Assessing Regional Weather's Impact on Spinal Cord Injury Survivors, Caregivers, and General Public in Miami, Florida.

(1) Background: Climate change is increasing the already frequent diverse extreme weather events (EWE) across geographic locations, directly and indirectly impacting human health. However, current ongoing research fails to address the magnitude of these indirect impacts, including healthcare access. Vulnerable populations such as persons with spinal cord injury (pSCI) face added physiologic burden such as thermoregulation or mobility challenges like closure of public transportation. Our exploratory research assessed commute and transport to healthcare facilities as well as the knowledge, attitudes and behaviors (KAB) of pSCI regarding EWE and climate change when compared to pSCI caregivers (CG) and the general public (GP). (2) Methods: A KAB survey was employed to conduct a cross-sectional assessment of pSCI, CG, and GP in Miami from October through November 2019 using snowball sampling. Descriptive and logistic regression statistical analyses were used. (3) Results: Of 65 eligible survey respondents, 27 (41.5%) were pSCI, 11 (17%) CG, and 27 (41.5%) GP. Overall, pSCI reported EWE, particularly flooding and heavy rain, affecting their daily activities including healthcare appointments, more frequently than CG or GP. The overall models for logistic regression looking at commute to and attendance of healthcare appointments were statistically significant. pSCI self-report being less vulnerable than others, and a large proportion of each group was not fully convinced climate change is happening. (4) Conclusions: This study provided insight to the KAB of 3 population subgroups in Miami, Florida. pSCI are significantly more vulnerable to the effects of regional weather events yet exhibit disproportionate self-perception of their vulnerability. Continued and more comprehensive research is needed to characterize the barriers that vulnerable populations face during weather events.

Engaging Mood Brain Circuits with Psilocybin (EMBRACE): a study protocol for a randomized, placebo-controlled and delayed-start, neuroimaging trial in depression.

BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability worldwide across domains of health and cognition, affecting overall quality of life. Approximately one third of individuals with depression do not fully respond to treatments (e.g., conventional antidepressants, psychotherapy) and alternative strategies are needed. Recent early phase trials suggest psilocybin may be a safe and efficacious intervention with rapid-acting antidepressant properties. Psilocybin is thought to exert therapeutic benefits by altering brain network connectivity and inducing neuroplastic changes that endure for weeks post-treatment. Although early clinical results are encouraging, psilocybin's acute neurobiological effects on neuroplasticity have not been fully investigated. We aim to examine for the first time how psilocybin acutely (intraday) and subacutely (weeks) alters functional brain networks implicated in depression. METHODS: Fifty participants diagnosed with MDD or persistent depressive disorder (PDD) will be recruited from a tertiary mood disorders clinic and undergo 1:1 randomization into either an experimental or control arm. Participants will be given either 25 mg psilocybin or 25 mg microcrystalline cellulose (MCC) placebo for the first treatment. Three weeks later, those in the control arm will transition to receiving 25 mg psilocybin. We will investigate whether treatments are associated with changes in arterial spin labelling and blood oxygenation level-dependent contrast neuroimaging assessments at acute and subacute timepoints. Primary outcomes include testing whether psilocybin demonstrates acute changes in (1) cerebral blood flow and (2) functional brain activity in networks associated with mood regulation and depression when compared to placebo, along with changes in MADRS score over time compared to placebo. Secondary outcomes include changes across complementary clinical psychiatric, cognitive, and functional scales from baseline to final follow-up. Serum peripheral neurotrophic and inflammatory biomarkers will be collected at baseline and follow-up to examine relationships with clinical response, and neuroimaging measures. DISCUSSION: This study will investigate the acute and additive subacute neuroplastic effects of psilocybin on brain networks affected by depression using advanced serial neuroimaging methods. Results will improve our understanding of psilocybin's antidepressant mechanisms versus placebo response and whether biological measures of brain function can provide early predictors of treatment response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06072898. Registered on 6 October 2023.

5-Hydroxytryptamine 5HT2C receptors form a protein complex with N-methyl-D-aspartate GluN2A subunits and activate phosphorylation of Src protein to modulate motoneuronal depolarization.

