bioRxiv Subject Collection: Neuroscience's Journal
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Monday, June 23rd, 2025
| Time |
Event |
| 12:30a |
Neurobiological and Chemical Characterization of the Cyanobacterial Metabolite Veraguamide E
Ver Es structure was validated by {superscript 1}H NMR, HRMS, and molecular networking analyses. Computational docking and NMR titration confirmed direct, saturable, and tight binding of Ver E to the human Sigma-2 receptor/transmembrane protein 97 ({sigma}2R/TMEM97). Functional calcium imaging in primary mouse sensory neurons revealed that Ver E increases intracellular Ca{superscript 2} levels without modulating store-operated calcium entry (SOCE). Multi-well microelectrode array experiments using human induced pluripotent stem cell (hiPSC) derived nociceptors showed that Ver E significantly reduced neuronal activity at physiological temperatures, but not under heat-stress conditions. Ver E exhibited no cytotoxicity at concentrations up to 30 {micro}M in HEK293 cells, and immunocytochemistry confirmed that it does not alter phosphorylated eIF2 (p-eIF2) expression, indicating a mechanism distinct from integrated stress response modulators. Collectively, these findings position Ver E as a non-toxic compound capable of selectively modulating neuronal excitability, thereby advancing the development of novel therapeutics for pain management.
SignificanceNatural products have long been recognized as a rich source of therapeutics, accounting for over 60% of currently approved small-molecule drugs and underscoring their pivotal role in drug discovery. Marine cyanobacteria produce structurally diverse secondary metabolites with a wide array of biological activities. Among these are the veraguamides, a family of depsipeptides that have shown promise as future therapeutics in our recent studies. This work presents a detailed biological and chemical characterization of veraguamide E (Ver E), isolated from a Panamanian marine cyanobacterial collection. The {sigma}2R/TMEM97 system has been identified as a promising target to address unmet need for non-opioid therapeutics which can modulate neuronal excitability in the context of chronic pain. Discovery and identification of novel compounds which modulate this system can help us better understand its function as well as allow us to develop future therapeutics targeting this pathway.
HighlightsO_LIVeraguamide E specifically binds {sigma}2R/TMEM97 receptor with high affinity.
C_LIO_LIComputational docking and NMR confirm a distinct binding mechanism.
C_LIO_LIVer E modulates calcium signaling in mouse DRG neurons and human iPSC-derived nociceptors.
C_LIO_LIVer E demonstrates no detectable cytotoxicity in human cell lines.
C_LI | | 12:30a |
Reward impulsivity is linked to addictive-like behaviors towards sweet food and sugary drinks but not fatty food
Overconsumption of hyperpalatable food is a worldwide problem. Although many previous studies have shown the link between monetary delay discounting and propensity to overconsume food, the studies did not focus on the link between delay discounting and various subcategories of palatable food. In the present study, we investigate the link between the individual propensity to choose smaller immediate rather than larger delayed reward and the degree of problematic eating behavior for five types of palatable food (sweets, sugary drinks, fatty food, salty snacks, and starchy food). The delay discounting task was used to measure propensity to choose immediate rather than delayed rewards, while the degree of addictive-like behavior was measured using the modified Yale food addiction scale (mYFAS) for each food category. Both model-free and model-based analysis showed that there is a significant correlation between the addiction score for sweet food and the tendency to choose smaller immediate rather than larger delayed rewards. A model-based analysis showed the same significant correlation for sugary drinks. However, no such correlation was observed for other food categories (fatty, salty, or starchy food), suggesting that reward impulsivity may play different roles in addictive-like behavior towards various food categories. | | 3:46p |
Nuclear Receptor Transcription factors promote axon regeneration in the Adult Corticospinal Tract
Transcription factors are potent levers for neural repair, but systematic pipelines to uncover factors that unlock adult corticospinal regeneration are lacking. By intersecting developmental RNA-seq with ATAC-seq footprints, we pinpointed two nuclear-receptor transcription factors--NR2F1 and NR2F6, neither previously linked to CNS axon growth--as top candidates. Forced expression of either factor doubled neurite length in culture, and each proved highly effective in vivo: after unilateral pyramidotomy they drove robust midline sprouting, while after complete thoracic crush they supported long-tract CST regeneration that restored hip lift, partial swing trajectories and grip strength. Multi-omics dissection revealed complementary mechanisms: NR2F1 re-engaged chromatin-remodelling and cytoskeletal networks, whereas NR2F6, via a conserved corepressor domain, imposed a broad translational down-shift, bound predominantly to distal enhancers and re-packaged chromatin into new topologically associating domains that cluster growth genes with freshly activated regulatory hubs. These discoveries establish NR2F1 and NR2F6 as novel pro-regenerative TFs, demonstrate their potency across lesion types, and expose repression-driven translational control and enhancer-TAD reconfiguration as previously unrecognised axes of CNS repair. | | 6:32p |
Asymmetric distribution of mitochondrial Ca2+ regulators specifies compartment-specific mitochondrial function and neuronal development
Neuronal polarization is essential for functional compartmentalization, enabling dendritic synaptic integration and axonal action potential generation. While structural differences in mitochondria across compartments have been identified, their functional distinctions remain unclear. Here, we uncovered compartment-specific mitochondrial Ca2+ dynamics and their molecular determinants. In axonal mitochondria, Ca2+ uptake through MCU occurs independently of ER-stored Ca2+ release, with faster matrix Ca2+ clearance than dendritic mitochondria, where Ca2+ uptake predominantly originates from ER Ca2+. The ER-independent mitochondrial Ca2+ uptake in axonal mitochondria is mediated by enriched MCU-regulating proteins, MICU1 and MICU2, while higher NCLX expression facilitates rapid Ca2+ clearance. Moreover, NCLX knockdown, which functionally mimics a mental retardation-associated mutation, caused more significant axonal branching defects compared to dendrites in vivo, aligning with its enrichment in axons. These findings highlight fundamental Ca2+-modulating features and developmental importance of neuronal mitochondria in a compartment-specific manner and reveal the key underlying molecular mechanisms. | | 6:32p |
