Polyamines (PAs) are evolutionarily conserved metabolites that connect protein quality control with lysosomal, mitochondrial, and redox homeostasis. Their metabolism is situated at a critical intersection of cell-sustaining and neurodegenerative pathways. Here, we synthesize evidence across Alzheimer's disease, Parkinson's disease, polyglutamine repeat disorders, amyotrophic lateral sclerosis, and multiple system atrophy, each of which differ in vulnerability to changes in PA metabolism. Although previous reviews have investigated polyamines in individual neurodegenerative disorders, few have compared their roles across the broader spectrum of neurodegenerative proteinopathies. Here, we address this gap by synthesizing evidence across multiple diseases to examine how PAs influence disease-associated protein aggregation and clearance, and how these effects depend on PA species, concentration, cellular context, disease stage, subcellular localization, redox state, and lysosomal and mitochondrial capacity. Human tissue and biofluid studies report disease-associated changes in PA metabolites, pathway enzymes, and transporter remodeling, as a function of neurodegenerative disorders. Mechanistic studies reveal that spermidine and spermine can alter the assembly, condensation, compartmentalization, and clearance of various neurotoxic proteins, whereas the effects of putrescine are more system- and concentration-dependent. These effects engage both shared pathways and distinct mechanisms, depending on protein identity, cell type, and subcellular location. Curiously, PA manipulation may be protective in one context yet harmful in another. The framework that we propose can distinguish adaptive remodeling from pathogenic dysregulation and can guide disease-relevant therapeutic strategies.

Neural injury and functional recovery after ischemic stroke are strongly time dependent. The acute phase is dominated by energy failure, ionic disequilibrium, excitotoxicity, spreading depolarization, and amplification of inflammation; the subacute phase is characterized by progressive network reorganization and competing forms of plasticity; and the chronic phase predominantly involves adaptive remodeling of residual networks. As the principal inhibitory neurotransmitter system in the central nervous system, gamma-aminobutyric acid (GABA) does not exert uniformly protective or detrimental effects throughout the course of stroke. Instead, its effects are jointly determined by intervention timing, the cellular source of GABA, receptor subtype and synaptic or extrasynaptic localization, transporter and metabolic status, and chloride homeostasis. After summarizing GABA synthesis and metabolism, receptors, transporters, and chloride homeostasis, this review follows the temporal course of ischemic stroke to discuss the protective effects of GABAergic inhibition against excitotoxicity and neuroinflammation during the acute phase, the bidirectional effects of GABA and tonic inhibition during the subacute phase, and the relationships among GABAergic tone, intrahemispheric and interhemispheric network reorganization, and windows of plasticity during the chronic phase. We further summarize preclinical and clinical evidence for receptor modulators, agents targeting GABA or chloride transport, monoamine oxidase B inhibitors, and non-invasive brain stimulation. We emphasize that effective targeting of the GABAergic system requires modulation tailored to disease phase, cellular source, receptor subtype, and spatial context, rather than indiscriminate enhancement or suppression of GABAergic signaling.

Acute basal ganglia ischemic stroke (BGIS) often leads to motor dysfunction, but the mechanisms of functional reorganization, particularly the underlying molecular basis, remain unclear. This study aimed to investigate the local and global functional reorganization patterns and their associated molecular basis in acute BGIS. Regional homogeneity (ReHo) and seed-based functional connectivity (FC) analyses were used to assess local and global brain connectivity, respectively. We identified a key classification feature using support vector machine (SVM) and logistic regression (LR) models combined with SHapley Additive exPlanations (SHAP) analysis, which was then spatially correlated with Allen Human Brain Atlas (AHBA) transcriptomic data via partial least squares (PLS) regression, followed by functional enrichment analysis. Compared with healthy controls (HCs), BGIS patients demonstrated decreased ReHo in the bilateral precentral gyri, along with reduced interhemispheric FC between these regions. The SVM and LR models effectively distinguished patients from HCs (AUCs = 0.877 and 0.868, respectively), identifying this reduced interhemispheric FC (seeded in the right precentral gyrus) as the top discriminative feature based on SHAP. Genes spatially correlated with this feature were enriched in synaptic function, ion homeostasis, and energy metabolism in the contralesional hemisphere. In summary, disrupted interhemispheric FC between the bilateral precentral gyri represents a key neuroimaging marker in acute BGIS. This disconnection was associated with transcriptomic signatures of synaptic inhibition and metabolic reorganization. Our multimodal findings advance the understanding of post-stroke motor dysfunction.