N-Methyl-D-aspartate (NMDA)-gated ion channels are known to play a critical role in motoneuron depolarization, but the molecular mechanisms modulating NMDA activation in the spinal cord are not well understood. This study demonstrates that activated 5HT2C receptors enhance NMDA depolarizations recorded electrophysiologically from motoneurons. Pharmacological studies indicate involvement of Src tyrosine kinase mediates 5HT2C facilitation of NMDA. RT-PCR analysis revealed edited forms of 5HT2C were present in mammalian spinal cord, indicating the availability of G-protein-independent isoforms. Spinal cord neurons treated with the 5HT2C agonist MK 212 showed increased Src(Tyr-416) phosphorylation in a dose-dependent manner thus verifying that Src is activated after treatment. In addition, 5HT2C antagonists and tyrosine kinase inhibitors blocked 5HT2C-mediated Src(Tyr-416) phosphorylation and also enhanced NMDA-induced motoneuron depolarization. Co-immunoprecipitation of synaptosomal fractions showed that GluN2A, 5HT2C receptors, and Src tyrosine kinase form protein associations in synaptosomes. Moreover, immunohistochemical analysis demonstrated GluN2A and 5HT2C receptors co-localize on the processes of spinal neurons. These findings reveal that a distinct multiprotein complex links 5-hydroxytryptamine-activated intracellular signaling events with NMDA-mediated functional activity.

The Physiology of Neurogenic Obesity: Lessons from Spinal Cord Injury Research.

BACKGROUND: A spinal cord injury (SCI) from trauma or disease impairs sensorimotor pathways in somatic and autonomic divisions of the nervous system, affecting multiple body systems. Improved medical practices have increased survivability and life expectancy after SCI, allowing for the development of extensive metabolic comorbidities and profound changes in body composition that culminate in prevalent obesity. SUMMARY: Obesity is the most common cardiometabolic component risk in people living with SCI, with a diagnostic body mass index cutoff of 22 kg/m2 to account for a phenotype of high adiposity and low lean mass. The metameric organization of specific divisions of the nervous system results in level-dependent pathology, with resulting sympathetic decentralization altering physiological functions such as lipolysis, hepatic lipoprotein metabolism, dietary fat absorption, and neuroendocrine signaling. In this manner, SCI provides a unique opportunity to study in vivo the "neurogenic" components of certain pathologies that otherwise are not readily observable in other populations. We discuss the unique physiology of neurogenic obesity after SCI, including the altered functions mentioned above as well as structural changes such as reduced skeletal muscle and bone mass and increased lipid deposition in the adipose tissue, skeletal muscle, bone marrow, and liver. KEY MESSAGE: The study of neurogenic obesity after SCI gives us a unique neurological perspective on the physiology of obesity. The lessons learned from this field can guide future research and advancements to inform the study of obesity in persons with and without SCI.

Therapeutic Lifestyle Intervention Targeting Enhanced Cardiometabolic Health and Function for Persons with Chronic Spinal Cord Injury in Caregiver/Care-Receiver Co-Treatment: A Study Protocol of a Multisite Randomized Controlled Trial.

BACKGROUND: Chronic spinal cord injury (SCI) significantly accelerates morbidity and mortality, partly due to the increased risk of cardiometabolic diseases (CMD), including neurogenic obesity, dyslipidemia, and impaired glucose metabolism. While exercise and dietary interventions have shown some transient benefits in reducing CMD risk, they often fail to improve clinically relevant disease markers and cardiovascular events. Moreover, SCI also places caregiving demands on their caregivers, who themselves experience health and functional decline. This underscores the need for more substantial interventions that incorporate appropriate physical activity, heart-healthy nutrition, and behavioral support tailored to the SCI population. OBJECTIVES: This randomized clinical trial (RCT) protocol will (1) assess the health and functional effects, user acceptance, and satisfaction of a 6-month comprehensive therapeutic lifestyle intervention (TLI) adapted from the National Diabetes Prevention Program (DPP) for individuals with chronic SCI and (2) examine the impact of a complementary caregiver program on the health and function of SCI caregivers and evaluate user acceptance and satisfaction. Caregivers (linked with their partners) will be randomized to 'behavioral support' or 'control condition'. METHODS: Dyadic couples comprise individuals with SCI (18-65 years, >1-year post-injury, ASIA Impairment Scale A-C, injury levels C5-L1) and non-disabled SCI caregivers (18-65 years). Both groups undergo lock-step circuit resistance training, a calorie-restricted Mediterranean-style diet, and 16 educational sessions focused on diet/exercise goals, self-monitoring, psychological and social challenges, cognitive behavioral therapy, and motivational interviewing. The outcome measures encompass the cardiometabolic risks, cardiorespiratory fitness, inflammatory stress, multidimensional function, pain, life quality, independence, self-efficacy, program acceptance, and life satisfaction for SCI participants. The caregiver outcomes include multidimensional function, pain, quality of life, independence, and perceived caregiver burden. DISCUSSION/CONCLUSIONS: This study evaluates the effects and durability of a structured, multi-modal intervention on health and function. The results and intervention material will be disseminated to professionals and consumers for broader implementation. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02853149 Registered 2 August 2016.

