BACKGROUND AND HYPOTHESIS:The amygdala, crucial for mood, anxiety, fear, and reward regulation, shows neuroanatomical and molecular divergence in psychiatric disorders like schizophrenia, bipolar disorder and major depression. This region is also emerging as an important regulator of metabolic and immune pathways. The goal of this study is to address the paucity of molecular studies in the human amygdala. We hypothesize that diagnosis-specific gene expression alterations contribute to the unique pathophysiological profiles of these disorders. STUDY DESIGN:We used a cohort of subjects diagnosed with SCZ, BPD or MDD, and nonpsychiatrically ill control subjects (n = 15/group), together with our bioinformatic 3-pod analysis consisting of full transcriptome pathway analysis, targeted pathway analysis, leading-edge gene analysis and iLINCS perturbagen analysis. STUDY RESULTS:We identified altered expression of metabolic pathways in each disorder. Subjects with SCZ displayed downregulation of mitochondrial respiration and nucleotide metabolism pathways. In comparison, we observed upregulation of mitochondrial respiration pathways in subjects with MDD, while subjects with BPD displayed enrichment of pathways involved in carbohydrate metabolism. Several pathways associated with brain metabolism including immune system processes and calcium ion transport were also differentially altered between diagnosis groups. CONCLUSION:Our findings suggest metabolic pathways, including downregulation of energy metabolism pathways in SCZ and upregulation of energy metabolism pathways in MDD, are uniquely altered in the amygdala in these disorders, which may impact approaches for therapeutic strategies.

There is growing interest in the impact of internal body states on the brain and behavior. The detrimental effects of chronic lung inflammation on mental health are well recognized, however, underlying mechanisms are not known. Here, using a murine model of allergic asthma we report compromised fear extinction in mice with severe but not mild airway inflammation (AI); an effect abolished by anti-interleukin-17A (IL-17A) antibodies. Investigation of innate immune cells, microglia as-well-as transcriptomic signatures in the subfornical organ (SFO), a brain interoceptive node lacking a traditional blood-brain-barrier, revealed significant alterations in severe AI mice. IL-17 Receptor A (IL-17RA) was expressed in SFO microglia and upregulated in severe AI mice. Notably, ablation of microglial IL-17RA improved fear extinction in severe AI mice. Furthermore, we identified direct SFO projections to the infralimbic (IL) cortex, a key area regulating extinction. Importantly, chemogenetic inhibition of the SFO-IL circuit led to improved fear extinction in severe AI mice. Collectively, we report a unique body-to-brain interoceptive mechanism engaging the SFO microglia and an SFO-to-IL circuit, through which airway inflammatory mediators compromise fear extinction. Beyond asthma, our findings are relevant to other pulmonary pathologies (e.g. bacterial pneumonia, ARDS, COVID-19) highlighting a risk for cortical dysfunction and fear pathologies such as PTSD.

Antipsychotics represent mainstay treatment of schizophrenia and are also prescribed on- and off-label in other severe mental illnesses. Newer antipsychotic use is associated with severe metabolic side effects such as obesity and type 2 diabetes. Leptin is a hormone secreted by adipose tissue, and it acts on the brain to decrease body weight by reducing food intake and stimulating energy expenditure. Leptin also improves glucose and lipid metabolism. In this study, we examined the short-term impact of olanzapine, a commonly used second-generation antipsychotic, on the central leptin-mediated regulation of energy balance, glucose and lipid metabolism, and hypothalamic kinase activity. Male SD rats were given an acute intracerebroventricular (ICV) injection of either leptin or vehicle, combined with subcutaneous olanzapine or vehicle. As expected, ICV leptin decreased food intake and, importantly, olanzapine did not block this effect. Administration of leptin, olanzapine, or their combination reduced the average respiratory exchange ratio (RER) during the light-cycle, indicating increased fat oxidation. In the dark-cycle, leptin decreased the average RER regardless of olanzapine administration, and in the presence of leptin, olanzapine did not affect the average RER. Olanzapine treatment produced transient glucose intolerance during the IPGTT, an effect no longer observed with leptin co-treatment, though no significant differences in AUC, fasting serum glucose, insulin, or HOMA-IR were observed between any groups. Olanzapine and leptin treatment differentially activated hypothalamic kinases. In conclusion, the regulation of food intake and fuel preference by central leptin remains intact despite acute olanzapine administration, and leptin may transiently attenuate olanzapine-induced glucose intolerance.

