bioRxiv Subject Collection: Neuroscience's Journal
[Most Recent Entries]
[Calendar View]
Sunday, September 21st, 2025
| Time |
Event |
| 1:16a |
Mirror manifolds: partially overlapping neural subspaces for speaking and listening
Participants in conversations need to associate words their speakers but also retain those words general meanings. For example, someone talking about their hand is not referring to the other speakers hand, but the word hand still carries speaker-general information (e.g., having five fingers). These two requirements impose a cross-speaker generalization / differentiation dilemma that is not well addressed by existing theories. We hypothesized that the brain resolves the dilemma by use of a vectorial semantic code that blends collinear and orthogonal coding subspaces. To test this hypothesis, we examined semantic encoding in populations of hippocampal single neurons recorded during conversations between epilepsy patients and healthy partners in the epilepsy monitoring unit (EMU). We found clear semantic encoding for both spoken and heard words, with strongest encoding just around the time of utterance for production, and just after it for reception. Crucially, hippocampal neurons codes for word meaning were poised between orthogonalized and collinearized. Moreover, different semantic categories were orthogonalized to different degrees; body parts and names were most differentiated between speakers; function words and verbs were least differentiated. Finally, the hippocampus used the same coding principle to separate different partners in three-person conversations, with greater orthogonalization between self and other than between two others. Together, these results suggest a new solution to the problem of binding word meanings with speaker identity. | | 1:16a |
Subclinical anxiety is associated with reduced self-distancing and enhanced guilt-related connectivity between anterior temporal and subgenual cingulate cortices
Excessive self-blaming emotions are commonly observed in anxiety disorders, with mounting evidence indicating the presence of qualitatively similar symptomatology in subclinical and clinical populations. Prior work points to a central role of the superior anterior temporal lobe (sATL) in the guilt processing circuitry, together with network organisation differences associated with subclinical anxiety. This study aimed to extend these findings by exploring links of trait-anxiety with (i) self-blaming emotions and associated behaviours, and (ii) guilt-dependent neural activity and connectivity. We also explored the role of resting-state fMRI in linking these phenomena. Increased anxiety was linked to stronger self-blaming emotions, and more pronounced self-attacking and hiding. When experiencing negative emotions about themselves (i.e. shame and self-anger), anxious individuals were also less likely to disengage from self-focused thoughts. These behavioural findings were paralleled by enhanced guilt-related connectivity between the left sATL and bilateral posterior subgenual cingulate cortex. The relevance of temporal lobe activity for self-blaming emotions was also evident in the resting-state data. Interestingly, while the approach-avoidance motivation towards guilt memories was unrelated to anxiety, this emotional dimension showed distinct contributions of the left and right sATL, with task-related activity of the former and connectivity of the latter associated with, respectively, more approach and avoidance. As such, the results of the current study link the self-blaming bias of anxious individuals to specific maladaptive patterns of behaviour. Furthermore, the work provides robust evidence for the important role of ATL-related circuitry in guilt processing, supporting its broader involvement in social conceptual processing. | | 9:21a |
Subcellular interactions of neuropeptide Y and corticotropin-releasing factor in the central nucleus of the amygdala in the mouse
Neuropeptide Y (NPY) is ubiquitously distributed throughout the central nervous system. Recognized as a mediator of stress resilience, NPY has been shown to counteract the excitatory effects of the neuropeptide corticotropin-releasing factor (CRF), that orchestrates the stress response. In the mouse, while NPY and CRF exhibit a high degree of neuroanatomical association in the central nucleus of the amygdala (CeA) indicating potential significant interactions, the synaptic organizations of these neuropeptides have not been elucidated. In the present study, we determined the interactions between NPY and CRF in the CeA. Immunofluorescence microscopy presented that NPY-immunoreactive varicose processes were distributed throughout the CeA and contacted CRF-containing neurons. Using electron microscopy, immunoperoxidase labeling for NPY and gold-silver labeling for CRF showed that NPY-labeled axon terminals (NPY-t) form synapses with CRF-labeled dendrites (CRF-d). Semi-quantitative analysis revealed that 163 of NPY-t directly target CRF-d. In addition, approximately 85% of NPY-t form symmetric synapses with CRF-d while approximately 1% form asymmetric synapses. These findings provide the first ultrastructural evidence that NPY-containing axon terminals make direct contact with CRF-containing dendrites in the CeA. This suggests that the CRF-containing neurons in the CeA may be a key site for NPY action, potentially influencing brain regions involved in stress responses and stress-related psychiatric disorders, and alcohol use disorders. | | 4:31p |
BAG3 coordinates astrocytic proteostasis of Alzheimer's disease-linked proteins via proteasome, autophagy, and retromer complex interactions