Characterization of Gastrointestinal Hormone Dysfunction and Metabolic Pathophysiology in Experimental Spinal Cord Injury.

Cardiometabolic disease is a leading complication of spinal cord injury (SCI) that contributes to premature all-cause cardiovascular morbidity and early death. Despite widespread reports that cardioendocrine disorders are more prevalent in individuals with SCI than those without disability, a well-defined pathophysiology has not been established. Autonomic dysfunction accompanying disruption of autonomic spinal tracts may contribute to dysregulation of energy metabolism via uncoupling of integrated hunger and satiation signals. In governing human feeding behaviors, these signals are controlled by a network of enteroendocrine cells that line the gastrointestinal (GI) tract. These cells regulate GI peptide release and autonomic systems that maintain direct neuroendocrine communication between the GI tract and appetite circuitry of the hypothalamus and brainstem. Here we investigate gene-expression and physiological changes in GI peptides and hormones, as well as changes in physiological response to feeding, glucose and insulin challenge, and evaluate GI tissue cytoarchitecture after experimental SCI. Adult female mice (C57BL/6) were subjected to a severe SCI (65 kDyne) at T9, and a sham control group received laminectomy only. The SCI results in chronic elevation of fasting plasma glucose levels and an exaggerated glucose response after an oral glucose and insulin tolerance test. Mice with SCI also exhibit significant alteration in gut hormone genes, plasma levels, physiological response to prandial challenge, and cell loss and gross tissue damage in the gut. These findings demonstrate that SCI has widespread effects on the GI system contributing to component cardiometabolic disease risk factors and may inform future therapeutic and rehabilitation strategies in humans.

Systemic inflammation after spinal cord injury: A review of biological evidence, related health risks, and potential therapies.

Individuals with chronic traumatic spinal cord injury (SCI) develop progressive multi-system health problems that result in clinical illness and disability. Systemic inflammation is associated with many of the common medical complications and acquired diseases that accompany chronic SCI, suggesting that it contributes to a number of comorbid pathological conditions. However, many of the mechanisms that promote persistent systemic inflammation and its consequences remain ill-defined. This review describes the significant biological factors that contribute to systemic inflammation, major organ systems affected, health risks, and the potential treatment strategies. We aim to highlight the need for a better understanding of inflammatory processes, and to establish appropriate strategies to address inflammation in SCI.

Selective Myostatin Inhibition Spares Sublesional Muscle Mass and Myopenia-Related Dysfunction after Severe Spinal Cord Contusion in Mice.

Clinically relevant myopenia accompanies spinal cord injury (SCI), and compromises function, metabolism, body composition, and health. Myostatin, a transforming growth factor (TGF)ß family member, is a key negative regulator of skeletal muscle mass. We investigated inhibition of myostatin signaling using systemic delivery of a highly selective monoclonal antibody - muSRK-015P (40 mg/kg) - that blocks release of active growth factor from the latent form of myostatin. Adult female mice (C57BL/6) were subjected to a severe SCI (65 kdyn) at T9 and were then immediately and 1 week later administered test articles: muSRK-015P (40 mg/kg) or control (vehicle or IgG). A sham control group (laminectomy only) was included. At euthanasia, (2 weeks post-SCI) muSRK-015P preserved whole body lean mass and sublesional gastrocnemius and soleus mass. muSRK-015P-treated mice with SCI also had significantly attenuated myofiber atrophy, lipid infiltration, and loss of slow-oxidative phenotype in soleus muscle. These outcomes were accompanied by significantly improved sublesional motor function and muscle force production at 1 and 2 weeks post-SCI. At 2 weeks post-SCI, lean mass was significantly decreased in SCI-IgG mice, but was not different in SCI-muSRK-015P mice than in sham controls. Total energy expenditure (kCal/day) at 2 weeks post-SCI was lower in SCI-immunoglobulin (Ig)G mice, but not different in SCI-muSRK-015P mice than in sham controls. We conclude that in a randomized, blinded, and controlled study in mice, myostatin inhibition using muSRK-015P had broad effects on physical, metabolic, and functional outcomes when compared with IgG control treated SCI animals. These findings may identify a useful, targeted therapeutic strategy for treating post-SCI myopenia and related sequelae in humans.