Ventriculoperitoneal (VP) shunts are a common use for the treatment of hydrocephalus, which is a condition causing excessive cerebrospinal fluid (CSF) buildup in the brain. The shunt drains the CSF from the brain and into the abdomen, where it can be absorbed by the body. Although a widely used and successful procedure, it is unclear whether neurosurgical placement of this shunt may directly cause psychiatric abnormalities, especially regarding the dopaminergic system. In this paper, we first review relevant literature and discuss the dopamine circuitry in the brain. The literature suggests a shunt-associated clinical syndrome, which may include a reduction in facial and/or verbal expressivity, reduced willful movement, rigidity, and vertical gaze palsy. Typical presentation occurs within three months of a shunt revision. In patients with a VP shunt, these signs may be a strong indicator of mechanical or functional shunt malfunction. We then present two cases of hydrocephalus managed with a VP shunt, where both patients developed symptoms suggestive of psychosis and/or dopamine pathway pathology after shunt placement. We conclude that clinicians should have a suspicion for shunt-associated symptomology in patients with a history of recently treated hydrocephalus who present with psychomotor, personality, or cognitive changes.

Introduction Current antipsychotic treatments for schizophrenia are insufficient for cognitive symptoms, underscoring the need for novel treatment targets. Several lines of evidence suggest that altered brain bioenergetics, such as impaired glycolysis metabolism and mitochondrial function, are involved in schizophrenia (1) and disorders of aging (2). We previously reported in schizophrenia higher brain lactate levels that correlated with lower cognitive performance, and higher brain glucose levels that corrected with neuronal insulin resistance at a trend level and poorer memory performance (3, 4). Whether brain bioenergetics are compounded by aging in people with schizophrenia remains unknown. This project investigated brain levels of lactate and glucose, brain global oxygenation fraction, and the relation to cognitive function in younger and older people with schizophrenia. Methods Younger and older (35 years and older) people with schizophrenia (n=44) and healthy controls (n=50) participated in this project. Proton magnetic resonance spectroscopy (1H-MRS) was used to measure lactate and glucose across three brain regions (anterior cingulate (AC), occipital cortex (OC), and thalamus (Th)). Lactate was detected using a spectral editing sequence [MEGA-PRESS; TR/TE=2000/140ms, editing pulses at 4.1 ppm (ON) and 5.35 (OFF)] and glucose using a short TE STEAM sequence (TR/TE/TM=2000ms/20ms/10ms). NEX=160 and water NEX=16 for each voxel and sequence. Spectra were preprocessed and modeled with GANNET for lactate and inhouse matlab code and LCModel for glucose. Brain global oxygen extraction fraction (OEF) was measured with TRUST (TR=3000ms, TI=1020ms, voxel size = 3.4X3.4X4.5mm3, labeling slab thickness=100mm) was used to calculate global oxygen extraction fraction (OEF). Fasting blood glucose and insulin were measured to calculate peripheral insulin resistance (HOMO-IR), and general cognitive function was assessed with the MATRICS ConsensusCognitive Battery (MCCB). Brain lactate and glucose were analyzed with 2 (diagnostic group) X 2 (age group) X 3 (region) ANOVAs with repeated measures for region. Brain oxygen extraction fraction was analyzed with a 2 (diagnostic group) X 2 (age group) ANOVA. Correlations were conducted to explore the relationships between the brain measures and general cognitive function. Results For glucose, there was a significant main effect of diagnostic group such that glucose levels for the three regions were higher in schizophrenia vs controls (F=5.5, p =0.025); and there was a trend main effect for age group with the older group having higher levels than the younger group (F=3.8, p =0.056). For lactate, there was a significant main effect of age group with the older group having lower levels than the younger group (F=9.3, p = 0.003), and a trend for an interaction such that the schizophrenia group showed a greater reduction from younger to older groups (F=3.36, p =0.07). There was a significant interaction for OEF, with the control group showing the typical pattern of higher OEF in the older age group but this was not observed in the schizophrenia group (F=4.99, p = 0.028). In older people with schizophrenia only, higher thalamus glucose levels were related to poorer general cognitive function (r=-0.63, p = 0.009). In younger people with schizophrenia only, higher thalamus lactate was related to poorer general cognitive function (r=-0.52, p = 0.027). Higher peripheral HOMO-IR was significantly related to higher glucose in all three brain regions only in the younger group with schizophrenia (all r’s > 0.48, p’s < 0.032). Conclusions These findings provide further support for abnormal brain bioenergetics in schizophrenia and suggest different mechanisms may occur with aging. The younger group was characterized by higher brain lactate that was related to poorer cognitive function, whereas the older group was characterized by higher brain glucose that was related to poorer cognitive function. Higher levels of brain may reflect altered mitochondrial function, impaired astrocyte-neuron lactate shuttle, and higher levels of glucose likely reflect impaired brain glucose utilization related to brain insulin resistance. An alternative energy source to glucose, such as ketones, may be beneficial particularly for those older living with schizophrenia.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by profound neuronal and cognitive decline, with increasing evidence implicating astrocyte dysfunction in disease pathology. While traditional therapeutic approaches have primarily targeted neurons, the crucial role of astrocytes in metabolism, neurotransmission, amyloid-beta clearance, and neuroinflammation underscores their potential as therapeutic targets. In this study, we employed a multiomic integrative analysis combining transcriptomic and kinomic profiling of human induced pluripotent stem cell (hiPSC)-derived astrocytes from patients with familial AD (fAD) compared to healthy controls (HCs). Our transcriptomic analysis identified 1249 significantly differentially expressed genes, highlighting a pronounced upregulation of inflammatory genes (SERPINA3, IL6R, IL1RAP, TNFRSF11A) and a concomitant downregulation of genes essential for synaptic support and ion channel function (STMN2, NMNAT2, SCN2A, GRIN1). Kinomic profiling revealed dysregulated kinase activities within DYRK, GSK, and MAPK families, further implicating altered kinase signaling pathways in astrocyte dysfunction. Integration of these datasets pinpointed critical molecular hubs, notably within the PI3K signaling and inflammatory pathways, highlighting targets such as JAK2, STAT3, and AKT1 as potential modulators of disease progression. Furthermore, leveraging the Library of Integrated Network-Based Cellular Signatures (LINCS) platform, we identified chemical perturbagens, including fluticasone propionate and Akt inhibitors, capable of reversing the transcriptomic signatures associated with fAD astrocytes. This integrative multiomic approach not only enhances our understanding of astrocyte-specific molecular mechanisms in AD but also provides novel targets for therapeutic intervention aimed at mitigating astrocyte-driven neurodegeneration.

