered in a sex-specific manner in T. gondii + TBI mice. Structural MRI found that male, but not female, T. gondii + TBI mice had a significantly larger lesion size compared to their uninfected counterparts at 18-weeks post-injury. Similarly, diffusion MRI revealed that T. gondii + TBI mice had exacerbated white matter tract abnormalities, particularly in male mice. These novel findings indicate that a pre-existing T. gondii infection affects the pathophysiological aftermath of TBI in a sex-dependent manner, and may be an important modifier to consider in the care and prognostication of TBI patients.

Treatment with the vascular endothelial growth factor-A antibody, bevacizumab, has sex-specific effects in a rat model of mild traumatic brain injury.

Mild traumatic brain injury (mTBI) involves damage to the cerebrovascular system. Vascular endothelial growth factor-A (VEGF-A) is an important modulator of vascular health and VEGF-A promotes the brain's ability to recover after more severe forms of brain injury; however, the role of VEGF-A in mTBI remains poorly understood. Bevacizumab (BEV) is a monoclonal antibody that binds to VEGF-A and neutralises its actions. To better understand the role of VEGF-A in mTBI recovery, this study examined how BEV treatment affected outcomes in rats given a mTBI. Adult Sprague-Dawley rats were assigned to sham-injury + vehicle treatment (VEH), sham-injury + BEV treatment, mTBI + VEH treatment, mTBI + BEV treatment groups. Treatment was administered intracerebroventricularly via a cannula beginning at the time of injury and continuing until the end of the study. Rats underwent behavioral testing after injury and were euthanized on day 11. In both females and males, BEV had a negative impact on cognitive function. mTBI and BEV treatment increased the expression of inflammatory markers in females. In males, BEV treatment altered markers related to hypoxia and vascular health. These novel findings of sex-specific responses to BEV and mTBI provide important insights into the role of VEGF-A in mTBI.

Gene expression changes in the cerebellum are associated with persistent post-injury pain in adolescent rats exposed to early life stress.

Chronic pain develops following injury in approximately 20% of adolescents, at twice the rate in females than males. Adverse childhood experiences also increase the risk for poor health outcomes, such as chronic pain. Emerging literature suggests the cerebellum to be involved in pain processing, however detailed explorations into how the cerebellum contributes to pain are lacking. Therefore, this study aimed to characterise chronic pain outcomes and cerebellar gene expression changes following early life stress and injury in both sexes. The adverse childhood experience of neglect was modelled using a maternal separation (MS) paradigm, which was combined with a subsequent injury (mild traumatic brain injury (mTBI) or plantar incision surgery) in adolescent male and female Sprague-Dawley rats. We measured behavioural nociceptive sensitivity, systemic modulators of pain such as calcitonin gene-related protein (CGRP) and Substance P, as well as gene expression of IL1ß, GFAP, GR, MR, GABRA1, CNR1, MAOA, and DAT1 in the cerebellum to examine associations between pain and neuroinflammation, the stress response, inhibitory neurotransmission, and monoaminergic function. We found increases in mechanical nociceptive sensitivity following plantar incision surgery. Sex differences were observed in anxiety-like behaviour and neuroinflammation, whereas systemic pain modulators showed cumulative effects with the addition of stressors. Most interestingly however, the increases in nociceptive sensitivity were associated with the suppressed expression of cerebellar genes that regulate stress, inhibition, cannabinoid function, and dopaminergic function, alongside sex-dependent distinctions for genes involved in inflammation and injury. This study highlights a novel link between nociception and molecular function in the cerebellum. Further investigation into how the cerebellum contributes to pain in males and females will facilitate novel therapeutic insights and opportunities.

Regulation of Microglial Signaling by Lyn and SHIP-1 in the Steady-State Adult Mouse Brain.

Chronic neuroinflammation and glial activation are associated with the development of many neurodegenerative diseases and neuropsychological disorders. Recent evidence suggests that the protein tyrosine kinase Lyn and the lipid phosphatase SH2 domain-containing inositol 5' phosphatase-1 (SHIP-1) regulate neuroimmunological responses, but their homeostatic roles remain unclear. The current study investigated the roles of Lyn and SHIP-1 in microglial responses in the steady-state adult mouse brain. Young adult Lyn-/- and SHIP-1-/- mice underwent a series of neurobehavior tests and postmortem brain analyses. The microglial phenotype and activation state were examined by immunofluorescence and flow cytometry, and neuroimmune responses were assessed using gene expression analysis. Lyn-/- mice had an unaltered behavioral phenotype, neuroimmune response, and microglial phenotype, while SHIP-1-/- mice demonstrated reduced explorative activity and exhibited microglia with elevated activation markers but reduced granularity. In addition, expression of several neuroinflammatory genes was increased in SHIP-1-/- mice. In response to LPS stimulation ex vivo, the microglia from both Lyn-/- and SHIP-1-/- showed evidence of hyper-activity with augmented TNF-α production. Together, these findings demonstrate that both Lyn and SHIP-1 have the propensity to control microglial responses, but only SHIP-1 regulates neuroinflammation and microglial activation in the steady-state adult brain, while Lyn activity appears dispensable for maintaining brain homeostasis.