bioRxiv Subject Collection: Neuroscience's Journal
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Sunday, July 13th, 2025
| Time |
Event |
| 4:42a |
Multiplicative couplings facilitate rapid learning and information gating in recurrent neural networks
The brain consists of reciprocal connectivity and loops between recurrent neural networks (RNNs) and feedforward neural networks (FNNs). However, how their interactions facilitate learning remains unknown. Here we propose a multiplicative RNN-FNN coupling mechanism and report remarkable computational strengths in learning. The multiplicative interaction imposes a Hebbian-weight amplification onto synaptic-neuronal coupling, enabling context-dependent gating and rapid switching. We demonstrate that multiplicative coupling-driven synaptic plasticity achieves 2-100 folds of speed improvement in supervised, reinforcement and unsupervised learning settings, boosting memory capacity, model robustness and generalization of RNNs. We further demonstrate the efficacy and biological plausibility of multiplicative gating in modeling multiregional circuits, including a prefrontal cortex-mediodorsal thalamus network for context-dependent decision making, a cortico-thalamic-cortical network for working memory and attention, and an entorhinal cortex-hippocampus network for visuospatial navigation and sequence replay. Take together, our results offer insights into multi-plasticity, attractor dynamics and computation of recurrent neural circuits and profound neuroscience-inspired applications. | | 4:42a |
Cellular basis for cortical network aging in primates
Large-scale brain networks are vulnerable to change with aging and become dysregulated. How these networks are altered at the cellular level remains unclear owing to challenges of bridging data across scales. Here, we integrate in vivo cortical similarity networks with whole brain spatial transcriptomics to characterize the aging brain in a lifespan cohort of macaques (N=64, ages 1-26 years). Deep-layer excitatory neurons and oligodendrocytes emerged as dominant correlates of cortical similarity, linking infragranular cell type composition to macroscopic network structure. Age-related declines in network strength were most pronounced in transmodal networks, including default mode and limbic, and aligned with regions enriched in inhibitory and glial cell types. Parvalbumin-enriched chandelier cells showed the strongest association with regional vulnerability, suggesting a role in network disconnection. Cell-type enrichment was conserved across species, with both human and macaque transcriptomic data aligning with the cortical functional hierarchy. These findings uncover a cellular basis for cortical network aging and highlight the value of imaging-transcriptomic integration across scales. | | 6:18a |
Individual differences in learning and decision-making: the role of COMT Val158Met polymorphism in transitive inference
Understanding the ordinal relationships between items requires constructing a rank order supporting decision-making between options. This process depends on the ability to learn reciprocal relationships and to select the best option available when making a choice. In such forms of decision-making, the prefrontal cortex (PFC) plays a crucial role in encoding the relative value of alternatives as a decision is formed. Higher-order cognitive abilities are influenced by genetic factors that affect dopamine availability in the PFC, potentially contributing to individual differences. Here, we examined the performance of 83 participants in a transitive inference task (TI), grouped by genotype based on the Val158Met single-nucleotide polymorphism in the Catechol-O-Methyltransferase (COMT) gene. The task included a learning phase in which participants acquired the reciprocal relationships among a set of hierarchically ranked items (A>B>C>D>E>F), followed by a test phase in which they were required to compare all possible item pairs and select the higher-ranked one. While genotype did not significantly influence test-phase performance, it did affect learning efficiency. Specifically, Val homozygotes took a longer learning procedure than both heterozygotes and Met homozygotes during the learning phase. Drift diffusion modelling (DDM) revealed that task performance was explained by the efficiency of evidence accumulation, which was lower in Val homozygotes, accounting for their poorer performance not only during initial learning but also when required to switch to a reversed hierarchical structure (A<B<C<D<E<F). These findings suggest that individual differences in inferential decision-making and cognitive flexibility may be partially driven by genetically determined variations in prefrontal dopamine availability. | | 6:18a |
Bioenergetic and Protein Processing Imbalances Synergize in iPSC-Dopamine neurons from Individuals with Idiopathic Parkinsons Disease
Patient induced pluripotent stem cell (iPSC)-based models represent a powerful human system to gain insights into the etiopathology of Parkinsons disease (PD). Here, we study several iPSC-derived dopamine neuron (iPSC-DAN) lines, from individuals with idiopathic PD, which is the most common form of PD. Specifically, using iPSC-DAN differentiated for 50-55 days, we performed an in-depth analysis of different bioenergetic pathways and cellular quality control mechanisms in the cells. Our results showed wide ranging impairments in oxidative phosphorylation (OXPHOS), glycolysis and creatine kinase pathways in the PD dopamine (DA) neurons. Specifically, the PD neurons exhibited reduced oxygen consumption rates (OCR) at baseline and after challenges with mitochondrial inhibitors, as well as decreased glycolytic reserves measured via ECAR. This translated to lower OCR:ECAR ratios signifying more reliance on glycolysis vs OXPHOS in the PD cells. Moreover, a mislocalization of creatine kinase B to mitochondria was seen in the PD cells. These energetic changes synergized with the enhanced expression of mitochondrial fission proteins, disrupted mitophagy and oxidative stress. Additionally, the PD neurons contained more monomeric, phosphorylated and aggregated forms of alpha synuclein and displayed reduced viability. Ultrastructural examination through immuno-electron microscopy showed more alpha synuclein gold particles directly associated with mitochondria and packing autophagic vesicles. In essence, these data capture a web of key changes in human iPSC-DAN from idiopathic PD subjects associated with neuronal degeneration. | | 6:18a |
ALS-Linked FUS and SOD1 Mutations Elevate MCM2 in Human Motor Neurons
BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by progressive motor neuron loss. In typically post-mitotic neurons, abnormal reactivation of cell cycle regulators and DNA replication licensing factors is observed in ALS pathogenesis. Emerging evidence links components of the minichromosome maintenance (MCM) complex, notably MCM2, to replication stress and genomic instability, implying a mechanistic role in ALS pathogenesis.