Neurodevelopmental disorders (NDDs) are a category of pervasive disorders of the developing nervous system with few or no recognized biomarkers. A significant portion of the risk for NDDs, including attention deficit hyperactivity disorder (ADHD), is contributed by the environment, and exposure to pyrethroid pesticides during pregnancy has been identified as a potential risk factor for NDD in the unborn child. We recently showed that low-dose developmental exposure to the pyrethroid pesticide deltamethrin in mice causes male-biased changes to ADHD- and NDD-relevant behaviors as well as the striatal dopamine system. Here, we used an integrated multiomics approach to determine the broadest possible set of biological changes in the mouse brain caused by developmental pyrethroid exposure (DPE). Using a litter-based, split-sample design, we exposed mouse dams during pregnancy and lactation to deltamethrin (3 mg/kg or vehicle every 3 days) at a concentration well below the EPA-determined benchmark dose used for regulatory guidance. We raised male offspring to adulthood, euthanized them, and pulverized and divided whole brain samples for split-sample transcriptomics, kinomics and multiomics integration. Transcriptome analysis revealed alterations to multiple canonical clock genes, and kinome analysis revealed changes in the activity of multiple kinases involved in synaptic plasticity, including the mitogen-activated protein (MAP) kinase ERK. Multiomics integration revealed a dysregulated protein-protein interaction network containing primary clusters for MAP kinase cascades, regulation of apoptosis, and synaptic function. These results demonstrate that DPE causes a multi-modal biophenotype in the brain relevant to ADHD and identifies new potential mechanisms of action.