Cardiometabolic risks and atherosclerotic disease in ApoE knockout mice: Effect of spinal cord injury and Salsalate anti-inflammatory pharmacotherapy.

OBJECTIVE: To test in mice with a double mutation of the ApoE gene (ApoE-/-) whether spinal cord injury (SCI) hastens the native trajectory of, and established component risks for, atherosclerotic disease (AD), and whether Salsalate anti-inflammatory pharmacotherapy attenuates the impact of SCI. METHODS: ApoE-/- mice were anesthetized and underwent a T9 laminectomy. Exposed spinal cords were given a contusion injury (70 k-dynes). Sham animals underwent all surgical procedures, excluding injury. Injured animals were randomized to 2 groups: SCI or SCI+Salsalate [120 mg/Kg/day i.p.]. Mice were serially sacrificed at 20-, 24-, and 28-weeks post-SCI, and body mass was recorded. At sacrifice, heart and aorta were harvested intact, fixed in 10% buffered formalin, cleaned and cut longitudinally for en face preparation. The aortic tree was stained with oil-red-O (ORO). AD lesion histomorphometry was calculated from the proportional area of ORO. Plasma total cholesterol, triglycerides and proatherogenic inflammatory cytokines (PAIC's) were analyzed. RESULTS: AD lesion in the aortic arch progressively increased in ApoE-/-, significant at 24- and 28-weeks. AD in SCI is significantly greater at 24- and 28-weeks compared to time-controlled ApoE-/-. Salsalate treatment attenuates the SCI-induced increase at these time points. Body mass in all SCI groups are significantly reduced compared to time-controlled ApoE-/-. Cholesterol and triglycerides are significantly higher with SCI by 24- and 28-weeks, compared to ApoE-/-, and Salsalate reduces the SCI-induced effect on cholesterol. PAIC's interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor α (TNFα), monocyte chemoattractant protein-1 (MCP-1), and chemokine (C-C motif) ligand 5 (CCL-5) are significantly greater with SCI compared to ApoE-/- at varying timepoints. Salsalate confers a marginal reducing effect on PAIC's by 28-weeks compared to SCI. Regression models determine that each PAIC is a significant and positive predictor of lesion. (p's <0.05). CONCLUSIONS: SCI accelerates aortic AD and associated risk factors, and anti-inflammatory treatment may attenuate the impact of SCI on AD outcomes. PAIC's IL-1ß, IL-6, TNFα, MCP-1, and CCL-5 may be effective predictors of AD.

Rats Lacking Dopamine Transporter Display Increased Vulnerability and Aberrant Autonomic Response to Acute Stress.

The activity of the hypothalamus-pituitary-adrenal (HPA) axis is pivotal in homeostasis and presides the adaptative response to stress. Dopamine Transporter (DAT) plays a key role in the regulation of the HPA axis. We used young adult female DAT Knockout (KO) rats to assess the effects of DAT ablation (partial, heterozygous DAT+/-, or total, homozygous DAT-/-) on vulnerability to stress. DAT-/- rats show profound dysregulation of pituitary homeostasis, in the presence of elevated peripheral corticosterone, before and after acute restraint stress. During stress, DAT-/- rats show abnormal autonomic response at either respiratory and cardiovascular level, and delayed body temperature increase. DAT+/- rats display minor changes of hypophyseal homeostatic mechanisms. These rats display a similar pituitary activation to that of the control animals, albeit in the presence of higher release of peripheral corticosterone than DAT-/- after stress, and reduced temperature during stress. Our data indicate that DAT regulates the HPA axis at both the central and peripheral level, including autonomic function during stress. In particular, the partial deletion of DAT results in increased vulnerability to stress in female rats, which display central and peripheral alterations that are reminiscent of PTSD, and they might provide new insights in the pathophysiology of this disorder.