Background: Bcl-2-associated athanogene 3 (BAG3) is a mediator of chaperone assisted selective autophagy, and in the brain, most highly expressed in astrocytes. However, its role in astrocytes remains poorly defined. Given the genetic and pathological links of BAG3 to proteostasis and neurodegenerative diseases, we investigated how BAG3 contributes to astrocyte function and Alzheimer's disease (AD). Methods: SnRNA-seq of the human brain determined cell type expression of BAG3. CRISPR/Cas9 gene editing in human iPSCs, followed by tandem mass tag-mass spectrometry and RNA-sequencing was performed to assess proteomic and transcriptomic changes following BAG3 loss. Co-immunoprecipitation of BAG3 in human astrocytes defined the interactome, with top interactors being validated by western blot (WB), AlphaFold modeling, and proximity ligation assays. In astrocytes, autophagic flux, lysosomal phenotypes, proteasome activity, and endocytic uptake were measured in BAG3 KO and BAG3 WT. Finally, BAG3 expression was assessed in postmortem AD brain by WB and snRNA-seq, and its functional relevance to amyloid-{beta} (A{beta}) degradation was tested in co-cultures of BAG3 KO iAs with familial AD neurons. Results: In human brain and iPSC models, BAG3 was most highly expressed in astrocytes. Further, BAG3 loss caused greater proteomic disruption in astrocytes than in neurons. In the absence of BAG3, astrocytes showed reduced autophagy, diminished lysosome abundance and activity, and decreased proteasome function. To uncover molecular binding partners of BAG3 that might influence these phenotypes, we performed co-immunoprecipitation, revealing interactions with HSPB8 and other heat shock proteins, proteasome regulators (PSMD5, PSMF1), and the retromer component, VPS35. Integration of BAG3 KO transcriptomic and proteomic datasets pinpointed AD-relevant proteins under post-translational control of BAG3, which included GFAP, BIN1, and HSPB8. HSPB8 levels were markedly reduced in BAG3-deficient astrocytes with overexpression partially rescuing its levels. Loss of astrocytic BAG3 impaired A{beta} clearance in co-culture with APP/PSEN1 mutant neurons, directly linking BAG3 to a disease-relevant astrocyte function. Finally, analysis of postmortem brain tissue revealed BAG3 marks a stress-responsive astrocyte subtype in the brain of aged individuals with AD. Conclusions: BAG3 binds to key regulators of autophagy, proteasome activity, and retromer function to coordinate astrocyte proteostasis, lysosomal function, and A{beta} clearance. These findings position BAG3 as a potential therapeutic target and coordinator of glial protein quality control in neurodegeneration. | | 4:31p |
The effect of quercetin on the fluorescent intensity of neurofibrillary tangles that correspond to Alzheimers disease within Drosophila melanogaster
Alzheimers disease (AD) is a neurodegenerative disease that accounts for more than 60% of all dementia cases, and over seven million Americans above 65 years old were affected with AD in 2024 (Gaugler et al., 2024). A symptom of AD is severe memory loss, which leads to lowered brain function and a need for intensive care. Currently, AD only has five symptomatic approved drugs. However, there is a lack of research in the progression of AD through the neurofibrillary tangle mechanism. Tau is a microtubule stabilizing protein that becomes unstable when hyperphosphorylated. Hyperphosphorylated tau misfolds, resulting in toxic aggregates that accumulate to create neurofibrillary tangles. Saffron decreased tau fibrillation, neurotoxicity and slowed the neurofibrillary tangle formation (Patel et al., 2024). Therefore, quercetin, an antioxidant present in saffron, was hypothesized to reduce the intensity of the neurofibrillary tangles within Drosophila melanogaster , commonly known as the fruit fly, exhibiting AD. Drosophila melanogaster has easily modifiable genes and shares a similar genetic sequence with humans, which is ideal to research if the effect of a supplement in flies could have a similar effect on humans. This study found that quercetin had no significant effect on the intensity of the neurofibrillary tangles within Drosophila melanogaster . The ANOVA statistical test showcased that the p-value was above 0.05 between flies exhibiting AD and flies exhibiting AD with supplemented quercetin. Possible error sources include the fluorescence of brain tissue present and the large constant areameasured for each brain image. | | 6:31p |
Mapping the Cerebello-Hippocampal Circuit: Normative Patterns and Sex-Dependent Connectivity
Cerebello hippocampal (CBHP) interactions have been implicated in spatial abilities and reinforcement learning, yet their relationship to behavior and differences in connectivity with sex in early adulthood are unclear. Resting CBHP network patterns have yet to be established in young adults. Mapping the normative resting-state CBHP connectivity pattern is essential for identifying when CBHP circuitry becomes behaviorally relevant across the lifespan and for detecting early circuit-level deviations that may precede neurodegenerative or endocrine disruption. We combined resting-state functional MRI (rsfMRI) with measures of cognition in 1,081 healthy young adults (22 to 37 years, 54% women) from the Human Connectome Project S1200 to map CBHP functional connectivity (FC), examine sex differences, and define its relationship with performance across episodic memory, visuospatial, and executive function tasks. Region of interest (ROI)-to-ROI FC between the right cerebellum and left hippocampus were quantified. In our CB-HP mapping, we found: 1) negative relationships