Substance use disorders (SUDs) are a critical public health challenge characterized by high relapse rates, with existing treatments often proving inadequate. The focus of this review is to provide an update on the current state of transcranial magnetic stimulation (TMS) as a therapeutic intervention for SUDs and discuss neuroimaging-guided TMS practices. This review explores the neurobiology underlying SUDs, emphasizing the roles of the prefrontal cortex, striatal circuits, and dopaminergic pathways, and examines the theory that TMS modulates neurocircuitry to impact addiction-related behaviors. We discuss TMS procedural aspects and provide a comparative analysis of TMS protocols, focusing on repetitive, deep, single-pulse, paired-pulse, and a more recent approach, theta burst stimulation. We review recent randomized clinical trials (RCTs) to demonstrate reductions in cravings and use across SUDs as well as highlight the need for standardized protocols. We emphasize the power of combining neuroimaging techniques to show functional connectivity changes in the brain and identify potential biomarkers predictive of SUD treatment response, an unexplored area of discussion. With these topics, this review highlights the potential of TMS as a versatile and effective therapeutic modality for SUDs, especially when combined with neuroimaging. Key findings emphasize the necessity for future research to address methodological challenges, such as standardizing protocols and optimizing stimulation parameters. The integration of neuroimaging provides insights into functional connectivity changes, enabling enhanced precision and individualized treatment strategies. By validating TMS approaches and incorporating multimodal techniques, this field can advance toward a more robust clinical utility in addressing the complex neurocircuitry of addiction-related behaviors underlying SUDs.

Glutamate excitotoxicity plays a critical role in neurodegeneration by triggering NMDA receptor hyperactivation, leading to elevated synaptic calcium levels and subsequent neuronal death. To better understand how glutamate affects neurons in neurological diseases, we conducted a comprehensive analysis of molecular changes at the transcriptome and kinome levels. We used primary cortical cultures from rat embryos to study glutamate-induced excitotoxicity. Intermediate doses of glutamate (250 μM) produced significant neurotoxic effects, whereas high and low doses resulted in less cell mortality, aligning with previous findings related to calcium influx. Transcriptional analysis identified BTG2, NPAS4, and CCN1 as the most significantly differentially expressed genes following 250 μM glutamate treatment in neurons. Dkk2, a Wnt antagonist, exhibited the highest log fold change among the significantly differentially expressed genes. Gene set enrichment analysis identified 1127 significant pathways. Perturbagen analysis revealed 2811 unique concordant signatures and 1071 unique discordant signatures. Kinome array profiling indicated activation of PKA and PKG kinases, which regulate signaling pathways essential for synaptic plasticity-related gene expression. Multi-omic integration of transcriptome and kinome data revealed enrichment of response to oxidative stress, actin filament organization, and regulation of apoptotic processes pathways. The Wnt signaling pathway emerged as a pivotal factor in the early stages of axon differentiation and growth, as well as in shaping axonal behavior and dendrite development. Moreover, the interplay between MAPK and Wnt signaling pathways likely impacts cellular differentiation processes. Our findings highlight a prominent role for p38/MAPK and stress-activated MAPK pathways, with specific activation of the MAPK/ERK signaling pathway in response to excitotoxic neuronal damage in vitro. In conclusion, glutamate excitotoxicity induces molecular changes at the transcriptome and kinome levels that include elements of the MAPK and WNT biological pathways.

Suicide is a major public health priority, and its molecular mechanisms appear to be related to imbalanced purine metabolism in the brain. This exploratory study investigates purinergic gene expression in the postmortem dorsolateral prefrontal cortex (DLPFC) tissue isolated from subjects with major depressive disorder (MDD) who died by suicide (MDD-S, n = 10), MDD subjects who did not die by suicide (MDD-NS, n = 6) and non-psychiatrically ill controls (CTL, n = 9–10). Purinergic system transcripts were assayed by quantitative polymerase chain reactions (qPCR) in superficial and deep gray matter as well as white matter DLPFC cortical layers using laser microdissection (LMD). Across all subjects, regardless of sex, P2RY12 (F(2,23) = 5.40, p = 0.004) and P2RY13 (KW statistic = 11.82, p = 0.001) transcript levels were significantly greater in MDD-S compared to MDD-NS subjects. Several other perturbations were observed in the white matter tissue isolated from females: NT5E (F(2,10) = 13.37, p = 0.001) and P2RY13 (F(2,9) = 3.99, p = 0.011, controlled for age) transcript expression was significantly greater in MDD-S vs. MDD-NS female groups. ENTPD2 (F(2,10) = 5.20, p = 0.03), ENTPD3 (F(2,10) = 28.99, p < 0.0001), and NT5E (F(2,10) = 13.37, p = 0.001) were among the transcripts whose expression was significantly elevated in MDD-S vs. CTL female groups. Transcripts that exhibited significantly altered expression in the superficial and deep gray matter included ENTPD2, NT5E, PANX1, and P2RY13 (p ≤ 0.05). Our medication analysis revealed that the expression of these transcripts was not significantly altered by antidepressants. This is the first study to holistically quantify the purinergic metabolic pathway transcripts in suicide and MDD utilizing human postmortem brain tissue. Our preliminary findings support evidence implicating changes in purinergic P2 receptors in the brain in suicide and provide support for broader purinergic system dysregulation in mood disorders.