Temporal lobe epilepsy (TLE) exhibits spatially heterogeneous cortical atrophy, yet how these distributed patterns drive unified pathophysiology remains unknown. Here, we test the hypothesis that locally discrete atrophic regions coalesce into functionally coherent networks associated with unified molecular mechanisms. Using large-scale normative modeling of patient-specific regional atrophy and functional connectivity mapping, we demonstrate that marked variability in atrophic loci coalesce into remarkable functional convergence within temporal-limbic circuitry in TLE patients. This convergence was selectively enriched in glial-immune gene pathways, with transcriptomic analysis revealing astrocytic markers as key molecular substrates. Cross-sectional disease-duration analyses showed functional coupling shifts toward unimodal cortices with disease chronicity, while fronto-parietal network coupling strength predicted anti-seizure medication responsiveness, suggesting a network-based stratification biomarker. Our findings suggest that spatially dispersed cortical atrophy in TLE converges on a shared temporal-limbic functional network. The spatial association of this network with glial-immune transcriptomic signature, together with its associations with disease duration and anti-seizure medication response, provides a multiscale framework for understanding the network-level pathology of TLE.

The brain is a highly complex organ composed of diverse, specialized cell types whose coordinated functions underpin cognition and behavior. While extensive research has elucidated neuronal signaling mechanisms, the metabolic interactions between distinct brain cells that sustain energy homeostasis are not yet comprehensively understood. Recently, brain energy metabolism has gained significant attention as a unifying factor in the pathogenesis of neurodegenerative diseases such as Alzheimer's and Parkinson's, potentially opening new avenues for therapeutic development. In this review, we provide an overview of brain energy metabolism, examine its role in neurodegeneration, and highlight current challenges and future perspectives in the field.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system frequently associated with cognitive impairment, which critically depends on the integrity of the prefrontal cortex (PFC) and its mesocortical dopaminergic inputs. However, direct experimental evidence linking prefrontal dopamine dysfunction to MS-related cognitive deficits is limited. Here, we investigated the contribution of mesocortical dopaminergic transmission to cognitive and behavioral alterations using the cuprizone model of demyelination in male Wistar rats. After six weeks of 1% cuprizone administration, we combined ex vivo electrophysiology in the rostral ventral tegmental area (rVTA) and medial PFC (mPFC), in vivo microdialysis of extracellular dopamine in the mPFC, behavioral assessment of cognition and anxiety-like behavior, gait analysis, and plasma corticosterone measurements. Cuprizone reduced the spontaneous firing rate of rVTA dopaminergic neurons and decreased glutamatergic miniature excitatory postsynaptic current frequency. In the mPFC, cuprizone increased pyramidal neuron excitability and presynaptic glutamatergic transmission, while impairing long-term potentiation and reducing NMDA receptor-mediated currents. Microdialysis showed reduced basal extracellular dopamine levels in the mPFC which, together with the results on the EPM and the marked decrease observed in plasma corticosterone, indicate blunted mesocortical and hypothalamic-pituitary-adrenal axis responsiveness. Cuprizone-treated rats exhibited working memory deficits with preserved performance in a task not strictly PFC-dependent, reduced anxiety-like behavior, and subtle gait changes. These findings suggest that cuprizone-induced intoxication disrupts VTA-mPFC circuitry, leading to mesocortical dopamine hypofunction, altered cortical plasticity, and executive dysfunction, and support targeting mesocortical dopamine transmission as a potential strategy for MS-related cognitive symptoms.