ObjectiveTo determine whether ALS-associated mutations in FUS and SOD1 influence MCM2 expression and localisation in human induced pluripotent stem cell (hiPSC)-derived spinal motor neurons (MNs).
MethodsWe differentiated isogenic hiPSC lines carrying FUS P525L-GFP and R495QfsX527, a SOD1 mutant line, and matched wild-type controls into spinal MNs ([≥]28 days in vitro). QRT-PCR quantified MCM2 mRNA levels ({Delta}{Delta}Ct method; n=3 biological replicates, technical triplicates). Protein expression was assessed by Western blot densitometry (n=3). Subcellular distribution of MCM2 in FUS mutants was evaluated by immunofluorescence (pilot, N=1; [≥]50 cells quantified).
ResultsFUS P525L MNs exhibited a modest, non-significant increase in MCM2 mRNA (1.3-fold vs. WT; p=0.1319) but a significant 1.8-fold elevation in MCM2 protein levels (p=0.034). The R495QfsX527 line showed a comparable trend at the transcript level (1.2-fold; p > 0.05) and a 1.6-fold increase in protein (p = 0.041). SOD1 mutant MNs demonstrated a pronounced 2.3-fold MCM2 protein upregulation (p=0.008). Immunofluorescence in FUS mutant MNs revealed no significant nuclear-to-cytoplasmic shift in MCM2 localisation, indicating that elevated MCM2 levels are not driven by subcellular mislocalization.
ConclusionALS-linked FUS and SOD1 mutations upregulate MCM2 protein in human spinal MNs, suggesting post-transcriptional or stability-driven regulation. The absence of relocalisation in FUS mutants shows that this impact is caused by overexpression rather than mislocalisation. MCM2 may be a biomarker of disease-associated replication stress. Future studies will explore whether MCM2 overexpression exacerbates DNA damage or serves as a compensatory response, clarifying its role in ALS pathogenesis. | | 8:16a |
Differences in brain activity during sentence repetition in people who stutter: a combined analysis of four fMRI studies
Our understanding of the neural correlates of developmental stuttering benefits from the use of functional MRI (fMRI) during speech production. Despite two decades of research, however, we have reached little consensus. In the current study, we analysed pooled fMRI data from four different studies that used the same sentence reading task and methodological approach. The combined sample included 56 adolescents and adults who stutter and 53 demographically matched typically fluent controls. A sparse-sampling design was used in each study, in which participants spoke during the silent period between measurements of brain activity. Sentence reading evoked activity in both groups across frontal and temporal regions bilaterally. At statistical thresholds corrected for family-wise error, there were no significant group differences. An uncorrected threshold was applied to explore group differences in areas previously identified in earlier fMRI studies on stuttering. People who stutter (PWS) showed greater activity compared with controls in right frontal pole, right anterior insula extending to frontal operculum, left planum temporale, and midbrain, at the level of red nucleus. In contrast, PWS showed lower activity in left superior frontal sulcus, subgenual medial prefrontal cortex, right anterior temporal lobe, and portions of inferior parietal lobe bilaterally including the angular gyrus on the left. Despite pooling data across multiple studies to achieve a relatively large sample, group differences in regions involved in speech-motor control only emerged at an uncorrected voxel-wise threshold. Some of these findings align with previous fMRI studies, such as increased activity in the right anterior insular cortex. | | 9:30p |
Autophagy-driven Presynaptic Reorganization as a Molecular Signature of Brain Resilience.