ProNGF, the precursor protein of mature nerve growth factor (NGF), plays a complex role in neural signaling and has been implicated in neurodegeneration through its apoptotic signaling with the p75NTR receptor. For example, in Alzheimer's disease increased levels of proNGF are associated with cholinergic neuron loss and excitatory/inhibitory imbalance. This study deploys cutting edge a bioinformatic analyses of RNAseq data from TgproNGF#3 mice models that express furin-resistant proNGF. The TgproNGF#3 mouse mimics the pathological accumulation of the precursor NGF protein observed in these diseased brains. Our analysis revealed that proNGF accumulation in the hippocampus and entorhinal regions leads to early downregulation of genes critical for neuronal communication, such as pion and KCNAB2, and later to the upregulation of stress-related and signaling genes, including Neurod1, Neurod2, and Gnai1. These shifts in gene regulation suggest that while the brain attempts to counteract the excess in proNGF, its delay and inefficacy may contribute to early-stage Alzheimer's disease processes.

Glutamate transporters are important for regulating extracellular glutamate levels, impacting neural function and metabolic homeostasis. This study explores the behavioral, lifespan, and proteomic profiles in Caenorhabditis elegans strains with either glt-4 or glt-5 null mutations, highlighting contrasting phenotypes. Δglt-4 mutants displayed impaired mechanosensory and chemotactic responses, reduced lifespans, and decreased expression levels of ribosomal proteins and chaperonins involved in protein synthesis and folding. In contrast, Δglt-5 mutants displayed heightened chemorepulsion, extended lifespans, and upregulation of mitochondrial pyruvate carriers and cytoskeletal proteins. Proteomic profiling via mass spectrometry identified 53 differentially expressed proteins in Δglt-4 mutants and 45 in Δglt-5 mutants. Δglt-4 mutants showed disruptions in ribonucleoprotein complex organization and translational processes, including downregulation of glycogen phosphorylase and V-type ATPase subunits, while Δglt-5 mutants revealed altered metabolic protein expression, such as increased levels of mitochondrial pyruvate carriers and decreased levels of fibrillarin and ribosomal proteins. Gene ontology enrichment analysis highlighted differential regulation of protein biosynthesis and metabolic pathways between the strains. Overall, these findings underscore the distinct, tissue-specific roles of GLT-4 and GLT-5 in C. elegans, with broader implications for glutamate regulation and systemic physiology. The results also reinforce the utility of C. elegans as a model for studying glutamate transporters' impact on behavior, longevity, and proteostasis.

In bioinformatics, pathway analyses are used to interpret biological data by mapping measured molecules with known pathways to discover their functional processes and relationships. Pathway analysis has become an essential tool for interpreting large-scale omics data, translating complex gene sets into actionable experimental insights. However, issues inherent to pathway databases and misinterpretations of pathway relevance often result in “pathway fails,” where findings, though statistically significant, lack biological applicability. For example, the Tumor Necrosis Factor (TNF) pathway was originally annotated based on its association with observed tumor necrosis, while it is multifunctional across diverse physiological processes in the body. This review broadly evaluates pathway analysis interpretation, including embedding-based, semantic similarity-based, and network-based approaches to clarify their ideal use-case scenarios. Each method for interpretation is assessed for its strengths, such as high-quality visualizations and ease of use, as well as its limitations, including data redundancy and database compatibility challenges. Despite advancements in the field, the principle of “garbage in, garbage out” (GIGO) shows that input quality and method choice are critical for reliable and biologically meaningful results. Methodological standardization, scalability improvements, and integration with diverse data sources remain areas for further development. By providing critical guidance with contextual examples such as TNF, we aim to help researchers align their objectives with the appropriate method. Advancing pathway analysis interpretation will further enhance the utility of pathway analysis, ultimately propelling progress in systems biology and personalized medicine.