Effects of ursolic acid on sub-lesional muscle pathology in a contusion model of spinal cord injury.

Spinal Cord Injury (SCI) results in severe sub-lesional muscle atrophy and fiber type transformation from slow oxidative to fast glycolytic, both contributing to functional deficits and maladaptive metabolic profiles. Therapeutic countermeasures have had limited success and muscle-related pathology remains a clinical priority. mTOR signaling is known to play a critical role in skeletal muscle growth and metabolism, and signal integration of anabolic and catabolic pathways. Recent studies show that the natural compound ursolic acid (UA) enhances mTOR signaling intermediates, independently inhibiting atrophy and inducing hypertrophy. Here, we examine the effects of UA treatment on sub-lesional muscle mTOR signaling, catabolic genes, and functional deficits following severe SCI in mice. We observe that UA treatment significantly attenuates SCI induced decreases in activated forms of mTOR, and signaling intermediates PI3K, AKT, and S6K, and the upregulation of catabolic genes including FOXO1, MAFbx, MURF-1, and PSMD11. In addition, UA treatment improves SCI induced deficits in body and sub-lesional muscle mass, as well as functional outcomes related to muscle function, motor coordination, and strength. These findings provide evidence that UA treatment may be a potential therapeutic strategy to improve muscle-specific pathological consequences of SCI.

A lifestyle intervention program for successfully addressing major cardiometabolic risks in persons with SCI: a three-subject case series.

INTRODUCTION: This study is a prospective case series analyzing the effects of a comprehensive lifestyle intervention program in three patients with chronic paraplegia having major risks for the cardiometabolic syndrome (CMS). CASE PRESENTATION: Individuals underwent an intense 6-month program of circuit resistance exercise, nutrition using a Mediterranean diet and behavioral support, followed by a 6-month extension (maintenance) phase involving minimal support. The primary goal was a 7% reduction of body mass. Other outcomes analyzed insulin resistance using the HOMA-IR model, and plasma levels of fasting triglycerides and high-density lipoprotein cholesterol. All participants achieved the goal for 7% reduction of body mass and maintained the loss after the MP. Improvements were observed in 2/3 subjects for HOMA-IR and high-density lipoprotein cholesterol. All participants improved their risk for plasma triglycerides. DISCUSSION: We conclude, in a three-person case series of persons with chronic paraplegia, a lifestyle intervention program involving circuit resistance training, a calorie-restrictive Mediterranean-style diet and behavioral support, results in clinically significant loss of body mass and effectively reduced component risks for CMS and diabetes. These results were for the most part maintained after a 6-month MP involving minimal supervision.

Supplemental substances derived from foods as adjunctive therapeutic agents for treatment of neurodegenerative diseases and disorders.

Neurodegenerative disorders and diseases (NDDs) that are either chronically acquired or triggered by a singular detrimental event are a rapidly growing cause of disability and/or death. In recent times, there have been major advancements in our understanding of various neurodegenerative disease states that have revealed common pathologic features or mechanisms. The many mechanistic parallels discovered between various neurodegenerative diseases suggest that a single therapeutic approach may be used to treat multiple disease conditions. Of late, natural compounds and supplemental substances have become an increasingly attractive option to treat NDDs because there is growing evidence that these nutritional constituents have potential adjunctive therapeutic effects (be it protective or restorative) on various neurodegenerative diseases. Here we review relevant experimental and clinical data on supplemental substances (i.e., curcuminoids, rosmarinic acid, resveratrol, acetyl-L-carnitine, and ω-3 (n-3) polyunsaturated fatty acids) that have demonstrated encouraging therapeutic effects on chronic diseases, such as Alzheimer's disease and neurodegeneration resulting from acute adverse events, such as traumatic brain injury.

Reducing cardiometabolic disease in spinal cord injury.

Accelerated cardiometabolic disease is a serious health hazard after spinal cord injuries (SCI). Lifestyle intervention with diet and exercise remains the cornerstone of effective cardiometabolic syndrome treatment. Behavioral approaches enhance compliance and benefits derived from both diet and exercise interventions and are necessary to assure that persons with SCI profit from intervention. Multitherapy strategies will likely be needed to control challenging component risks, such as gain in body mass, which has far reaching implications for maintenance of daily function as well as health.

Neuroendocrine and cardiac metabolic dysfunction and NLRP3 inflammasome activation in adipose tissue and pancreas following chronic spinal cord injury in the mouse.