Sleep-wake disturbances are among the most prevalent and persistent consequences of traumatic brain injury (TBI), yet the circuit mechanisms underlying post-traumatic alterations in rapid eye movement sleep (REM) and associated cortical oscillations remain incompletely understood. Previous work has shown that REM-associated theta oscillations are determined by a Supramammillary (SuM) - hippocampal vesicular glutamate transporter 2 (Vglut2) circuit. First, we examined whether severe focal penetrating TBI (pTBI) suppresses REM and REM-associated theta power. Secondly, we examined whether these changes are associated with alterations in hypothalamic neuropeptide systems and SuM-hippocampal glutamatergic signaling. Adult male Sprague-Dawley rats (pTBI, n = 7; Sham, n = 6) were exposed to pTBI or sham procedures. After sham/TBI surgeries, EEG/EMG data was continuously sampled for 14 days by using telemetric implants, enabling analyses of sleep-wake states and cortical oscillations. At 14 days post injury, animals were sacrificed and brain tissue was sampled for immunohistochemical and in situ hybridization analyses. We analyzed orexin A (OXA) and melanin-concentrating hormone (MCH) in the lateral hypothalamus (LHA), Vglut2 in the SuM and hippocampus (CA2 and dentate gyrus), and nitric oxide synthase 1 (NOS1) in the SuM. pTBI resulted in reduced wakefulness during the light phase, increased non-REM sleep (NREM), and reduced REM. Power spectral density analyses of EEG data showed reduced theta (4-8 Hz) power during wake, REM, and NREM. Also, alpha (8-12 Hz) and sigma (12-16 Hz) reduced, in contrast to delta (1-4 Hz) power which increased across all vigilance states. Histological analyses showed reduced OXA and MCH in the LHA in pTBI animals. Similarly, Vglut2 transcript levels were reduced in the lateral SuM, and Vglut2 immunoreactivity was decreased in hippocampal CA2 and dentate gyrus. NOS1 expression in the SuM was not altered. Correlation analyses showed an association between the Vglut2 reduction in the SuM-hippocampal circuit and REM-theta oscillations. For the first time, we show that severe focal pTBI produces a sustained suppression of REM and REM associated theta oscillations, associated with decreased Vglut2 within the SuM-hippocampal circuit. These findings provide a framework linking SuM-hippocampal circuit dysfunction to post-traumatic REM sleep disturbances. Further research is needed to study potential causal effects of TBI on suppression of the SuM-hippocampal circuit and effects on hippocampal dependent cognitive functions.

Persistent apoptotic cell burden and unresolved inflammation contribute to secondary injury after traumatic brain injury (TBI). Efferocytosis, the phagocytic removal of apoptotic cells, is a key mechanism for resolving inflammation and supporting tissue repair; however, the pathways that regulate this process after TBI remain poorly defined. We investigated the cell-specific role of efferocytosis receptor MERTK in adult male mice subjected to controlled cortical impact (CCI) injury. Conditional Mertk deletion was induced in either endothelial cells using a VE-cadherin Cre driver or Cx3cr1-expressing cells using a Cx3cr1 Cre driver. Lesion volume, blood-brain barrier (BBB) permeability, apoptotic cell accumulation, efferocytosis, cerebral blood flow (CBF), and behavioral recovery were assessed. MERTK and GAS6 were increased in the injured cortex after CCI injury and were detected in endothelial cells and Cx3cr1-expressing cells. Endothelial-specific deletion of Mertk reduced endothelial MERTK expression but did not significantly alter CCI-induced tissue damage, BBB disruption, apoptotic cell accumulation, or myeloid MERTK upregulation. In contrast, deletion of Mertk in Cx3cr1-expressing cells increased lesion volume and BBB permeability after injury compared to wild-type controls. Mertk deletion in Cx3cr1-expressing cells also led to greater accumulation of activated caspase-3+ and TUNEL+ apoptotic cells, with reduced engulfment by Cx3cr1+ phagocytes, indicating impaired efferocytosis. Mertk-deficient mice further showed reduced cerebral blood flow at 3 and 7 days after injury and impaired motor and cognitive recovery. These findings identify MERTK in Cx3cr1-expressing cells as a regulator of efferocytosis and support a protective role in limiting tissue damage, preserving vascular integrity, and promoting functional recovery after TBI in male mice.