Neural circuits must remain functionally stable while responding flexibly to changing demands, stressors, and aging-related decline. While this balance is thought to be maintained through plasticity programs that integrate molecular, metabolic, and activity-dependent signals to reconfigure synapses structurally and functionally, direct mechanistic models of how such adaptations are orchestrated remain scarce. Here, we show that targeted impairment of autophagy in the Drosophila mushroom body (MB), a key sleep-regulatory and integrative center in the fly brain, triggers a brain-wide remodeling at presynaptic active zones (AZ). Quantitative proteomics revealed a specific upregulation of AZ scaffold proteins (including BRP, RIM, and Unc13A), accompanied by reduced levels of calcium channel subunits and increased Shaker-type potassium channels. These changes occurred largely independent of transcription and highlight a coordinated, excitability-tuning response centered on the AZ. Behaviorally, MB-specific autophagy impairment increased sleep and modestly extended lifespan. These adaptations resembled a previously described resilience program termed PreScale, which promotes restorative sleep homeostasis in response to sleep deprivation and early, still reversible brain aging. Conversely, overexpression of Atg5 in the MB delayed the onset of PreScale. Notably, autophagic disruption confined to MB neurons also caused widespread, non-cell autonomous accumulation of Ref(2)P and ATG8a-positive aggregates across the brain, revealing systemic propagation of proteostatic stress. Together, our findings identify MB autophagy as a key regulator of synaptic architecture and sleep-associated resilience. Such early acting programs may actively preserve circuit function and behavioral output by regulating synaptic plasticity, and define a genetically tractable model for how local stress signals can orchestrate brain-wide adaptation via post-transcriptional synaptic reprogramming. | | 9:30p |
High-Throughput Tracking of Freely Moving Drosophila Reveals Variations in Aggression and Courtship Behaviors
Aggression is a nearly universal behavior used to secure food, territory, and mates across species, including the fruit fly Drosophila melanogaster. In fruit flies, both sexes display aggression through stereotypical motor patterns. This, along with their sophisticated genetic and molecular toolkit, makes Drosophila melanogaster an excellent model for studying aggression. While male- and female-specific aggressive motor programs have been qualitatively described, automated systems for quantifying these behaviors in freely moving flies remain limited in their ability to combine high-resolution analysis with high throughput. Here, we pair a high-resolution, high-throughput imaging system (the Kestrel) with DeepLabCut pose estimation to create a pipeline that tracks multiple freely moving fly pairs and quantifies social dynamics with high fidelity. We validated body-part tracking using published benchmarks. The platform reliably reproduced a known phenotype: heightened female aggression following thermogenetic activation of cholinergic pC1 neurons in female brain. It also detected increased unilateral wing extension, a courtship display inversely related to aggression, between two males upon activating a previously uncharacterized ~40-neuron group in the male brain. Pose-based analysis revealed locomotive differences between experimental and control groups, and subtle, genotype-specific variations in head butts and UWEs. This workflow enables high-throughput screening and mechanistic dissection of social behaviors. | | 9:30p |
Impact of sex and glial tau expression on heat shock protein induction in a Drosophila model of tauopathy
Heat shock proteins (Hsps) are central components of the cellular stress response and serve as the first line of defense against protein misfolding and aggregation. Disruption of this proteostasis network is a hallmark of neurodegenerative diseases, including tauopathies -- a class of neurodegenerative diseases characterized by intracellular tau accumulation in neuronal and glial cells. Although specific Hsps are enriched in glial cells, and some have been shown to directly bind tau and influence its aggregation, the broader interplay between Hsps and tau remains poorly understood. In particular, it is unclear whether tau expression affects the heat shock response, and whether this interaction is modulated in a sex-specific fashion. Here, we used a Drosophila model of tauopathy to examine both inducible and constitutive Hsp expression in response to heat stress in the context of glial tau expression. We found that Hsp expression displays sexually dimorphic expression patterns at basal levels and in response to heat stress. Moreover, tau expression in glia disrupts the normal induction of specific heat shock proteins following heat stress. This work provides new insight into how tau interacts with the cellular stress response, and highlights sex-specific differences in Hsp regulation. Understanding these molecular connections is crucial to understanding how the presence of tau in glial cells influences the stress response, and potentially contributes to tauopathy pathogenesis. | | 9:30p |
KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS
Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by mutations in the Survival Motor Neuron 1 (SMN1) gene, leading to decreased SMN levels and motor neuron dysfunction. SMN-restoring therapies offer clinical benefit, but the downstream molecular consequences of SMN reduction remain incompletely understood. Here, we demonstrate that SMN deficiency results in downregulation of KIF5A in human neurons and in a mouse model of SMA. We provide evidence that reduced SMN levels impair axon regeneration, which is rescued by KIF5A overexpression and that the RNA-binding protein SMN functions to stabilize KIF5A mRNA. These findings provide evidence of a molecular link between SMA and ALS pathophysiology, highlighting KIF5A as a new SMN target. Our findings suggest SMN-independent interventions targeting KIF5A could represent a complementary therapeutic approach for SMA and other motor neuron diseases. |
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