CVD (cardiovascular disease) represents a leading cause of mortality in chronic SCI (spinal cord injury). Several component risk factors are observed in SCI; however, the underlying mechanisms that contribute to these risks have not been defined. Central and peripheral chronic inflammation is associated with metabolic dysfunction and CVD, including adipokine regulation of neuroendocrine and cardiac function and inflammatory processes initiated by the innate immune response. We use female C57 Bl/6 mice to examine neuroendocrine, cardiac, adipose and pancreatic signaling related to inflammation and metabolic dysfunction in response to experimentally induced chronic SCI. Using immuno-histochemical, -precipitation, and -blotting analysis, we show decreased POMC (proopiomelanocortin) and increased NPY (neuropeptide-Y) expression in the hypothalamic ARC (arcuate nucleus) and PVN (paraventricular nucleus), 1-month post-SCI. Long-form leptin receptor (Ob-Rb), JAK2 (Janus kinase)/STAT3 (signal transducer and activator of transcription 3)/p38 and RhoA/ROCK (Rho-associated kinase) signaling is significantly increased in the heart tissue post-SCI, and we observe the formation and activation of the NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome in VAT (visceral adipose tissue) and pancreas post-SCI. These data demonstrate neuroendocrine signaling peptide alterations, associated with central inflammation and metabolic dysfunction post-SCI, and provide evidence for the peripheral activation of signaling mechanisms involved in cardiac, VAT and pancreatic inflammation and metabolic dysfunction post-SCI. Further understanding of biological mechanisms contributing to SCI-related inflammatory processes and metabolic dysfunction associated with CVD pathology may help to direct therapeutic and rehabilitation countermeasures.

Alterations in mouse hypothalamic adipokine gene expression and leptin signaling following chronic spinal cord injury and with advanced age.

Chronic spinal cord injury (SCI) results in an accelerated trajectory of several cardiovascular disease (CVD) risk factors and related aging characteristics, however the molecular mechanisms that are activated have not been explored. Adipokines and leptin signaling are known to play a critical role in neuro-endocrine regulation of energy metabolism, and are now implicated in central inflammatory processes associated with CVD. Here, we examine hypothalamic adipokine gene expression and leptin signaling in response to chronic spinal cord injury and with advanced age. We demonstrate significant changes in fasting-induced adipose factor (FIAF), resistin (Rstn), long-form leptin receptor (LepRb) and suppressor of cytokine-3 (SOCS3) gene expression following chronic SCI and with advanced age. LepRb and Jak2/stat3 signaling is significantly decreased and the leptin signaling inhibitor SOCS3 is significantly elevated with chronic SCI and advanced age. In addition, we investigate endoplasmic reticulum (ER) stress and activation of the uncoupled protein response (UPR) as a biological hallmark of leptin resistance. We observe the activation of the ER stress/UPR proteins IRE1, PERK, and eIF2alpha, demonstrating leptin resistance in chronic SCI and with advanced age. These findings provide evidence for adipokine-mediated inflammatory responses and leptin resistance as contributing to neuro-endocrine dysfunction and CVD risk following SCI and with advanced age. Understanding the underlying mechanisms contributing to SCI and age related CVD may provide insight that will help direct specific therapeutic interventions.

A novel protein complex in membrane rafts linking the NR2B glutamate receptor and autophagy is disrupted following traumatic brain injury.

Hyperactivation of N-methyl-D-aspartate receptors (NRs) is associated with neuronal cell death induced by traumatic brain injury (TBI) and many neurodegenerative conditions. NR signaling efficiency is dependent on receptor localization in membrane raft microdomains. Recently, excitotoxicity has been linked to autophagy, but mechanisms governing signal transduction remain unclear. Here we have identified protein interactions between NR2B signaling intermediates and the autophagic protein Beclin-1 in membrane rafts of the normal rat cerebral cortex. Moderate TBI induced rapid recruitment and association of NR2B and pCaMKII to membrane rafts, and translocation of Beclin-1 out of membrane microdomains. Furthermore, TBI caused significant increases in expression of key autophagic proteins and morphological hallmarks of autophagy that were significantly attenuated by treatment with the NR2B antagonist Ro 25-6981. Thus, stimulation of autophagy by NR2B signaling may be regulated by redistribution of Beclin-1 in membrane rafts after TBI.