between the entire HP axis and cerebellar regions: vermis VII; lobules VI, VIIb, and VIII; Crus I & II, and 2) positive relationships between most of the HP axis and ventral/medial cerebellar regions. We revealed sex differences in CB-HP such that females had greater FC than males between anterior to mid-hippocampal regions and medial cerebellar regions: vermis IV-VI; lobules VI, VIII, IX; and Crus II. We predicted CBHP FC patterns would show strong positive associations with cognitive measures (i.e., episodic memory, visuospatial processing, working memory, and executive function); however, we did not find any associations after multiple comparisons correction (pFDR > 0.05). Together, our findings detail a functional atlas of the CBHP circuit in young adulthood and highlight sex differences within. Our results provide a foundation for understanding functionally based gradients between these two regions. | | 6:31p |
PI-FC: Pre-training Individual-specific Functional Connectome through State-invariant Contrastive Learning
Functional MRI enables non-invasive mapping of brain connectivity, yet its clinical translation remains hindered by uncontrolled state-dependent variability that obscures individual-specific signatures during routine scanning. Here we introduce PI-FC - a deep learning framework leveraging state-invariant contrastive learning to extract stable individual brain signatures across diverse arousal levels, cognitive states, and temporal scales spanning tens of seconds to hours. PI-FC achieves equivalent phenotypic prediction accuracy using substantially reduced scanning time, and eliminates state-dependent effects varying task demands and brain states. Trained on 36,119 subjects across 8 independent datasets, our model demonstrates superior cross-site generalization and outperforms traditional functional connectome (FC) in predicting neuropsychiatric conditions including schizophrenia, autism, depression, and anxiety. Furthermore, PI-FC enables zero-shot inference of brain age, biological sex, and cognitive ability without site-specific retraining. Overall, PI-FC represents a robust, clinically scalable framework that overcomes fundamental barriers to real-world deployment of precision functional neuroimaging. | | 6:31p |
PEDF peptides rescue defects in neurite morphogenesis and intracellular calcium response in cortical neurons from mice exposed to valproic acid
Pigment epithelial-derived factor (PEDF) is a multifunctional protein produced predominantly by the retinal pigment epithelium and expressed in many tissues, including the brain, highlighting its participation in crucial processes, such as neuroprotection and angiogenesis. Some neurodevelopmental disorders, such as ASD, are characterized by neurodevelopmental abnormalities, including altered neurite formation, spine formation, and neuronal activities. Many efforts have been made to resolve NDDs, but until now, some symptoms remain untargeted. PEDF is involved in many steps of neurodevelopment. The treatment of PEDF peptide might improve the outcome of NDD symptoms by altering neuronal morphologies. We used PEDF peptides that contain different functional domains to study the effect of administering PEDF peptides on neuronal morphology in a prenatal valproic acid (VPA)-exposed mouse model. We identified that the treatment with PEDF peptides rectified the abnormalities in neurite formation and spine formation in VPA-exposed cortical neurons. In vitro calcium imaging showed abnormalities in the spontaneous activity in VPA-exposed cortical neurons. Treatment of a short PEDF peptide normalized intracellular calcium response to the control level. Accordingly, PEDF peptides have the prospect of serving as potential treatments for patients with neurodevelopmental disorders, such as ASD. | | 6:31p |
PELICAN: a Longitudinal Image Processing Pipeline for Analyzing Structural Magnetic Resonance Images in Aging and Neurodegenerative Disease Populations
Structural magnetic resonance imaging (MRI) allows for accurate non-invasive assessment of the brain's structure and its longitudinal changes. Availability of large scale longitudinal MRI datasets enables us to probe brain changes in health and disease, and derive longitudinal trajectories of brain morphometry based measures to estimate brain atrophy and other disease-related abnormalities. In contrast to their cross-sectional counterparts, image processing pipelines that have been designed for longitudinal data can reduce noise in the derived measurements by disentangling the within and between subject variabilities, improving the sensitivity of the downstream models in detecting more subtle longitudinal changes. Here we present PELICAN, our open source multi-contrast longitudinal image processing pipeline, that has been designed and extensively validated for use in longitudinal settings and populations with neurodegenerative disorders. PELICAN can use population specific average templates as intermediate targets to derive accurate nonlinear registrations for cases with substantial levels of atrophy, which commonly used pipelines struggle to process. We evaluated PELICAN's performance across over 34,000 MRIs from multiple aging and neurodegenerative disorder cohorts, and compared its reliability and failure rates against FreeSurfer as a widely used image processing tool, showing superior performance of PELICAN compared to FreeSurfer, both in terms of failure rate and reliability. Our results demonstrate that PELICAN can be used to accurately process MRIs of individuals with neurodegenerative disease who present with greater levels of atrophy and white matter lesion burden. |
|