Optimal inhibitory-to-excitatory ratio governs slow and fast oscillations for enhanced neural communication
Neural oscillations at distinct frequency bands facilitate communication within and between neural populations. While single-frequency oscillations are well-characterized, the simultaneous emergence of slow (beta) and fast (gamma) oscillations within the same network remains unclear. Here, we demonstrate that multi-frequency oscillations naturally arise when the ratio of inhibitory-to-excitatory synaptic strength falls within a specific regime using a biologically plausible Izhikevich model. We show that this regime maximizes both information capacity and transmission efficiency, suggesting an optimal balance for neural communication. Deviations from this range lead to single-frequency oscillations and reduced communication efficiency, mirroring disruptions observed in neurological disorders. These findings provide mechanistic insight into how the brain leverages multiple oscillatory frequencies for efficient information processing and suggest a potential biomarker for impaired neural communication. | | 6:32p |
The neural processes underpinning flexible semantic retrieval in visual and auditory modalities
Contemporary accounts of semantic cognition propose that conceptual knowledge is supported by a heteromodal conceptual store and controlled retrieval processes. However, it remains unclear how the neural basis of semantic control varies across modalities. Recent models of cortical organization suggest that control networks are distributed along a unimodal-to-heteromodal cortical gradient, with the semantic control network (SCN) located in more heteromodal cortex than the domain-general multiple demand network (MDN). We used fMRI to examine how these networks respond to semantic control demands in visual and auditory tasks. Participants judged the semantic relatedness of spoken and written word pairs. On half of the trials, a task cue specified the semantic feature to guide retrieval; on the remaining trials, no such cue was given. The SCN showed greater activation when task knowledge was available, consistent with a role in the top-down control of semantic retrieval across modalities. In contrast, the MDN showed greater activation for spoken words, likely reflecting increased demands in speech perception. These findings demonstrate a dissociation between control networks, with SCN involvement modulated by task structure and MDN activity influenced by input modality. | | 6:32p |
Climbing fibers selectively recruit disinhibitory interneurons to enhance dendritic calcium signaling in cerebellar Purkinje cells
Climbing fiber (CF) inputs to Purkinje cells (PCs) instruct plasticity and learning in the cerebellum. Paradoxically, CFs also excite molecular layer interneurons (MLIs), a cell-type that inhibits PCs and can restrict plasticity and learning. However, two types of MLIs with opposing influences have recently been identified: MLI1s inhibit PCs, reduce dendritic calcium signals, and suppress plasticity of granule cell to PC synapses, whereas MLI2s inhibit MLI1s and disinhibit PCs. To determine how CFs can activate MLIs without also suppressing the PC calcium signals necessary for plasticity and learning, we investigated the specificity of CF inputs onto MLIs. Serial EM reconstructions indicate that CFs contact both MLI subtypes without making conventional synapses, but more CFs contact each MLI2 via more sites with larger contact areas. Slice experiments indicate that CFs preferentially excite MLI2s via glutamate spillover. In agreement with these anatomical and slice experiments, in vivo Neuropixels recordings show that spontaneous CF activity excites MLI2s, inhibits MLI1s, and disinhibits PCs. In contrast, learning-related sensory stimulation produced more complex responses, driving convergent CF and granule cell inputs that could either activate or suppress MLI1s. This balance was robustly shifted toward MLI1 suppression when CFs were synchronously active, in turn elevating the PC dendritic calcium signals necessary for LTD. These data provide mechanistic insight into why CF synchrony can be highly effective at inducing cerebellar learning by revealing a critical disinhibitory circuit that allows CFs to act through MLIs to enhance PC dendritic calcium signals necessary for plasticity. | | 6:32p |
Late onset of striatal projection neuron hyperexcitability in Fmr1-/y mice
AbstractFragile X Syndrome (FXS), the most common genetic cause of intellectual disability and autism spectrum disorder (ASD), results from silencing of the FMR1 gene and consequent loss of Fragile X Messenger Ribonucleoprotein (FMRP). FMRP deficiency disrupts neural development, leading to behavioral and motor deficits associated with striatal dysfunction. While structural and functional abnormalities in striatal projection neurons (SPNs) have been observed in adult Fmr1 knockout (KO) mice, their developmental onset and contribution to early FXS pathophysiology remain unknown. In this study, we examined the postnatal maturation of SPN in the dorsomedial striatum (DMS) of Fmr1 KO mice, assessing glutamatergic synaptic inputs and intrinsic excitability. During postnatal development, Fmr1 deficient SPNs in DMS display normal synaptic and intrinsic properties, consistent with typical maturation. In contrast, by P60, SPNs of mice exhibit pronounced hyperexcitability, characterized by increased membrane resistance, reduced rheobase, and slower action potential kinetics. These perturbations affect both Dopamine 1 receptor-expressing (D1-SPN) and D2 receptor-expressing (D2-SPN) SPNs, though some action potential dynamics are selectively impaired in D1-SPNs. Chronic aripiprazole treatment, a widely prescribed therapy for FXS-related symptoms, fails to normalize SPN excitability, highlighting its limited efficacy in addressing core SPN dysfunction. Our findings reveal a late-onset hyperexcitability in DMS SPNs of Fmr1 KO mice, suggesting a progressive emergence of striatal neuron abnormalities over development. These results underscore the importance of developmental timing in FXS pathophysiology and emphasize the need for targeted interventions to address striatal circuit dysfunction. |
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