Protein kinases are central to healthy brain function, regulating critical cellular processes through complex signaling networks. However, understanding differences in kinase signaling of brain cells remains a preeminent challenge of neuroscience. This study aimed to characterize kinase pathways enriched in astrocytes and microglia isolated from male and female murine prefrontal cortex. Using the PamGene PamStation®12 platform, we discovered cell-type-specific kinomic profiles and computationally reconstructed each cell type’s unique active signaling protein-protein interaction network. Notably, our analysis revealed minimal overlap between kinase activity and respective cell-subtype specific kinase transcriptional profiles identified in the Allen Mouse Whole Brain Transcriptomic Cell Type Atlas, highlighting an important limitation of relying solely on gene mRNA expression levels for functional inference in kinase focused studies. These findings also suggest that cell- and sex-specific protein kinase signaling may influence susceptibility to deleterious brain conditions and consequently underscore the importance of considering activity as a biological variable in systems research, offering a new framework for developing targeted therapeutic interventions in precision medicine. ### Competing Interest Statement The authors have declared no competing interest. National Institutes of Health, https://ror.org/01cwqze88, 1T32GM144873-01, R01MH107487, R01MH121102, R01AG057598, R01AG083628

The enterovirus Coxsackievirus B3 causes a range of serious health problems, including aseptic meningitis, myocarditis, and pancreatitis. Currently, Coxsackievirus B3 has no targeted antiviral treatments or vaccines, leaving supportive care as the primary management option. Understanding how Coxsackievirus B3 interacts with and alters the blood–brain barrier may help identify new therapies to combat this often-devastating infection. We reanalyzed a previously published RNA sequencing dataset for Coxsackievirus B3-infected human-induced pluripotent stem-cell-derived brain endothelial cells (iBECs) to examine how Coxsackievirus B3 altered mRNA expression. By integrating GSEA, EnrichR, and iLINCs-based perturbagen analysis, we present a novel, systems-level approach to uncover potential drug repurposing candidates for CVB3 infection. We found dynamic changes in host transcriptomic response to Coxsackievirus B3 infection at 2- and 5-day infection time points. Downregulated pathways included ribosomal biogenesis and protein synthesis, while upregulated pathways included a defense response to viruses, and interferon production. Using iLINCs transcriptomic analysis, MEK, PDGFR, and VEGF inhibitors were identified as possible novel antiviral therapeutics. Our findings further elucidate Coxsackievirus B3-associated pathways in (iBECs) and highlight potential drug repurposing candidates, including pelitinib and neratinib, which may disrupt Coxsackievirus B3 pathology at the blood–brain barrier (BBB).

Background: Emerging evidence suggests that biological sex shapes glioma biology and therapeutic response. Methods: We performed a sex-stratified analysis of CGGA (Chinese Glioma Genome Atlas) RNA sequencing data comparing low-grade glioma (LGG) with high-grade glioma (HGG) and glioblastoma (GBM). Using the 3PodR framework, we integrated differential expression analysis with Gene Set Enrichment Analysis (GSEA), EnrichR, leading-edge analysis, and iLINCS drug repurposing. Results: These comparisons provide a proxy for biological processes underlying malignant transformation. In LGG vs. HGG, 973 significantly differentially expressed genes (DEGs) were identified in females and 1236 in males, with 15.5% and 33.5% unique to each sex, respectively. In LGG vs. GBM, 2011 DEGs were identified in females and 2537 in males, with 12.6% and 30.7% being unique. Gene-level contrasts included GLI1 upregulation in males and downregulation in females, GCGR upregulation in males, MYOD1 upregulation in females, and HIST1H2BH downregulation in males. Additional top DEGs included PRLHR, DGKK, DNMBP-AS1, HOXA9, CTB-1I21.1, RP11-47I22.1, HPSE2, SAA1, DLK1, H19, PLA2G2A, and PI3. In both sexes, LGG-HGG and LGG-GBM grade comparisons converged on neuronal and synaptic programs, with enrichment of glutamatergic receptor genes and postsynaptic modules, including GRIN2B, GRIN2A, GRIN2C, GRIN1, and CHRNA7. In contrast, collateral pathways diverged by sex: females showed downregulation of mitotic and chromosome-segregation programs, whereas males showed reduction of extracellular matrix and immune-interaction pathways. Perturbagen analysis nominated signature-reversing compounds across sexes, including histone deacetylase inhibitors, Aurora kinase inhibitors, microtubule-targeting agents such as vindesine, and multi-kinase inhibitors targeting VEGFR, PDGFR, FLT3, PI3K, and MTOR. Conclusions: Glioma grade comparisons reveal a shared neuronal-synaptic program accompanied by sex-specific transcriptional remodeling. These findings support sex-aware therapeutic strategies that pair modulation of neuron-glioma coupling with chromatin- or receptor tyrosine kinase/angiogenic-targeted agents, and they nominate biomarkers such as GLI1, MYOD1, GCGR, PRLHR, and HIST1H2BH for near-term validation.