Sleep deprivation is a prevalent health problem that amplifies pain and prolongs recovery after tissue injury, yet the neural and astrocytic mechanisms underlying this relationship remain poorly defined. Here, we demonstrate that sleep deprivation activates locus coeruleus noradrenergic neurons and elevates spinal norepinephrine levels. Norepinephrine acts on spinal dorsal horn astrocytes through α1-adrenergic receptors, upregulating the astrocyte-enriched GABA transporter GAT-3. The increase in astrocytic GAT-3 was accompanied by reduced spinal GABA content and enhanced activation of spinoparabrachial projection neurons. Chemogenetic inhibition of spinal-projecting locus coeruleus noradrenergic neurons reduced astrocytic GAT-3 expression, increased spinal GABA content, attenuated acute mechanical hypersensitivity, and shortened the duration of incision-evoked mechanical hypersensitivity. These findings support a model in which LC-spinal noradrenergic signaling regulates astrocytic GAT-3 expression and contributes to sleep deprivation-induced hyperalgesia. This mechanistic framework highlights astrocytic GAT-3 as a potential therapeutic target.

Missense mutations in UBQLN2 are linked to dominant inheritance of amyotrophic lateral sclerosis (ALS) which is frequently accompanied by frontotemporal dementia (FTD). The encoded UBQLN2 protein functions to maintain proteostasis, collapse of which is increasingly being realized as the cause of many neurodegenerative diseases. During investigations of our UBQLN2 mouse models of ALS/FTD, we observed a significant decline in Tank-binding kinase 1 (TBK1) protein in end-stage mice. The decline could be significant, as haploinsufficiency of TBK1 expression is linked to ALS/FTD. To determine whether the reduction in TBK1 levels is responsible for driving pathogenesis, we crossed P497S UBQLN2 transgenic (Tg) mice with BacTBK1 Tg mice that overexpress TBK1 and analyzed the progeny for signs of pathology. The analysis revealed that double transgenic mice had a significant reduction in neurodegeneration in both the brain and spinal cord (SC) compared to P497S single-Tg mice. Double immunofluorescence staining of P497S mouse tissue revealed TBK1 colocalizes with UBQLN2 aggregates in spinal motor neurons. Biochemical extraction studies of mouse brain tissue revealed increased enrichment of TBK1 along with wild type and mutant UBQLN2 proteins in detergent-insoluble material, suggesting TBK1 gets sequestered by UBQLN2 aggregates. GST-pulldown assays revealed that UBQLN2 binds directly with TBK1, but paradoxically the P497S mutation was found to reduce TBK1 binding. Turnover studies indicated that loss of UBQLN2 destabilizes TBK1, providing another route for its reduction. These findings lead us to propose that efforts directed toward increasing TBK1 expression may provide a therapeutic approach for treating ALS/FTD caused by UBQLN2 mutations.

Human genetics has substantially advanced our understanding of the Rho GTPase signaling network in brain development and established its dysregulation as an important mechanism underlying neurodevelopmental disorders (NDDs). Through the spatiotemporal control of actin cytoskeleton dynamics, canonical and atypical Rho GTPases, together with their guanine nucleotide exchange factors, GTPase-activating proteins, guanine nucleotide dissociation inhibitors, and downstream effectors, regulate major stages of corticogenesis, including neural progenitor proliferation and polarity, neuronal migration, axonal and dendritic development, synapse formation, and circuit maturation. Recent genomic studies have expanded the spectrum of Rho GTPase-related disorders by identifying pathogenic variants in core pathway genes, including RAC1, RAC3, CDC42, RHOA, and RHOBTB2, as well as in regulators and pathway-associated genes such as TRIO, OPHN1, ARHGEF9, ARHGAP31, DENND5A, DENND5B, and AUTS2. These findings indicate that genetically heterogeneous conditions, including autism spectrum disorder, intellectual disability, developmental and epileptic encephalopathies, and structural brain abnormalities, converge on shared developmental processes governing cytoskeletal remodeling, neuronal morphogenesis, synaptic organization, and connectivity. In this Review, we integrate the molecular architecture of Rho GTPase signaling with its physiological roles throughout corticogenesis and link individual signaling modules and disease-associated genes to clinical phenotypes and experimentally validated pathogenic mechanisms. This framework highlights how disruption of distinct components of the Rho GTPase network produces overlapping neurodevelopmental phenotypes through perturbation of common cellular and developmental programs.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration in the motor cortex and spinal cord. Aging is a key risk factor for ALS, and cellular senescence - a hallmark of aging marked by irreversible cell-cycle arrest and a pro-inflammatory senescence-associated secretory phenotype - has been implicated in neurodegeneration, yet its role in ALS progression remains incompletely understood. Here, we show that molecular markers of cellular senescence emerge in the motor cortex and spinal cord alongside declines in neural and neuromuscular function in TDP-43[Q331K] ALS mice, supporting senescence as an early feature of ALS pathology. To test whether reduced senescence ameliorates ALS pathology, we evaluated longitudinal senolytic treatment with dasatinib and quercetin (D&Q) in TDP-43[Q331K] mice. D&Q treatment improved motor behavior, neuromuscular function, and reduced axonal damage as measured by plasma neurofilament light chain, accompanied by robust improvements in motor cortex excitability and preservation of layer V neuron counts. At the cellular level, cortical microglia were implicated as a potential mediator of senolytic benefits based on reduced microglial TDP-43 burden and senescence markers. Together, these findings identify cellular senescence as an early, disease-relevant, and modifiable feature of ALS pathology.

Chronic stress during adolescence is a major risk factor for adult psychiatric disorders, yet the long-term impact of learning-related aversive stress remains poorly understood. This study established an mice model of learning demand stress by escalating the fixed ratio (FR) number of escape responses to foot shocks in a negative reinforcement learning paradigm. Remarkably, mice that performed proficiently (high-susceptible, H-Su) during this aversive learning task in adolescent developed late-onset impairments in social interaction and novel object recognition in young adulthood, whereas poorly performing mice (low-susceptible, L-Su) exhibited normal behaviors. Furthermore, in vivo electrophysiology revealed a significant increase in spontaneous tonic firing of substantia nigra pars compacta (SNc) dopamine neurons selectively in H-Su mice. Whole-cell patch-clamp recordings showed increased intrinsic excitability (enhanced Ih currents and L-type calcium channel currents), reduced miniature excitatory postsynaptic current (mEPSC), and increased paired-pulse ratio in H-Su mice. Chemogenetic inhibition of SNc dopamine neurons in H-Su mice rescued social interaction deficits. In summary, our findings suggest that adolescent aversive learning stress can program late-onset SNc dopamine neuron hyperexcitability and behavioral dysfunctions in young adulthood.

APOE ε4 carriers exhibit heightened pro-inflammatory responses and microglial dysregulation compared to non-carriers. CX3CL1 is a biomarker involved in microglial signaling and Alzheimer's disease. It can be cleaved by proteases such as matrix metalloproteinases (MMPs), which are associated with memory and vasculature remodeling. We examined the role of MMP-9 in the pathway involving the association of CX3CL1 with cerebrospinal fluid (CSF) biomarkers for amyloid and tau in APOE ε4 carriers (APOE4+) compared to non-carriers (APOE4-). We further examined the association between APOE4 groups and inflammatory profiles. CSF samples were collected from 115 cognitively unimpaired VA-eligible Veterans enrolled in the Brain Amyloid and Vascular Effects of Eicosapentaenoic Acid (BRAVE) study (NCT02719327). We found that Aβ42 and Aβ42/Aβ40 were lower in APOE4+ carriers compared to non-carriers. Additionally, p-tau217 was higher among APOE4+ participants compared to APOE4- participants; however, p-tau217/tau was not different between carrier groups. In moderated mediation models, MMP-9 mediated the effect of CX3CL1 on Aβ42/Aβ40, p-tau217/tau and p-tau217/Aβ42 among APOE4+ carriers only. Lastly, we found a correlation between CX3CL1 and a composite pro-inflammatory z score, as well as lower ICAM-1 and VCAM-1 baseline levels in the APOE4+ group. However, CX3CL1 correlated with an anti-inflammatory z score in the APOE4- group, suggesting different inflammatory roles of CX3CL1 in APOE4+ carriers vs non-carriers. These findings suggest that the association of MMP-9 and CX3CL1 plays a unique role in tau and amyloid regulation among APOE4+ carriers, and that early dysregulation of immune systems may occur in cognitively unimpaired APOE4+ individuals.